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  • CLASSES

    First generation (sedating) Antihistamines

    DEA CLASS

    OTC, Rx

    DESCRIPTION

    H1-antagonist of the ethanolamine class; has significant antimuscarinic activity and produces marked sedation; used as a single agent for short-term OTC treatment of insomnia; in single ingredient and combination OTC products for allergy and cold symptoms.

    COMMON BRAND NAMES

    Aldex AN, Doxytex, Unisom

    HOW SUPPLIED

    Aldex AN Oral Tab Chew: 5mg
    Doxylamine/Doxylamine Succinate/Unisom Oral Tab: 25mg
    Doxytex Oral Liq: 2.5mg, 2.5mL

    DOSAGE & INDICATIONS

    For the short-term treatment of insomnia (less than 2 weeks).
    Oral dosage
    Adults

    25 mg PO given once daily 30 minutes before bedtime as needed. If insomnia persists continuously for more than 2 weeks, the patient should be evaluated.

    Geriatric Adults

    25 mg PO given once daily 30 minutes before bedtime as needed. If insomnia persists continuously for more than  2 weeks, the patient should be evaluated. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of sedative/hypnotics in long-term care facility (LTCF) residents. Daily dose thresholds are not available for doxylamine as a sedative; use the lowest effective dose. All sleep medications should be used in accordance with approved product labeling. If the sleep agent is used routinely and is beyond the manufacturer's recommendations for duration of use, the facility should attempt a quarterly taper unless clinically contraindicated as defined in the OBRA guidelines.

    Children and Adolescents 12 years and older

    25 mg PO given once daily 30 minutes before bedtime as needed. If insomnia persists continuously for more than 2 weeks, the patient should be evaluated.

    For the treatment of symptoms associated with allergic rhinitis, including rhinorrhea, sneezing, itching of the nose or throat, or itchy/watery eyes.
    Oral dosage
    Adults, Adolescents, and Children 12 years

    10 mg PO every 4 to 6 hours as needed. Max: 6 doses  or 60 mg per 24 hours. Doxylamine has not been evaluated by FDA for the treatment of allergic rhinitis.

    Children 6 to 11 years

    5 mg PO every 4 to 6 hours as needed; not to exceed 6 doses (30 mg) in 24 hours. Doxylamine has not been evaluated by FDA for the treatment of allergic rhinitis.

    Children 2 to 5 years

    2.5 mg PO every 4 to 6 hours as needed; not to exceed 6 doses (15 mg) in 24 hours. Doxylamine has not been evaluated by FDA for the treatment of allergic rhinitis.

    MAXIMUM DOSAGE

    Adults

    25 mg/day PO for insomnia; 60 mg/day for allergic rhinitis.

    Elderly

    25 mg/day PO for insomnia; 60 mg/day PO for allergic rhinitis.

    Adolescents

    25 mg/day PO for insomnia; 60 mg/day PO for allergic rhinitis.

    Children

    >= 12 years: 25 mg/day PO for insomnia; 60 mg/day PO for allergic rhinitis.
    6—11 years: 30 mg/day PO for allergic rhinitis ONLY.
    2—5 years: 15 mg/day PO for allergic rhinitis ONLY.
    < 2 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage reduction may be warranted for patients with hepatic impairment but no quantitative guidelines are available; doxylamine is extensively metabolized in the liver.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Doxylamine may be administered without regard to meals.
    If used for sleep, the dose should be administered 30 minutes before bedtime. The non-prescription use of doxylamine for insomnia should be limited to 2 weeks; prolonged insomnia may be suggestive of an underlying medication condition which warrants further evaluation.

    Oral Liquid Formulations

    Use a calibrated, spoon, dropper, or cup to measure dosage.
    If the product is an oral suspension, shake well before measuring each dose.

    STORAGE

    Aldex AN:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Doxytex:
    - Store at room temperature (between 59 to 86 degrees F)
    Unisom:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Driving or operating machinery

    Doxylamine causes drowsiness. Patients receiving doxylamine should be advised to avoid driving or operating machinery until the effects of the drug are known. Alcohol consumption may intensify the sedative effects of the drug and should be avoided. When used as a treatment for insomnia, doxylamine should be administered only prior to bedtime.

    Asthma, chronic obstructive pulmonary disease (COPD)

    Use antihistamines with caution in patients with asthma. The anticholinergic activity of H1-antagonists may result in thickened bronchial secretions in the respiratory tract thereby aggravating an acute asthmatic attack or chronic obstructive pulmonary disease (COPD). Although antihistamines should be avoided during an acute asthmatic attack, these anticholinergic effects do not preclude the use of antihistamines in all asthmatics or COPD patients, particularly if the above respiratory symptom is not a primary component of the illness. Because doxylamine exhibits a significant amount of anticholinergic activity, the use of an H1-antagonist with less anticholinergic activity is preferable when therapy is indicated.

    Bladder obstruction, cardiac disease, GI obstruction, ileus, peptic ulcer disease, prostatic hypertrophy, pyloric stenosis, urinary retention

    The anticholinergic effects of doxylamine may result in a worsening of symptoms in any patient with bladder obstruction, GI obstruction or ileus, stenosing peptic ulcer disease, pyloric stenosis, benign prostatic hypertrophy, or urinary retention. These precautions are most significant when using antihistamines such as doxylamine or those from the phenothiazine group. The quinidine-like local anesthetic and anticholinergic effects of sedating antihistamines are responsible for the adverse cardiac effects which have been observed including tachycardia, ECG changes, hypotension, and arrhythmias. Although these cardiovascular effects are uncommon, doxylamine should be used conservatively in those with cardiac disease since this patient population is susceptible to the anticholinergic effects of the drug.

