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  • CLASSES

    Other Agents with Antihistaminic Action
    Phenothiazine Antiemetics

    BOXED WARNING

    Extravasation, intraarterial administration, intravenous administration, subcutaneous administration, tissue necrosis

    In September 2009, the FDA required the manufactures of parenteral promethazine to include a boxed warning emphasizing the established risk of severe tissue necrosis, gangrene, or other tissue damage associated with the intravenous administration of the drug. The use of promethazine via intraarterial administration or subcutaneous administration is contraindicated due to such risks. Proper intravenous administration is well generally tolerated; however, due to the increased risk of severe tissue necrosis and injury, the preferred route of administration is deep intramuscular injection. Inadvertent intraarterial or subcutaneous injection, perivascular extravasation, and intraneuronal or peri-neuronal infiltration of the dug is likely to result in major adverse reactions ranging from burning, irritation, and pain to tissue necrosis and gangrene in the affected extremity. Reported serious injuries, in some cases, have required surgical intervention including fasciotomy, skin grafts, and/or amputation; the most common amputations involved the fingers and hands. Additionally, injection into or near a nerve may result in permanent nerve damage resulting in paralysis. Monitor for signs and symptoms of potential tissue damage including burning or pain at the site of injection, phlebitis, swelling, and blistering. If any of these symptoms occur, the injection should be immediately stopped. In addition, inform patients of the risks of intravenous administration of promethazine and advise them to immediately report side effects that occur while receiving the injection as well as those that may develop hours to days after an injection.

    DEA CLASS

    Rx

    DESCRIPTION

    Phenothiazine derivative with primarily antihistaminic effects and also has antiemetic, anticholinergic, sedative actions
    Not an effective neuroleptic; used in cough and cold products for antihistaminic actions; also commonly used for post-operative nausea/vomiting
    Contraindicated in pediatric patients less than 2 years of age due to risk of fatal respiratory depression
    Intravenous administration not recommended as it carries a risk of severe tissue damage

    COMMON BRAND NAMES

    Anergan-50, Pentazine, Phenadoz, Phenergan, Promethegan

    HOW SUPPLIED

    Anergan-50/Pentazine/Phenergan/Promethazine/Promethazine Hydrochloride Intramuscular Inj Sol: 1mL, 25mg, 50mg
    Anergan-50/Pentazine/Phenergan/Promethazine/Promethazine Hydrochloride Intravenous Inj Sol: 1mL, 25mg, 50mg
    Phenadoz/Phenergan/Promethazine/Promethazine Hydrochloride/Promethegan Rectal Supp: 12.5mg, 25mg, 50mg
    Phenergan/Promethazine/Promethazine Hydrochloride Oral Tab: 12.5mg, 25mg, 50mg
    Promethazine/Promethazine Hydrochloride Oral Sol: 5mL, 6.25mg

    DOSAGE & INDICATIONS

    For the prevention of motion sickness.
    Oral or Rectal dosage
    Adults

    25 mg PO or PR 30—60 minutes before departure, then every 12 hours as needed.

    Geriatric

    Sedating drugs may cause confusion and over-sedation in the elderly; therefore, elderly patients should generally be started on low doses of promethazine and closely observed.

    Children and Adolescents 2 years and older

    0.25 to 0.5 mg/kg/dose (Max: 25 mg/dose) PO given 30 minutes to 2 hours prior to travel and every 6 to 12 hours as needed. Use the lowest possible effective dose, and avoid concomitant use of other respiratory depressants. FDA-approved labeling recommends 12.5 to 25 mg PO or PR twice daily as needed ; however, this dose may be excessive for smaller children. In general, promethazine should be reserved for patients with moderate to severe motion sickness.

    For the treatment of active nausea/vomiting, including post-operative nausea/vomiting (PONV) and for post-operative nausea/vomiting (PONV) prophylaxis.
    Oral or Rectal dosage
    Adults

    12.5 to 25 mg PO or PR every 4 to 6 hours as needed.

    Geriatric

    12.5 to 25 mg PO or PR every 4 to 6 hours as needed. Begin with the lowest dosage and titrate based on clinical response, observing carefully for sedation and other adverse effects.

    Children and Adolescents 2 years and older

    0.25 to 1 mg/kg/dose PO or PR (Max: 25 mg/dose) every 4 to 6 hours as needed. Use the lowest possible effective dose, and avoid concomitant use of other respiratory depressants. The FDA-approved labeling recommends 1.1 mg/kg/dose PO or PR (Max: 25 mg/dose) every 4 to 6 hours as needed.

    Intramuscular or Intravenous dosage

    NOTE: Deep IM injection is the preferred parenteral route of administration. IV administration has been associated with severe tissue damage.

    Adults

    12.5 to 25 mg IM or IV every 4 to 6 hours as needed. When used for postoperative nausea and vomiting control, concomitantly administered analgesics and barbiturates should be reduced accordingly. According to treatment guidelines, 6.25 to 12.5 mg IV administered at surgery induction has some efficacy in PONV prophylaxis; however, evidence is not strong enough to recommend as first line therapy.

    Geriatric

    12.5 to 25 mg IM or IV every 4 to 6 hours as needed. Begin with the lowest dosage and titrate based on response, observing carefully for sedation and other adverse effects. When used for postoperative nausea and vomiting control, concomitantly administered analgesics and barbiturates should be reduced accordingly. According to treatment guidelines, 6.25 to 12.5 mg IV administered at surgery induction has some efficacy in PONV prophylaxis; however, evidence is not strong enough to recommend as first line therapy.

    Children and Adolescents 2 years and older

    0.25 to 1 mg/kg/dose IM or IV (Max: 25 mg/dose) every 4 to 6 hours as needed. Use the lowest possible effective dose, and avoid concomitant use of other respiratory depressants. The FDA-approved labeling recommends using doses no higher than 6.25 to 12.5 mg/dose IM or IV every 4 to 6 hours as needed. Dosage should not exceed one-half of the recommended adult dosage.

    For the treatment of allergic reactions to blood or plasma, for anaphylaxis as an adjunct to epinephrine and other standard measures after the acute symptoms have been controlled, or other uncomplicated allergic conditions, such as pruritus.
    Oral or Rectal dosage
    Adults

    The average dose is 25 mg PO or PR at bedtime. However, 12.5 mg PO or PR may be given before meals and at bedtime, if necessary. Geriatric patients should generally be started on low doses of promethazine and closely observed.

    Children and Adolescents 10 years and older

    6.25 mg to 12.5 mg/dose PO or PR 3 times daily or 25 mg PO or PR as a single dose once daily at bedtime. If necessary, doses up to 12.5 mg may be taken up to 4 times daily (before meals and at bedtime). Max: 50 mg/day.[33877] [43929] [43930] Alternatively, 10 mg/dose PO twice daily, increased to 20 mg/dose PO given 3 times daily or 25 mg/dose PO twice daily (Max: 60 mg/day) has been recommended.[59104] [59107] A dosage of 0.25 to 1 mg/kg/dose (Max: 25 mg/dose) has been recommended for other indications.[50034] Use the lowest effective dose, and avoid the concomitant use of other respiratory depressants.[33877] [43929] [43930] In general, second-generation antihistamines (e.g., cetirizine, loratadine, fexofenadine) are considered first-line therapy in the management of pediatric allergic conditions.[59104]

    Children 5 to 9 years

    5 to 10 mg/dose PO twice daily or 10 to 25 mg PO as a single dose once daily at bedtime. Max: 25 mg/day. FDA-approved labeling recommends 6.25 to 12.5 mg/dose PO or PR given 3 times daily or 25 mg PO or PR as a single dose once daily at bedtime. If necessary, doses up to 12.5 mg may be taken up to 4 times daily (before meals and at bedtime). Max: 50 mg/day. Of note, this dose may be excessive for smaller children. A dosage of 0.25 to 1 mg/kg/dose (Max: 25 mg/dose) has been recommended for other indications. Use the lowest effective dose, and avoid the concomitant use of other respiratory depressants. In general, second-generation antihistamines (e.g., cetirizine, loratadine, fexofenadine) are considered first-line therapy in the management of pediatric allergic conditions.

    Children 2 to 4 years

    5 mg/dose PO twice daily or 5 to 15 mg PO as a single dose once daily at bedtime. Max: 15 mg/day PO. FDA-approved labeling recommends 6.25 to 12.5 mg/dose PO or PR given 3 times daily or 25 mg PO or PR as a single dose once daily at bedtime. If necessary, doses up to 12.5 mg may be taken up to 4 times daily (before meals and at bedtime). Max: 50 mg/day. Of note, this dose may be excessive for smaller children. A dosage of 0.25 to 1 mg/kg/dose (Max: 25 mg/dose) has been recommended for other indications. Use the lowest effective dose, and avoid the concomitant use of other respiratory depressants. In general, second-generation antihistamines (e.g., cetirizine, loratadine, fexofenadine) are considered first-line therapy in the management of pediatric allergic conditions.

    Intramuscular or Intravenous dosage
    Adults

    The average dose is 25 mg IM or IV; dose may be repeated within 2 hours, if necessary. Used when oral therapy is impossible or contraindicated. Geriatric patients may need lower dose.

    Children and Adolescents 2 years and older

    Not a first-line therapy. FDA-approved labeling does not provide dosing; per literature, do not exceed 12.5 mg/dose (50% of adult dosage). The dose may be repeated in 2 hours if necessary before switching to the oral route. European labeling recommends 6.25 to 12.5 mg/dose IM for children 5 to 10 years of age. A dosage of 0.25 to 1 mg/kg/dose IM or IV (Max: 25 mg/dose) has been recommended for other indications. Use the lowest effective dose, and avoid the concomitant use of other respiratory depressants. Not a first-line therapy. In general, second-generation antihistamines are considered first-line therapy in the management of pediatric allergic conditions.

    For sedation induction.
    For sedation in obstetrics.
    Intramuscular or Intravenous dosage

    NOTE: Deep IM injection is the preferred parenteral route of administration. IV administration has been associated with severe tissue damage. Do not give at a rate > 25 mg/min IV; consider dilution prior to administration and giving over 10 to 15 minutes (see Administration).

    Pregnant females

    25—50 mg IM or IV during the early stages of labor and 25—75 mg after labor is established; repeat dosage once or twice, every 4 hours as needed. Maximum total dose is 100 mg per 24-hour period for patients in labor.

    For relief of apprehension and to induce quiet sleep from which the patient can be easily aroused.
    Oral, Rectal, Intramuscular, or Intravenous dosage

    NOTE: Deep IM injection is the preferred parenteral route of administration. IV administration has been associated with severe tissue damage. Do not give at a rate > 25 mg/min IV; consider dilution prior to administration and giving over 10 to 15 minutes (see Administration).

    Adults

    25—50 mg PO, PR, IM, or IV at bedtime.

    Geriatric

    Sedating drugs may cause confusion and over-sedation in the elderly; therefore, elderly patients should generally be started on low doses of promethazine and closely observed.

