Prolixin Decanoate

First Generation Antipsychotics

Oral Administration

May take with or without food. If stomach upset or nausea occur, take with food.

Oral Liquid Formulations

Oral concentrate: Administer using a calibrated measuring device. Dilute fluphenazine just prior to administration with 120—240 mL of water, saline, milk, 7-Up, carbonated orange beverage, or the following juices: apricot, orange, pineapple, prune, tomato or V-8 juices. Do not mix with beverages containing caffeine (coffee, cola), tannics (tea), or pectinates (apple juice) or with other liquid medications. Avoid spilling the solution on the skin and clothing.
Oral elixir: Administer fluphenazine using a calibrated measuring device. Avoid spilling the solution on the skin and clothing.

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Slight yellow to amber color does not alter potency. However, markedly discolored solutions should be discarded.

Intramuscular Administration

Intramuscular (IM) injection (fluphenazine hydrochloride only):
Fluphenazine HCl is administered via IM injection only, do not administer intravenously or subcutaneously.
No dilution necessary. However, if irritation occurs, subsequent IM doses may be diluted with 0.9% Sodium Chloride Injection or 2% procaine.
Inject slowly and deeply into the upper, outer quadrant of the gluteal muscle using a dry syringe and needle.
Keep patient in a recumbent position for at least 30 minutes following injection to minimize hypotensive effects.
Rotate the site of injection to avoid irritation or sterile abscess formation with repeat administration.
 
Intramuscular Depot injection (fluphenazine decanoate or fluphenazine enanthate):
Fluphenazine decanoate or enanthate injections are administered via IM or subcutaneous injection only, do not administer intravenously.
Fluphenazine depot injections must be drawn up using a dry syringe and needle of at least 21-gauge.
Do not dilute.
Inject slowly and deeply into the upper outer quadrant of the gluteal muscle.
Keep patient in a recumbent position for at least 30 minutes following the initial injection to minimize hypotensive effects. Once dose-stabilized on depot formulation, this precaution may be modified for ambulatory patients as clinically appropriate for the individual.
Rotate the site of injection to avoid irritation or sterile abscess formation with repeat administration.

Subcutaneous Administration

Subcutaneous injection (fluphenazine decanoate or fluphenazine enanthate):
Fluphenazine decanoate or enanthate injections are administered via IM or subcutaneous injection only, do not administer intravenously.
Fluphenazine depot injection solutions must be drawn up using a dry syringe and a needle of at least 21-gauge.
Do not dilute.
Inject subcutaneously taking care not to inject intradermally.
Keep patient in a recumbent position for at least 30 minutes following the initial injection to minimize hypotensive effects. Once dose-stabilized on depot formulation, this precaution may be modified for ambulatory patients as clinically appropriate for the individual.
Rotate the site of injection to avoid irritation or sterile abscess formation with repeat administration.

Severe

neuroleptic malignant syndrome / Delayed / Incidence not known
tardive dyskinesia / Delayed / Incidence not known
seizures / Delayed / Incidence not known
cerebral edema / Early / Incidence not known
pancytopenia / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
laryngeal edema / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
retinopathy / Delayed / Incidence not known
corneal opacification / Delayed / Incidence not known
visual impairment / Early / Incidence not known
asphyxia / Early / Incidence not known
cardiac arrest / Early / Incidence not known
torsade de pointes / Rapid / Incidence not known
ileus / Delayed / Incidence not known
stroke / Early / Incidence not known
SIADH / Delayed / Incidence not known
water intoxication / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known

Moderate

constipation / Delayed / 1.0-10.0
hypotension / Rapid / 0-1.0
dystonic reaction / Delayed / Incidence not known
pseudoparkinsonism / Delayed / Incidence not known
akathisia / Delayed / Incidence not known
psychosis / Early / Incidence not known
myasthenia / Delayed / Incidence not known
peripheral edema / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
eosinophilia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
erythema / Early / Incidence not known
atopic dermatitis / Delayed / Incidence not known
contact dermatitis / Delayed / Incidence not known
blurred vision / Early / Incidence not known
orthostatic hypotension / Delayed / Incidence not known
hypertension / Early / Incidence not known
QT prolongation / Rapid / Incidence not known
sinus tachycardia / Rapid / Incidence not known
galactorrhea / Delayed / Incidence not known
urinary retention / Early / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
hyperprolactinemia / Delayed / Incidence not known
ejaculation dysfunction / Delayed / Incidence not known
infertility / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
hyperthermia / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known
glycosuria / Early / Incidence not known
hyperglycemia / Delayed / Incidence not known
hypoglycemia / Early / Incidence not known

Mild

drowsiness / Early / 1.0-10.0
xerostomia / Early / 10.0
dizziness / Early / Incidence not known
headache / Early / Incidence not known
lethargy / Early / Incidence not known
nasal congestion / Early / Incidence not known
fever / Early / Incidence not known
purpura / Delayed / Incidence not known
seborrhea / Delayed / Incidence not known
photosensitivity / Delayed / Incidence not known
skin hyperpigmentation / Delayed / Incidence not known
hyperhidrosis / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
pruritus / Rapid / Incidence not known
miosis / Early / Incidence not known
mydriasis / Early / Incidence not known
breast enlargement / Delayed / Incidence not known
libido decrease / Delayed / Incidence not known
mastalgia / Delayed / Incidence not known
amenorrhea / Delayed / Incidence not known
polyuria / Early / Incidence not known
gynecomastia / Delayed / Incidence not known
menstrual irregularity / Delayed / Incidence not known
injection site reaction / Rapid / Incidence not known
hypersalivation / Early / Incidence not known
nausea / Early / Incidence not known
weight gain / Delayed / Incidence not known
hypothermia / Delayed / Incidence not known
polydipsia / Early / Incidence not known

Dementia, geriatric, stroke

Geriatric patients may be more susceptible to the actions and adverse effects of phenothiazines, including tardive dyskinesia, dystonias, orthostatic hypotension, anticholinergic effects, prolonged QT interval, and risk for falls and fractures. Initiate treatment with lower doses followed by careful dosage titration and close monitoring. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients and the use of phenothiazines in this population should be avoided if possible due to an increase in morbidity and mortality in elderly patients with dementia receiving antipsychotics. Deaths have typically resulted from heart failure, sudden death, or infections. An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatal events, has also been reported. The Beers Criteria consider antipsychotics to be potentially inappropriate medications (PIMs) in elderly patients and should be avoided except for treating schizophrenia, bipolar disorder, or short-term antiemetic use during chemotherapy. The Beers panel recommends avoiding fluphenazine in geriatric patients with delirium, dementia, lower urinary tract symptoms/benign prostatic hyperplasia in men, or Parkinson's disease. Non-pharmacological strategies are first-line options for treating delirium- or dementia-related behavioral problems unless they have failed or are not possible and the patient is a substantial threat to self or others. If antipsychotic use is necessary in geriatrics with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk strategies. Due to the potential for antipsychotic-induced hyponatremia and SIADH, sodium levels should be closely monitored when fluphenazine is initiated and after dose changes. According to the federal Omnibus Budget Reconciliation Act (OBRA) regulations in residents of long-term care facilities, antipsychotic therapy should only be initiated in a patient with behavioral or psychological symptoms of dementia (BPSD) when the patient is a danger to self or others or has symptoms due to mania or psychosis. For acute conditions persisting beyond 7 days, appropriate non-pharmacologic interventions must be attempted, unless clinically contraindicated and documented. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Antipsychotics are subject to periodic review for effectiveness, medical necessity, gradual dose reduction (GDR), or rationale for continued use. Refer to the OBRA guidelines for complete information.

Prolixin, Prolixin Decanoate

Rx

Piperazine phenothiazine antipsychotic; 2 mg orally equivalent to 100 mg of oral chlorpromazine, the prototype antipsychotic; depot IM injections (i.e., fluphenazine decanoate or fluphenazine enanthate) available for chronic disorders; increased risk of death in elderly patients treated for dementia-related psychosis.

For the treatment of schizophrenia. Oral dosage Adults

Initially, 2.5 mg to 10 mg/day PO, given in 2 or 3 divided doses (every 6 or 8 hours); may increase gradually as needed and tolerated. A therapeutic effect is often achieved with less than 20 mg/day, given as divided doses at 6 to 8 hour intervals. Usual Max: 20 mg/day PO, in divided doses. Patients with severe symptoms not adequately controlled with lower dosages may require titration up to 40 mg/day acutely; however, chronic use of such dosages is not established. After response has been obtained, gradual reduction of the dosage to 1 mg/day to 5 mg/day PO for maintenance therapy, often as a single daily dose, is recommended. Adjust to lowest effective and tolerated dose.

Geriatric Adults

Initially, 1 mg to 2.5 mg PO daily as a single dose or in divided doses depending on tolerability. May increase gradually as needed and tolerated. A therapeutic effect is often achieved with less than 20 mg/day, given as divided doses at 6 to 8 hour intervals. Usual Max: 20 mg/day PO, in divided doses. Patients with severe symptoms may require up to 40 mg/day acutely; however, chronic use of such dosages is not established. After response has been obtained, gradual reduction of the dosage to 1 mg/day to 5 mg/day PO for maintenance therapy, often as a single daily dose, is recommended. Adjust to lowest effective and tolerated dose.