    Closed-angle glaucoma, contact lenses

    Doxylamine should be avoided, if possible, in patients with closed-angle glaucoma and an H1-antagonist with less anticholinergic effects should be instituted. 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 doxylamine, including possible precipitation of undiagnosed glaucoma. Ocular effects resulting from the anticholinergic effects of doxylamine also include dry eyes or blurred vision, which may be of significance in the elderly and wearers of contact lenses.

    Hepatic disease

    The primary metabolic route of doxylamine appears to be hepatic. The metabolism of the drug may be reduced in the presence of hepatic impairment. Those with significant hepatic disease receiving H1-antagonists should be monitored for liver function and side effects. Dosage reduction may be required in these patients.

    Children, infants, neonates

    Do not use doxylamine as a sleep aid in children under 12 years of age. Doxylamine is marketed for allergic rhinitis in children. Use of sedating antihistamines in children has been associated with paradoxical CNS stimulation and may increase the risk of seizures. There have also been a number of cases of respiratory depression, sleep apnea, and SIDS in infants and children receiving phenothiazine antihistamines. The mechanism of this reaction is not yet known; therefore, H1-antagonists should be used with extreme caution in neonates and infants with a family history of SIDS or sleep apnea.

    Pregnancy

    Doxylamine is available over-the-counter and, therefore, has not been assigned a pregnancy risk category. Doxylamine, in combination with pyridoxine and dicyclomine, became available in 1956 for the treatment of nausea and vomiting during pregnancy; dicyclomine was removed from the product in 1976 due to lack of efficacy as an antiemetic. Doxylamine in combination with pyridoxine continued to be available under the brand name Bendectin until 1983 when litigation over possible teratogenetic effects resulted in its voluntary withdrawal by the manufacturer. There have been numerous reports of fetal abnormalities including cardiac anomalies, cleft palate, congenital limb defects, and pyloric stenosis; however, many studies have failed to show an association between the drug and teratogenetic effects. The data regarding doxylamine do not support evidence of teratogenesis, either alone or in combination with pyridoxine. Although Bendectin is no longer available in the United States, the product is still available in Canada as Diclectin for use as an antiemetic during pregnancy. H1-antagonists are not recommended for use in the last 2 weeks of pregnancy due to a possible association between these drugs and retrolental fibroplasia in premature neonates. Non-pharmacologic methods (e.g., fluids, rest) are recommended to be tried first during pregnancy for symptomatic relief of colds or allergies; pharmacologic treatment of insomnia during pregnancy is generally not recommended.

    Breast-feeding

    According to the manufacturer, doxylamine is not recommended for use during breast-feeding. Data regarding the transfer of doxylamine into human milk are not available; however, the molecular weight of doxylamine suggests that passage into human breast milk is possible. Maternal exposure to H1-antagonists has also been reported to induce irritability or sedation in 9.4% of breast-fed infants. Sedating antihistamines have been associated with CNS adverse events, including respiratory depression, apnea, and seizures, when administered directly to infants and children. Non-drug methods or, if medication is needed, non-sedating antihistamines are preferred alternatives. 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, health care providers are encouraged to report the adverse effect to the FDA.

    Anticholinergic medications, geriatric

    Doxylamine has significant anticholinergic effects which may be additive with other anticholinergic medications in any patient. Geriatric patients are more susceptible to the anticholinergic effects of drugs since there is a decline in endogenous cholinergic activity that occurs with age. According to the Beers Criteria, first generation antihistamines, such as doxylamine, are considered potentially inappropriate medications (PIMs) for use in geriatric patients and should be avoided in this population 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 including confusion, dry mouth, constipation, and other anticholinergic actions and toxicity in geriatric patients compared to younger adults. In addition, the Beers expert panel recommends avoiding drugs with strong anticholinergic properties, such as doxylamine, in geriatric patients with the following disease states or symptoms due to the potential for exacerbation of the condition or increased risk of adverse effects: dementia/cognitive impairment (adverse CNS effects), delirium/high risk of delirium (possible new-onset or worsening delirium), or lower urinary tract symptoms/benign prostatic hyperplasia in men (possible urinary retention or hesitancy). The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. Antihistamines (e.g., first generation agents) have strong anticholinergic properties and are not considered medications of choice in older individuals. If administered, antihistamines should be used in the smallest possible dose in individuals who are susceptible to anticholinergic side effects or who are receiving other medications with anticholinergic properties. 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. The OBRA guidelines provide criteria for use and tapering requirements for sedating antihistamines used as sedative/hypnotics, such as doxylamine.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known

    Moderate

    myasthenia / Delayed / Incidence not known
    confusion / Early / Incidence not known
    palpitations / Early / Incidence not known
    impaired cognition / Early / Incidence not known
    hallucinations / Early / Incidence not known
    delirium / Early / Incidence not known
    dyskinesia / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    dystonic reaction / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    urinary retention / Early / Incidence not known
    constipation / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known