    Children >= 2 years and Adolescents

    1.1 mg/kg/dose PO or PR (Max: 25 mg/dose). While an exact dosage of parenteral promethazine is not provided by the manufacturer, the FDA-approved product label recommends not exceeding one-half of the recommended adult dosage (12.5—25 mg/dose). A dosage of 0.25—1 mg/kg/dose IM/IV (Max: 25 mg) has been recommended for other indications. Use the lowest possible effective dose, and avoid other respiratory depressants. When used in the preoperative or postoperative setting, concomitantly administered analgesics and barbiturates should be reduced accordingly.

    For preoperative or postoperative procedural sedation, as an adjunct to analgesics.
    Oral, Rectal, Intramuscular, or Intravenous dosage
    Adults

    25 to 50 mg PO, PR, IM, or IV as a single dose. When used in the preoperative or postoperative setting, concomitantly administered analgesics and barbiturates should be reduced accordingly. Use the lowest effective dose for geriatric patients and closely observe for over-sedation. Deep IM injection is the preferred parenteral route of administration. IV administration has been associated with severe tissue damage. Do not give at a rate greater than 25 mg/minute IV; consider dilution prior to administration and giving over 10 to 15 minutes.

    Children and Adolescents 2 years and older

    1.1 mg/kg/dose PO or PR (Max: 25 mg/dose). While an exact dosage of parenteral promethazine is not provided by the manufacturer, the FDA-approved product label recommends not exceeding one-half of the recommended adult dosage (12.5 to 25 mg/dose). A dosage of 0.25 to 1 mg/kg/dose IM or IV (Max: 25 mg/dose) has been recommended for other indications. Use the lowest possible effective dose, and avoid other respiratory depressants. Concomitantly administered analgesics and barbiturates should be reduced accordingly.

    For the treatment of acute peripheral vestibular nystagmus†.
    Oral dosage
    Adults

    12.5 to 25 mg PO every 4 to 6 hours for up to 48 hours has been recommended. It is advisable to individualize the dosage based upon clinical response and tolerability.

    For pregnancy-induced nausea/vomiting†, including hyperemesis gravidarum†.
    Oral, Rectal, Intramuscular, or Intravenous dosage

    NOTE: Deep IM injection is the preferred parenteral route of administration. IV administration has been associated with severe tissue damage. Do not give at a rate faster than 25 mg/min IV; consider dilution prior to administration and giving over 10 to 15 minutes.

    Pregnant females

    12.5 to 25 mg PO, PR, IM, or IV every 4 to 6 hours as needed is recommended by the American College of Obstetricians and Gynecologists (ACOG); promethazine can be added to other modalities such as pyridoxine or doxylamine if necessary. Pooled trial data indicate that phenothiazines significantly decrease nausea and vomiting compared to placebo, including in patients with severe nausea and vomiting.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    50 mg/dose; generally 100 mg/day. Dosage should not exceed maximum recommendations per indication.

    Geriatric

    50 mg/dose; generally 100 mg/day. Dosage should not exceed maximum recommendations per indication.

    Adolescents

    1.1 mg/kg/dose PO/PR/IM/IV (Max: 25 mg/dose). Dosage should not exceed maximum recommendations per indication.

    Children

    >= 2 years: 1.1 mg/kg/dose PO/PR/IM/IV (Max: 25 mg/dose). Dosage should not exceed maximum recommendations per indication.
    < 2 years: Use is contraindicated due to the risk for fatal respiratory depression.

    Infants

    Use is contraindicated due to the risk for fatal respiratory depression.

    Neonates

    Use is contraindicated due to the risk for fatal respiratory depression.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Those with significant hepatic disease should be monitored closely. Dosage adjustments may be required in these patients but no quantitative recommendations as available.

    Renal Impairment

    No dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Promethazine may be administered without regard to meals.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution has developed color or contains precipitate.
    For intravenous or intramuscular use only. Subcutaneous injection or intraarterial injection are contraindicated because of the risk of serious tissue injury including gangrene.
    To avoid the possibility of physical and/or chemical incompatibility, consult specialized literature before diluting promethazine injection with any injectable solution or combining with any other medication.

    Intravenous Administration

    Although NOT the preferred route, intravenous promethazine administration is an option in concentrations <= 25 mg/ml at a rate of <= 25 mg/minute through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. Do NOT use a concentration > 25 mg/ml intravenously because of the risk of serious tissue injury. Exercise extreme care to avoid perivascular extravasation or unintentional intra-arterial injection as pain, severe chemical irritation, severe distal vessel spasms, and resultant gangrene requiring amputation are likely under such circumstances. Aspiration of dark blood does not preclude intra-arterial needle placement because blood is discolored upon contact with promethazine injection. Use of syringes with rigid plungers or of small-bore needles might obscure typical arterial backflow.
    Instruct the patient to immediately report any pain, burning, or discomfort, and also ask the patient and watch the area for any signs or symptoms such as swelling, blisters, or erythema during and after intravenous administration. Immediately stop the injection for any discomfort, and evaluate for inadvertent intraarterial infusion or perivascular extravasation. If unintentional intra-arterial injection or extravasation occurs, sympathetic block and heparinization may be useful.
    The Institute for Safe Medication Practices (ISMP) also recommends consideration of the following items to prevent or minimize tissue damage when giving IV promethazine. Stock only the 25 mg/ml concentration. Consider 6.25 to 12.5 mg of promethazine as the starting IV dose, especially for elderly patients. Require further dilution from 25 mg/ml to reduce vesicant effects and enable slow administration. Administer only through a large-bore vein (preferably via a central venous access site but absolutely no hand or wrist veins). Check patency of the access site before administration. Administer through a running IV line at the port furthest from the patient’s vein over 10—15 minutes. Revise preprinted order forms to ensure orders for promethazine reflect the safety measures listed above. Build an alert to appear on computer-generated medication administration records (MARs), electronic MARs, and on automated dispensing cabinet screens for nurses to view each time they access and administer a dose of promethazine, reminding them that the drug is a vesicant and should be diluted and administered slowly through a running IV. Also, consider alternative drugs including removal of promethazine from the formulary.

    Intramuscular Administration

    Inject promethazine deeply into a large muscle; deep intramuscular injection is the preferred route of administration. Aspirate prior to injection to avoid injection into a blood vessel.

    Rectal Administration

    Instruct patient on proper use of suppository (see Patient Information).
    Moisten the promethazine suppository with water prior to insertion. If suppository is too soft because of storage in a warm place, chill in the refrigerator for 30 minutes or run cold water over it before removing the wrapper.

    STORAGE

    Generic:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Anergan-50:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in a cool, well ventilated, dry place
    - Store in carton until time of use
    Pentazine :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in a cool, well ventilated, dry place
    - Store in carton until time of use
    Phenadoz :
    - Refrigerate (between 36 and 46 degrees F)
    Phenergan:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Promethegan :
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Agranulocytosis, bone marrow suppression, coma, jaundice, phenothiazine hypersensitivity

    Promethazine is contraindicated for use in patients with a known phenothiazine hypersensitivity. Cross-sensitivity may occur. This contraindication includes patients who have experienced agranulocytosis, blood dyscrasias, bone marrow suppression, or jaundice due to phenothiazine therapy. Promethazine is also contraindicated in patients who are in a coma.

    Extravasation, intraarterial administration, intravenous administration, subcutaneous administration, tissue necrosis

    In September 2009, the FDA required the manufactures of parenteral promethazine to include a boxed warning emphasizing the established risk of severe tissue necrosis, gangrene, or other tissue damage associated with the intravenous administration of the drug. The use of promethazine via intraarterial administration or subcutaneous administration is contraindicated due to such risks. Proper intravenous administration is well generally tolerated; however, due to the increased risk of severe tissue necrosis and injury, the preferred route of administration is deep intramuscular injection. Inadvertent intraarterial or subcutaneous injection, perivascular extravasation, and intraneuronal or peri-neuronal infiltration of the dug is likely to result in major adverse reactions ranging from burning, irritation, and pain to tissue necrosis and gangrene in the affected extremity. Reported serious injuries, in some cases, have required surgical intervention including fasciotomy, skin grafts, and/or amputation; the most common amputations involved the fingers and hands. Additionally, injection into or near a nerve may result in permanent nerve damage resulting in paralysis. Monitor for signs and symptoms of potential tissue damage including burning or pain at the site of injection, phlebitis, swelling, and blistering. If any of these symptoms occur, the injection should be immediately stopped. In addition, inform patients of the risks of intravenous administration of promethazine and advise them to immediately report side effects that occur while receiving the injection as well as those that may develop hours to days after an injection.

    Seizure disorder

    Phenothiazine derivatives lower the seizure threshold through their effect on GABA; therefore, promethazine should be avoided, if possible, in patients with a seizure disorder or those receiving anticonvulsants. Extreme caution should be used when combining phenothiazine agents with other agents that can lower the seizure threshold, such as opioids or local anesthetics (see Drug Interactions).

    Acute bronchospasm, asthma, chronic obstructive pulmonary disease (COPD), respiratory depression, sleep apnea, sulfite hypersensitivity

    Because promethazine exhibits a significant amount of anticholinergic activity, it should be avoided in those who have experienced a worsening in respiratory status due to H1-antagonist therapy. The anticholinergic activity of H1-antagonists, such as promethazine, may result in thickened bronchial secretions in the respiratory tract thereby aggravating an acute asthmatic attack or chronic obstructive pulmonary disease (COPD). Although H1-antagonists should be avoided during an acute asthmatic attack or acute bronchospasm, the anticholinergic effects of promethazine do not preclude use in all asthmatic or COPD patients, particularly if the above respiratory symptom is not a primary component of the illness. Antihistamines (usually non-sedating H1-antagonists with minimal anticholinergic activity) are frequently used in patients who have allergic rhinitis as a component of their asthma. However, the package labeling for promethazine states that antihistamines are contraindicated for use in the specific treatment of lower respiratory tract symptoms including asthma and should be avoided in patients with significant respiratory depression, including COPD and sleep apnea. Promethazine injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthma episodes, in certain susceptible individuals. Sulfite hypersensitivity is more common in patients with asthma.

    Hepatic disease, hepatic encephalopathy

    Promethazine is extensively metabolized in the liver. The metabolism of promethazine may be reduced in the presence of hepatic disease, hepatic encephalopathy, or liver impairment. Those with significant hepatic disease receiving H1-antagonists should be monitored for liver function and side effects; dosage adjustments may be required in some patients. Promethazine should be avoided in pediatric patients whose signs or symptoms suggest the possibility of hepatic encephalopathy or other hepatic disease.

    Children, dehydration, infants, neonates, Reye's syndrome

    Promethazine is contraindicated for use in children < 2 years of age, including infants and neonates due to the risk for fatal respiratory depression. Seizures and/or paradoxical CNS stimulation may also occur in this age group. Promethazine should be used cautiously in children > 2 years of age due to these reasons. If promethazine is used in children 2 years or older, the lowest possible effective dose should be given, and the concomitant use of other respiratory depressants should be avoided. There have been a number of cases of respiratory depression, sleep apnea, and SIDS in children receiving phenothiazine antihistamines at various weight-based dosages. The mechanism of this reaction is not yet known; therefore, promethazine should be used with extreme caution, if at all, in children with a family history of SIDS or sleep apnea. In general, antiemetics are not recommended for treatment of uncomplicated vomiting in children. Extrapyramidal symptoms that may occur in children receiving promethazine may be confused with signs of undiagnosed primary disease; thus the drug should be avoided in children whose signs or symptoms suggest the possibility of Reye's syndrome, hepatic encephalopathy or other hepatic disease. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonic reactions with the use of promethazine.

