Amitriptyline Interactions
- Amantadine
- Amiodarone
- Amoxapine
- Amprenavir
Anticonvulsants
Antimuscarinics
Anxiolytics, Sedatives, and Hypnotics
- Aprepitant
- Arsenic Trioxide
- Astemizole
- Atazanavir
Barbiturates
Benzodiazepines
- Bepridil
- Bretylium
- Buprenorphine
- Bupropion
- Butorphanol
- Cimetidine
- Cisapride
- Clonidine
- Clozapine
- Cocaine
- Delavirdine
- Dexfenfluramine
- Dexmethylphenidate
- Disopyramide
- Disulfiram
- Dofetilide
- Donepezil
- Dronabinol, THC
- Droperidol
- Duloxetine
- Entacapone
- Erythromycin
Estrogens
- Ethanol
- Fenfluramine
- Flecainide
- Fluconazole
- Furazolidone
- Galantamine
- Gatifloxacin
- Gefitinib
General Anesthetics
- Grepafloxacin
- Guanabenz
- Guanadrel
- Guanethidine
- Guanfacine
- Halofantrine
- Haloperidol
- Imatinib, STI-571
- Kava Kava, Piper methysticum
- Labetalol
- Levodopa
- Levofloxacin
- Levomethadyl
- Linezolid
- Lithium
- Loxapine
- Maprotiline
- Methyldopa
- Methylphenidate
- Mibefradil
- Mirtazapine
- Modafinil
Monoamine oxidase inhibitors (MAOIs)
- Moxifloxacin
- Nalbuphine
- Olanzapine
Opiate Agonists
Oral contraceptives
- Palonosetron
Parasympathomimetics
- Pentazocine
Phenothiazines
- Pimozide
- Pramipexole
- Pregabalin
- Probucol
- Procainamide
- Procarbazine
- Propafenone
- Quinidine
Radiopaque Contrast Agents
- Reserpine
- Risperidone
- Ritonavir
- Rivastigmine
- Ropinirole
- S-adenosyl-L-methionine, SAM-e
Sedating H1-blockers
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin-Receptor Agonists
Skeletal Muscle Relaxants
- Sotalol
- Sparfloxacin
- St. John’s Wort, Hypericum perforatum
Sympathomimetics
- Tacrine
- Terfenadine
Thyroid hormones
- tobacco
- Tolcapone
- Tramadol
- Trazodone
Tricyclic antidepressants
- Valerian, Valeriana officinalis
- Venlafaxine
- Voriconazole
- Warfarin
- Ziprasidone
Amitriptyline Interactions
The use of amitriptyline with other tricyclic antidepressants is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Related cyclic antidepressants, like amoxapine and maprotiline, are also not recommended for concurrent use for similar reasons. 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.
Use caution in the concurrent administration of tricyclic antidepressants (TCAs) and phenothiazines. Both drug classes are metabolized via similar pathways (CYP2D6), and additive side effects may occur due to structural similarities and resultant similarity of pharmacologic effects, like antimuscarinic activity. Mesoridazine and thioridazine are considered contraindicated for concurrent use with TCAs due to the potential risk of QTc interval prolongation and the potential for serious cardiovascular effects. Cardiac effects (e.g., prolonged QT interval, arrhythmias), CNS effects, orthostatic hypotension, or antimuscarinic effects may occur with any phenothiazine, and these effects may be additive to those of the TCAs. 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.
Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and torsades de pointes via pharmacokinetic or pharmacodynamic interactions. Due to the potential for serious cardiac side effects, TCAs are generally considered contraindicated for use with dofetilide (class III antiarrhythmic activity). TCAs should not be used with mibefradil, as mibefradil may seriously impair TCA clearance.