    Mild

    agitation / Early / Incidence not known
    insomnia / Early / Incidence not known
    headache / Early / Incidence not known
    fatigue / Early / Incidence not known
    drowsiness / Early / Incidence not known
    appetite stimulation / Delayed / Incidence not known
    dizziness / Early / Incidence not known
    weakness / Early / Incidence not known
    restlessness / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    tremor / Early / Incidence not known
    diplopia / Early / Incidence not known
    lethargy / Early / Incidence not known
    xerophthalmia / Early / Incidence not known
    mydriasis / Early / Incidence not known
    irritability / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    xerostomia / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    diarrhea / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Concomitant use of codeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of codeine 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. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of codeine.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of dihydrocodeine 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. Dihydrocodeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of codeine 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. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of codeine.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Additive CNS depression may occur if dichloralphenazone is used concomitantly with any of the sedating H1 blockers. Use caution with this combination. Dosage reduction of one or both agents may be necessary.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with sedating H1-blockers may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent 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.
    Acetaminophen; Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with sedating H1-blockers may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    Acetaminophen; Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants can potentiate respiratory depression and, or sedation. In addition, chlorpheniramine and diphenhydramine inhibit CYP2D6, an enzyme responsible for the metabolism of propoxyphene. Monitor these patients. Overdosage of propoxyphene in combination with other potent CNS depressants is a major cause of drug-related death; fatalities within the first hour of overdosage are not uncommon.
    Acetaminophen; Tramadol: (Moderate) An enhanced CNS depressant effect may occur when sedating h1-blockers are combined with other CNS depressants including tramadol.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS activity. Use with caution.
    Alfentanil: (Moderate) Concomitant use of alfentanil with other CNS depressants, such as sedating H1 blockers can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Alosetron: (Moderate) Alosetron, if combined with drugs that possess anticholinergic properties like sedating H1 blockers, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    Amantadine: (Moderate) Medications with significant anticholinergic activity may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Additive drowsiness may also occur.
    Ambenonium Chloride: (Moderate) The therapeutic benefits of ambenonium may be diminished when coadministered with drugs known to exhibit anticholinergic properties including sedating H1-blockers. When concurrent use cannot be avoided, monitor the patient for reduced ambenonium efficacy.
    Amobarbital: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Amoxapine: (Moderate) Additive anticholinergic effects may be seen when amoxapine is used concomitantly with drugs are known to possess relatively significant antimuscarinic properties, including sedating h1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature Additive sedation may also occur.
    Amphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
    Amphetamine; Dextroamphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
    Anticholinergics: (Moderate) The anticholinergic effects of sedating H1-blockers may be enhanced when combined with other antimuscarinics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur when antimuscarinics are combined with sedating antihistamines.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and doxylamine could result in additive depressant effects. Careful monitoring is recommended during combined use. A dose reduction of one or both drugs may be warranted.
    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 the anxiolytics, sedatives, and hypnotics, including barbiturates or benzodiazepines.
    Aripiprazole: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.
    Asenapine: (Moderate) Using drugs that can cause CNS depression, such as sedating H1-blockers, concomitantly with asenapine may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Concomitant use of codeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of codeine 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. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of codeine.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of dihydrocodeine 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. Dihydrocodeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of dihydrocodeine.
    Aspirin, ASA; Carisoprodol: (Moderate) Carisoprodol is metabolized to meprobamate, a significant CNS depressant. Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants. Additive effects of sedation and dizziness, which can impair the ability to undertake tasks requiring mental alertness, may occur if carisoprodol is taken with sedating H1-blockers. Utilize appropriate caution if carisoprodol is coadministered with another CNS depressant.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Carisoprodol is metabolized to meprobamate, a significant CNS depressant. Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants. Additive effects of sedation and dizziness, which can impair the ability to undertake tasks requiring mental alertness, may occur if carisoprodol is taken with sedating H1-blockers. Utilize appropriate caution if carisoprodol is coadministered with another CNS depressant. (Moderate) Concomitant use of codeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of codeine 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. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of codeine.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with sedating H1-blockers may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent 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.
    Atracurium: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Atropine; Difenoxin: (Moderate) An enhanced CNS depressant effect may occur when diphenoxylate/difenoxin is combined with other CNS depressants. Diphenoxylate/difenoxin decreases GI motility. Other drugs that also decrease GI motility, such as sedating H1 blockers, may produce additive effects with diphenoxylate/difenoxin if used concomitantly.
    Atropine; Diphenoxylate: (Moderate) An enhanced CNS depressant effect may occur when diphenoxylate/difenoxin is combined with other CNS depressants. Diphenoxylate/difenoxin decreases GI motility. Other drugs that also decrease GI motility, such as sedating H1 blockers, may produce additive effects with diphenoxylate/difenoxin if used concomitantly.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Azelastine: (Major) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including sedating H1-blockers; avoid concurrent use.
    Azelastine; Fluticasone: (Major) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including sedating H1-blockers; avoid concurrent use.
    Baclofen: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including skeletal muscle relaxants, such as baclofen.
    Barbiturates: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Belladonna; Opium: (Moderate) Enhanced CNS depressant effects may occur when opium is combined with other CNS depressants, such as sedating H1 blockers.
    Benzodiazepines: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Benzphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers. This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
    Brompheniramine; 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 sedating h1-blockers.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Buprenorphine: (Moderate) If concurrent use of doxylamine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. 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: (Moderate) If concurrent use of doxylamine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. 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.
    Buspirone: (Moderate) The combination of buspirone and other CNS depressants, such as sedating h1-blockers, can increase the risk for sedation.
    Butabarbital: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Butorphanol: (Moderate) Concomitant use of butorphanol with sedating H1-blockers can potentiate the effects of butorphanol on CNS and/or respiratory depression. Use together with caution. If a CNS depressant needs to be used with butorphanol, use the smallest effective dose and the longest dosing frequency of butorphanol.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and sedating H1-blockers. CNS depressants can potentiate the effects of cannabidiol.
