(a mee TRIP ti leen & per FEN a zeen)
Treatment of patients with moderate-to-severe anxiety and/or agitation and depression; schizophrenia with depressive symptoms
Hypersensitivity to amitriptyline, perphenazine, or any component of the formulation (cross-sensitivity with other phenothiazines may exist); bone marrow depression; use with or within 14 days of MAO inhibitors; CNS depression (due to barbiturate, alcohol, opioid, analgesic, or antihistamine use); during the acute recovery phase of MI
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of perphenazine/amitriptyline or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression wand certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Perphenazine/amitriptyline is not approved for use in pediatric patients.
Increased mortality in elderly patients with dementia-related psychosis:Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies sugges that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Perphenazine and amitriptyline is not approved for the treatment of patients with dementia-related psychosis.
Depression and anxiety: Oral:
Initial: One tablet (amitriptyline 25 mg/perphenazine 2 mg or amitriptyline 25 mg/perphenazine 4 mg) 3-4 times/day or 1 tablet (amitriptyline 50 mg/perphenazine 4 mg) 2 times/day; initial therapeutic response may be observed after several days or upwards of a few weeks or longer (maximum daily dose: amitriptyline 200 mg/perphenazine 16 mg)
Maintenance: Smallest dose necessary for symptom relief; usually 1 tablet (amitriptyline 25 mg/perphenazine 2 mg or amitriptyline 25 mg/perphenazine 4 mg) 2-4 times/day or 1 tablet (amitriptyline 50 mg/perphenazine 4 mg) 2 times/day
Schizophrenia and depression: Oral:
Initial: Two tablets (amitriptyline 25 mg/perphenazine 4 mg) 3 times/day; if necessary, a fourth dose may be given at bedtime; initial therapeutic response may be observed after several days or upwards of a few weeks or longer (maximum daily dose: amitriptyline 200 mg/perphenazine 16 mg) (maximum: 64 mg/day of perphenazine)
Maintenance: Smallest dose necessary for symptom relief; usually 1 tablet (amitriptyline 25 mg/perphenazine 2 mg or amitriptyline 25 mg/perphenazine 4 mg) 2-4 times/day or 1 tablet (amitriptyline 50 mg/perphenazine 4 mg) 2 times/day
Discontinuation of therapy: Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of withdrawal symptoms and allow for the detection of re-emerging symptoms. Evidence supporting ideal taper rates is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. In addition for long-term treated patients, WFSBP guidelines recommend tapering over 4-6 months. If intolerable withdrawal symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (APA, 2010; Bauer, 2002; Haddad, 2001; NCCMH, 2010; Schatzberg, 2006; Shelton, 2001; Warner, 2006).
MAO inhibitor recommendations:
Switching to or from an MAO inhibitor intended to treat psychiatric disorders:
Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of amitriptyline/perphenazine.
Allow 14 days to elapse between discontinuing amitriptyline/perphenazine and initiation of an MAO inhibitor intended to treat psychiatric disorders.
Use with reversible MAO inhibitors (such as linezolid or IV methylene blue):
Do not initiate amitriptyline/perphenazine in patients receiving linezolid or IV methylene blue; consider other interventions for psychiatric condition.
If urgent treatment with linezolid or IV methylene blue is required in a patient already receiving amitriptyline/perphenazine and potential benefits outweigh potential risks, discontinue amitriptyline/perphenazine promptly and administer linezolid or IV methylene blue. Monitor for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or IV methylene blue, whichever comes first. May resume amitriptyline/perphenazine 24 hours after the last dose of linezolid or IV methylene blue.
Oral: One tablet (amitriptyline 10 mg/perphenazine 4 mg) 3-4 times/day
Discontinuation of therapy: Refer to adult dosing.
MAO inhibitor recommendations: Refer to adult dosing.
No dosage adjustment provided in manufacturer 's labeling.
Use caution; no dosage adjustment provided in manufacturer 's labeling.