    Labor, obstetric delivery, pregnancy

    Promethazine is classified under FDA pregnancy risk category C. Because there are no adequate studies in pregnant women, promethazine should be considered during pregnancy only when the benefits of therapy outweigh the risks to the fetus. Guidance regarding the use of promethazine during labor and obstetric delivery is varied. According to its manufacturers, promethazine may be used alone or as an adjunct to narcotic analgesics during labor. Limited data suggest that its use is not associated with any appreciable effect on the duration of labor or delivery and does not increase the risk or need for intervention in the newborn; the effect on later growth and development of the newborn is unknown. The effects of promethazine on respiration in the exposed neonate are unclear. Although respiratory depression was observed in a study including a small group of patients, data from three large studies demonstrated no such effect. In addition, investigators in a separate study concluded that promethazine should be avoided during labor due to transient behavioral and electroencephalographic changes (persisting for < 3 days) observed in exposed newborns. Promethazine administered to a pregnant woman within 2 weeks of delivery may inhibit platelet aggregation in the newborn. Although the clinical significance of this is unknown, neonatal impairment is comparable to disorders associated with a definite bleeding state. Finally, diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations.

    Breast-feeding

    According to the manufacturer, it is not known whether promethazine is excreted in human milk, and accounting for its potential to cause harm to a nursing infant, a decision should be made whether to discontinue nursing or the drug. Like other phenothiazine derivatives, promethazine is expected to have low excretion into breast milk, and occasional short-term use is probably compatible with posing little risk to a nursing infant. However, if multiple doses are to be used, the infant should be monitored for excess sedation or paradoxical CNS stimulation. Theoretically, promethazine can lower basal prolactin secretion and may interfere with the establishment of lactation. An antiemetic without a potent histamine blocking action, such as prochlorperazine, may be considered as an alternative. Potential side effects include sedation in the infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Contact lenses, glaucoma

    Promethazine should be avoided, if possible, in patients with open-angle or closed-angle glaucoma and an H1-antagonist with less anticholinergic effects should be substituted. An increase in intraocular pressure may occur from the anticholinergic actions of the drug, precipitating an acute attack of glaucoma. Elderly patients are more susceptible to the anticholinergic effects of promethazine, including possible precipitation of undiagnosed glaucoma. Other ocular effects resulting from the anticholinergic effects of promethazine include dry eyes or blurred vision. This may be of significance in the elderly and wearers of contact lenses.

    Bladder obstruction, GI obstruction, ileus, prostatic hypertrophy, urinary retention

    Promethazine has substantial anticholinergic effects and a worsening of symptoms may be seen in patients with bladder obstruction, GI obstruction or ileus, benign prostatic hypertrophy, or urinary retention. These precautions are most significant when using antihistamines from the ethanolamine or phenothiazine group. In general, the elderly tend to be more susceptible to the anticholinergic effects of drugs since there is a decline in endogenous cholinergic activity that occurs with age.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Use promethazine with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation.

    Radiographic contrast administration

    Phenothiazines can lower the seizure threshold. Because of a potential increased risk of seizures, phenothiazines should not be used during intrathecal radiographic contrast administration. Phenothiazines should be discontinued 48 hours before the myelography and should not be resumed until at least 24 hours after the procedure. Promethazine should not be used for the control of nausea and vomiting associated with these procedures.

    CNS depression, driving or operating machinery, ethanol intoxication

    Promethazine can cause drowsiness and CNS depression. Patients receiving promethazine should be advised to avoid driving or operating machinery or other hazardous tasks until the effects of the drug are known. The combination of promethazine with other CNS depressants, such as ethanol, sedative/hypnotics, narcotics, other antihistamines, general anesthetics, or tricyclic antidepressants may augment CNS and/or respiratory depression. If such use cannot be avoided, a dose reduction in one or both agents may be required. Patients should avoid ethanol intoxication if taking promethazine.

    Diabetes mellitus

    Phenothiazines have been reported to increase blood sugar. Since promethazine is a phenothiazine antihistamine, patients with diabetes mellitus should routinely monitor their blood glucose during concomitant phenothiazine therapy.

    Anticholinergic medications, geriatric

    Reported clinical experience with promethazine has not identified differences in response between older and younger adult patients. Howeveer, the elderly are more sensitive to anticholinergic side effects of sedating antihistamines such as promethazine. Use of other anticholinergic medications may increase the risk of these effects in any patient, particularly the elderly. Sedating drugs may cause confusion and over-sedation in the elderly; therefore, elderly patients should generally be started on low doses of promethazine and closely observed. According to the Beers Criteria, first-generation antihistamines are considered potentially inappropriate medications (PIMs) in geriatric patients and should be avoided because they are highly anticholinergic, there is reduced clearance in advanced age, tolerance develops when used as hypnotics, and there is a greater risk of anticholinergic effects (e.g., confusion, dry mouth, constipation) and toxicity compared to younger adults. Avoid drugs with strong anticholinergic activity in geriatric patients with the following conditions due to the potential for symptom exacerbation or adverse effects: dementia/cognitive impairment (adverse CNS effects), delirium/high risk of delirium (new-onset or worsening delirium), or lower urinary tract symptoms/benign prostatic hyperplasia in men (urinary retention or hesitancy). The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; cough, cold, and allergy medications should be used only for a limited duration (less than 14 days) unless there is documented evidence of enduring symptoms that cannot otherwise be alleviated, as first-generation antihistamines have strong anticholinergic properties and are not medications of choice in older individuals. If administered, use the smallest possible dose. Anticholinergics may cause excessive sedation, confusion, cognitive impairment, distress, dry mouth, constipation, and urinary retention. Many of these effects may lead to other adverse consequences, such as falls. Also according to OBRA, phenothiazine-related antiemetics such as promethazine should be used cautiously. Potential adverse consequences of phenothiazine-related antiemetics include sedation, dizziness, drowsiness, postural hypotension, neuroleptic malignant syndrome, lowering of the seizure threshold, anticholinergic effects (e.g., constipation, dry mouth, blurred vision, urinary retention), extrapyramidal symptoms (e.g., pseudoparkinsonism, dystonic reaction, akathisia, tardive dyskinesia), altered cardiac conduction, and arrhythmias.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    tardive dyskinesia / Delayed / Incidence not known
    torticollis / Delayed / Incidence not known
    neuroleptic malignant syndrome / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    ileus / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    retinopathy / Delayed / Incidence not known
    corneal opacification / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    muscle paralysis / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    cyanosis / Early / Incidence not known
    thrombosis / Delayed / Incidence not known
    respiratory depression / Rapid / Incidence not known
    apnea / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    akathisia / Delayed / 4.0-14.0
    excitability / Early / 9.7-9.7
    confusion / Early / 3.2-3.2
    dyspnea / Early / 3.2-3.2
    dystonic reaction / Delayed / 1.0-1.0
    pseudoparkinsonism / Delayed / 1.0-1.0
    euphoria / Early / Incidence not known
    blurred vision / Early / Incidence not known
    hallucinations / Early / Incidence not known
    delirium / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    urinary retention / Early / Incidence not known
    constipation / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    platelet dysfunction / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    priapism / Early / Incidence not known
    galactorrhea / Delayed / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    ejaculation dysfunction / Delayed / Incidence not known
    erythema / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    hyperthermia / Delayed / Incidence not known