Tricyclic antidepressants should be avoided where possible in combination with cardiac drugs known to prolong the QT interval such as bepridil; Class IA antiarrhythmics (disopyramide, procainamide, quinidine); Class III antiarrhythmics (amiodarone, bretylium, ibutilide, sotalol); flecainide; probucol, and propafenone. The need to coadminister TCAs with any of these therapies should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA. In addition to effects on the EKG, disopyramide has significant anticholinergic effects that are additive to those of the TCAs.
Tricyclic antidepressants (TCAs) may prolong the QT interval, particularly in overdose. However, due to the potential for serious cardiac side effects with astemizole or terfenadine, it is advisable to avoid their use with other drugs that might prolong the QT interval, including the TCAs.
Cisapride exhibits many important drug interactions that affect its safety and efficacy profile; the manufacturer only offers cisapride therapy through an investigational limited access program due to the need to appropriately screen for eligible patients. Cisapride has been implicated as a cause of QT prolongation, particularly in patients with known risk factors or when cisapride has been combined with drugs that increase cisapride serum concentrations or exhibit additive effects on cardiac repolarization. Tricyclic antidepressants may prolong the QT interval, particularly in overdose. Due to the potential for serious cardiac side effects, TCAs are contraindicated for use along with cisapride. In addition to adverse cardiac effects, the antimuscarinic effects of the TCAs may hinder the therapeutic actions of cisapride on GI motility.
Tricyclic antidepressants may prolong the QT interval, particularly in overdose. Some quinolones have been associated with QT prolongation and in rare cases, torsades de pointes (TdP). Grepafloxacin was voluntarily withdrawn from marketing in the United States on October 27, 1999 due to severe cardiovascular adverse reactions, including 3 cases of TdP. Prior to its discontinuation, grepafloxacin was contraindicated in patients receiving drugs known to cause QT prolongation such as tricyclic antidepressants. Sparfloxacin is associated with an established risk for QT prolongation and TdP, and is contraindicated in patients receiving drugs that can cause QT prolongation, such as tricyclic antidepressants. Rare cases of TdP has been reported with gatifloxacin, levofloxacin, and moxifloxacin. Although these drugs have been associated with a possible risk for TdP, substantial evidence is currently lacking to establish causality. According to the manufacturers, medications which could prolong the QT interval should be used with caution when given concurrently with gatifloxacin, levofloxacin, and moxifloxacin. The risk of TdP during such therapy may be reduced by avoiding concurrent administration to patients with significant risk factors for TdP (e.g., hypokalemia, significant bradycardia, and cardiomyopathy). Examples of other general risk factors for TdP include congenital long QT syndrome, female sex, elderly patients, hypomagnesemia, and underlying cardiac disease. Recommended dosages and infusion rates for the quinolone drugs should not be exceeded.
Tricyclic antidepressants may prolong the QT interval, particularly in overdose. Due to the potential for serious cardiac side effects, pimozide, which may also cause QT interval prolongation, is considered contraindicated for use along with TCAs.
According to the drug’s manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone should also be avoided for concurrent use with other drugs that may be associated with QT prolongation, considering an assessment of the level of probability for drug-induced QT prolongation and torsades de pointes and individual patient risk factors for torsades de pointes. Drugs which have been reported to prolong the QT interval include tricyclic antidepressants.
Tricyclic antidepressants may prolong the QT interval, particularly in overdose. Arsenic trioxide may also cause QT interval prolongation. Due to the potential for adverse cardiac effects, avoid use of tricyclic antidepressants during arsenic trioxide therapy when possible.
Concurrent use of monoamine oxidase inhibitors (MAOIs) including selegiline and drugs with MAO-inhibiting activity such as furazolidone, linezolid, or procarbazine) with tricyclic antidepressants (TCAs) can cause hyperpyrexia, hypertension, or seizures. The combination should be avoided whenever possible. Tricyclic antidepressants should not be added to an existing MAOI regimen because the reuptake blockade will be unopposed due to the existing inhibition of the main elimination pathway. An interval of 14 days is recommended between cessation of an irreversible MAOI agent and initiation of tricyclic antidepressant therapy and vice-versa. In the rare patient for whom TCA-MAOI combination therapy is necessary, the interaction can be minimized by initiating therapy with a tricyclic antidepressant first, and then beginning MAOI therapy at low doses, followed by a very gradual increase. The tricyclic antidepressant should inhibit the uptake of tyramine from food in the GI tract; subsequent addition of a MAOI should not lead to high levels of tyramine with careful monitoring.