Intramuscular or Subcutaneous dosage (fluphenazine decanoate in oil long-acting injection) Adults

The usual initial dose 12.5 mg to 25 mg IM or subcutaneously; subsequent doses and frequency are determined by the patient's response and tolerability. According to the manufacturer, a single injection may be effective for up to 3 to 4 weeks, and can be as long as 6 weeks in a few patients on maintenance therapy. However, the Patient Outcome Research Team (PORT) consensus guidelines recommend a dosage range and interval for maintenance therapy of 6.25 mg to 25 mg administered every 2 weeks. For doses greater than 50 mg, increase cautiously in increments of 12.5 mg. Do not exceed 100 mg/dose. It may be advisable that patients with no history of taking phenothiazines be treated initially with a shorter-acting form of fluphenazine before administering the decanoate to determine response to fluphenazine and to establish an appropriate dosage. Those with known hypersensitivity to phenothiazines or who are predisposed to undue reactions should have therapy initiated with oral or immediate-release parenteral fluphenazine hydrochloride before receiving fluphenazine decanoate. When the pharmacologic effects and an appropriate dosage are apparent, an equivalent dose of fluphenazine decanoate may be administered. CONVERSION FROM IMMEDIATE-RELEASE FLUPHENAZINE TO FLUPHENAZINE DECANOATE: There is no exact formula for conversion from oral therapy to the decanoate; however, results from 1 study indicated that 20 mg fluphenazine hydrochloride orally daily was equivalent to 25 mg of fluphenazine decanoate every 3 weeks. This represents an approximate conversion ratio of 12.5 mg of decanoate every 3 weeks for every 10 mg of fluphenazine orally daily. Oral medication should be discontinued after the first injection has been given. Prior to the third dose, determine if the patient may be able to have the dose reduced, to compensate for accumulation toward steady state. The dose may be reduced by either giving a lower dose at the same interval or the same dose at longer intervals. Failure to reduce the dose as steady state is approached can result in avoidable adverse effects, particularly akathisia. Do not increase the dose to prolong the dosing interval. NOTE: Fluphenazine decanoate is not indicated for acute symptom management. It is a long-acting parenteral antipsychotic intended for use in the management of patients requiring prolonged parenteral antipsychotic therapy.

For the treatment of acute agitation associated with psychotic disorders. Intramuscular dosage (immediate-release fluphenazine hydrochloride injection solution) Adults

The usual starting dose is 1.25 mg IM. Depending on the severity and duration of symptoms, the total initial daily dosage may range from 2.5 mg/day to 10 mg/day and should be divided and given at 6 to 8 hour intervals. Doses exceeding 10 mg/day should be used cautiously. In general, the parenteral dose has been found to be approximately one-third to one-half the oral dose. Convert to oral therapy as soon as oral administration is possible or acute symptoms have subsided.

For the treatment of severe behavioral or psychological symptoms of dementia† (BPSD)†. Oral dosage Geriatric Adults

Initially, 1 to 2.5 mg/day PO, in divided doses once or twice per day. Gradual titration of no more than 1 to 2.5 mg/day every 4 to 7 days is recommended to achieve desired result and limit adverse effects. As daily dosages increase, administer in 2 to 3 divided doses as needed in order to control symptoms or side effects. Antipsychotics are not FDA-approved for this indication and the labeling of all antipsychotics contains a boxed warning noting an increased risk of death in geriatric patients being treated for behavioral problems associated with dementia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antipsychotics in long-term care facility (LTCF) residents with dementia-related behavioral symptoms. OBRA Max: 4 mg/day PO in residents meeting the OBRA criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. In addition, the facility must attempt a gradual dose reduction (GDR) in 2 separate quarters, at least 1 month apart, within the first year of admission to the facility or after the facility has initiated an antipsychotic, unless clinically contraindicated. After the first year, a GDR must be attempted annually unless clinically contraindicated. The GDR may be considered clinically contraindicated if the target symptoms returned or worsened after the most recent GDR attempt within the facility and the physician has documented justification for why attempting additional dose reductions at that time would likely impair the resident's function or increase distressed behavior.

†Indicates off-label use

Hepatic Impairment

Fluphenazine decanoate and fluphenazine enanthate are depot injection formulations that are contraindicated in patients with hepatic impairment. In general, phenothiazines are contraindicated in patients with liver damage.