Store at 20 ‚ °C to 25 ‚ °C (68 ‚ °F to 77 ‚ °F). Protect from light.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Amitriptyline hydrochloride 10 mg and perphenazine 2 mg
Amitriptyline hydrochloride 10 mg and perphenazine 4 mg
Amitriptyline hydrochloride 25 mg and perphenazine 2 mg
Amitriptyline hydrochloride 25 mg and perphenazine 4 mg
Amitriptyline hydrochloride 50 mg and perphenazine 4 mg
Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification
AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy
Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy
Alpha-/Beta-Agonists (Direct-Acting): Tricyclic Antidepressants may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Management: Avoid, if possible, the use of direct-acting alpha-/beta-agonists in patients receiving tricyclic antidepressants. If combined, monitor for evidence of increased pressor effects and consider reductions in initial dosages of the alpha-/beta-agonist. Exceptions: Dipivefrin. Consider therapy modification
Alpha1-Agonists: Tricyclic Antidepressants may enhance the vasopressor effect of Alpha1-Agonists. Tricyclic Antidepressants may diminish the vasopressor effect of Alpha1-Agonists. Monitor therapy
Alpha2-Agonists: Tricyclic Antidepressants may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine; Brimonidine (Ophthalmic). Consider therapy modification
Alpha2-Agonists (Ophthalmic): Tricyclic Antidepressants may diminish the therapeutic effect of Alpha2-Agonists (Ophthalmic). Monitor therapy
Altretamine: May enhance the orthostatic hypotensive effect of Tricyclic Antidepressants. Monitor therapy
Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy
Amisulpride: Antipsychotic Agents may enhance the adverse/toxic effect of Amisulpride. Avoid combination
Amphetamines: Tricyclic Antidepressants may enhance the stimulatory effect of Amphetamines. Tricyclic Antidepressants may also potentiate the cardiovascular effects of Amphetamines. Monitor therapy
Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy
Analgesics (Opioid): Antipsychotic Agents (Phenothiazines) may enhance the hypotensive effect of Analgesics (Opioid). Monitor therapy
Analgesics (Opioid): Anticholinergic Agents may enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy
Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Antacids: May decrease the absorption of Antipsychotic Agents (Phenothiazines). Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy
Antidepressants (Serotonin Reuptake Inhibitor/Antagonist): Antipsychotic Agents (Phenothiazines) may enhance the adverse/toxic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). Specifically, this may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Antidepressants (Serotonin Reuptake Inhibitor/Antagonist) may enhance the hypotensive effect of Antipsychotic Agents (Phenothiazines). Monitor therapy
Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Antimalarial Agents: May increase the serum concentration of Antipsychotic Agents (Phenothiazines). Monitor therapy
Anti-Parkinson Agents (Dopamine Agonist): May diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson agents. Consider therapy modification
Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Aspirin: Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of Aspirin. Monitor therapy
Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification
Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination
Barbiturates: May increase the metabolism of Tricyclic Antidepressants. Consider therapy modification
Beta2-Agonists: Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy
Beta-Blockers: Antipsychotic Agents (Phenothiazines) may enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Exceptions: Atenolol; Levobunolol; Metipranolol; Nadolol. Monitor therapy
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification
BuPROPion: May decrease the metabolism of Tricyclic Antidepressants. Management: Seek alternatives when possible. Monitor patients receiving these combinations closely for increased serum concentrations (when testing is available) and toxic effects of the tricyclic antidepressant. Consider therapy modification
Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
CarBAMazepine: May increase the metabolism of Tricyclic Antidepressants. Monitor therapy
Cimetidine: May decrease the metabolism of Tricyclic Antidepressants. Monitor therapy
Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination
Cinacalcet: May increase the serum concentration of Tricyclic Antidepressants. Management: Seek alternatives when possible. If these combinations are used, monitor closely for increased effects/toxicity and/or elevated serum concentrations (when testing is available) of the tricyclic antidepressant. Consider therapy modification
Cisapride: Amitriptyline may enhance the arrhythmogenic effect of Cisapride. Avoid combination
Citalopram: Tricyclic Antidepressants may enhance the adverse/toxic effect of Citalopram. Tricyclic Antidepressants may increase the serum concentration of Citalopram. Citalopram may increase the serum concentration of Tricyclic Antidepressants. Management: Consider alternatives to this combination when possible. Monitor for adverse effects of tricyclic antidepressants (TCAs), including serotonin syndrome and QT-interval prolongation, when a TCA is being used in combination with citalopram. Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy
Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification
Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination
Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy
Desmopressin: Tricyclic Antidepressants may enhance the adverse/toxic effect of Desmopressin. Monitor therapy
Dexmethylphenidate: May enhance the adverse/toxic effect of Tricyclic Antidepressants. Dexmethylphenidate may increase the serum concentration of Tricyclic Antidepressants. Monitor therapy
Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy
Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Dronedarone: Tricyclic Antidepressants may enhance the arrhythmogenic effect of Dronedarone. Avoid combination
Dronedarone: Antipsychotic Agents (Phenothiazines) may enhance the arrhythmogenic effect of Dronedarone. Avoid combination
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification
DULoxetine: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. DULoxetine may decrease the metabolism of Tricyclic Antidepressants. Management: Use these drugs in combination with caution. Monitor closely for signs and symptoms of serotonin toxicity/serotonin syndrome. Consider therapy modification
Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination
Escitalopram: Tricyclic Antidepressants may enhance the adverse/toxic effect of Escitalopram. Escitalopram may increase the serum concentration of Tricyclic Antidepressants. Management: Consider alternatives to this combination when possible. Monitor for adverse effects of tricyclic antidepressants (TCAs), including serotonin syndrome and QT-interval prolongation, when a TCA is being used in combination with escitalopram. Consider therapy modification
Fluconazole: Amitriptyline may enhance the QTc-prolonging effect of Fluconazole. Fluconazole may increase the serum concentration of Amitriptyline. Monitor therapy
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification
FLUoxetine: May enhance the adverse/toxic effect of Tricyclic Antidepressants. FLUoxetine may increase the serum concentration of Tricyclic Antidepressants. Management: Consider alternatives to this combination when possible. Monitor for adverse effects of tricyclic antidepressants (TCAs), including serotonin syndrome and QT-interval prolongation, when a TCA is being used in combination with fluoxetine. Consider therapy modification