Depending on the specific agent, additive anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like the tricyclic antidepressants (TCAs). Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. In addition, clozapine is metabolized by CYP1A2 and CYP2D6 isoenzymes; many TCAs are also metabolized via CYP2D6 and could compete for the same metabolic pathway. Rarely, clozapine therapy or TCA therapy, at elevated serum concentrations, may produce clinically significant prolongation of the QTc interval. Clinicians should monitor for clozapine or TCA- induced side effects or toxicity if the drugs are used together.
Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other antimuscarinics. Amitriptyline has the greatest anticholinergic effects of the TCAs. The following drugs are known to possess relatively significant antimuscarinic properties and should be used together cautiously with the TCAs: antimuscarinics, the sedating H1-blockers, and other drugs such as amantadine, loxapine, and olanzapine. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
General anesthetics may produce additive CNS depression when used in patients taking tricyclic antidepressants. In addition, halogenated anesthetics, like halothane, have been reported to prolong the QT interval and should be given cautiously to patients on TCAs.
Tricyclic antidepressants (TCAs) block the action of guanadrel, guanethidine, guanabenz preventing or significantly reducing the expected antihypertensive effects. The interaction between methyldopa and TCAs may be similar but is not as well established. Reserpine and other rauwolfia alkaloids may have decreased antihypertensive effects in the presence of tricyclic antidepressants, and a ‘stimulating’ effect has been noted in depressed patients taking reserpine along with a TCA. Avoid use of TCAs concurrently with these antihypertensive drug categories when possible.
Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine’s antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
Tricyclic antidepressants can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Increased dosages of guanfacine may be required in patients who are receiving tricyclic antidepressants concurrently. In addition, concurrent tricyclic antidepressants may enhance the potential for rebound hypertension following guanfacine discontinuation. If guanfacine is withdrawn in the presence of tricyclic antidepressants, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
An increased incidence of labetalol-induced tremor has been reported in patients being treated concurrently with tricyclic antidepressants.
Cimetidine can inhibit the systemic clearance of tricyclic antidepressants (TCAs) that undergo oxidative metabolism, resulting in increased plasma levels of the antidepressant. The interaction has been documented in the literature via several case reports and pharmacokinetic studies. In some case reports, clinical symptoms of toxicity were observed. Patients should be monitored for TCA-related side effects and toxicity if cimetidine is added; when possible, choose an alternative H2-blocker for treatment. It does not appear that the other H2-receptor antagonists significantly affect the pharmacokinetics of the TCAs.
The risk of developing cardiac arrhythmias or CNS toxicity may be increased when cocaine is used in patients receiving tricyclic antidepressants. If local anesthesia with cocaine is essential in a patient receiving a tricyclic antidepressant, lower doses of cocaine and/or electrocardiographic monitoring may be necessary in conjunction with close clinical monitoring.
Haloperidol can potentiate the actions of other CNS depressants such as tricyclic antidepressants (TCAs). Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects. Limited data suggest that haloperidol may inhibit the metabolism of some tricyclic antidepressants, however, the clinical significance of this interaction is uncertain. Haloperidol is an inhibitor of hepatic CYP2D6, and coadministration with many TCAs (which are CYP2D6 substrates) may lead to elevated TCA serum concentrations, potentiating toxicity. Haloperidol has also been associated with a possible risk for QT prolongation and/or torsades de pointes, particularly when excessive doses are used or in overdose. Haloperidol should be used cautiously with other agents that may have this effect (e.g., tricyclic antidepressants).