    Mild

    drowsiness / Early / 38.0-71.0
    injection site reaction / Rapid / 21.0-21.0
    xerostomia / Early / 9.7-9.7
    insomnia / Early / 3.2-3.2
    nightmares / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    fatigue / Early / Incidence not known
    diplopia / Early / Incidence not known
    dizziness / Early / Incidence not known
    agitation / Early / Incidence not known
    tremor / Early / Incidence not known
    syncope / Early / Incidence not known
    xerophthalmia / Early / Incidence not known
    mydriasis / Early / Incidence not known
    purpura / Delayed / Incidence not known
    fever / Early / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    menstrual irregularity / Delayed / Incidence not known
    mastalgia / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known
    skin irritation / Early / Incidence not known
    nasal congestion / Early / Incidence not known
    hypothermia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Minor) Abarelix can cause QT prolongation. In a single, active-controlled, clinical study comparing abarelix to LHRH agonist plus nonsteroidal antiandrogen, periodic electrocardiograms were performed. Both therapies prolonged the mean QTc interval by >10 msec from baseline. In approximately 20% of 340 patients, the QTc increased more than 30 milliseconds from baseline or the end-of-treatment QTc values were more than 450 milliseconds. The effect of abarelix on the QT interval may be due to androgen deprivation or other variables, as similar effects were seen in men that received a gonadotropin-releasing hormone (GnRH) agonist with a nonsteroidal antiandrogen. Patients with a baseline QTc value greater than 450 milliseconds may not be appropriate candidates for abarelix receipt. Prescribers need to weigh the potential benefits and risks of abarelix use in patients with prolonged QT syndrome or in patients taking other drugs that may prolong the QT interval. Agents with a possible risk for QT prolongation and TdP include phenothiazines.
    Acarbose: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Acetaminophen; Butalbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as dichloralphenazone. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Acetaminophen; Diphenhydramine: (Moderate) Additive anticholinergic and sedative effects may be seen when Promethazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with phenothiazines may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression. Furthermore, oxycodone is metabolized in part by 2D6 to oxymorphone, which represents < 15% of the total administered dose. Concurrent use of some agents that inhibit CYP2D6 (e.g., quinidine) has not been shown to result in clinically significant interactions. However, many phenothiazines are inhibitors of CYP2D6 (e.g., chlorpromazine, perphenazine, thioridazine) and may potentially increase the effects of oxycodone. Also, severe hypotension may be potentiated with concurrent phenothiazine usage or other drug that compromises vasomotor tone.
    Acetaminophen; Pentazocine: (Moderate) Concomitant use of pentazocine with other CNS depressants, such as phenothiazines, can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously with phenothiazines.
    Acetaminophen; Propoxyphene: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. A dose reduction of one or both drugs may be needed.
    Acetaminophen; Tramadol: (Moderate) Caution is advisable during concurrent use of tramadol and promethazine. Seizures have been reported in patients receiving monotherapy with both tramadol and promethazine at recommended doses. Concomitant use of tramadol and promethazine may increase the risk of seizures. In addition, due to the primary CNS effects of promethazine, caution is advisable during use of other centrally acting medications such as tramadol. Impairment of metabolism of tramadol by CYP2D6 inhibitors, such as promethazine, may increase the risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may decrease tramadol analgesic efficacy.
    Acetohexamide: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
    Alfentanil: (Moderate) Concomitant use of alfentanil with other CNS depressants, including the phenothiazines, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Alfuzosin: (Moderate) Use caution when administering alfuzosin with promethazine due to the potential for QT prolongation. Alfuzosin may prolong the QT interval in a dose-dependent manner. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Alogliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Alogliptin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Alogliptin; Pioglitazone: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Alosetron: (Moderate) Alosetron, if combined with drugs that possess anticholinergic properties like phenothiazines, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    Alpha-glucosidase Inhibitors: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Alprazolam: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Amantadine: (Moderate) Although the mechanism of amantadine is not clear, it appears it potentiates the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs should be avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic actions of phenothiazines can be additive to those of amantadine, and may increase the risk of antimuscarinic-related side effects. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation.
    Amifampridine: (Major) Carefully consider the need for concomitant treatment with phenothiazines and amifampridine, as coadministration may increase the risk of seizures. Consider an alternative to the phenothiazine. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Phenothiazines may lower seizure threshold and should be used with caution with concomitant medications which may also affect seizure threshold.
    Amikacin: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Aminoglycosides: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Aminolevulinic Acid: (Moderate) Phenothiazines may increase the photosensitizing effects of photosensitizing agents used in photodynamic therapy. Patients should limit ultra-violet exposure.
    Amiodarone: (Major) The concomitant use of amiodarone and other drugs known to prolong the QT interval should only be done after careful assessment of risks versus benefits, especially when the coadministered agent might decrease the metabolism of amiodarone. If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with amiodarone include promethazine. Promethazine carries a possible risk of QT prolongation. Additionally, amiodarone inhibits CYP2D6 and may theoretically increase concentrations of promethazine, which is metabolized by CYP2D6. Monitor for side effects like sedation and changes in heart rate or rhythm.
    Amitriptyline: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Amitriptyline; Chlordiazepoxide: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities. (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Amlodipine; Celecoxib: (Moderate) A dosage adjustment may be warranted for promethazine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of promethazine. Celecoxib is a CYP2D6 inhibitor, and promethazine is a CYP2D6 substrate.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Amobarbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Amoxapine: (Moderate) Additive anticholinergic effects are possible during coadministration of promethazine and amoxapine. Additive drowsiness and sedation are also possible. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with clarithromycin include promethazine. Promethazine carries a possible risk of QT prolongation.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with clarithromycin include promethazine. Promethazine carries a possible risk of QT prolongation.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include promethazine. Promethazine carries a possible risk of QT prolongation.
    Anticholinergics: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Anxiolytics; Sedatives; and Hypnotics: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
    Apomorphine: (Moderate) Use promethazine with apomorphine with caution; avoid use if possible due to an increased risk for QT prolongation and sedation. Promethazine and apomorphine may reduce the effectiveness of each other through opposing effects on dopamine. Apomorphine causes considerable somnolence, and concomitant administration of apomorphine and CNS depressants like promethazine could result in additive CNS effects. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. promethazine is associated with a possible risk for QT prolongation.
    Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as phenothiazines.
    Aripiprazole: (Moderate) Both promethazine and aripiprazole are associated with a possible risk for QT prolongation; therefore, caution is advisable during coadministration. In addition, because aripiprazole is partially metabolized by CYP2D6, patients should be monitored for aripiprazole-related adverse reactions during concurrent use of a CYP2D6 inhibitor such as promethazine. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor. Coadministration of phenothiazines such as promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with arsenic trioxide include promethazine. Promethazine carries a possible risk of QT prolongation. ECGs should be monitored at initiation, weekly (and more frequently in clinically unstable patients), during arsenic trioxide therapy.
    Artemether; Lumefantrine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include artemether; lumefantrine. Additionally, lumefantrine is an inhibitor and promethazine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased promethazine concentrations. Concomitant use warrants caution due to the potential for increased side effects, such as sedation. (Major) The administration of artemether is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Promethazine has been reported to cause QT prolongation. Consider ECG monitoring if co-administration is not avoidable.
    Articaine; Epinephrine: (Moderate) The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of phenothiazines. This blockade can cause an apparently paradoxical condition called epinephrine reversal, which can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Due to the risk of additive QT prolongation and potential for serious arrhythmias, asenapine should be avoided in combination with other drugs having an association with QT prolongation. Co-administration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when promethazine is used concomitantly with other drugs having antimuscarinic activity such as orphenadrine. Additive sedation may also occur.
    Aspirin, ASA; Carisoprodol: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential for additive hypotension and excessive CNS effects (sedation and dizziness), which can impair the ability to undertake tasks requiring mental alertness.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential for additive hypotension and excessive CNS effects (sedation and dizziness), which can impair the ability to undertake tasks requiring mental alertness.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with phenothiazines may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression. Furthermore, oxycodone is metabolized in part by 2D6 to oxymorphone, which represents < 15% of the total administered dose. Concurrent use of some agents that inhibit CYP2D6 (e.g., quinidine) has not been shown to result in clinically significant interactions. However, many phenothiazines are inhibitors of CYP2D6 (e.g., chlorpromazine, perphenazine, thioridazine) and may potentially increase the effects of oxycodone. Also, severe hypotension may be potentiated with concurrent phenothiazine usage or other drug that compromises vasomotor tone.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
    Atenolol; Chlorthalidone: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Atomoxetine: (Moderate) Use atomoxetine and promethazine together with caution as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Promethazine is a phenothiazine associated with a possible risk for QT prolongation.
    Atropine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Atropine; Difenoxin: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Diphenoxylate is a synthetic opiate derivative that appears to exert its effect locally and centrally on the smooth muscle cells of the GI tract to inhibit GI motility and slow excess GI propulsion. The effects can be additive to other agents with CNS and anticholinergic effects, such as the phenothiazines. In some cases, constipation might occur, and effects on the CNS or bladder function may also be additive.
    Atropine; Diphenoxylate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Diphenoxylate is a synthetic opiate derivative that appears to exert its effect locally and centrally on the smooth muscle cells of the GI tract to inhibit GI motility and slow excess GI propulsion. The effects can be additive to other agents with CNS and anticholinergic effects, such as the phenothiazines. In some cases, constipation might occur, and effects on the CNS or bladder function may also be additive.
    Atropine; Edrophonium: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including phenothiazines.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including phenothiazines.
    Azilsartan; Chlorthalidone: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Azithromycin: (Major) Avoid coadministration of azithromycin with promethazine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Promethazine is associated with possible risk for QT prolongation.
    Baclofen: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Barbiturates: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Bedaquiline: (Major) Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Promethazine carries a possible risk of QT prolongation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Belladonna; Opium: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Bendroflumethiazide; Nadolol: (Moderate) Concomitant treatment with nadolol and phenothiazines, especially in large doses, can have an additive hypotensive effect. (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Benzodiazepines: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Benztropine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Bepridil: (Severe) Patients receiving other drugs which have the potential for QT prolongation, such as phenothiazines, have an increased risk of developing proarrhythmias during bepridil therapy. According to the manufacturer, bepridil is contraindicated for use with drugs that prolong the QT interval due to the risk of TdP.
    Bethanechol: (Moderate) Drugs that possess antimuscarinic properties, such as promethazine, are pharmacologic opposites of bethanechol. These agents should not be used with bethanechol except when the specific intent is to counteract excessive actions of one or the other.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include metronidazole.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Brexpiprazole: (Major) Caution is advisable during concurrent use of brexpiprazole and promethazine. Brexpiprazole is partially metabolized by CYP2D6 and promethazine is an inhibitor of CYP2D6. The manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Therefore, if promethazine is used in combination with brexpiprazole and a moderate to strong CYP3A4 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions. Because promethazine is a phenothiazine, the risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use. It may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary.
    Brimonidine; Timolol: (Moderate) Timolol interacts with phenothiazines by adding to the overall hypotensive effect.
    Bromocriptine: (Major) Avoid concurrent use of phenothiazines and bromocriptine when possible. Bromocriptine may interact with dopamine antagonists such as the phenothiazines. The phenothiazines are noted to result in a decreased efficacy of bromocriptine. The prolactin-lowering effect of bromocriptine is antagonized; the elevation in prolactin levels produced by phenothiazines persists with chronic administration. In addition, bromocriptine, a dopamine agonist, may theoretically diminish the effectiveness of central dopamine antagonists such as the phenothiazines; however, such interactions are not certain.
    Brompheniramine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including phenothiazines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Brompheniramine; Pseudoephedrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Buprenorphine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, caution and close monitoring are advisable if concurrent use of promethazine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Promethazine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of promethazine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, caution and close monitoring are advisable if concurrent use of promethazine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Promethazine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of promethazine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients.
    Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients. (Moderate) Patients receiving phenothiazines and naltrexone concomitantly have had symptoms of somnolence and lethargy.
    Buspirone: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as buspirone. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Butabarbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as phenothiazines, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
    Cabergoline: (Moderate) Cabergoline should generally not be coadministered with phenothiazines due to mutually antagonistic effects on dopaminergic function. The dopamine antagonist action of phenothiazines may diminish the prolactin-lowering ability of cabergoline while the dopamine agonist effects of cabergoline may exacerbate a psychotic disorder, reducing the effectiveness of antipsychotics such as phenothiazines.
    Canagliflozin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Canagliflozin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and phenothiazines. CNS depressants can potentiate the effects of cannabidiol.
    Capsaicin; Metaxalone: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Carbamazepine: (Moderate) The concomitant use of the phenothiazines and carbamazepine can increase CNS depression and reduce anticonvulsant effectiveness through a lowering of the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments. Carbamazepine is a potent inducer of the cytochrome P-450 hepatic oxidase system, and can reduce plasma concentrations of the phenothiazines. If a phenothiazine and carbamazepine must be used together, dosage adjustments of the phenothiazine may be required.
    Carbetapentane; Chlorpheniramine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including phenothiazines.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including phenothiazines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Additive anticholinergic and sedative effects may be seen when Promethazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including phenothiazines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including phenothiazines.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including phenothiazines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including phenothiazines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including phenothiazines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including phenothiazines.
    Carbetapentane; Pyrilamine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including phenothiazines.
    Carbidopa; Levodopa: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Carbidopa; Levodopa; Entacapone: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Carbinoxamine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Carbinoxamine; Phenylephrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Carbinoxamine; Pseudoephedrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Cariprazine: (Moderate) Consider an alternative to promethazine treatment if possible. If these drugs must be used together, use with caution. The use of promethazine, a phenothiazine, with cariprazine, an antipsychotic, may increase the risk of additive adverse effects such as CNS depression, drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, or extrapyramidal symptoms.
    Carisoprodol: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential for additive hypotension and excessive CNS effects (sedation and dizziness), which can impair the ability to undertake tasks requiring mental alertness.
    Carteolol: (Moderate) Concomitant treatment with carteolol and phenothiazines, especially in large doses, can have an additive hypotensive effect.
    Celecoxib: (Moderate) A dosage adjustment may be warranted for promethazine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of promethazine. Celecoxib is a CYP2D6 inhibitor, and promethazine is a CYP2D6 substrate.
    Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
    Central-acting adrenergic agents: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Ceritinib: (Major) Avoid coadministration of ceritinib with promethazine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Cetrorelix: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
    Cevimeline: (Moderate) Coadministration may result in increased cevimeline plasma concentrations. Cevimeline is partially metabolized by CYP2D6; promethazine inhibits CYP2D6.
    Charcoal: (Major) Phenothiazine absorption is reduced when coadministered with activated charcoal. Concomitant administration of phenothiazines and activated charcoal dietary supplements is not recommended. Activated charcoal may be appropriate in phenothiazine overdose situations, as charcoal absorbs the phenothiazines and also enhances drug elimination.
    Chlophedianol; Dexbrompheniramine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as dexbrompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Chloral Hydrate: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
    Chlordiazepoxide: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Chlordiazepoxide; Clidinium: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Chloroquine: (Major) Avoid coadministration of chloroquine with promethazine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Promethazine is associated with a possible risk for QT prolongation.