FluvoxaMINE: May enhance the adverse/toxic effect of Tricyclic Antidepressants. FluvoxaMINE may increase the serum concentration of Tricyclic Antidepressants. Management: Consider alternatives to this combination when possible. Monitor for adverse effects of tricyclic antidepressants (TCAs), including serotonin syndrome and QT-interval prolongation, when a TCA is being used in combination with fluvoxamine. Consider therapy modification
Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Avoid combination
Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination
Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification
HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Iobenguane I 123: Tricyclic Antidepressants may diminish the therapeutic effect of Iobenguane I 123. Avoid combination
Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy
Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy
Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination
Linezolid: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Avoid combination
Lithium: May enhance the neurotoxic effect of Tricyclic Antidepressants. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
MAO Inhibitors: May enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Exceptions: Linezolid; Methylene Blue; Tedizolid. Avoid combination
Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Consider therapy modification
Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification
Methylene Blue: Tricyclic Antidepressants may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination
Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination
Methylphenidate: May enhance the adverse/toxic effect of Tricyclic Antidepressants. Methylphenidate may increase the serum concentration of Tricyclic Antidepressants. Monitor therapy
Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy
MetyroSINE: May enhance the adverse/toxic effect of Tricyclic Antidepressants. Monitor therapy
MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy
Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy
MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification
Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy
Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy
Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy
Moxonidine: Tricyclic Antidepressants may diminish the therapeutic effect of Moxonidine. Avoid combination
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Nicorandil: Tricyclic Antidepressants may enhance the hypotensive effect of Nicorandil. Monitor therapy
NSAID (COX-2 Inhibitor): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). Monitor therapy
NSAID (Nonselective): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (Nonselective). Monitor therapy
OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination
Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification
Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination
PARoxetine: May enhance the adverse/toxic effect of Tricyclic Antidepressants. PARoxetine may increase the serum concentration of Tricyclic Antidepressants. Management: Consider alternatives to this combination when possible. Monitor for adverse effects of tricyclic antidepressants (TCAs), including serotonin syndrome and QT-interval prolongation, when a TCA is being used in combination with paroxetine. Consider therapy modification
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification
Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy
Piribedil [INT]: Antipsychotic Agents may diminish the therapeutic effect of Piribedil [INT]. Piribedil [INT] may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Avoid combination
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy
Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification
Protease Inhibitors: May increase the serum concentration of Tricyclic Antidepressants. Monitor therapy
Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy
QuiNIDine: Tricyclic Antidepressants may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may increase the serum concentration of Tricyclic Antidepressants. Consider therapy modification
Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy
RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy
Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to secretin. Consider therapy modification
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy
Serotonin Modulators: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy
Sertraline: May enhance the adverse/toxic effect of Tricyclic Antidepressants. Sertraline may increase the serum concentration of Tricyclic Antidepressants. Management: Consider alternatives to this combination when possible. Monitor for adverse effects of tricyclic antidepressants (TCAs), including serotonin syndrome and QT-interval prolongation, when a TCA is being used in combination with sertraline. Consider therapy modification
Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification
Sodium Phosphates: Tricyclic Antidepressants may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure and/or loss of consciousness may be increased in patients with significant sodium phosphate induced fluid/electrolyte abnormalities. Monitor therapy
St Johns Wort: May increase the metabolism of Tricyclic Antidepressants. The risk of serotonin syndrome may theoretically be increased. Consider therapy modification
Sulfonylureas: Cyclic Antidepressants may enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy
Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Avoid combination
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification
Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification
Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Terbinafine (Systemic): May increase the serum concentration of Amitriptyline. Management: Monitor for increased effects/toxicity of amitriptyline during concomitant administration with terbinafine. Reduced dosages of amitriptyline may be needed. Consider therapy modification
Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination
Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Thyroid Products: May enhance the arrhythmogenic effect of Tricyclic Antidepressants. Thyroid Products may enhance the stimulatory effect of Tricyclic Antidepressants. Monitor therapy
Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification
Topiramate: May enhance the CNS depressant effect of Amitriptyline. Topiramate may increase serum concentrations of the active metabolite(s) of Amitriptyline. Topiramate may increase the serum concentration of Amitriptyline. Monitor therapy
TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Valproate Products: May increase the serum concentration of Tricyclic Antidepressants. Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy
Vitamin K Antagonists (eg, warfarin): Tricyclic Antidepressants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy
Yohimbine: Tricyclic Antidepressants may increase the serum concentration of Yohimbine. Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification
Vital signs; lipid profile, fasting blood glucose/HbA1c; BMI, weight; mental status, abnormal involuntary movement scale (AIMS), extrapyramidal symptoms (EPS), suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased)
False-positive pregnancy test (perphenazine)
See individual agents.