The use of risperidone along with tricyclic antidepressants should be approached with caution. While occasionally risperidone is used to augment tricyclic antidepressant therapy in refractory cases, there is a potential for additive pharmacodynamic interactions, which might augment side effects like sedation. Pharmacokinetic interactions have not been reported with the combination of risperidone and amitriptyline; the drugs do not affect the pharmacokinetics of one another. Risperidone has been associated with a possible risk for QT prolongation and/or torsades de pointes; however, data are currently lacking to establish causality in association with torsades de pointes. Excessive doses (e.g., overdose) of risperidone may be associated with a higher risk of QT prolongation. Risperidone should be used cautiously with other agents that may prolong the QT interval (e.g. tricyclic antidepressants).
Evidence suggests that mirtazapine enhances central noradrenergic and serotonergic activity. This action may be duplicative to the tricyclic antidepressants (TCAs) and the two drugs should be used together with caution, due to a theoretical potential for additive pharmacology and/or side effects (e.g., drowsiness, serotonin syndrome). While one small study in healthy subjects (n=24) reported that the combination of mirtazapine with a tricyclic antidepressant (e.g., amitriptyline) may be tolerable and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy.
Skeletal muscle relaxants should be combined cautiously with tricyclic antidepressants (TCAs) because they could cause additive CNS depressant effects. Depending on the specific agent (e.g., cyclobenzaprine, and orphenadrine), additive anticholinergic effects may also be seen. 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. Cyclobenzaprine is structurally very similar to tricyclic antidepressants (TCAs) such as amitriptyline. Clinically and in terms of toxicology or side effect profiles, cyclobenzaprine differs little from the TCAs. Such effects include potential for antimuscarinic effects such as dry mouth, urinary difficulty, and impairment of gastrointestinal motility. As with the TCAs, cardiac adverse effects of cyclobenzaprine would be expected in overdose or in cases of excessive pharmacology. In general, the concurrent use of cyclobenzaprine with tricyclic antidepressants should be avoided whenever possible due to the potential for adverse effects resulting from similar pharmacology; consider alternative agents for skeletal muscle relaxation. Patients should be monitored for excessive adverse effects from either agent.
Ethanol and anxiolytics, sedatives, and hypnotics, dronabinol, THC, or other CNS depressants should be combined cautiously with tricyclic antidepressants because they could cause additive depressant effects and possible respiratory depression or hypotension. Some benzodiazepines have been reported to increase the concentrations of tricyclic antidepressants or metabolites when coadministered, but studies have been conflicting. The combination of benzodiazepines and TCAs is commonly used and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent.
In vitro drug interaction studies in human liver microsomes indicate that amitriptyline inhibits the metabolism of tramadol via CYP2D6, suggesting that concomitant administration of TCAs could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tricyclic antidepressants may decrease the seizure threshold and have been associated with increased risk of seizures when given concurrently with tramadol.
Pain medications such as pure opiate agonists, buprenorphine, butorphanol, nalbuphine, or pentazocine should be combined cautiously with tricyclic antidepressants because they could cause additive depressant effects and possible respiratory depression or hypotension. Combining tricyclic antidepressants with opiate agonists may lead to additive effects on intestinal motility or bladder function. Specific opiate agonists warrant greater cautions; levomethadyl (an opiate agonist) is associated with an established risk of QT prolongation and/or torsades de pointes, particularly at high drug concentrations. Levomethadyl is contraindicated in combination with other agents that may prolong the QT interval. Agents with potential to prolong the QT interval include tricyclic antidepressants (when given in excessive doses or overdosage).
Tricyclic antidepressants exhibit antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant. Other medications for Parkinson’s disease, such as entacapone, pramipexole, ropinirole, or tolcapone may cause additive drowsiness when combined with tricyclic antidepressants.