    Chlorothiazide: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Chlorpheniramine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Chlorpheniramine; Dextromethorphan: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Chlorpheniramine; Phenylephrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Chlorpromazine: (Major) The use of promethazine, a phenothiazine antiemetic, with phenothiazine antipsychotics such as chlorpromazine should be avoided if possible. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). Promethazine has also been associated with QT prolongation. The duplicative actions of the drugs may result in an increased risk for side effects. Coadministration of promethazine and phenothiazine antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Chlorpropamide: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
    Chlorthalidone: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Chlorthalidone; Clonidine: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Chlorzoxazone: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Ciprofloxacin: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include ciprofloxacin.
    Cisapride: (Severe) Promethazine carries a possible risk of QT prolongation. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Because of the potential for TdP, coadministration is contraindicated.
    Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended. Promethazine carries a possible risk of QT prolongation.
    Clarithromycin: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with clarithromycin include promethazine. Promethazine carries a possible risk of QT prolongation.
    Clemastine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as clemastine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Clindamycin; Tretinoin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Clobazam: (Major) A dosage reduction of CYP2D6 substrates, such as phenothiazines, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Elevated concentrations of phenothiazines occurring through inhibition of CYP2D6 may increase the risk of adverse effects, including QT prolongation and torsade de pointes. Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects which may be potentiated during concurrent use of conventional antipsychotics including phenothiazines. Antipsychotics may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with promethazine. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Clomipramine: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Clonazepam: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Clorazepate: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Clozapine: (Major) Coadministration of promethazine and clozapine may increase the risk of QT prolongation and other adverse effects. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Promethazine is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine; elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, and seizures. Monitor for adverse reactions if use together is not avoidable. Consideration should be given to reducing the clozapine dose if necessary.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
    Codeine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Codeine; Promethazine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    COMT inhibitors: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Monitor for changes in movement, moods, or behaviors. In addition, coadministration of COMT inhibitors and phenothiazines may result in additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Crizotinib: (Major) Avoid coadministration of crizotinib with promethazine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Cyclobenzaprine: (Moderate) Cyclobenzaprine and promethazine, a phenothiazine with sedating antihistaminic activity, both exhibit anticholinergic activity, and anticholinergic side effects can be additive. Monitor for anticholinergic-related effects such as constipation and urinary retention. Additive CNS depression causing sedation and/or dizziness is also possible. Dosage adjustments of either or both drugs may be necessary.
    Dantrolene: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Dapagliflozin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Dapagliflozin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Dapagliflozin; Saxagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
    Dasatinib: (Moderate) Monitor for evidence of QT prolongation during concurrent use of dasatinib and promethazine as concurrent use may increase the risk of QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Degarelix: (Major) Avoid coadministration of degarelix with promethazine due to the risk of reduced efficacy of degarelix; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; degarelix is a GnRH analog. Additionally, androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Desipramine: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Deutetrabenazine: (Moderate) For patients taking a deutetrabenazine dosage more than 24 mg/day with promethazine, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Monitor for signs and symptoms of neuroleptic malignant syndrome (NMS), restlessness, and agitation. If NMS is diagnosed, immediately discontinue deutetrabenazine, and provide intensive symptomatic treatment and medical monitoring. Recurrence of NMS has been reported with resumption of drug therapy. If akathisia or parkinsonism develops during treatment, the deutetrabenazine dose should be reduced; discontinuation may be required. Deutetrabenazine is a reversible, dopamine depleting drug and promethazine is a dopamine antagonist. The risk for parkinsonism, NMS, or akathisia may be increased with concomitant administration. Additionally, concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as promethazine, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dexchlorpheniramine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Dexmedetomidine: (Moderate) Coadministration of dexmedetomidine with phenothiazines to lead to an enhancement of anesthetic, sedative, or cardiovascular effects. Dosage reduction of either agent may be required.
    Dexmethylphenidate: (Moderate) Antipsychotics, such as phenothiazines, and dexmethylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Dexmethylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of dexmethylphenidate.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Additive anticholinergic and sedative effects may be seen when Promethazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Dextromethorphan; Quinidine: (Severe) Quinidine (including dextromethorphan; quinidine) administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6, such as promethazine, as the effects on the QT interval may be increased during concurrent use of these agents.
    Diazepam: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Dicyclomine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Diethylpropion: (Minor) Use of diethylpropion with phenothiazines may antagonize the anorectic effects of diethylpropion.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Dimenhydrinate: (Moderate) Additive anticholinergic and sedative effects may be seen when Promethazine is used with first generation antihistamines, such as dimenhydrinate. Patients should be informed to read non-prescription motion sickness, allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
    Dipeptidyl Peptidase-4 Inhibitors: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Diphenhydramine: (Moderate) Additive anticholinergic and sedative effects may be seen when Promethazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic and sedative effects may be seen when Promethazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Diphenhydramine; Ibuprofen: (Moderate) Additive anticholinergic and sedative effects may be seen when Promethazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
    Diphenhydramine; Naproxen: (Moderate) Additive anticholinergic and sedative effects may be seen when Promethazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
    Diphenhydramine; Phenylephrine: (Moderate) Additive anticholinergic and sedative effects may be seen when Promethazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Disopyramide: (Major) Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with disopyramide include promethazine. Additive anticholinergic effects may also occur, and may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Dofetilide: (Major) Coadministration of dofetilide and promethazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Dolasetron: (Moderate) Administer dolasetron with caution in combination with promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with promethazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Donepezil: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Dorzolamide; Timolol: (Moderate) Timolol interacts with phenothiazines by adding to the overall hypotensive effect.
    Doxepin: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Doxylamine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Doxylamine; Pyridoxine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Dronabinol: (Moderate) Use caution if coadministration of phenothiazines with dronabinol is necessary. Administration of dronabinol with phenothiazines (e.g., prochlorperazine) has resulted in improved antiemetic efficacy as compared to either drug alone, without additional toxicity. However, it is also possible that coadministration may result in additive dizziness, confusion, somnolence, and other CNS effects.
    Dronedarone: (Severe) Dronedarone administration is associated with a dose-related increase in the QTc interval. Promethazine carries a possible risk of QT prolongation. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. Any drug with known potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a potential risk for QT prolongation that should be used cautiously and with close monitoring with droperidol include promethazine. In addition, promethazine has sedating actions and may have additive or potentiating sedative and other CNS effects with droperidol.
    Drospirenone; Ethinyl Estradiol: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as promethazine. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with promethazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider alternatives to efavirenz when coadministering with promethazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with promethazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
    Eliglustat: (Major) Coadministration of promethazine and eliglustat may result in increased concentrations of the phenothiazine and an increased risk of QT prolongation. If coadministration is necessary, use great caution and monitor closely. Consider reducing the dosage of promethazine and titrating to clinical effect. Promethazine is a CYP2D6 substrate associated with a possible risk of QT prolongation. Eliglustat is a CYP2D6 inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
    Empagliflozin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Empagliflozin; Linagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Empagliflozin; Linagliptin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Empagliflozin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering rilpivirine with promethazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering rilpivirine with promethazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Encorafenib: (Major) Avoid coadministration of encorafenib and promethazine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Entrectinib: (Major) Avoid coadministration of entrectinib with promethazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Epinephrine: (Moderate) The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of phenothiazines. This blockade can cause an apparently paradoxical condition called epinephrine reversal, which can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Eribulin: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include eribulin.
    Ertugliflozin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Ertugliflozin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Ertugliflozin; Sitagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Erythromycin: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include erythromycin.
    Erythromycin; Sulfisoxazole: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include erythromycin.
    Escitalopram: (Moderate) Use escitalopram with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Esketamine: (Major) Closely monitor patients receiving esketamine and promethazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
    Estazolam: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Eszopiclone: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
    Ethanol: (Major) Patients should generally be counseled to avoid alcohol use during phenothiazine therapy, due to additive central nervous system (CNS) depression and the potential to increase psychomotor impairment. Phenothiazines may increase, prolong, or intensify the sedative action of other CNS depressants, such as alcohol.
    Ethinyl Estradiol: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Desogestrel: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Etonogestrel: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Norelgestromin: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Norethindrone: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Norgestimate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethinyl Estradiol; Norgestrel: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Ethosuximide: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Ethotoin: (Moderate) Phenothiazines, when used concomitantly with Hydantoins (e.g., phenytoin, ethotoin) can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. In addition to these pharmacodynamic interactions, several individual anticonvulsant agents interact in multiple ways with phenothiazines. Chlorpromazine may interfere with the metabolism of phenytoin and thus precipitate phenytoin toxicity.
    Ezogabine: (Moderate) Use caution during concurrent use of ezogabine and promethazine as concurrent use may increase the risk of QT prolongation. Ezogabine has been associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Felbamate: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and promethazine. Concurrent use may result in additive CNS depression.
    Fentanyl: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Fingolimod: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include fingolimod.
    Flavoxate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Flecainide: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include flecainide.
    Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as phenothiazines, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
    Fluconazole: (Moderate) Use fluconazole with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Flucytosine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.
    Fluocinolone; Hydroquinone; Tretinoin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Fluoxetine: (Moderate) Use fluoxetine with caution in combination with promethazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Fluoxetine; Olanzapine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone. (Moderate) Use fluoxetine with caution in combination with promethazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Fluphenazine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with phenothiazine antipsychotics such as fluphenazine should be avoided if possible. Co-administration of promethazine and antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. In addition, promethazine is associated with QT prolongation and fluphenazine is associated with a possible risk of QT prolongation. Concomitant administration would increase the risk of QT prolongation.
    Flurazepam: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Fluvoxamine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
    Food: (Major) It is recommended that patients avoid the use of marijuana, by any route, if they are treated for a psychiatric history, including psychosis and bipolar disorder, as the cannabinoids (the psychoactive ingredients, such as THC) in marijuana can produce psychotoxic effects and may exacerbate psychiatric disorders. A high frequency of use and use of products with high-potency of THC are potential risk factors for psychiatric effects. Additionally, additive CNS effects, such as sedation or CNS depression are possible. Clinical studies suggest that cannabis use may reduce the efficacy of some antipsychotic drugs. In addition, several cannabinoids in marijuana appear to influence the activity of CYP enzymes and P-glycoprotein, which may alter the concentrations of antipsychotics and influence either safety or efficacy, For example, the smoking of marijuana influences the metabolism of some medications in a manner similar to tobacco by inducing CYP1A2.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as promethazine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Fosphenytoin: (Moderate) Phenothiazines, when used concomitantly with Hydantoins (e.g., phenytoin, ethotoin) can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. In addition to these pharmacodynamic interactions, several individual anticonvulsant agents interact in multiple ways with phenothiazines. Chlorpromazine may interfere with the metabolism of phenytoin and thus precipitate phenytoin toxicity.
    Fospropofol: (Moderate) Fospropofol potentiates respiratory and CNS depression and may enhance the sedative, respiratory depressive, and hypotensive effects of phenothiazines. A reduced dose of fospropofol may be needed for sedation if it is used in conjunction with other medications that cause CNS depression.
    Gabapentin: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and promethazine. Concomitant use of gabapentin with promethazine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
    Galantamine: (Moderate) Promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of galantamine. When concurrent use cannot be avoided, monitor the patient for reduced galantamine efficacy.
    Ganirelix: (Moderate) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as phenothiazines, should not be administered concomitantly with ganirelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
    Gemifloxacin: (Moderate) Gemifloxacin should be used cautiously with promethazine as concurrent use may increase the risk of QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. Promethazine is a phenothiazine associated with possible risk for QT prolongation.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and promethazine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Gentamicin: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with promethazine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Glimepiride: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
    Glimepiride; Pioglitazone: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Glimepiride; Rosiglitazone: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Glipizide: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
    Glipizide; Metformin: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Glyburide: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
    Glyburide; Metformin: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Goserelin: (Major) Avoid coadministration of goserelin with promethazine due to the risk of reduced efficacy of goserelin; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; goserelin is a GnRH analog. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
    Granisetron: (Moderate) Use granisetron with caution in combination with promethazine due to increased risk for QT prolongation and torsade de pointes (TdP). Granisetron has been associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Guaifenesin; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Guanidine: (Minor) Bone marrow suppression is associated with guanidine therapy. Avoid concomitant use of other drugs known to cause bone marrow suppression such as phenothiazines.
    Halobetasol; Tazarotene: (Moderate) The manufacturer states that tazarotene should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Halofantrine: (Severe) Halofantrine is considered to have a well-established risk for QT prolongation and torsades de pointes. Halofantrine should be avoided in patients receiving drugs which may induce QT prolongation, such as phenothiazines.
    Halogenated Anesthetics: (Moderate) Halogenated anesthetics carry a possible risk for QT prolongation and torsade de pointes (TdP). Promethazine carries a possible risk of QT prolongation and should be used cautiously with these anesthetics, with proper blood pressure and heart rate monitoring.
    Haloperidol: (Moderate) Caution is advisable when combining haloperidol concurrently with promethazine as concurrent use may increase the risk of QT prolongation and other antipsychotic-related adverse effects including drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Mild to moderately increased haloperidol concentrations have also been reported when haloperidol was given concomitantly with promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, promethazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as haloperidol. The likelihood of pharmacodynamic interactions varies based upon the individual properties of the coadministered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Histrelin: (Major) Avoid coadministration of histrelin with promethazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Hydantoins: (Moderate) Phenothiazines, when used concomitantly with Hydantoins (e.g., phenytoin, ethotoin) can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. In addition to these pharmacodynamic interactions, several individual anticonvulsant agents interact in multiple ways with phenothiazines. Chlorpromazine may interfere with the metabolism of phenytoin and thus precipitate phenytoin toxicity.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics. (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; phenothiazines are CYP2D6 inhibitors.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Hydrocodone: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydromorphone: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydroxychloroquine: (Major) Avoid coadministration of promethazine and hydroxychloroquine due to an increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with promethazine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, additive anticholinergic effects and CNS depression may also occur. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Promethazine is associated with a possible risk for QT prolongation.
    Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with phenothiazines may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression. Furthermore, oxycodone is metabolized in part by 2D6 to oxymorphone, which represents < 15% of the total administered dose. Concurrent use of some agents that inhibit CYP2D6 (e.g., quinidine) has not been shown to result in clinically significant interactions. However, many phenothiazines are inhibitors of CYP2D6 (e.g., chlorpromazine, perphenazine, thioridazine) and may potentially increase the effects of oxycodone. Also, severe hypotension may be potentiated with concurrent phenothiazine usage or other drug that compromises vasomotor tone.
    Ibutilide: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include ibutilide.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Due to the risk of additive QT prolongation and potential for serious arrhythmias, other drugs having an association with QT prolongation are best avoided with iloperidone. Co-administration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Imipramine: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Incretin Mimetics: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Indacaterol; Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Indapamide: (Moderate) Indapamide may cause electrolyte disturbances, which may increase the potential for proarrhythmic effects of selected phenothiazines.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with promethazine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Insulins: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Iohexol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Iopamidol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Iopromide: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Ioversol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Ipecac: (Major) Ipecac has been shown to be effective in producing emesis in patients who have ingested antiemetics, provided ipecac is given promptly (usually within 1 hour of antiemetic consumption). If ipecac is administered after antiemetic therapy has begun to exert therapeutic effects, ipecac may be less effective. It is suggested the irritating GI effects of ipecac lead to emesis following antiemetic consumption.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
    Isoniazid, INH; Rifampin: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
    Isosulfan Blue: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Itraconazole: (Moderate) Use itraconazole with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with promethazine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Kanamycin: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Ketoconazole: (Moderate) Use ketoconazole with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Lamotrigine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Lefamulin: (Major) Avoid coadministration of lefamulin with promethazine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and phenothiazines. Dosage adjustments of lemborexant and the phenothiazine may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with promethazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Leuprolide: (Major) Avoid coadministration of leuprolide with promethazine due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of leuprolide with promethazine due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Levetiracetam: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Levodopa: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Levofloxacin: (Moderate) Levofloxacin should be used cautiously with other agents, such as promethazine, that may prolong the QT interval or increase the risk of torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Levofloxacin has been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Levomethadyl: (Severe) Levomethadyl is associated with an established risk of QT prolongation and/or torsades de pointes. Levomethadyl is contraindicated in combination with other agents that may prolong the QT interval, including the phenothiazines.
    Levorphanol: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Linagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Linagliptin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Lithium: (Moderate) Lithium should be used cautiously and with close monitoring with promethazine. Both lithium and promethazine have been associated with QT prolongation. Because lithium has the potential to impair cognitive and motor skills, caution is advisable during concurrent use of other medications with centrally-acting effects including antihistamines such as promethazine.
    Lofexidine: (Moderate) Monitor ECG for QT prolongation and excessive sedation during concurrent use of lofexidine and promethazine. Lofexidine prolongs the QT interval and torsade de pointes (TdP) has been reported during postmarketing use. Promethazine is associated with a possible risk of QT prolongation and TdP. In addition, lofexidine can potentiate the effects of CNS depressants, including promethazine.
    Lomefloxacin: (Minor) Phenothiazines may cause additive photosensitization with quinolones. Patients should take care and use proper techniques to limit sunlight and UV exposure.
    Long-acting beta-agonists: (Moderate) Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Use cautiously with promethazine, which has been reported to cause QT prolongation.
    Loperamide: (Moderate) Coadministration of loperamide with promethazine may increase the risk for QT prolongation and torsade de pointes (TdP). Promethazine is associated with a possible risk for QT prolongation and high doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. In addition, the plasma concentrations of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with promethazine, a potent CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (Moderate) Coadministration of loperamide with promethazine may increase the risk for QT prolongation and torsade de pointes (TdP). Promethazine is associated with a possible risk for QT prolongation and high doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. In addition, the plasma concentrations of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with promethazine, a potent CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with promethazine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Lorazepam: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Loxapine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with antipsychotics such as loxapine should be avoided if possible. Coadministration of promethazine with loxapine may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
    Lumateperone: (Moderate) Coadministration of phenothiazines, such as promethazine, and antipsychotics, such as lumateperone, may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Lurasidone: (Moderate) The use of promethazine, a phenothiazine, with antipsychotics such as lurasidone should be avoided if possible. Co-administration of promethazine with lurasidone may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as promethazine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as phenothiazines. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as maprotiline. Additive drowsiness and sedation are also possible. Clinicians should note that additive anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Meclizine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with meclizine. Patients should be informed to read non-prescription product labels carefully for additional interacting motion sickness medications.
    Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving promethazine as concurrent use may increase the risk of QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Meglitinides: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Melatonin: (Moderate) Melatonin may exhibit pharmacodynamic interactions with the phenothiazines. Melatonin has been co-administered in studies with thioridazine. No clinically significant pharmacokinetic interactions were found. However, melatonin co-administration resulted in increased feelings of cognitive impairment compared to thioridazine alone. Patients may need to be informed of the possibility of additive central nervous system (CNS) effects, such as sedation, dizziness, and CNS impairment.
    Mepenzolate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Mephobarbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Meprobamate: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
    Mequinol; Tretinoin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Mestranol; Norethindrone: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Metaxalone: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Metformin; Pioglitazone: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Metformin; Repaglinide: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Metformin; Rosiglitazone: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Metformin; Saxagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Metformin; Sitagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
    Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Drugs with a potential risk for QT prolongation that should be used cautiously with methadone include promethazine. Additionally, use of methadone with another CNS depressant can lead to additive sedation, respiratory depression, hypotension, or coma. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; for example, in opioid-naive adults, use an initial methadone dose of 2.5 mg every 12 hours. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Methocarbamol: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Methohexital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Methoxsalen: (Moderate) Use methoxsalen and phenothiazines together with caution; the risk of severe burns/photosensitivity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Methscopolamine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Methsuximide: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Methyclothiazide: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Methylphenidate: (Moderate) Antipsychotics, such as phenothiazines, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Metoclopramide: (Severe) Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Phenothiazine antiemetics are also central dopamine antagonists and have been associated with extrapyramidal symptoms and rarely, neuroleptic malignant syndrome. In addition, because both phenothiazines and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and phenothiazine antiemetics; however, coadministration should generally be avoided if possible.
    Metolazone: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; phenothiazines are CYP2D6 inhibitors.
    Metronidazole: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include metronidazole.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as phenothiazines, should be used with caution. Additive drowsiness and/or dizziness is possible.
    Metyrosine: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.
    Midazolam: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Midostaurin: (Moderate) The concomitant use of midostaurin and promethazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Data from a small study evaluating the influence of intravenous promethazine on cardiac repolarization concluded that although promethazine may prolong the QT interval, it has no influence on the transmural dispersion of repolarization; therefore, the risk of torsadogenic action with promethazine is very low.
    Mifepristone: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include mifepristone.
    Miglitol: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as phenothiazines. Caution should be exercised when using these agents concurrently.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as promethazine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
    Mitotane: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including opiate agonists, may cause additive CNS effects.
    Molindone: (Moderate) Co-administration of promethazine with molindone may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Monoamine oxidase inhibitors: (Major) The concurrent use of promethazine with monoamine oxidase inhibitors (MAOIs), is not recommended because of an increase in the intensity and prolongation of CNS depressant and anticholinergic effects or hypotensive actions. An increased incidence of extrapyramidal effects have been reported when some MAOIs and phenothiazines are used concomitantly and this possibility should be considered with promethazine, which has a phenothiazine-related structure. In general, sedating antihistamines such as promethazine should be avoided within 2 weeks of therapy with a MAOI if possible.
    Morphine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half (for extended-release morphine tablets, start with 15 mg every 12 hours); use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Morphine; Naltrexone: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half (for extended-release morphine tablets, start with 15 mg every 12 hours); use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Moxifloxacin: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include moxifloxacin.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants, including phenothiazines, can potentiate the effects of nabilone on respiratory depression.
    Nadolol: (Moderate) Concomitant treatment with nadolol and phenothiazines, especially in large doses, can have an additive hypotensive effect.
    Nafarelin: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Nalbuphine: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as phenothiazines, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Naltrexone: (Moderate) Patients receiving phenothiazines and naltrexone concomitantly have had symptoms of somnolence and lethargy.
    Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with promethazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as promethazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with promethazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as promethazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nilotinib: (Moderate) QT interval prolongation may be additive if nilotinib and promethazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Promethazine is associated with a possible risk for QT prolongation.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as phenothiazines. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with phenothiazines.
    Non-Ionic Contrast Media: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Norepinephrine: (Minor) The alpha-adrenergic effects of norepinephrine can be blocked during concurrent administration of phenothiazines. This blockade can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction. Patients taking phenothiazines can possibly have reduced pressor response to ephedrine, phenylephrine, or norepinephrine, but these drugs are preferred over epinephrine if a vasopressor agent is required. According to the manufacturers of the various phenothiazines, norepinephrine or phenylephrine may be used if a vasopressor is needed.
    Norfloxacin: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include norfloxacin.
    Nortriptyline: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Octreotide: (Moderate) Use octreotide cautiously in patients receiving promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Moderate) Ofloxacin should be used cautiously with promethazine as concurrent use may increase the risk of QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
    Ondansetron: (Major) If ondansetron and promethazine must be coadministered, ECG monitoring is recommended. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Oritavancin: (Moderate) Promethazine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of promethazine may be reduced if these drugs are administered concurrently.
    Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when promethazine is used concomitantly with other drugs having antimuscarinic activity such as orphenadrine. Additive sedation may also occur.
    Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with promethazine. Osilodrostat is associated with dose-dependent QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Osimertinib: (Major) Avoid coadministration of promethazine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of promethazine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Oxazepam: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Oxybutynin: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Oxycodone: (Moderate) Concomitant use of oxycodone with phenothiazines may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression. Furthermore, oxycodone is metabolized in part by 2D6 to oxymorphone, which represents < 15% of the total administered dose. Concurrent use of some agents that inhibit CYP2D6 (e.g., quinidine) has not been shown to result in clinically significant interactions. However, many phenothiazines are inhibitors of CYP2D6 (e.g., chlorpromazine, perphenazine, thioridazine) and may potentially increase the effects of oxycodone. Also, severe hypotension may be potentiated with concurrent phenothiazine usage or other drug that compromises vasomotor tone.
    Oxymorphone: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking promethazine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Promethazine is associated with a possible risk for QT prolongation.
    Paliperidone: (Major) According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Promethazine, a phenothiazine antiemetic/antihistamine, has been associated with QT prolongation. Coadministration of promethazine and antipsychotics such as paliperidone may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from concurrent use of a phenothiazine and atypical antipsychotic has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Panobinostat: (Major) The co-administration of panobinostat with promethazine or promethazine combination products such as meperidine; promethazine and phenylephrine; promethazine is not recommended; QT prolongation has been reported with panobinostat and promethazine. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of promethazine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and promethazine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
    Paromomycin: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Paroxetine: (Moderate) Promethazine is a substrate for CYP2D6 and paroxetine is a potent inhibitor of CYP2D6. Because promethazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. In addition, both paroxetine and promethazine exhibit anticholinergic effects that may be additive during combined therapy. The risk of other adverse effects of promethazine may also be increased, including sedation and extrapyramidal symptoms.
    Pasireotide: (Moderate) Use caution when using pasireotide in combination with promethazine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval, such as promethazine, is not advised; pazopanib and promethazine have been reported to prolong the QT interval. If pazopanib and promethazine must be continued, closely monitor the patient for QT interval prolongation.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to promethazine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while promethazine is a CYP2D6 substrate.
    Pemoline: (Major) Concurrent use of antipsychotics, including phenothiazines, and pemoline should generally be avoided. The drugs may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. The pharmacology of pemoline is poorly understood, but the drug may block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of pemoline.
    Pentamidine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include pentamidine.
    Pentazocine: (Moderate) Concomitant use of pentazocine with other CNS depressants, such as phenothiazines, can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously with phenothiazines.
    Pentazocine; Naloxone: (Moderate) Concomitant use of pentazocine with other CNS depressants, such as phenothiazines, can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously with phenothiazines.
    Pentobarbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Pergolide: (Major) Phenothiazines are dopamine-receptor antagonists and may antagonize the effects of dopamine agonists, such as pergolide. Concomitant use should be avoided.
    Perphenazine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with phenothiazine antipsychotics such as perphenazine should be avoided if possible. Promethazine is associated with QT prolongation and perphenazine is associated with a possible risk of QT prolongation. Concomitant administration would increase the risk of QT prolongation. Coadministration may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
    Perphenazine; Amitriptyline: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) The use of promethazine, a phenothiazine antiemetic, with phenothiazine antipsychotics such as perphenazine should be avoided if possible. Promethazine is associated with QT prolongation and perphenazine is associated with a possible risk of QT prolongation. Concomitant administration would increase the risk of QT prolongation. Coadministration may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
    Phenobarbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Phentermine; Topiramate: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Phenylephrine; Promethazine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Phenytoin: (Moderate) Phenothiazines, when used concomitantly with Hydantoins (e.g., phenytoin, ethotoin) can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. In addition to these pharmacodynamic interactions, several individual anticonvulsant agents interact in multiple ways with phenothiazines. Chlorpromazine may interfere with the metabolism of phenytoin and thus precipitate phenytoin toxicity.
    Photosensitizing agents (topical): (Moderate) Phenothiazines may increase the photosensitizing effects of photosensitizing agents used in photodynamic therapy. Patients should limit ultra-violet exposure.
    Pilocarpine: (Moderate) Avoid using pilocarpine in combination with other drugs known to have anticholinergic effects as the therapeutic efficacy of either agent may be reduced.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as promethazine.