    Capsaicin; Metaxalone: (Moderate) Concomitant administration of metaxalone with other CNS depressants can potentiate the sedative effects of either agent.
    Carbetapentane; Chlorpheniramine: (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 sedating h1-blockers.
    Carbetapentane; Chlorpheniramine; 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 sedating h1-blockers.
    Carbetapentane; Diphenhydramine; 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 sedating h1-blockers.
    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 sedating h1-blockers.
    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 sedating h1-blockers.
    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 sedating h1-blockers.
    Carbetapentane; Phenylephrine; Pyrilamine: (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 sedating h1-blockers.
    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 sedating h1-blockers.
    Carbetapentane; Pyrilamine: (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 sedating h1-blockers.
    Carbidopa; Levodopa; Entacapone: (Moderate) COMT inhibitors, such as entacapone or tolcapone, should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution should be used when cariprazine is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics like doxylamine.
    Carisoprodol: (Moderate) Carisoprodol is metabolized to meprobamate, a significant CNS depressant. Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants. Additive effects of sedation and dizziness, which can impair the ability to undertake tasks requiring mental alertness, may occur if carisoprodol is taken with sedating H1-blockers. Utilize appropriate caution if carisoprodol is coadministered with another CNS depressant.
    Cetirizine: (Major) Dry mouth, drowsiness and other antihistamine-related side effects may occur in patients receiving cetirizine. Due to the duplicative and additive nature of the pharmacology of cetirizine, concurrent use of sedating antihistamines (H1-blockers) is not recommended.
    Cetirizine; Pseudoephedrine: (Major) Dry mouth, drowsiness and other antihistamine-related side effects may occur in patients receiving cetirizine. Due to the duplicative and additive nature of the pharmacology of cetirizine, concurrent use of sedating antihistamines (H1-blockers) is not recommended.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of codeine 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. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of codeine.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of dihydrocodeine 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. Dihydrocodeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of dihydrocodeine 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. Dihydrocodeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpromazine: (Moderate) Additive effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as doxylamine, a sedating H1-blocker. Phenothiazines, such as thioridazine and chlorpromazine, may exhibit pronounced anticholinergic and sedative effects. 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 CNS effects may also occur.
    Chlorzoxazone: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Cisatracurium: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Clobazam: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
    Clozapine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant, and additive anticholinergic effects may be observed during use of other medications with anticholinergic activity such as doxylamine. Clozapine may also cause additive sedation with doxylamine.
    Codeine: (Moderate) Concomitant use of codeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of codeine 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. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of codeine.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of codeine 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. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of codeine.
    Codeine; Phenylephrine; Promethazine: (Moderate) Additive anticholinergic effects may be seen when promethazine is used concomitantly with other drugs with antimuscarinic activity like sedating H1-blockers. 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. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including sedating H1-blockers. (Moderate) Concomitant use of codeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of codeine 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. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of codeine.
    Codeine; Promethazine: (Moderate) Additive anticholinergic effects may be seen when promethazine is used concomitantly with other drugs with antimuscarinic activity like sedating H1-blockers. 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. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including sedating H1-blockers. (Moderate) Concomitant use of codeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of codeine 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. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of codeine.
    COMT inhibitors: (Moderate) COMT inhibitors, such as entacapone or tolcapone, should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation.
    Cyclobenzaprine: (Moderate) Cyclobenzaprine possesses antimuscarinic properties, which can cause dry mouth, urinary difficulties and slowing of gastrointestinal motility. If used with other drugs with antimuscarinic properties, such as sedating H1-blockers, anticholinergic side effects can be additive. Particular attention should be paid to GI problems because of the possible development of paralytic ileus. Additive CNS depression causing sedation and/or dizziness is also possible. Dosage adjustments of either or both drugs may be necessary.
    Dantrolene: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Desloratadine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of desloratadine with CNS depressants such as other H1-blockers.
    Desloratadine; Pseudoephedrine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of desloratadine with CNS depressants such as other H1-blockers.
    Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as doxylamine, may have additive effects and worsen drowsiness or sedation.
    Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with sedating antihistamines is likely to lead to an enhancement of CNS depression.
    Dextroamphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
    Dextromethorphan; Promethazine: (Moderate) Additive anticholinergic effects may be seen when promethazine is used concomitantly with other drugs with antimuscarinic activity like sedating H1-blockers. 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. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including sedating H1-blockers.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression, and death. Prior to concurrent use of dihydrocodeine 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. Dihydrocodeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Chlorpheniramine and diphenhydarmine are moderate inhibitors of CYP2D6. Coadministration may result in a reduction in the analgesic effect of dihydrocodeine.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Disopyramide: (Moderate) The anticholinergic effects of sedating H1-blockers may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including disopyramide. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Donepezil: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Donepezil; Memantine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Doxacurium: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with antihistamines is necessary. Concurrent use of dronabinol, THC with antihistamines may result in additive drowsiness, hypertension, tachycardia, and possibly cardiotoxicity.
    Droperidol: (Moderate) Sedating H1-blockers have additive or potentiating sedative and other CNS effects with droperidol. Following administration of droperidol, lower doses of the other CNS depressant may need to be used.
    Entacapone: (Moderate) COMT inhibitors, such as entacapone or tolcapone, should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation.
    Eszopiclone: (Moderate) A reduction in the dose of eszopiclone and concomitantly administered CNS depressants, such as sedating H1-blockers, should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ethanol: (Moderate) Drowsiness may occur with the use of sedating antihistamines. Caution patients about the simultaneous use of alcohol, and caution that the effects of alcohol may be increased. Additive drowsiness and psychomotor impairment may occur.
    Etomidate: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Ezogabine: (Moderate) Caution is advisable during concurrent use of ezogabine and medications that may affect voiding such as doxylamine, a sedating antihistamine (H1-blocker). Ezogabine has caused urinary retention requiring catheterization in some cases. The anticholinergic effects of doxylamine on the urinary tract may be additive. Additive sedation or other CNS effects may also occur.