Renal Impairment

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

Abarelix: (Minor) Abarelix can cause QT prolongation. In a single, active-controlled, clinical study comparing abarelix to LHRH agonist plus nonsteroidal antiandrogen, periodic electrocardiograms were performed. Both therapies prolonged the mean QTc interval by >10 msec from baseline. In approximately 20% of 340 patients, the QTc increased more than 30 milliseconds from baseline or the end-of-treatment QTc values were more than 450 milliseconds. The effect of abarelix on the QT interval may be due to androgen deprivation or other variables, as similar effects were seen in men that received a gonadotropin-releasing hormone (GnRH) agonist with a nonsteroidal antiandrogen. Patients with a baseline QTc value greater than 450 milliseconds may not be appropriate candidates for abarelix receipt. Prescribers need to weigh the potential benefits and risks of abarelix use in patients with prolonged QT syndrome or in patients taking other drugs that may prolong the QT interval. Agents with a possible risk for QT prolongation and TdP include phenothiazines.
Acarbose: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Chlorpheniramine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Acetaminophen; Codeine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as dichloralphenazone. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
Acetaminophen; Diphenhydramine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with phenothiazines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with phenothiazines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor for signs of hypotension after starting or titrating the dosage of oxycodone. There is an increased risk of severe hypotension in patients whose ability to maintain blood pressure has already been compromised by concurrent administration of phenothiazines.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Adagrasib: (Minor) QT/QTc prolongation can occur with concomitant use of adagrasib and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Alfentanil: (Moderate) Concomitant use of alfentanil with other CNS depressants, including the phenothiazines, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
Alfuzosin: (Minor) Use caution when administering alfuzosin with fluphenazine due to the potential for QT prolongation. Alfuzosin may prolong the QT interval in a dose-dependent manner. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Alogliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Alogliptin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Alogliptin; Pioglitazone: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Alosetron: (Moderate) Alosetron, if combined with drugs that possess anticholinergic properties like phenothiazines, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
Alpha-glucosidase Inhibitors: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Alprazolam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Amantadine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Amifampridine: (Major) Carefully consider the need for concomitant treatment with phenothiazines and amifampridine, as coadministration may increase the risk of seizures. Consider an alternative to the phenothiazine. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Phenothiazines may lower seizure threshold and should be used with caution with concomitant medications which may also affect seizure threshold.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Aminoglycosides: (Minor) When used for the treatment of nausea and vomiting, antiemetic phenothiazines may effectively mask symptoms that are associated with ototoxicity induced by aminoglycosides.
Aminolevulinic Acid: (Moderate) Phenothiazines may increase the photosensitizing effects of photosensitizing agents used in photodynamic therapy. Patients should limit ultra-violet exposure.
Amiodarone: (Minor) The concomitant use of amiodarone and other drugs known to prolong the QT interval should only be done after careful assessment of risks versus benefits. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Drugs with a possible risk for QT prolongation include fluphenazine.
Amisulpride: (Minor) Monitor ECGs for QT prolongation when amisulpride is administered with fluphenazine. Amisulpride causes dose- and concentration- dependent QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation.
Amitriptyline: (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
Amlodipine; Celecoxib: (Moderate) A dosage adjustment may be warranted for fluphenazine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of fluphenazine. Celecoxib is a CYP2D6 inhibitor, and fluphenazine is a CYP2D6 substrate.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Amobarbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Amoxapine: (Moderate) Use caution during co-administration of amoxapine and antipsychotics. Amoxapine exhibits some antipsychotic activity and may increase the risk of tardive dyskinesia or neuroleptic malignant syndrome (NMS) when antipsychotics are given concurrently. CNS effects, orthostatic hypotension, anticholinergic effects, and lowering of seizure threshold are potential problems with the combined use of amoxapine and antipsychotics.
Amoxicillin; Clarithromycin; Omeprazole: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with fluphenazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while fluphenazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Anagrelide: (Minor) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include fluphenazine.
Anticholinergics: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Anxiolytics; Sedatives; and Hypnotics: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
Apomorphine: (Major) Use fluphenazine with apomorphine with caution; avoid use if possible due to an increased risk for QT prolongation and sedation. Also, the effectiveness of either agent may be decreased due to opposing effects on dopamine; consider if an atypical antipsychotic would be a suitable alternative to fluphenazine. Additive CNS depression is also possible. Limited data indicate that QT prolongation is possible with fluphenazine administration. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as phenothiazines.
Aripiprazole: (Major) Fluphenazine,a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as aripiprazole. Co-administration of fluphenazine with atypical agents (e.g., lurasidone and others) may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Arsenic Trioxide: (Minor) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation that should be used cautiously with arsenic trioxide include fluphenazine.
Artemether; Lumefantrine: (Minor) Concurrent use of fluphenazine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if fluphenazine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Articaine; Epinephrine: (Moderate) Monitor blood pressure during concomitant epinephrine and phenothiazine use. Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
Asenapine: (Moderate) Asenapine has been associated with QT prolongation. According to the manufacturer, asenapine should be avoided in combination with other agents also known to have this effect (e.g., fluphenazine). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Coadministration of asenapine with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when fluphenazine is used concomitantly with other drugs having antimuscarinic activity such as orphenadrine.
Aspirin, ASA; Carisoprodol: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential for additive hypotension and excessive CNS effects (sedation and dizziness), which can impair the ability to undertake tasks requiring mental alertness.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential for additive hypotension and excessive CNS effects (sedation and dizziness), which can impair the ability to undertake tasks requiring mental alertness.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with phenothiazines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with phenothiazines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor for signs of hypotension after starting or titrating the dosage of oxycodone. There is an increased risk of severe hypotension in patients whose ability to maintain blood pressure has already been compromised by concurrent administration of phenothiazines.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with fluphenazine as there is a potential for elevated concentrations of fluphenazine and cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Fluphenazine and cobicistat are substrates and inhibitors of CYP2D6.
Atenolol; Chlorthalidone: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Atomoxetine: (Minor) Use caution if atomoxetine is administered with fluphenazine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Fluphenazine is also associated with a possible risk for QT prolongation.
Atropine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Atropine; Difenoxin: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Diphenoxylate is a synthetic opiate derivative that appears to exert its effect locally and centrally on the smooth muscle cells of the GI tract to inhibit GI motility and slow excess GI propulsion. The effects can be additive to other agents with CNS and anticholinergic effects, such as the phenothiazines. In some cases, constipation might occur, and effects on the CNS or bladder function may also be additive.
Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including phenothiazines.
Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including phenothiazines.
Azilsartan; Chlorthalidone: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Azithromycin: (Major) Avoid coadministration of azithromycin with fluphenazine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Baclofen: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of baclofen and phenothiazines due to the risk for additive CNS depression.
Barbiturates: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Bedaquiline: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with fluphenazine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Fluphenazine, a phenothiazine, is also associated with a theoretical risk for QT prolongation.
Belladonna; Opium: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with fluphenazine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking fluphenazine, reduce initial dosage and titrate to clinical response. If fluphenazine is initiated a patient taking an opioid agonist, use a lower initial dose of fluphenazine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Benzodiazepines: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Benztropine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Minor) QT/QTc prolongation can occur with concomitant use of metronidazole and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Bismuth Subsalicylate: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of phenothiazines may produce additive effects.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of phenothiazines may produce additive effects. (Minor) QT/QTc prolongation can occur with concomitant use of metronidazole and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Brexpiprazole: (Major) Caution is advisable during concurrent use of brexpiprazole with other antipsychotics such as phenothiazines. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use of brexpiprazole and phenothiazines; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the coadministered antipsychotic agent, with low-potency agents (e.g., thioridazine, chlorpromazine) having an increased likelihood of causing sedation, orthostasis, and anticholinergic effects, and high-potency agents (e.g., fluphenazine) having an increased likelihood of causing extrapyramidal effects. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Bromocriptine: (Major) Avoid concurrent use of phenothiazines and bromocriptine when possible. Bromocriptine may interact with dopamine antagonists such as the phenothiazines. The phenothiazines are noted to result in a decreased efficacy of bromocriptine. The prolactin-lowering effect of bromocriptine is antagonized; the elevation in prolactin levels produced by phenothiazines persists with chronic administration. In addition, bromocriptine, a dopamine agonist, may theoretically diminish the effectiveness of central dopamine antagonists such as the phenothiazines; however, such interactions are not certain.
Brompheniramine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Brompheniramine; Phenylephrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Brompheniramine; Pseudoephedrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Bupivacaine; Epinephrine: (Moderate) Monitor blood pressure during concomitant epinephrine and phenothiazine use. Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
Buprenorphine: (Moderate) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of phenothiazines and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Phenothiazines including fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if co-administered with drugs with a risk of QT prolongation. Also, concomitant use of buprenorphine with other CNS depressants, such as phenothiazines, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. 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. Consider a dose reduction of one or both 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) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of phenothiazines and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Phenothiazines including fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if co-administered with drugs with a risk of QT prolongation. Also, concomitant use of buprenorphine with other CNS depressants, such as phenothiazines, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. 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. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures and may have an additive effect with phenothiazines on lowering the seizure threshold. Low initial dosing and slow titration is recommended if this combination must be used. In addition, bupropion is a strong inhibitor of CYP2D6. Dosage reductions of fluphenazine, a CYP2D6 substrate, may be needed during coadministration with bupropion. Increased serum concentrations of fluphenazine may result in extrapyramidal symptoms, somnolence, or other adverse effects.
Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures and may have an additive effect with phenothiazines on lowering the seizure threshold. Low initial dosing and slow titration is recommended if this combination must be used. In addition, bupropion is a strong inhibitor of CYP2D6. Dosage reductions of fluphenazine, a CYP2D6 substrate, may be needed during coadministration with bupropion. Increased serum concentrations of fluphenazine may result in extrapyramidal symptoms, somnolence, or other adverse effects. (Moderate) Patients receiving phenothiazines and naltrexone concomitantly have had symptoms of somnolence and lethargy.
Butabarbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Butalbital; Acetaminophen: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Butalbital; Acetaminophen; Caffeine: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as phenothiazines, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
Cabergoline: (Moderate) Cabergoline should generally not be coadministered with phenothiazines due to mutually antagonistic effects on dopaminergic function. The dopamine antagonist action of phenothiazines may diminish the prolactin-lowering ability of cabergoline while the dopamine agonist effects of cabergoline may exacerbate a psychotic disorder, reducing the effectiveness of antipsychotics such as phenothiazines.
Cabotegravir; Rilpivirine: (Minor) Caution is advised when administering rilpivirine with fluphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
Canagliflozin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
Canagliflozin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and phenothiazines. CNS depressants can potentiate the effects of cannabidiol.
Capsaicin; Metaxalone: (Moderate) Phenothiazines can potentiate the CNS-depressant action of skeletal muscle relaxants like metaxalone. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Carbidopa; Levodopa: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Carbidopa; Levodopa; Entacapone: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Carbinoxamine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Cariprazine: (Major) Avoid use of these drugs together due to duplicative therapeutic effects and additive risks for drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. Cariprazine, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. The use of cariprazine with other antipsychotic agents, such as the phenothiazines, would be expected to have additive risks for pharmacologic effects and adverse reactions. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during combined use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Carisoprodol: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential for additive hypotension and excessive CNS effects (sedation and dizziness), which can impair the ability to undertake tasks requiring mental alertness.
Celecoxib: (Moderate) A dosage adjustment may be warranted for fluphenazine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of fluphenazine. Celecoxib is a CYP2D6 inhibitor, and fluphenazine is a CYP2D6 substrate.
Celecoxib; Tramadol: (Moderate) A dosage adjustment may be warranted for fluphenazine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of fluphenazine. Celecoxib is a CYP2D6 inhibitor, and fluphenazine is a CYP2D6 substrate. (Moderate) Concurrent use of tramadol and fluphenazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that fluphenazine is a weak CYP2D6 inhibitor and has the potential to decrease the metabolism of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by fluphenazine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and fluphenazine.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Central-acting adrenergic agents: (Moderate) Monitor blood pressure and for unusual drowsiness or excessive sedation during concomitant central-acting adrenergic agent and phenothiazine use. Concomitant use increases the risk for additive hypotension and CNS depression.
Ceritinib: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as ceritinib.
Cetrorelix: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Charcoal: (Major) Phenothiazine absorption is reduced when coadministered with activated charcoal. Concomitant administration of phenothiazines and activated charcoal dietary supplements is not recommended. Activated charcoal may be appropriate in phenothiazine overdose situations, as charcoal absorbs the phenothiazines and also enhances drug elimination.
Chlophedianol; Dexbrompheniramine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as dexbrompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlordiazepoxide: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Chlordiazepoxide; Amitriptyline: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression. (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
Chlordiazepoxide; Clidinium: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Chloroquine: (Major) Avoid coadministration of chloroquine with fluphenazine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Fluphenazine is associated with a possible risk for QT prolongation.
Chlorothiazide: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Chlorpheniramine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interactin