    Pimozide: (Severe) Coadministration of promethazine and pimozide is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Promethazine is also an inhibitor of CYP2D6. Elevated pimozide concentrations occurring through inhibition of CYP3A4, CYP2D6, and/or CYP1A2 can lead to QT prolongation, ventricular arrhythmias, and sudden death. Co-administration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Pioglitazone: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Pitolisant: (Major) Avoid coadministration of pitolisant with promethazine as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like promethazine, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Plazomicin: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Porfimer: (Major) Avoid coadministration of porfimer with phenothiazines due to the risk of increased photosensitivity. Porfimer is a light-activated drug used in photodynamic therapy; all patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like phenothiazines may increase the risk of a photosensitivity reaction.
    Posaconazole: (Moderate) Use posaconazole with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Pramipexole: (Major) Pramipexole is a potent dopamine-receptor agonist. Dopamine-receptor antagonists, including antipsychotics (e.g., phenothiazines, haloperidol, loxapine, molindone, pimozide, and thiothixene), should be avoided concurrently because they may antagonize the effects of pramipexole. In general, the atypical antipsychotics are less likely to interfere with antiparkinson treatments than traditional antipsychotic agents (e.g., phenothiazines). However, antipsychotics should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    Pramlintide: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Pregabalin: (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and promethazine. Concomitant use of pregabalin with promethazine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
    Prilocaine; Epinephrine: (Moderate) The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of phenothiazines. This blockade can cause an apparently paradoxical condition called epinephrine reversal, which can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction.
    Primaquine: (Moderate) Exercise caution when administering primaquine in combination with promethazine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Primidone: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Procainamide: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include procainamide.
    Procarbazine: (Moderate) CNS depressants, such as phenothiazines, can potentiate the CNS depression caused by procarbazine therapy, so these drugs should be used together cautiously.
    Prochlorperazine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with other phenothiazines such as prochlorperazine should be avoided if possible. These medications represent duplicative therapy. In addition, coadministration of promethazine and prochlorperazine may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. In addition, promethazine is associated with QT prolongation and prochlorperazine is associated with a possible risk of QT prolongation. Concomitant administration would increase the risk of QT prolongation.
    Propafenone: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include propafenone.
    Propantheline: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Propoxyphene: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. A dose reduction of one or both drugs may be needed.
    Protriptyline: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Quazepam: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Quetiapine: (Major) Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Due to the risk of additive QT prolongation and potential for serious arrhythmias, avoid co-use with quetiapine if possible. In addition, co-administration of promethazine with antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk appears to be increased during combined use versus use of an antipsychotic alone.
    Quinidine: (Severe) Quinidine (including dextromethorphan; quinidine) administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6, such as promethazine, as the effects on the QT interval may be increased during concurrent use of these agents.
    Ranolazine: (Moderate) Use caution if ranolazine is administered with promethazine as concurrent use may increase the risk of QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, concurrent use may result in additive QT prolongation.
    Rasagiline: (Moderate) Phenothiazines may reduce the beneficial effects of rasagiline by blocking dopamine. Additive CNS effects are possible; advise against engaging in tasks requiring mental alertness until the effects of the drug combination are known to the patient. Monoamine oxidase type B inhibitors increase the availability of central dopamine. Antipsychotics may induce pseudoparkinisonism (e.g., shuffling gait, tremor), thereby exacerbating Parkinson's disease symptoms. In addition, dopaminergic medications, including rasagiline, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Very sedating antipsychotics like low potency phenothiazines (e.g., chlorpromazine, thioridazine) are especially problematic in exacerbating sedation or hypotension.
    Remifentanil: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Ribociclib: (Major) Avoid coadministration of ribociclib with promethazine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with promethazine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Rifabutin: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
    Rifampin: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
    Rifamycins: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
    Rifapentine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
    Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with promethazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Risperidone: (Moderate) Use risperidone and promethazine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, coadministration may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Rivastigmine: (Moderate) Promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of rivastigmine. When concurrent use cannot be avoided, monitor the patient for reduced rivastigmine efficacy.
    Rolapitant: (Major) Use caution if promethazine and rolapitant are used concurrently, and monitor for promethazine-related adverse effects. Promethazine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with promethazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Promethazine carries a possible risk of QT prolongation.
    Ropinirole: (Major) Ropinirole is a potent dopamine-receptor agonist. Dopamine-receptor antagonists, including antipsychotics (e.g., phenothiazines) should be avoided concurrently because they may antagonize the effects of ropinirole. Antipsychotics should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    Rosiglitazone: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Rotigotine: (Major) Avoid use together unless the benefits outweigh potential for reduced medication efficacy. Rotigotine is a dopamine-receptor agonist. Dopamine-receptor antagonists, including antipsychotics (e.g., phenothiazines), should be avoided concurrently because they may antagonize the effects of rotigotine. Monitor for an altered clinical response to drug therapy and for additive CNS effects if used together.
    Safinamide: (Moderate) Phenothiazines may reduce the beneficial effects of safinamide by blocking dopamine. Additive CNS effects are possible; advise against engaging in tasks requiring mental alertness until the effects of the drug combination are known to the patient. Monoamine oxidase type B inhibitors increase the availability of central dopamine. Antipsychotics may induce pseudoparkinsonism (e.g., shuffling gait, tremor), thereby exacerbating Parkinson's disease symptoms. In addition, dopaminergic medications, including safinamide, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Very sedating antipsychotics, like low potency phenothiazines (e.g., chlorpromazine, thioridazine), are especially problematic in exacerbating sedation or hypotension.
    Saquinavir: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval including promethazine. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Saxagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Scopolamine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Secobarbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
    Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with promethazine is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Promethazine is associated with a possible risk for QT prolongation.
    Sertraline: (Moderate) Use caution and monitor patients for QT prolongation when administering promethazine with sertraline. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure). In addition, sertraline is a CYP2D6 inhibitor and might increase promethazine concentrations, leading to sedation or other antihistaminic side effects.
    SGLT2 Inhibitors: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Short-acting beta-agonists: (Minor) Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Use cautiously with promethazine, which has been reported to cause QT prolongation.
    Sibutramine: (Major) Sibutramine is a serotonin reuptake inhibitor. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering sibutramine with drugs that are dopamine antagonists such as promethazine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Simvastatin; Sitagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving promethazine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Sitagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Sodium Oxybate: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Solifenacin: (Moderate) Promethazine carries a possible risk of QT prolongation. Solifenacin is associated with a possible risk for QT prolongation and TdP and should be used cautiously with promethazine. Additive drowsiness and anticholinergic effects may also be seen when drugs with antimuscarinic properties like solifenacin are used concomitantly with promethazine. Additive antimuscarinic effects may be seen on GI smooth muscle, bladder function, the CNS, the eye, and temperature regulation.
    Sorafenib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sorafenib with prochlorperazine is necessary; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib has been associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Sotalol: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include sotalol.
    Sparfloxacin: (Severe) Phenothiazines have been associated with orthostatic hypotension and a risk of QT prolongation and/or torsades de pointes. Sparfloxacin also prolongs the QT interval and could lead to additive orthostatic hypotension and/or prolonged QT syndrome and torsade de pointes when combined with a phenothiazine and should be avoided.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort is known to cause photosensitivity. In theory, it is possible that additive photosensitizing effects may result from the concomitant use of St. John's Wort with other photosensitizing drugs such as phenothiazines.
    Streptomycin: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Sufentanil: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Sulfonylureas: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
    Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Sunitinib can prolong the QT interval.
    Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with promethazine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP).
    Tamoxifen: (Moderate) Use caution if coadministration of promethazine with tamoxifen is necessary due to the risk of QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as promethazine. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Tapentadol: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Tazarotene: (Moderate) The manufacturer states that tazarotene should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Telavancin: (Moderate) Due to increased risk of QT interval prolongation and torsade de pointes (TdP), use caution if telavancin is administered with promehtazine. Both promethazine and telavancin have been associated with QT prolongation.
    Telithromycin: (Moderate) Use caution as coadministration of telithromycin and promethazine may increase the risk for QT prolongation and torsade de pointes (TdP). Promethazine carries a possible risk of QT prolongation. Telithromycin is associated with QT prolongation and TdP.
    Temazepam: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Teniposide: (Moderate) Acute central nervous system (CNS) depression, hypotension, and metabolic acidosis have been observed in patients receiving investigational infusions of high-dose teniposide who were pretreated with antiemetics with CNS-depressant activities (e.g., phenothiazine and related antiemetics). The depressant effects of the antiemetic agents and the alcohol content of the teniposide formulation may place patients receiving higher than recommended doses of teniposide at risk for central nervous system depression.
    Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to cause QT prolongation. Promethazine carries a possible risk of QT prolongation. In addition, tetrabenazine is a selective, reversible, centrally-acting dopamine depleting drug and promethazine is a central dopamine antagonist. The risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, neuroleptic malignant syndrome, or extrapyramidal symptoms may be increased.
    Thalidomide: (Major) Avoid the concomitant use of thalidomide with opiate agonists; antihistamines; antipsychotics; anxiolytics, sedatives, and hypnotics; and other central nervous system depressants due to the potential for additive sedative effects.
    Thiazide diuretics: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Thiazolidinediones: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Thiopental: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Thioridazine: (Severe) Due to the risk of additive QT prolongation and potential for serious arrhythmias, the concurrent use of promethazine and thioridazine is considered contraindicated. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes.
    Thiothixene: (Major) Caution is advisable during concurrent use of thiothixene and the phenothiazine antipsychotics. Thiothixene use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of phenothiazines and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. Administration of thiothixene with antipsychotics that are metabolized by CYP2D6, such as phenothiazines, should be approached with great caution. Thiothixene has been shown to inhibit CYP2D6 in vitro and serum concentrations of phenothiazines may increase.
    Tiagabine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Timolol: (Moderate) Timolol interacts with phenothiazines by adding to the overall hypotensive effect.
    Tobacco: (Moderate) Tobacco smoke may accelerate the metabolism of phenothiazines. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, the sudden cessation of tobacco smoking may result in a reduced clearance of these antipsychotics, despite the initiation of a nicotine replacement product. Monitor patients carefully when changes in smoking status occur.
    Tobramycin: (Minor) Antiemetics, like promethazine, should be used carefully with aminoglycosides because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). These agents block the histamine or acetylcholine response that causes nausea due to vestibular (inner ear) emetic stimuli such as motion.
    Tolazamide: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
    Tolbutamide: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
    Tolterodine: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include tolterodine,
    Topiramate: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Toremifene: (Major) Avoid coadministration of promethazine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Tramadol: (Moderate) Caution is advisable during concurrent use of tramadol and promethazine. Seizures have been reported in patients receiving monotherapy with both tramadol and promethazine at recommended doses. Concomitant use of tramadol and promethazine may increase the risk of seizures. In addition, due to the primary CNS effects of promethazine, caution is advisable during use of other centrally acting medications such as tramadol. Impairment of metabolism of tramadol by CYP2D6 inhibitors, such as promethazine, may increase the risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may decrease tramadol analgesic efficacy.
    Trazodone: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Promethazine has been reported to cause QT prolongation. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may also occur when it is combined with other CNS depressants including trazodone.
    Tretinoin, ATRA: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Triazolam: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Tricyclic antidepressants: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Trifluoperazine: (Moderate) Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Promethazine should be used with caution with other phenothiazines that carry a theoretical risk of QT prolongation including trifluoperazine. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
    Trihexyphenidyl: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including promethazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Trimethobenzamide: (Moderate) Trimethobenzamide has CNS depressant effects and may cause drowsiness. The concurrent use of trimethobenzamide with other medications that cause CNS depression such as the phenothiazines may potentiate drowsiness or other common side effects of either medication. In addition, the administration of trimethobenzamide to patients who have recently received CNS-depressive drugs has resulted in opisthotonus, seizures, coma, and extrapyramidal symptoms.
    Trimipramine: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Triprolidine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as triprolidine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Triptorelin: (Major) Avoid coadministration of triptorelin with promethazine due to the risk of reduced efficacy of triptorelin; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; triptorelin is a GnRH analog. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
    Trospium: (Moderate) Additive anticholinergic effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as trospium.
    Valproic Acid, Divalproex Sodium: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant.
    Vandetanib: (Major) Avoid coadministration of vandetanib with promethazine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Vardenafil: (Moderate) Use vardenafil with caution in combination with promethazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vemurafenib include promethazine. Concomitant use of vemurafenib and promethazine may also theoretically result in increased promethazine concentrations. Promethazine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity if co-use cannot be avoided.
    Venlafaxine: (Moderate) Monitor for evidence of QT prolongation if promethazine is coadministered with venlafaxine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with phenothiazines is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like phenothiazines may increase the risk of a photosensitivity reaction.
    Vigabatrin: (Major) Vigabatrin should not be used with phenothiazines, which is associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
    Voriconazole: (Moderate) Caution is advised when administering voriconazole with promethazine as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Vorinostat: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include vorinostat.
    Zaleplon: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
    Ziconotide: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as phenothiazines. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
    Ziprasidone: (Moderate) Concomitant use of ziprasidone and promethazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of typical adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Zolpidem: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
    Zonisamide: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, it is not known whether promethazine is excreted in human milk, and accounting for its potential to cause harm to a nursing infant, a decision should be made whether to discontinue nursing or the drug. Like other phenothiazine derivatives, promethazine is expected to have low excretion into breast milk, and occasional short-term use is probably compatible with posing little risk to a nursing infant. However, if multiple doses are to be used, the infant should be monitored for excess sedation or paradoxical CNS stimulation. Theoretically, promethazine can lower basal prolactin secretion and may interfere with the establishment of lactation. An antiemetic without a potent histamine blocking action, such as prochlorperazine, may be considered as an alternative. Potential side effects include sedation in the infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: The predominant action of promethazine is antagonism of H1-receptors. Although promethazine is classified as a phenothiazine, its ability to antagonize dopamine is approximately one-tenth that of chlorpromazine. For this reason, promethazine is not used as a neuroleptic.Like other H1-antagonists, promethazine does not prevent the release of histamine, as do cromolyn and nedocromil, but competes with free histamine for binding at H1-receptor sites. Histamine receptors in the GI tract, uterus, large blood vessels, and bronchial muscle are blocked. The relief of motion sickness and nausea/vomiting appear to be related to central anticholinergic actions and may implicate activity on the medullary chemoreceptor trigger zone. Other CNS receptor sites can also be affected, since promethazine is believed to indirectly reduce stimuli to the brain stem reticular system. Sedation is significant at concentrations achieved from therapeutic dosages. Mild antitussive activity has been attributed to promethazine, but this effect probably results from anticholinergic and sedative actions. Local anesthetic activity requires higher concentrations than those required to antagonize histamine receptors.