    Fentanyl: (Major) Avoid coadministration of fentanyl with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, hypotension, coma, and death. Reserve concomitant use of these drugs for patients in whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations possible and monitor patients closely for signs and symptoms of respiratory depression and sedation.
    Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as sedating H1-blockers, 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.
    Fluoxetine; Olanzapine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Fluphenazine: (Moderate) Additive effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as doxylamine, a sedating H1-blocker. Phenothiazines, such as thioridazine and chlorpromazine, may exhibit pronounced anticholinergic and sedative effects. 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 CNS effects may also occur.
    Fospropofol: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics like fospropofol.
    Gabapentin: (Moderate) Coadministration of gabapentin with anxiolytics, sedatives, and hypnotics may increase CNS depressive effects such as drowsiness and dizziness. Use caution when administering gabapentin with CNS depressants. Patients should limit activity until they are aware of how coadministration affects them.
    Galantamine: (Moderate) Concurrent use of sedating H1-blockers and galantamine should be avoided if possible. Galantamine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of galantamine.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Halogenated Anesthetics: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants such as the sedating H1-blockers. Additive anticholinergic effects may occur. 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 CNS effects may also occur.
    Heparin: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Hyaluronidase, Recombinant; Immune Globulin: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Hyaluronidase: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Hydantoins: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydromorphone: (Moderate) Concomitant use of hydromorphone with other central nervous system (CNS) depressants can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Examples of drugs associated with CNS depression include sedating H1-blockers. Prior to concurrent use of hydromorphone 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 hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with sedating H1-blockers may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent 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.
    Iloperidone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with iloperidone, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when iloperidone is given in combination with other centrally-acting medications, such as sedating H1-blockers.
    Isocarboxazid: (Major) Concurrent use of monoamine oxidase inhibitors (MAOIs) and sedating H1-blockers (sedating antihistamines) may result in additive sedation, anticholinergic effects, or hypotensive reactions. Consider alternative therapy to antihistamines where possible. If alternative combinations are not available, these medications may be used together with close monitoring. Many non-prescription products for coughs, colds, allergy, hay fever or insomnia contain sedating antihistamines. Patients receiving an MAOI should be counseled that it is essential to consult their healthcare provider or pharmacist prior to the use of any non-prescription products. Patients should also be advised against driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
    Kava Kava, Piper methysticum: (Major) The German Commission E warns that any substances that act on the CNS, including psychotropic agents, may interact with kava kava. While the interactions can be pharmacodynamic in nature, kava kava has been reported to inhibit many CYP isozymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11) and important pharmacokinetic interactions with CNS-active agents that undergo oxidative metabolism via these CYP isozymes are also possible.
    Ketamine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Levocetirizine: (Major) Dry mouth, drowsiness and other antihistamine-related side effects may occur in patients receiving cetirizine. Due to the duplicative and additive nature of the pharmacology of cetirizine, concurrent use of sedating antihistamines (H1-blockers) is not recommended.
    Levomethadyl: (Moderate) Enhanced CNS depressant effects may occur when levomethadyl is combined with other CNS depressants, such as sedating H1 blockers.
    Levorphanol: (Moderate) Concomitant use of levorphanol with other CNS depressants such as sedating H1-blockers can potentiate the effects of levorphanol on respiration, blood pressure, and alertness. Severe hypotension, respiratory depression, profound sedation, or coma may occur. Prior to concurrent use of levorphanol 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. When concomitant treatment with levorphanol with another CNS depressant is necessary, reduce the dose of 1 or both drugs. The initial dose of levorphanol should be reduced by approximately 50% or more when levorphanol is used with another drug that may depress respiration.
    Lithium: (Moderate) 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 doxylamine.
    Lofexidine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and doxylamine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
    Loratadine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as other H1-blockers.
    Loratadine; Pseudoephedrine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as other H1-blockers.
    Loxapine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. 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 CNS effects may also occur.
    Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications. Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur.
    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 sedating H1-blockers. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Meclizine: (Major) Meclizine is an H1-blocker which exhibits significant anticholinergic effects. The anticholinergic effects of meclizine may be enhanced when combined with other drugs with antimuscarinic activity, including other sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive sedation may also occur.
    Melatonin: (Moderate) Concomitant administration of sedating antihistamines and melatonin may cause additive CNS depression and should be used cautiously in combination. Especially use caution when combining melatonin with sedating antihistamines found in OTC sleep products, since over-sedation, CNS effects, or sleep-related behaviors may occur. Use of more than one agent for hypnotic purposes may increase the risk for over-sedation, CNS effects, or sleep-related behaviors. Be alert for unusual changes in moods or behaviors. Patients reporting unusual sleep-related behaviors likely should discontinue melatonin use.
    Meperidine: (Moderate) Enhanced CNS depressant effects may occur when meperidine is combined with other CNS depressants, such as sedating H1 blockers.
    Meperidine; Promethazine: (Moderate) Additive anticholinergic effects may be seen when promethazine is used concomitantly with other drugs with antimuscarinic activity like sedating H1-blockers. 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. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including sedating H1-blockers. (Moderate) Enhanced CNS depressant effects may occur when meperidine is combined with other CNS depressants, such as sedating H1 blockers.
    Mephobarbital: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including sedating H1-blockers.
    Mesoridazine: (Moderate) Additive effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as doxylamine, a sedating H1-blocker. Phenothiazines, such as thioridazine and chlorpromazine, may exhibit pronounced anticholinergic and sedative effects. 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 CNS effects may also occur.
    Metaxalone: (Moderate) Concomitant administration of metaxalone with other CNS depressants can potentiate the sedative effects of either agent.
    Methadone: (Moderate) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma; examples include sedating H1-blockers. 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; 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.
    Methamphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of sedating H1-blockers. This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine. Coadminister with caution and monitor for altered response to drug therapy.
    Methocarbamol: (Moderate) Methocarbamol may cause additive CNS depression if used concomitantly with other CNS depressants such as sedating H1-blockers. Combination therapy can cause additive effects of sedation and dizziness, which can impair the patient's ability to undertake tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary.