g antihistamines.
Chlorpheniramine; Codeine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Chlorpheniramine; Dextromethorphan: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Chlorpheniramine; Hydrocodone: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Phenylephrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Chlorpheniramine; Pseudoephedrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpromazine: (Moderate) Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). Fluphenazine, also a phenothiazine, is associated with a possible risk for QT prolongation. Coadministration of chlorpromazine with other phenothiazines may also increase the risk of phenothiazine-related adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
Chlorpropamide: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
Chlorthalidone: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Chlorthalidone; Clonidine: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Chlorzoxazone: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
Ciprofloxacin: (Minor) QT/QTc prolongation can occur with concomitant use of ciprofloxacin and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Cisapride: (Contraindicated) Coadministration of cisapride and fluphenazine is contraindicated due to the risk for serious adverse events, such as torsade de pointes (TdP). QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation and/or TdP.
Citalopram: (Minor) Citalopram causes dose-dependent QT interval prolongation. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended. Fluphenazine is associated with a possible risk for QT prolongation.
Clarithromycin: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with fluphenazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while fluphenazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Class IA Antiarrhythmics: (Minor) Fluphenazine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Clemastine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as clemastine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Clindamycin; Tretinoin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Clobazam: (Major) A dose reduction of CYP2D6 substrates, such as fluphenazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of fluphenazine occurring through inhibition of CYP2D6 may increase the risk of extrapyramidal symptoms, somnolence, or other serious adverse effects. In addition, phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
Clofazimine: (Minor) QT/QTc prolongation can occur with concomitant use of clofazimine and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Clomipramine: (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
Clonazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Clorazepate: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Clozapine: (Moderate) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, coadministration of clozapine with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent.
Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with fluphenazine as there is a potential for elevated concentrations of fluphenazine and cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Fluphenazine and cobicistat are substrates and inhibitors of CYP2D6.
Codeine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Codeine; Guaifenesin: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension. (Moderate) The use of promethazine, a phenothiazine antiemetic, with phenothiazine antipsychotics such as fluphenazine should be avoided if possible. Co-administration of promethazine and antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. In addition, promethazine is associated with QT prolongation and fluphenazine is associated with a possible risk of QT prolongation. Concomitant administration would increase the risk of QT prolongation.
Codeine; Promethazine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) The use of promethazine, a phenothiazine antiemetic, with phenothiazine antipsychotics such as fluphenazine should be avoided if possible. Co-administration of promethazine and antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. In addition, promethazine is associated with QT prolongation and fluphenazine is associated with a possible risk of QT prolongation. Concomitant administration would increase the risk of QT prolongation.
COMT inhibitors: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Crizotinib: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with fluphenazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have been associated with QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
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 most antipsychotic phenothiazines, 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.
Dantrolene: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
Dapagliflozin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
Dapagliflozin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Dapagliflozin; Saxagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with fluphenazine as there is a potential for elevated concentrations of fluphenazine and cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Fluphenazine and cobicistat are substrates and inhibitors of CYP2D6.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with fluphenazine as there is a potential for elevated concentrations of fluphenazine and cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Fluphenazine and cobicistat are substrates and inhibitors of CYP2D6.
Dasatinib: (Minor) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dasatinib and fluphenazine should be used together cautiously. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Degarelix: (Major) Avoid coadministration of degarelix with fluphenazine due to the risk of reduced efficacy of degarelix; QT prolongation may also occur. Fluphenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; degarelix is a GnRH analog. Additionally, androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Desipramine: (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
Desogestrel; Ethinyl Estradiol: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Desvenlafaxine: (Major) Dosage adjustments of some phenothiazines may be necessary during concurrent use of desvenlafaxine. Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer that primary substrates of CYP2D6, such as perphenazine, be dosed at the original level when co-administered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued. The dose of these CYP2D6 substrates should be reduced by up to one-half if co-administered with desvenlafaxine 400 mg/day.
Deutetrabenazine: (Moderate) The risk of QT prolongation may be increased with coadministration of deutetrabenazine and fluphenazine. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Monitor for signs and symptoms of neuroleptic malignant syndrome (NMS), restlessness, and agitation. If NMS is diagnosed, immediately discontinue deutetrabenazine, and provide intensive symptomatic treatment and medical monitoring. Recurrence of NMS has been reported with resumption of drug therapy. If akathisia or parkinsonism develops during treatment, the deutetrabenazine dose should be reduced; discontinuation may be required. Deutetrabenazine is a reversible, dopamine depleting drug and fluphenazine is a dopamine antagonist. The risk for parkinsonism, NMS, or akathisia may be increased with concomitant administration. Monitor for excessive sedation and somnolence during coadministration of fluphenazine and deutetrabenazine. Concurrent use may result in additive CNS depression.
Dexbrompheniramine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as dexbrompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as dexbrompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Dexchlorpheniramine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Dexmedetomidine: (Moderate) Consider a dosage reduction for dexmedetomidine or the phenothiazine during concomitant use due to the risk of additive CNS effects.
Dextromethorphan; Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures and may have an additive effect with phenothiazines on lowering the seizure threshold. Low initial dosing and slow titration is recommended if this combination must be used. In addition, bupropion is a strong inhibitor of CYP2D6. Dosage reductions of fluphenazine, a CYP2D6 substrate, may be needed during coadministration with bupropion. Increased serum concentrations of fluphenazine may result in extrapyramidal symptoms, somnolence, or other adverse effects.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Dextromethorphan; Quinidine: (Minor) Fluphenazine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Diazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Dicyclomine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Diethylpropion: (Minor) Use of diethylpropion with phenothiazines may antagonize the anorectic effects of diethylpropion.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Dimenhydrinate: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as dimenhydrinate. Patients should be informed to read non-prescription motion sickness, allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
Dipeptidyl Peptidase-4 Inhibitors: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Diphenhydramine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
Diphenhydramine; Ibuprofen: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
Diphenhydramine; Naproxen: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
Diphenhydramine; Phenylephrine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Diphenoxylate; Atropine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Diphenoxylate is a synthetic opiate derivative that appears to exert its effect locally and centrally on the smooth muscle cells of the GI tract to inhibit GI motility and slow excess GI propulsion. The effects can be additive to other agents with CNS and anticholinergic effects, such as the phenothiazines. In some cases, constipation might occur, and effects on the CNS or bladder function may also be additive.
Disopyramide: (Minor) Fluphenazine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Dofetilide: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as dofetilide.
Dolasetron: (Minor) Administer dolasetron with caution in combination with fluphenazine as concurrent use may increase the risk of QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Minor) Caution is advised when administering rilpivirine with fluphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Donepezil: (Minor) Administer fluphenazine and donepezil with caution as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation.
Donepezil; Memantine: (Minor) Administer fluphenazine and donepezil with caution as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation.
Dopamine: (Moderate) The vasoconstrictive properties of dopamine infusion can be decreased due to the alpha-adrenergic blocking capability of phenothiazines.
Doxepin: (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
Doxylamine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Doxylamine; Pyridoxine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Dronabinol: (Moderate) Use caution if coadministration of phenothiazines with dronabinol is necessary. Administration of dronabinol with phenothiazines (e.g., prochlorperazine) has resulted in improved antiemetic efficacy as compared to either drug alone, without additional toxicity. However, it is also possible that coadministration may result in additive dizziness, confusion, somnolence, and other CNS effects.
Dronedarone: (Contraindicated) Concurrent use of dronedarone and fluphenazine is contraindicated. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation and/or torsade de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Minor) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation that should be used cautiously with droperidol include fluphenazine. Droperidol may also cause increased CNS sedation when given with flurphenazine.
Drospirenone; Ethinyl Estradiol: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Duloxetine: (Moderate) Caution is advisable during concurrent use of fluphenazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of fluphenazine may occur. Phenothiazines are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor. In addition, fluphenazine is associated with a possible risk of QT prolongation; therefore, cardiac effects are possible.
Efavirenz: (Minor) Consider alternatives to efavirenz when coadministering with fluphenazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fluphenazine is associated with a possible risk for QT prolongation.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Consider alternatives to efavirenz when coadministering with fluphenazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fluphenazine is associated with a possible risk for QT prolongation.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Minor) Consider alternatives to efavirenz when coadministering with fluphenazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fluphenazine is associated with a possible risk for QT prolongation.
Eliglustat: (Minor) Coadministration of fluphenazine and eliglustat may result in increased concentrations of the phenothiazine and, theoretically, an increased risk of QT prolongation. If coadministration is necessary, use caution and monitor closely. Consider reducing the dosage of phenothiazine and titrating to clinical effect. Fluphenazine is a CYP2D6 substrate associated with a possible risk for QT prolongation. Eliglustat is a CYP2D6 inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with fluphenazine as there is a potential for elevated concentrations of fluphenazine and cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Fluphenazine and cobicistat are substrates and inhibitors of CYP2D6.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with fluphenazine as there is a potential for elevated concentrations of fluphenazine and cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Fluphenazine and cobicistat are substrates and inhibitors of CYP2D6.
Empagliflozin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
Empagliflozin; Linagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Empagliflozin; Linagliptin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Empagliflozin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Minor) Caution is advised when administering rilpivirine with fluphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Minor) Caution is advised when administering rilpivirine with fluphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Encorafenib: (Minor) Use caution if fluphenazine is administered with encorafenib. Encorafenib is associated with dose-dependent prolongation of the QT interval. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Entrectinib: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as entrectinib.
Ephedrine: (Major) Avoid use of ephedrine in patients receiving phenothiazines due to the risk of paradoxical vasodilation. Phenothiazines possess potent alpha-blocking properties, making the use of vasopressors with mixed alpha- and beta-agonist properties inappropriate. If a vasopressor is required, norepinephrine and phenylephrine are most appropriate.
Ephedrine; Guaifenesin: (Major) Avoid use of ephedrine in patients receiving phenothiazines due to the risk of paradoxical vasodilation. Phenothiazines possess potent alpha-blocking properties, making the use of vasopressors with mixed alpha- and beta-agonist properties inappropriate. If a vasopressor is required, norepinephrine and phenylephrine are most appropriate.
Epinephrine: (Moderate) Monitor blood pressure during concomitant epinephrine and phenothiazine use. Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Eribulin: (Minor) Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval, such as fluphenazine, must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Ertugliflozin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
Ertugliflozin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Ertugliflozin; Sitagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Erythromycin: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with fluphenazine. Erythromycin is associated with prolongation of the QT interval and TdP. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Escitalopram: (Minor) Use escitalopram with caution in combination with fluphenazine. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP). Fluphenazine is associated with a possible risk for QT prolongation.
Esketamine: (Moderate) Closely monitor patients receiving esketamine and fluphenazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep after a restful sleep.
Estazolam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Eszopiclone: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Ethinyl Estradiol; Norelgestromin: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Ethinyl Estradiol; Norgestrel: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Ethiodized Oil: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Ethosuximide: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Etomidate: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as general anesthetics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