    PHARMACOKINETICS

    Promethazine is administered orally, rectally, intramuscularly, and intravenously. It is highly protein-bound (80—93%) and is widely distributed in body tissues and fluids; it crosses the placenta and is excreted into breast milk. Metabolism occurs in the liver, producing inactive metabolites such as promethazine sulfoxide and other glucuronides. The elimination half-life is 10—14 hours, with excretion of metabolites in the urine and the feces.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6
    Promethazine is a substrate for and inhibitor of CYP2D6.
     

    Oral Route

    Onset of action occurs within 15—60 minutes after oral administration of promethazine. Antihistaminic and sedative effects are sustained for 4—6 hours and 2—8 hours, respectively.

    Intravenous Route

    Following intravenous administration of promethazine, onset of action occurs within 3—5 minutes. Antihistaminic and sedative effects are sustained for 4—6 hours and 2—8 hours, respectively.

    Intramuscular Route

    Onset of action occurs within 20 minutes after intramuscular administration of promethazine. Antihistaminic and sedative effects are sustained for 4—6 hours and 2—8 hours, respectively.

    Other Route(s)

    Rectal Route
    Onset of action occurs within 15—60 minutes after rectal administration of promethazine. Antihistaminic and sedative effects are sustained for 4—6 hours and 2—8 hours, respectively.