    Methohexital: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Metoclopramide: (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as sedating H1-blockers, should be used with caution. Additive drowsiness and/or dizziness is possible.
    Metyrosine: (Moderate) The concomitant administration of metyrosine with sedating H1-blockers can result in additive sedative effects.
    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 sedating H1-blockers. Caution should be exercised when using these agents concurrently.
    Mirtazapine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as doxylamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Mitotane: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Mivacurium: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Molindone: (Moderate) An enhanced CNS depressant effect may occur when sedating h1-blockers are combined with other CNS depressants including molindone.
    Monoamine oxidase inhibitors: (Major) Concurrent use of monoamine oxidase inhibitors (MAOIs) and sedating H1-blockers (sedating antihistamines) may result in additive sedation, anticholinergic effects, or hypotensive reactions. Consider alternative therapy to antihistamines where possible. If alternative combinations are not available, these medications may be used together with close monitoring. Many non-prescription products for coughs, colds, allergy, hay fever or insomnia contain sedating antihistamines. Patients receiving an MAOI should be counseled that it is essential to consult their healthcare provider or pharmacist prior to the use of any non-prescription products. Patients should also be advised against driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
    Morphine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine 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 morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Morphine; Naltrexone: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine 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 morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants, such as sedating H1-blockers, can potentiate the effects of nabilone on respiratory depression.
    Nalbuphine: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as sedating H1-blockers, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Nefazodone: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Neuromuscular blockers: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Olanzapine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Orphenadrine: (Moderate) Orphenadrine has mild anticholinergic activity. Depending on the specific agent, additive anticholinergic effects may be seen when orphenadrine is used concomitantly with sedating H1-blockers.
    Oxycodone: (Moderate) Concomitant use of oxycodone with sedating H1-blockers may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent 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.
    Oxymorphone: (Moderate) Concomitant use of oxymorphone with other CNS depressants may produce additive CNS depressant effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of oxymorphone 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 oxymorphone, a reduced dosage of oxymorphone (1/3 to 1/2 of the usual dose) and/or the CNS depressant is recommended. If the extended-release oxymorphone tablets are used concurrently with a CNS depressant, it is recommended to use an initial dosage of 5 mg PO every 12 hours. Monitor for sedation or respiratory depression.
    Paliperidone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when paliperidone is given in combination with other centrally-acting medications including sedating H1-blockers.
    Pancuronium: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Papaverine: (Moderate) Concurrent use of papaverine with potent CNS depressants such as doxylamine could lead to enhanced sedation.
    Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with sedating H1-blockers may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    Pentazocine; Naloxone: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with sedating H1-blockers may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    Pentobarbital: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    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 sedating H1-blockers.
    Perphenazine: (Moderate) Additive effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as doxylamine, a sedating H1-blocker. Phenothiazines, such as thioridazine and chlorpromazine, may exhibit pronounced anticholinergic and sedative effects. 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 CNS effects may also occur.
    Perphenazine; Amitriptyline: (Moderate) Additive effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as doxylamine, a sedating H1-blocker. Phenothiazines, such as thioridazine and chlorpromazine, may exhibit pronounced anticholinergic and sedative effects. 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 CNS effects may also occur.
    Phenelzine: (Major) Concurrent use of monoamine oxidase inhibitors (MAOIs) and sedating H1-blockers (sedating antihistamines) may result in additive sedation, anticholinergic effects, or hypotensive reactions. Consider alternative therapy to antihistamines where possible. If alternative combinations are not available, these medications may be used together with close monitoring. Many non-prescription products for coughs, colds, allergy, hay fever or insomnia contain sedating antihistamines. Patients receiving an MAOI should be counseled that it is essential to consult their healthcare provider or pharmacist prior to the use of any non-prescription products. Patients should also be advised against driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
    Phenobarbital: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Phenothiazines: (Moderate) Additive effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as doxylamine, a sedating H1-blocker. Phenothiazines, such as thioridazine and chlorpromazine, may exhibit pronounced anticholinergic and sedative effects. 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 CNS effects may also occur.
    Phentermine; Topiramate: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Phenylephrine; Promethazine: (Moderate) Additive anticholinergic effects may be seen when promethazine is used concomitantly with other drugs with antimuscarinic activity like sedating H1-blockers. 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. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including sedating H1-blockers.
    Pimozide: (Moderate) Due to the effects of pimozide on cognition, it should be used cautiously with other CNS depressants including sedating antihistamines. Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with pimozide. Additive drowsiness or other CNS effects may occur.
    Pramipexole: (Moderate) Concomitant use of pramipexole with other CNS depressants, such as sedating H1-blockers, can potentiate the sedation effects of pramipexole.
    Pregabalin: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including sedating H1-blockers, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Primidone: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Procarbazine: (Moderate) Use procarbazine and sedating H1-blockers together with caution; additive central nervous system depression may occur.
    Prochlorperazine: (Moderate) Additive effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as doxylamine, a sedating H1-blocker. Phenothiazines, such as thioridazine and chlorpromazine, may exhibit pronounced anticholinergic and sedative effects. 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 CNS effects may also occur.
    Promethazine: (Moderate) Additive anticholinergic effects may be seen when promethazine is used concomitantly with other drugs with antimuscarinic activity like sedating H1-blockers. 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. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including sedating H1-blockers.
    Propofol: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants can potentiate respiratory depression and, or sedation. In addition, chlorpheniramine and diphenhydramine inhibit CYP2D6, an enzyme responsible for the metabolism of propoxyphene. Monitor these patients. Overdosage of propoxyphene in combination with other potent CNS depressants is a major cause of drug-related death; fatalities within the first hour of overdosage are not uncommon.
    Quetiapine: (Moderate) Somnolence is a commonly reported adverse effect of quetiapine. Co-administration of quetiapine with sedating H1-blockers may result in additive effects. Additive drowsiness or other CNS effects may occur.
    Ramelteon: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as ramelteon.