Etonogestrel; Ethinyl Estradiol: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Felbamate: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and fluphenazine. Concurrent use may result in additive CNS depression.
Fentanyl: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Fingolimod: (Minor) Exercise caution when administering fingolimod concomitantly with fluphenazine. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Fluphenazine is associated with a possible risk for QT prolongation.
Flavoxate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Flecainide: (Minor) Flecainide should be used cautiously and with close monitoring with fluphenazine. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as phenothiazines, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
Fluconazole: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluconazole with fluphenazine. Fluconazole has been associated with QT prolongation and rare cases of TdP. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Flucytosine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.
Fluocinolone; Hydroquinone; Tretinoin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Fluoxetine: (Moderate) Use fluoxetine with caution in combination with fluphenazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Additionally, fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum fluphenazine concentrations, leading to side effects. QT prolongation and TdP have been reported in patients treated with fluoxetine. Fluphenazine is associated with a possible risk for QT prolongation.
Flurazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Fluvoxamine: (Minor) Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of fluvoxamine and fluphenazine. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Fluphenazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Foscarnet: (Minor) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as fluphenazine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Fluphenazine is associated with a possible risk for QT prolongation. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Fosphenytoin: (Moderate) Monitor phenytoin concentrations during concomitant therapy with fosphenytoin and phenothiazines; a fosphenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of fosphenytoin.
Fostemsavir: (Minor) Use fluphenazine and fostemsavir together with caution due to the potential for QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fluphenazine and gabapentin. Concurrent use may result in additive CNS depression.
Ganirelix: (Moderate) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as phenothiazines, should not be administered concomitantly with ganirelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Gemifloxacin: (Minor) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluphenazine with gemifloxacin. Fluphenazine is associated with a possible risk for QT prolongation. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Minor) Coadministration of gemtuzumab ozogamicin with fluphenazine may increase the potential for additive QT prolongation and risk of torsade de pointes (TdP). Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Fluphenazine is also associated with a possible risk for QT prolongation.
Gilteritinib: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and fluphenazine is necessary. Gilteritinib has been associated with QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Glasdegib: (Minor) Consider increased frequency of ECG monitoring if glasdegib and fluphenazine are coadministered due to the potential for additive effects on the QT interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Glimepiride: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
Glipizide: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
Glipizide; Metformin: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administ ered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Glyburide: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
Glyburide; Metformin: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Goserelin: (Major) Avoid coadministration of goserelin with fluphenazine due to the risk of reduced efficacy of goserelin; QT prolongation may also occur. Fluphenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; goserelin is a GnRH analog. Additionally, androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Granisetron: (Minor) Use granisetron with caution in combination with fluphenazine due to the risk of QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as granisetron.
Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Guaifenesin; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Guanidine: (Minor) Bone marrow suppression is associated with guanidine therapy. Avoid concomitant use of other drugs known to cause bone marrow suppression such as phenothiazines.
Halobetasol; Tazarotene: (Moderate) The manufacturer states that tazarotene should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Halogenated Anesthetics: (Minor) Halogenated anesthetics should be used cautiously and with close monitoring with fluphenazine. Halogenated anesthetics can prolong the QT interval and fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, phenothiazines can potentiate the CNS-depressant action of general anesthetics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
Haloperidol: (Moderate) Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Haloperidol is associated with a possible risk for QT prolongation and TdP. Coadministration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Histrelin: (Major) Avoid coadministration of histrelin with fluphenazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Fluphenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Additionally, androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Homatropine; Hydrocodone: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Hydrocodone: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking fluphenazine. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Hydromorphone: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and fluphenazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with fluphenazine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, additive anticholinergic effects and CNS depression may also occur. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Fluphenazine is associated with a possible risk for QT prolongation.
Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Ibuprofen; Oxycodone: (Major) Concomitant use of oxycodone with phenothiazines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with phenothiazines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor for signs of hypotension after starting or titrating the dosage of oxycodone. There is an increased risk of severe hypotension in patients whose ability to maintain blood pressure has already been compromised by concurrent administration of phenothiazines.
Ibutilide: (Minor) Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation and should be used cautiously with ibutilide. Ibutilide administration can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Iloperidone: (Moderate) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should not be used with other agents also known to have this effect, such as fluphenazine. In addition, coadministration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Imipramine: (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
Incretin Mimetics: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Indacaterol; Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Indapamide: (Moderate) Indapamide may cause electrolyte disturbances, which may increase the potential for proarrhythmic effects of selected phenothiazines.
Inotuzumab Ozogamicin: (Minor) Coadministration of inotuzumab ozogamicin with fluphenazine may increase the potential for additive QT prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. Fluphenazine is also associated with a possible risk for QT prolongation.
Insulins: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Iodixanol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iohexol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iomeprol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iopamidol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iopromide: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Ioversol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Ipecac: (Major) Phenothiazines, especially in large quantities, can cause a dystonic reaction. Due to the aspiration risk associated with emesis for a person with acute dystonia of the head or neck,avoid emesis induction for overdose cases.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Isocarboxazid: (Moderate) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Isoniazid, INH; Rifampin: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Isosulfan Blue: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Itraconazole: (Minor) Use itraconazole with caution in combination with fluphenazine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Ivosidenib: (Minor) Coadministration of ivosidenib with fluphenazine may increase the risk of QT prolongation. If concomitant use is necessary, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and fluphenazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Lansoprazole; Amoxicillin; Clarithromycin: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with fluphenazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while fluphenazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Lapatinib: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with fluphenazine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and fluphenazine. Concurrent use may result in additive CNS depression.
Lefamulin: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as lefamulin.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and phenothiazines. Dosage adjustments of lemborexant and the phenothiazine may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
Lenvatinib: (Minor) Use caution if coadministration of fluphenazine with lenvatinib is necessary. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as lenvatinib.
Leuprolide: (Major) Avoid coadministration of leuprolide with fluphenazine due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Fluphenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Additionally, androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Leuprolide; Norethindrone: (Major) Avoid coadministration of leuprolide with fluphenazine due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Fluphenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Additionally, androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Levodopa: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Levofloxacin: (Minor) QT/QTc prolongation can occur with concomitant use of levofloxacin and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and fluphenazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Levonorgestrel; Ethinyl Estradiol: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Levorphanol: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Lidocaine; Epinephrine: (Moderate) Monitor blood pressure during concomitant epinephrine and phenothiazine use. Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
Linagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Linagliptin; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Lithium: (Moderate) Some atypical antipsychotics are considered first-line adjunctive therapy to mood stabilizers such as lithium. Because both fluphenazine and lithium have been associated with QT prolongation, coadminister cautiously and with close monitoring. It is also advisable to monitor patients for neurotoxicity during co-administration. Neuroleptic malignant syndrome (NMS) has been observed occasionally during concurrent use of lithium and either atypical or conventional antipsychotics. Additive extrapyramidal effects have also been noted. Early case reports described an encephalopathic syndrome consisting of delirium, tremulousness, dyskinesia, seizures, leukocytosis, weakness, hyperpyrexia, confusion, extrapyramidal symptoms, elevations in laboratory values (e.g., liver function tests, blood urea nitrogen, fasting blood sugar) and, in some cases, irreversible brain damage, during use of lithium and conventional antipsychotics, particularly haloperidol. Subsequent rare reports of NMS or NMS-like reactions have been described during co-administration of lithium and atypical antipsychotics (e.g., aripiprazole, risperidone, olanzapine, clozapine). Following resolution of NMS, there are isolated instances of re-emergence of symptoms following re-initiation of lithium as monotherapy. Lithium may be a risk factor for antipsychotic-induced NMS; however, this hypothesis has not been confirmed. In many reported cases, confounding factors have been present (e.g., previous history of NMS, high dose therapy). The ability of antipsychotics alone to precipitate NMS and the rarity of the condition further complicate assessment of lithium as a risk factor.
Lofexidine: (Moderate) Monitor ECG for QT prolongation and monitor for additive sedation during concurrent use of lofexidine and fluphenazine. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Fluphenazine is associated with a possible risk for QT prolongation. Lofexidine may potentiate the effects of CNS depressants, including fluphenazine.
Loperamide: (Minor) QT/QTc prolongation can occur with concomitant use of loperamide and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Loperamide; Simethicone: (Minor) QT/QTc prolongation can occur with concomitant use of loperamide and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with fluphenazine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation.
Lorazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Loxapine: (Major) Caution is advisable during concurrent use of loxapine and other antipsychotics. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Lumateperone: (Moderate) Coadministration of antipsychotics, such as lumateperone and fluphenazine, may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from antipsychotic combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Lurasidone: (Major) Lurasidone administration has been associated with drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. The risk of these adverse effects may be increased during concurrent use of lurasidone with other antipsychotics. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Macimorelin: (Minor) Use of fluphenazine with macimorelin may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Maprotiline: (Moderate) Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fluphenazine include maprotiline. CNS effects, orthostatic hypotension, antimuscarinic effects) may occur during coadministration because maprotiline and phenothiazines are metabolized via similar pathways (CYP2D6), have structural similarities, and produce similar pharmacologic effects, like antimuscarinic activity. 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.
Meclizine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with meclizine. Patients should be informed to read non-prescription product labels carefully for additional interacting motion sickness medications.
Mefloquine: (Minor) Mefloquine should be used with caution in patients receiving fluphenazine as concurrent use may increase the risk of QT prolongation. There is evidence that the use of halofantrine after mefloquine causes significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation; however due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Meglitinides: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Melatonin: (Moderate) Monitor for unusual drowsiness and excessive duration during coadministration of melatonin and phenothiazines due to the risk for additive CNS depression.
Meperidine: (Major) Phenothiazines can potentiate the CNS-depressant action of other drugs such as meperidine. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
Meprobamate: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
Metaxalone: (Moderate) Phenothiazines can potentiate the CNS-depressant action of skeletal muscle relaxants like metaxalone. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects.
Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Metformin; Repaglinide: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Metformin; Rosiglitazone: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Metformin; Saxagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Metformin; Sitagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Methadone: (Minor) Fluphenazine should be used cautiously and with close monitoring with methadone. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In addition, phenothiazines can potentiate the CNS-depressant action of methadone. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Methocarbamol: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of methocarbamol and phenothiazines due to the risk for additive CNS depression; dosage adjustments may be necessary.