Major psychiatric warnings:
- Suicidal thinking/behavior: [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient 's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Amitriptyline is not FDA-approved for use in children <12 years of age; this combination is not FDA approved for use in children.
- The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
- Prescriptions should be written for the smallest quantity consistent with good patient care. The patients family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.
Concerns related to adverse effects:
- Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics.
- Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. Relative to other neuroleptics, perphenazine has a low potency of cholinergic blockade and relative to other antidepressants amitriptyline has a high potential for cholinergic blockade.
- Blood dyscrasias: Check blood counts periodically and discontinue at first signs of blood dyscrasias; use is contraindicated in patients with bone marrow suppression.
- Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (ie, Alzheimer disease).
- Extrapyramidal symptoms: May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia.
- Hyperprolactinemia: Perphenazine use is associated with increased prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.
- Neuroleptic malignant syndrome (NMS): Use of perphenazine may be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability.
- Ocular effects: Perphenazine may cause pigmentary retinopathy, and lenticular and corneal deposits, particularly with prolonged therapy.
- Orthostatic hypotension: Both agents may cause orthostatic hypotension (risk is very high relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
- Sedation: Both agents may cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is high relative to other antidepressants.
- SIADH and hyponatremia: Has been associated with the development of SIADH and hyponatremia.
- Temperature regulation: Impaired core body temperature regulation may occur with perphenazine use; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.
Disease-related concerns:
- Cardiovascular disease: Use both agents with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk of conduction abnormalities with this agent is high relative to other antidepressants.
- Dementia: [U.S. Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. This combination is not approved for the treatment of dementia-related psychosis.
- Diabetes: Use amitriptyline with caution in patients with diabetes mellitus; may alter glucose regulation.
- Glaucoma: Use with caution in patients with narrow-angle glaucoma; condition may be exacerbated by cholinergic blockade.
- Hepatic impairment: Use both agents with caution in patients with hepatic impairment.
- Mania/hypomania: May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. This combination is not FDA approved for the treatment of bipolar depression.
- Parkinson disease: Use perphenazine with caution in patients with Parkinson's disease; they may be more sensitive to adverse effects.
- Renal impairment: Use both agents with caution in patients with renal impairment.
- Seizure disorder: Use both agents with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.
Concurrent drug therapy issues:
- Antiemetic effects: Perphenazine may mask toxicity of other drugs or conditions (eg, intestinal obstruction, Reye syndrome, brain tumor) due to antiemetic effects.
- Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
- Elderly: Increased risk for developing tardive dyskinesia from perphenazine.
- Poor metabolizers: Use with caution in patients with reduced functional alleles of CYP2D6. Poor metabolizers may have higher plasma concentrations at usual doses, increasing risk for adverse reactions.
Other warnings/precautions:
- Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, light-headedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA, 2010; Fava, 2006; Haddad, 2001; Shelton, 2001; Warner, 2006).
- Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.
- Surgery: Recommended by the manufacturer to discontinue prior to elective surgery; risks exist for drug interactions with anesthesia and for cardiac arrhythmias. However, definitive drug interactions have not been widely reported in the literature and continuation of tricyclic antidepressants is generally recommended as long as precautions are taken to reduce the significance of any adverse events that may occur. Norepinephrine should be considered the vasopressor of choice for TCA-related hypotension (Pass, 2004). Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.
Adverse events were not observed in animal reproduction studies. See individual agents.
Amitriptyline increases the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane.
Perphenazine is a piperazine phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits alpha-adrenergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones.
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience fatigue, anxiety, nausea, vomiting, lack of appetite, or dry mouth. Have patient report immediately to prescriber signs of depression (depression, suicidal ideation, anxiety, emotional instability, illogical thinking), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), behavioral changes, angina, signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), severe dizziness, passing out, abnormal movements, twitching, tremors, rigidity, urinary retention, bruising, bleeding, loss of strength and energy, swelling of arm or leg, enlarged breasts, nipple discharge, sexual dysfunction, amenorrhea, signs of tardive dyskinesia (unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; and puffing cheeks), or signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.