    Rapacuronium: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Rasagiline: (Moderate) Concurrent use of monoamine oxidase inhibitors (MAOIs) and sedating H1-blockers (sedating antihistamines) may result in additive sedation, anticholinergic effects, or hypotensive reactions. Rasagiline may be less likely to produce these interactions than other MAOIs, due to MAO-B selectivity. However, consider alternatives therapy to antihistamines where possible. If alternative combinations are not available, these medications may be used together with close monitoring. Many non-prescription products for coughs, colds, allergy, hay fever or insomnia contain sedating antihistamines. Patients receiving rasagiline should be counseled that it is essential to consult their healthcare provider or pharmacist prior to the use of any non-prescription products. Patients should also be advised against driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
    Remifentanil: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Risperidone: (Moderate) Due to the primary CNS effects of risperidone, caution should be used when risperidone is given in combination with other centrally acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.
    Rituximab; Hyaluronidase: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Rivastigmine: (Moderate) Concurrent use of sedating H1-blockers and rivastigmine should be avoided if possible. Rivastigmine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of rivastigmine.
    Rocuronium: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Ropinirole: (Moderate) Concomitant use of ropinirole with other CNS depressants, such as sedating H1-blockers, can potentiate the sedation effects of ropinirole.
    Rotigotine: (Major) Concomitant use of rotigotine with other CNS depressants, such as doxylamine, can potentiate the sedation effects of rotigotine.
    Safinamide: (Moderate) 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. Because of possible additive effects, advise patients about the potential for increased somnolence during concurrent use of other sedating medications, such as sedating H1-blockers.
    Secobarbital: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Selegiline: (Major) Concurrent use of monoamine oxidase inhibitors (MAOIs) and sedating H1-blockers (sedating antihistamines) may result in additive sedation, anticholinergic effects, or hypotensive reactions. Consider alternative therapy to antihistamines where possible. If alternative combinations are not available, these medications may be used together with close monitoring. Many non-prescription products for coughs, colds, allergy, hay fever or insomnia contain sedating antihistamines. Patients receiving an MAOI should be counseled that it is essential to consult their healthcare provider or pharmacist prior to the use of any non-prescription products. Patients should also be advised against driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
    Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by concurrent medications, including H1-blockers. False study results are possible; thorough patient history is important in the interpretation of procedure results.
    Sodium Iodide: (Moderate) Antihistamines may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administration. In addition, medications that decrease salivation increase the time of radiation exposure to salivary glands. Consider discontinuing sedating H1-blockers prior to sodium iodide I-131 administration.
    Sodium Oxybate: (Severe) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs.
    Solifenacin: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like solifenacin are used concomitantly with other antimuscarinics, such as doxylamine.
    Succinylcholine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Sufentanil: (Moderate) Concomitant use of sufentanil with other CNS depressants can potentiate sufentanil-induced CNS and cardiovascular effects and the duration of these effects. A dose reduction of one or both drugs may be warranted.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Tacrine: (Moderate) Concurrent use of sedating H1-blockers and tacrine should be avoided if possible. Tacrine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of tacrine.
    Tapentadol: (Moderate) Additive CNS depressive effects are expected if tapentadol is used in conjunction with other CNS depressants. Severe hypotension, profound sedation, coma, or respiratory depression may occur. Prior to concurrent use of tapentadol 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 tapentadol, a reduced dosage of tapentadol and/or the CNS depressant is recommended. If the extended-release tapentadol tablets are used concurrently with a CNS depressant, it is recommended to use an initial tapentadol dose of 50 mg PO every 12 hours. Monitor patients for sedation and respiratory depression.
    Tasimelteon: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Tetrabenazine: (Moderate) Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as doxylamine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    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.
    Thiethylperazine: (Moderate) Additive effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as doxylamine, a sedating H1-blocker. Phenothiazines, such as thioridazine and chlorpromazine, may exhibit pronounced anticholinergic and sedative effects. 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 CNS effects may also occur.
    Thiopental: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
    Thioridazine: (Moderate) Additive effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as doxylamine, a sedating H1-blocker. Phenothiazines, such as thioridazine and chlorpromazine, may exhibit pronounced anticholinergic and sedative effects. 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 CNS effects may also occur.
    Thiothixene: (Moderate) Additive anticholinergic effects may be seen when antipsychotics, such as thiothixene, are used concomitantly with other drugs such as sedating H1-blockers. Additive drowsiness or other CNS effects may also occur.
    Tizanidine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Tolcapone: (Moderate) COMT inhibitors, such as entacapone or tolcapone, should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation.
    Topiramate: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Tramadol: (Moderate) An enhanced CNS depressant effect may occur when sedating h1-blockers are combined with other CNS depressants including tramadol.
    Tranylcypromine: (Major) Concurrent use of monoamine oxidase inhibitors (MAOIs) and sedating H1-blockers (sedating antihistamines) may result in additive sedation, anticholinergic effects, or hypotensive reactions. Consider alternative therapy to antihistamines where possible. If alternative combinations are not available, these medications may be used together with close monitoring. Many non-prescription products for coughs, colds, allergy, hay fever or insomnia contain sedating antihistamines. Patients receiving an MAOI should be counseled that it is essential to consult their healthcare provider or pharmacist prior to the use of any non-prescription products. Patients should also be advised against driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
    Trazodone: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Tricyclic antidepressants: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Trifluoperazine: (Moderate) Additive effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as doxylamine, a sedating H1-blocker. Phenothiazines, such as thioridazine and chlorpromazine, may exhibit pronounced anticholinergic and sedative effects. 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 CNS effects may also occur.
    Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like the sedating h1-blockers, may potentiate the effects of either trimethobenzamide or the sedating h1-blocker.
    Trospium: (Moderate) Additive anticholinergic effects may be seen when trospium is used concomitantly with drugs that are known to possess relatively significant antimuscarinic properties, including sedating H1-blockers. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function and temperature regulation. While CNS-related side effects such as drowsiness and blurred vision are not typically noted with trospium, they may occur in some patients.
    Tubocurarine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Vecuronium: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with sedating H1-blockers.
    Vilazodone: (Moderate) Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as anxiolytics, sedatives, and hypnotics. Also, Cyproheptadine is an antagonist of serotonin in the CNS, a property which may oppose some of the pharmacologic effects of vilazodone. Cyproheptadine has been used for the management of orgasm dysfunction caused by the serotonergic antidepressants and for the adjunctive treatment of serotonin syndrome; however, a reversal of antidepressant effects may occur when cyproheptadine is given in a routine manner along with the antidepressant. Clinically, cyproheptadine reportedly has interfered with the antidepressant and anti-bulimia actions of fluoxetine, but more data are needed to confirm a direct drug-drug interaction.
    Zaleplon: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Ziconotide: (Moderate) Sedating H1-blockers are CNS depressant medications that may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
    Ziprasidone: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Zolpidem: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.