Methohexital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Methoxsalen: (Moderate) Use methoxsalen and phenothiazines together with caution; the risk of severe burns/photosensitivity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
Methscopolamine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Methsuximide: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Methyclothiazide: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Metoclopramide: (Contraindicated) Avoid metoclopramide in patients receiving phenothiazine antipsychotics due to potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS). Also avoid the use of metoclopramide with phenothiazine antiemetics if possible due to these risks. Some manufacturer labels for metoclopramide contraindicate the use of these drugs together, while others state avoidance is necessary. If these agents must be used together, monitor closely for movement disorders and additive CNS effects. Discontinue these medications at the first signs of dyskinesia. Metoclopramide is a central dopamine antagonist and may cause EPS (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia). Tardive dyskinesia (TD) is a syndrome of potentially irreversible and disfiguring involuntary movements of the face or tongue, and sometimes of the trunk and/or extremities. Movements may be choreoathetotic in appearance. Phenothiazines are also central dopamine antagonists. In addition, both phenothiazines and metoclopramide can cause sedation, seizures, or increased prolactin levels.
Metolazone: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Metronidazole: (Minor) QT/QTc prolongation can occur with concomitant use of metronidazole and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as phenothiazines, should be used with caution. Additive drowsiness and/or dizziness is possible.
Metyrosine: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.
Midazolam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Midostaurin: (Minor) The concomitant use of midostaurin and fluphenazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Additionally, fluphenazine is associated with a possible risk for QT prolongation.
Mifepristone: (Minor) Due to a possible risk for QT prolongation and torsade de pointes (TdP), mifepristone and fluphenazine should be used together cautiously. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used. Drugs with a possible risk for QT prolongation that should be used cautiously with mifepristone include fluphenazine.
Miglitol: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as phenothiazines. Caution should be exercised when using these agents concurrently.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as fluphenazine may be increased when co-administered with mirabegron. Fluphenazine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
Mirtazapine: (Moderate) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mirtazapine and fluphenazine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Because both mirtazapine and fluphenazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
Mitotane: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including opiate agonists, may cause additive CNS effects.
Mobocertinib: (Minor) QT/QTc prolongation can occur with concomitant use of mobocertinib and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Molindone: (Major) Close monitoring is advisable during concurrent use of molindone with other antipsychotics. Because molindone shares certain pharmacological properties with other antipsychotics, additive cardiac effects (e.g., hypotension), CNS effects (e.g., drowsiness), anticholinergic effects (e.g., constipation, xerostomia), extrapyramidal effects, neuroleptic malignant syndrome, or seizures may occur. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Monoamine oxidase inhibitors: (Moderate) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
Morphine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Morphine; Naltrexone: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Moxifloxacin: (Minor) Concurrent use of fluphenazine and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants, including phenothiazines, can potentiate the effects of nabilone on respiratory depression.
Nafarelin: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Nalbuphine: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as phenothiazines, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
Naltrexone: (Moderate) Patients receiving phenothiazines and naltrexone concomitantly have had symptoms of somnolence and lethargy.
Neostigmine; Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Nilotinib: (Minor) QT interval prolongation may be additive if nilotinib and fluphenazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as phenothiazines. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with phenothiazines.
Non-Ionic Contrast Media: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Phenothiazines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Norepinephrine: (Minor) The alpha-adrenergic effects of norepinephrine can be blocked during concurrent administration of phenothiazines. This blockade can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction. Patients taking phenothiazines can possibly have reduced pressor response to ephedrine, phenylephrine, or norepinephrine, but these drugs are preferred over epinephrine if a vasopressor agent is required. According to the manufacturers of the various phenothiazines, norepinephrine or phenylephrine may be used if a vasopressor is needed.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Norethindrone; Ethinyl Estradiol: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Norgestimate; Ethinyl Estradiol: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Nortriptyline: (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
Ofloxacin: (Minor) QT/QTc prolongation can occur with concomitant use of ofloxacin and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Olanzapine: (Moderate) Concurrent use of olanzapine and fluphenazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of olanzapine with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Olanzapine; Fluoxetine: (Moderate) Concurrent use of olanzapine and fluphenazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of olanzapine with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. (Moderate) Use fluoxetine with caution in combination with fluphenazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Additionally, fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum fluphenazine concentrations, leading to side effects. QT prolongation and TdP have been reported in patients treated with fluoxetine. Fluphenazine is associated with a possible risk for QT prolongation.
Olanzapine; Samidorphan: (Moderate) Concurrent use of olanzapine and fluphenazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of olanzapine with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Oliceridine: (Moderate) Concomitant use of oliceridine with fluphenazine may cause excessive sedation and somnolence. Limit the use of oliceridine with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Omeprazole; Amoxicillin; Rifabutin: (Major) Rifamycins can increase the me tabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Ondansetron: (Minor) If ondansetron and fluphenazine must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Oritavancin: (Moderate) Fluphenazine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of fluphenazine may be reduced if these drugs are administered concurrently.
Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when fluphenazine is used concomitantly with other drugs having antimuscarinic activity such as orphenadrine.
Osilodrostat: (Minor) Monitor ECGs in patients receiving osilodrostat with fluphenazine. Osilodrostat is associated with dose-dependent QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation.
Osimertinib: (Minor) Use osimertinib and fluphenazine together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Oxaliplatin: (Minor) Monitor electrolytes and ECGs for QT prolongation if coadministration of fluphenazine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Oxazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Oxybutynin: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Oxycodone: (Major) Concomitant use of oxycodone with phenothiazines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with phenothiazines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor for signs of hypotension after starting or titrating the dosage of oxycodone. There is an increased risk of severe hypotension in patients whose ability to maintain blood pressure has already been compromised by concurrent administration of phenothiazines.
Oxymorphone: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Ozanimod: (Minor) Coadministration of ozanimod with fluphenazine may increase the potential for additive QT prolongation. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with torsade de pointes in patients with bradycardia. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Pacritinib: (Minor) QT/QTc prolongation can occur with concomitant use of pacritinib and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Fluphenazine has a possible risk of QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. In addition, coadministration of two antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Paroxetine: (Moderate) Monitor for an increase in paroxetine- and fluphenazine-related adverse reactions, including serotonin syndrome, extrapyramidal symptoms, and somnolence, if coadministration is necessary. Concomitant use may increase the exposure of both drugs. Both drugs are CYP2D6 substrates; paroxetine is a strong CYP2D6 inhibitor and fluphenazine is a weak CYP2D6 inhibitor.
Pasireotide: (Minor) Use caution when using pasireotide in combination with fluphenazine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Fluphenazine is associated with a possible risk for QT prolongation.
Pazopanib: (Minor) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation that should be avoided with pazopanib include fluphenazine.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to fluphenazine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while fluphenazine is a CYP2D6 substrate.
Pentamidine: (Minor) Pentamidine has been associated with QT prolongation. Drugs with a possible risk for QT prolongation should be used cautiously with pentamidine. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Pentazocine: (Moderate) Concomitant use of pentazocine with other CNS depressants, such as phenothiazines, can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously with phenothiazines.
Pentazocine; Naloxone: (Moderate) Concomitant use of pentazocine with other CNS depressants, such as phenothiazines, can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously with phenothiazines.
Pentobarbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
Perphenazine: (Moderate) Fluphenazine and perphenazine are phenothiazines that are associated with a possible risk for QT prolongation. Coadministration may represent duplicate therapy and increase the risk for QT prolongation. In addition, co-administration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
Perphenazine; Amitriptyline: (Moderate) Fluphenazine and perphenazine are phenothiazines that are associated with a possible risk for QT prolongation. Coadministration may represent duplicate therapy and increase the risk for QT prolongation. In addition, co-administration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
Phenelzine: (Moderate) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
Phenobarbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Phentermine; Topiramate: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
Phenytoin: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Photosensitizing agents (topical): (Moderate) Phenothiazines may increase the photosensitizing effects of photosensitizing agents used in photodynamic therapy. Patients should limit ultra-violet exposure.
Pilocarpine: (Moderate) Avoid using pilocarpine in combination with other drugs known to have anticholinergic effects as the therapeutic efficacy of either agent may be reduced.
Pimavanserin: (Minor) Pimavanserin may cause QT prolongation and should be avoided in patients receiving other medications known to prolong the QT interval. Fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if coadministered with drugs with a risk of QT prolongation.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Due to the risk of additive QT prolongation and potential for serious arrhythmias, the concurrent use of pimozide with fluphenazine is contraindicated. Concurrent use of pimozide with phenothiazines may increase the risk of adverse effects such as drowsiness, sedation, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. Many phenothiazines are inhibitors of CYP2D6, one of the metabolic pathways of pimozide.
Pioglitazone: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Pioglitazone; Glimepiride: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Pioglitazone; Metformin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Pitolisant: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as pitolisant.
Ponesimod: (Minor) Concurrent use of ponesimod and fluphenazine may increase the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Porfimer: (Major) Avoid coadministration of porfimer with phenothiazines due to the risk of increased photosensitivity. Porfimer is a light-activated drug used in photodynamic therapy; all patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like phenothiazines may increase the risk of a photosensitivity reaction.
Posaconazole: (Minor) Use posaconazole with caution in combination with fluphenazine as concurrent use may increase the risk of QT prolongation. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Pramipexole: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and pramipexole may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. In addition, coadministration may result in additive sedation.
Pramlintide: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Pregabalin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fluphenazine and pregabalin. Concurrent use may result in additive CNS depression.
Prilocaine; Epinephrine: (Moderate) Monitor blood pressure during concomitant epinephrine and phenothiazine use. Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
Primaquine: (Minor) Exercise caution when administering primaquine in combination with fluphenazine as concurrent use may increase the risk of QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, this phenothiazine may increase the risk of QT prolongation if coadministered with drugs with a risk of QT prolongation.
Primidone: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Procainamide: (Minor) Fluphenazine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Procarbazine: (Moderate) CNS depressants, such as phenothiazines, can potentiate the CNS depression caused by procarbazine therapy, so these drugs should be used together cautiously.
Prochlorperazine: (Moderate) Fluphenazine and prochlorperazine are phenothiazines that are associated with a possible risk for QT prolongation. Coadministration may represent duplicate therapy and increase the risk for QT prolongation. In addition, co-administration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
Promethazine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with phenothiazine antipsychotics such as fluphenazine should be avoided if possible. Co-administration of promethazine and antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. In addition, promethazine is associated with QT prolongation and fluphenazine is associated with a possible risk of QT prolongation. Concomitant administration would increase the risk of QT prolongation.
Promethazine; Dextromethorphan: (Moderate) The use of promethazine, a phenothiazine antiemetic, with phenothiazine antipsychotics such as fluphenazine should be avoided if possible. Co-administration of promethazine and antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. In addition, promethazine is associated with QT prolongation and fluphenazine is associated with a possible risk of QT prolongation. Concomitant administration would increase the risk of QT prolongation.
Promethazine; Phenylephrine: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension. (Moderate) The use of promethazine, a phenothiazine antiemetic, with phenothiazine antipsychotics such as fluphenazine should be avoided if possible. Co-administration of promethazine and antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. In addition, promethazine is associated with QT prolongation and fluphenazine is associated with a possible risk of QT prolongation. Concomitant administration would increase the risk of QT prolongation.
Propafenone: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluphenazine with propafenone. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
Propantheline: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Protriptyline: (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
Pseudoephedrine; Triprolidine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as triprolidine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Pyrilamine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Quazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Quetiapine: (Moderate) Concurrent use of quetiapine and fluphenazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of quetiapine with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Quinidine: (Minor) Fluphenazine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Quinine: (Major) Concurrent use of quinine and fluphenazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation and/or TdP.
Ranolazine: (Minor) Use ranolazine with caution in combination with fluphenazine as concurrent use may increase the risk of QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Rasagiline: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and rasagiline may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic to the phenothiazine, if appropriate. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Relugolix: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Remifentanil: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
Remimazolam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Ribociclib: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as ribociclib.
Ribociclib; Letrozole: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as ribociclib.
Rifabutin: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Rifampin: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Rifamycins: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Rifapentine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Rilpivirine: (Minor) Caution is advised when administering rilpivirine with fluphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Risperidone: (Moderate) Use risperidone and fluphenazine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, coadministration may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Rolapitant: (Major) Monitor for fluphenazine-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to fluphenazine may occur. Fluphenazine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Romidepsin: (Minor) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with fluphenazine. Romidepsin has been reported to prolong the QT interval. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Ropinirole: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and ropinirole may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Rosiglitazone: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Rotigotine: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and rotigotine may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. In addition, coadministration may result in additive sedation.
Safinamide: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and safinamide may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine if appropriate. If coadministration cannot be avoided, monitor for changes in movements, moods, or behaviors.
Saquinavir: (Contraindicated) Concurrent use of fluphenazine and saquinavir is contraindicated due to an increased risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Saxagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Scopolamine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Secobarbital: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines.
Selegiline: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of phenothiazines and selegiline due to the risk for additive CNS depression. It is also possible that dopamine antagonists, such as phenothiazines, could diminish the effectiveness of selegiline.
Selpercatinib: (Minor) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with fluphenazine is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Fluphenazine is associated with a possible risk for QT prolongation.
Sertraline: (Minor) Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval, such as fluphenazine; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure). If use together is necessary, use caution and monitor patients for QT prolongation. In addition, CYP2D6 substrates such as fluphenazine may require lower doses during concurrent use with sertraline, due to CYP2D6 inhibition by sertraline and the potential for arrhythmias or other adverse reactions associated with antipsychotics such as extrapyramidal symptoms.
SGLT2 Inhibitors: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
Siponimod: (Minor) In general, do not initiate treatment with siponimod in patients receiving fluphenazine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Fluphenazine is associated with a possible risk for QT prolongation.
Sitagliptin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Sodium Oxybate: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
Sodium Stibogluconate: (Minor) QT/QTc prolongation can occur with concomitant use of sodium stibogluconate and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Solifenacin: (Moderate) Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fluphenazine include solifenacin. Additive anticholinergic effects may also be seen with any of the antimuscarinics. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur in some patients.
Sorafenib: (Minor) Use caution if coadministration of sorafenib with fluphenazine is necessary due to the risk of additive QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Sorafenib is also associated with QTc prolongation; the manufacturer of sorafenib recommends avoiding coadministration with other drugs that cause QT prolongation.
Sotagliflozin: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
Sotalol: (Minor) Use caution during concurrent administration of fluphenazine and sotalol. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Sotalol administration is associated with QT prolongation and torsade de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and fluphenazine. CNS depressants can potentiate the effects of stiripentol.
Sufentanil: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
Sulfonylureas: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
Sunitinib: (Minor) Monitor for evidence of QT prolongation if sunitinib is administered with fluphenazine. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Sunitinib can prolong the QT interval.
Tacrolimus: (Minor) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with fluphenazine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Fluphenazine is associated witha possible risk for QT prolongation.
Tamoxifen: (Minor) Use caution if coadministration of fluphenazine with tamoxifen is necessary due to the risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Tapentadol: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Tazarotene: (Moderate) The manufacturer states that tazarotene should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Telavancin: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with fluphenazine. Telavancin has been associated with QT prolongation. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Temazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Terbinafine: (Moderate) In vitro studies have shown systemic terbinafine to inhibit hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as fluphenazine.
Tetrabenazine: (Major) Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc such as fluphenazine. In addition, concurrent use of fluphenazine and tetrabenazine should generally be avoided since the risk of adverse effects such as drowsiness, sedation, dizziness, orthostatic hypotension, neuroleptic malignant syndrome, or extrapyramidal symptoms may be increased.
Thalidomide: (Major) Avoid the concomitant use of thalidomide with opiate agonists; antihistamines; antipsychotics; anxiolytics, sedatives, and hypnotics; and other central nervous system depressants due to the potential for additive sedative effects.
Thiazide diuretics: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Thiazolidinediones: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
Thioridazine: (Contraindicated) Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation and/or torsade de pointes (TdP). Due to the risk of additive QT prolongation and potential for serious arrhythmias, the concurrent use of fluphenazine and thioridazine is considered contraindicated.
Thiothixene: (Major) Caution is advisable during concurrent use of thiothixene and the phenothiazine antipsychotics. Thiothixene use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of phenothiazines and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. Administration of thiothixene with antipsychotics that are metabolized by CYP2D6, such as phenothiazines, should be approached with great caution. Thiothixene has been shown to inhibit CYP2D6 in vitro and serum concentrations of phenothiazines may increase.
Tiagabine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Tizanidine: (Moderate) Use tizanidine and fluphenazine together with caution due to additive CNS depression. Monitor patients for symptoms of excess sedation.
Tobacco: (Major) Advise patients to avoid smoking tobacco while taking phenothiazines. Tobacco smoking may increase the clearance of phenothiazines, which may reduce their efficacy.
Tolazamide: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
Tolbutamide: (Moderate) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. Also, concomitant use may increase the risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure.
Tolterodine: (Moderate) Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fluphenazine include tolterodine. Additive anticholinergic effects may also be seen with any of the antimuscarinics. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur in some patients.
Topiramate: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
Toremifene: (Minor) Use toremifene and fluphenazine together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Tramadol: (Moderate) Concurrent use of tramadol and fluphenazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that fluphenazine is a weak CYP2D6 inhibitor and has the potential to decrease the metabolism of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by fluphenazine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and fluphenazine.
Tramadol; Acetaminophen: (Moderate) Concurrent use of tramadol and fluphenazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that fluphenazine is a weak CYP2D6 inhibitor and has the potential to decrease the metabolism of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by fluphenazine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and fluphenazine.
Tranylcypromine: (Moderate) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
Trazodone: (Minor) Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, the risk of QT prolongation may be increased if coadministered with drugs with a possible risk for QT prolongation, such as trazodone. In addition, phenothiazines can potentiate the CNS-depressant action of other drugs such as trazodone. Clinicians should note that additive CNS effects (e.g., oversedation, respiratory depression, and hypotension) may occur if fluphenazine is administered concomitantly with trazodone.
Tretinoin, ATRA: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Tretinoin; Benzoyl Peroxide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Triazolam: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Triclabendazole: (Minor) QT/QTc prolongation can occur with concomitant use of triclabendazole and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Tricyclic antidepressants: (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
Trifluoperazine: (Moderate) Fluphenazine and trifluoperazine are phenothiazines that are associated with a possible risk for QT prolongation. Coadministration may represent duplicate therapy and increase the risk for QT prolongation. In addition, co-administration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
Trihexyphenidyl: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Trimethobenzamide: (Moderate) Trimethobenzamide has CNS depressant effects and may cause drowsiness. The concurrent use of trimethobenzamide with other medications that cause CNS depression such as the phenothiazines may potentiate drowsiness or other common side effects of either medication. In addition, the administration of trimethobenzamide to patients who have recently received CNS-depressive drugs has resulted in opisthotonus, seizures, coma, and extrapyramidal symptoms.
Trimipramine: (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
Triprolidine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as triprolidine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Triptorelin: (Major) Avoid coadministration of triptorelin with fluphenazine due to the risk of reduced efficacy of triptorelin; QT prolongation may also occur. Fluphenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) recep tors; triptorelin is a GnRH analog. Additionally, androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Trospium: (Moderate) Additive anticholinergic effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as trospium.
Valproic Acid, Divalproex Sodium: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant thiazide diuretic and phenothiazine use. Thiazide diuretics may potentiate the orthostatic hypotension that may occur with phenothiazines.
Vandetanib: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. If concomitant use with vandetanib is necessary, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Vandetanib can also prolong the QT interval in a concentration-dependent manner; torsade de pointes (TdP) and sudden death have been reported in patients receiving vandetanib.
Vardenafil: (Minor) Use vardenafil with caution in combination with fluphenazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Fluphenazine is also associated with a possible risk for QT prolongation.
Vemurafenib: (Minor) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously with vemurafenib include fluphenazine.
Venlafaxine: (Moderate) Caution is advisable during concurrent use of fluphenazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of fluphenazine may occur. Phenothiazines are CYP2D6 substrates and SNRIs including venlafaxine are CYP2D6 inhibitors. In addition, both venlafaxine and fluphenazine are associated with a possible risk of QT prolongation; therefore, additive cardiac effects are possible.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with phenothiazines is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like phenothiazines may increase the risk of a photosensitivity reaction.
Vigabatrin: (Major) Vigabatrin should not be used with phenothiazines, which is associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
Vitamin C: (Moderate) Monitor for decreased efficacy of fluphenazine during coadministration. Coadministration of ascorbic acid and fluphenazine may result in decreased plasma concentrations of fluphenazine due to acidification of the urine by ascorbic acid and increased excretion of fluphenazine.
Voclosporin: (Minor) Concomitant use of voclosporin and fluphenazine may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Fluphenazine is associated with a possible risk for QT prolongation.
Vonoprazan; Amoxicillin; Clarithromycin: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with fluphenazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while fluphenazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Voriconazole: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with fluphenazine. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Vorinostat: (Minor) Vorinostat therapy is associated with a risk of QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously with vorinostat include fluphenazine. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs with a possible risk for QT prolongation.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with fluphenazine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluphenazine is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zaleplon: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
Ziconotide: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as phenothiazines. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Ziprasidone: (Major) Concomitant use of ziprasidone and fluphenazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation and may theoretically increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the coadministered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Zolpidem: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
Zonisamide: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.