    PREGNANCY AND LACTATION

    Pregnancy

    Doxylamine is available over-the-counter and, therefore, has not been assigned a pregnancy risk category. Doxylamine, in combination with pyridoxine and dicyclomine, became available in 1956 for the treatment of nausea and vomiting during pregnancy; dicyclomine was removed from the product in 1976 due to lack of efficacy as an antiemetic. Doxylamine in combination with pyridoxine continued to be available under the brand name Bendectin until 1983 when litigation over possible teratogenetic effects resulted in its voluntary withdrawal by the manufacturer. There have been numerous reports of fetal abnormalities including cardiac anomalies, cleft palate, congenital limb defects, and pyloric stenosis; however, many studies have failed to show an association between the drug and teratogenetic effects. The data regarding doxylamine do not support evidence of teratogenesis, either alone or in combination with pyridoxine. Although Bendectin is no longer available in the United States, the product is still available in Canada as Diclectin for use as an antiemetic during pregnancy. H1-antagonists are not recommended for use in the last 2 weeks of pregnancy due to a possible association between these drugs and retrolental fibroplasia in premature neonates. Non-pharmacologic methods (e.g., fluids, rest) are recommended to be tried first during pregnancy for symptomatic relief of colds or allergies; pharmacologic treatment of insomnia during pregnancy is generally not recommended.

    According to the manufacturer, doxylamine is not recommended for use during breast-feeding. Data regarding the transfer of doxylamine into human milk are not available; however, the molecular weight of doxylamine suggests that passage into human breast milk is possible. Maternal exposure to H1-antagonists has also been reported to induce irritability or sedation in 9.4% of breast-fed infants. Sedating antihistamines have been associated with CNS adverse events, including respiratory depression, apnea, and seizures, when administered directly to infants and children. Non-drug methods or, if medication is needed, non-sedating antihistamines are preferred alternatives. 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, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Doxylamine does not prevent the release of histamine, as do cromolyn and nedocromil, but rather competes with free histamine for binding at the H1-receptor sites. Like other antihistamines, doxylamine competitively antagonizes the effects of histamine on H1-receptors in the GI tract, uterus, large blood vessels, and bronchial muscle. Blockade of H1-receptors also suppresses the formation of edema, flare, and pruritus that result from histaminic activity. Unlike second generation antihistamines such as loratadine and cetirizine which selectively block peripheral H1-receptors, first generation antihistamines such as doxylamine bind non-selectively to H1-receptors centrally and peripherally. Thus, sedative effects are more likely to occur with first generation antihistamines, especially the ethanolamine group. Doxylamine belongs to the ethanolamine group, and thus is commonly promoted as a sleep-aid. Following prolonged use, tolerance can occur, but this may be beneficial, dependent on the indication for drug use, because of reduced sedative effects.
     
    H1-antagonists are structurally similar to anticholinergic agents and therefore possess anticholinergic properties of varying degrees. Ethanolamine derivatives have greater anticholinergic activity than do other antihistamines, thus commonly producing side effects such as dry mouth, blurred vision, constipation and urinary retention. These anticholinergic actions appear to be due to a central antimuscarinic effect which also may be responsible for the antiemetic effects seen with this class, although the exact mechanism is unknown.

    PHARMACOKINETICS

    Doxylamine is administered orally. In general, antihistamines have a large volume of distribution.
     
    The primary metabolic route for doxylamine appears to be N-dealkylation and N-acetyl conjugation in the liver, resulting in the formation of the metabolites N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and N-acetyl conjugates of these metabolites. The drug has an elimination half-life of 10 hours in healthy adults.

    Oral Route

    The exact bioavailability of doxylamine has not been described, however, H1-antagonists are generally well absorbed following oral administration. Their onset of action varies according to their solubility, with less soluble H1-antagonists having a slower onset of action and less likelihood of toxicity. Peak plasma concentrations of doxylamine are reached 2—3 hours following oral administration and the duration of action is 3—8 hours.