Fluphenazine/Fluphenazine Decanoate/Prolixin Decanoate Intramuscular Inj Sol: 1mL, 25mg
Fluphenazine/Fluphenazine Decanoate/Prolixin Decanoate Subcutaneous Inj Sol: 1mL, 25mg
Fluphenazine/Fluphenazine Hydrochloride Intramuscular Inj Susp: 1mL, 2.5mg
Fluphenazine/Fluphenazine Hydrochloride/Prolixin Oral Sol: 1mL, 2.5mg, 5mg, 5mL
Fluphenazine/Fluphenazine Hydrochloride/Prolixin Oral Tab: 1mg, 2.5mg, 5mg, 10mg

Adults

20 mg/day PO, with temporary use up to 40 mg/day in refractory patients; 100 mg/dose IM or subcutaneously of decanoate depot injection; 10 mg/day IM of the immediate-release injection.

Geriatric

20 mg/day PO, with temporary use up to 40 mg/day in refractory patients; 100 mg/dose IM or subcutaneously of decanoate depot injection; 10 mg/day IM of the immediate-release injection.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Not indicated.

Fluphenazine blocks postsynaptic dopamine receptors in the mesolimbic system and increases dopamine turnover by blockade of the D2 somatodendritic autoreceptor. After ~12 weeks of chronic therapy, depolarization blockade of dopamine tracts occur. The decrease in dopamine neurotransmission has been found to correlate with the antipsychotic effects. This D2 blockade is also responsible for the strong extrapyramidal effects observed with this drug. Dopamine blockade in the chemoreceptor trigger zone accounts for the antiemetic effects. Fluphenazine possesses weak anticholinergic and alpha-adrenergic receptor blocking effects. Blockade of alpha1-adrenergic receptors produces sedation, muscle relaxation, and cardiovascular effects such as hypotension, reflex tachycardia, and minor changes in ECG patterns.

Fluphenazine is administered orally, subcutaneously, and intramuscularly. Phenothiazines are widely distributed into body tissues and fluids, and they cross the blood-brain barrier. Fluphenazine is 99% bound to plasma proteins, predominantly to alpha-1 acid glycoprotein. Metabolism in the liver is extensive, with metabolites contributing to approximately 50% of antipsychotic activity. The elimination half-life of the oral formulation is 4.4 to 16.4 hours. The half-life of fluphenazine decanoate is 6 to 9 days after a single injection and 14 to 26 days for multiple doses. There is some conjugation with glucuronides, which, along with unconjugated metabolites, are excreted in the urine. Some excretion may occur via the biliary tract and feces.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6
Similar to most other phenothiazines, fluphenazine is a major substrate of CYP2D6. In vitro data suggest that fluphenazine inhibits CYP2D6 and has the potential to decrease the metabolism of CYP2D6 substrates. Results from one in vitro study indicate that fluphenazine is a moderate CYP1A2 inhibitor; however, the clinical significance is unknown.

Oral Route

Fluphenazine is rapidly absorbed following oral administration. The oral bioavailability is 2.7% and the time to peak plasma concentrations is 2 hours. Patients require careful adjustment on oral fluphenazine prior to conversion to depot injectable therapy.

Intramuscular Route

Immediate-release Injection (fluphenazine hydrochloride injection solution): Following IM administration of fluphenazine injection solution, the time to peak plasma concentrations occurs in 1.5 to 2 hours and has a duration of 6 to 8 hours from a single dose. The immediate-release IM dose is 33% to 50% of the oral dose.
 
Depot injection (fluphenazine decanoate injection in sesame oil): The time to peak plasma concentrations is 8 to 10 hours. The action of the decanoate injection begins within 24 hours, with an average interval between injections of 14 days (range: 7 to 28 days). Each patient requires careful adjustment on oral fluphenazine prior to conversion to depot therapy. Following the initiation of fluphenazine decanoate, the plasma concentrations will continue to rise and reach steady-state after 2 months. A controlled multicenter study in patients receiving 5 to 60 mg/day PO fluphenazine showed that 20 mg/day PO fluphenazine HCl was equivalent to 25 mg of fluphenazine decanoate injection IM every 3 weeks. This represents an approximate conversion ratio of 12.5 mg (0.5 mL) of fluphenazine decanoate every 3 weeks for every 10 mg of fluphenazine HCl given orally daily.

Subcutaneous Route

The depot injection (fluphenazine decanoate injection in sesame oil) may be given subcutaneously if necessary.

Pregnancy

Although the manufacturer of fluphenazine makes no recommendations about breast-feeding, other phenothiazines are not recommended for use in breast-feeding mothers. Phenothiazines are excreted into breast milk; drowsiness, lethargy, and developmental delays have been reported in the nursing infant. The physiology of the infant should be considered when evaluating the risk of exposure to phenothiazines. Phenothiazines may also induce hyperprolactinemia and galactorrhea, and thus may interfere with proper lactation. The effects of phenothiazine antipsychotic exposure on a nursing infant are unknown but may be of concern due to drowsiness or lethargy in the infant, a decline in developmental scores, and drug-induced galactorrhea in the mother. Due to individual variability in response to antipsychotics, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding; however, alternate medications for consideration include a second generation antipsychotic such as olanzapine or quetiapine. Data regarding the safety of atypical antipsychotics during breast-feeding are limited, and chronic administration of any antipsychotic during breast-feeding should be avoided if possible. Regardless of the antipsychotic used, the nursing infant should be closely monitored for excessive drowsiness, lethargy, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events. 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 administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.