The pressor response to norepinephrine infusions is greatly exaggerated in patients currently receiving tricyclic antidepressants. One drug information reference suggests that tricyclics potentiate the pharmacologic effects of direct-acting sympathomimetics (e.g., epinephrine and norepinephrine) but decrease the pressor response to indirect-acting sympathomimetics (e.g., amphetamines), however, the data are not consistent. Concomitant use of tricyclic antidepressants with sympathomimetics should be avoided whenever possible; use with caution when concurrent use cannot be avoided. Clinicians should presume that the pressor effects of ophthalmic or nasal vasoconstrictors (e.g., naphazoline, oxymetazoline, phenylephrine, or xylometazoline) might also be potentiated by tricyclic antidepressants in some cases.
Clinicians should be alert for pharmacokinetic or pharmacodynamic interactions between tricyclic antidepressants and the selective serotonin reuptake inhibitors (SSRIs) class of antidepressants. The SSRIs are known to inhibit isozymes of the cytochrome P-450 mixed-function oxidase system including CYP2D6 and/or CYP3A4, the isozymes responsible for metabolism of many of the tricyclic antidepressants. Cytochrome CYP2D6 is impaired most by fluoxetine and least by sertraline and is the isozyme most responsible for metabolism of tricyclic antidepressants. In several cases, symptoms of toxicity, including seizures, were reported when drugs from these 2 categories were used together. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. The CYP2D6 isozyme is a common pathway for both of these drugs and norfluoxetine also inhibits this enzyme. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if a SSRI-type drug is added. Clinicians should be particularly cautious in patients with fluoxetine due to the extremely long elimination half-life of its metabolite, norfluoxetine (7 - 9 days).
Thyroid hormones may increase receptor sensitivity and enhance the effects of tricyclic antidepressants. Older literature describes a variety of responses when tricyclic antidepressants are used concomitantly with thyroid hormones. One limited study states that small doses of thyroid hormone accelerated the onset of action of tricyclic antidepressants while several case reports have described cardiovascular toxicity as a result of this drug combination; other reports describe no interaction. Although this drug combination appears to be safe, clinicians should be aware of the remote possibility of exaggerated cardiovascular side effects such as arrhythmias and CNS stimulation.
Animal data indicate that some tricyclic antidepressants can inhibit the metabolism of warfarin, however, clinical data are extremely limited. A major review of warfarin drug interactions published in 1994 did not include tricyclic antidepressants as an offending agent. It appears that warfarin can be used safely in patients taking tricyclic antidepressants.
St. John’s wort, Hypericum perforatum appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4 and CYP1A2. Tricyclic antidepressants (TCAs) are metabolized extensively by hepatic CYP450 isoenzymes. CYP3A4 substrates in the TCA class include imipramine and trimipramine; CYP1A2 substrates include amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline. Co-administration of St. John’s wort could decrease the efficacy of these TCA’s. A pharmacokinetic interaction has been reported between St. John’s wort and amitriptyline; coadministration resulted in decreased amitriptyline and metabolite plasma concentrations. In addition, it is not known if additive pharmacodynamic effects (e.g., serotonin syndrome or other side effects) could occur as a result of coadministration of St. John’s wort with TCA’s. Therefore, coadministration is not currently recommended.
Tricyclic antidepressants may interact with herbal and dietary supplements, including kava kava, Piper methysticum or valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. These herbal products are probably best avoided in combination with prescription antidepressants unless closely monitored by a health care professional.
Modafinil inhibits the CYP2C19 and hepatic microsomal isoenzyme at pharmacologically relevant concentrations. Some tricyclic antidepressants (i.e., amitriptyline, clomipramine, imipramine, and trimipramine) are metabolized by this isoenzyme and may have prolonged elimination upon co-administration of modafinil. One case of a patient who experienced increased side effects and increased serum levels of clomipramine during modafinil treatment has been reported. Tricyclic antidepressants may be prescribed to the narcoleptic patient for the treatment of cataplexy; however, patients on tricyclic antidepressants and modafinil concurrently may require antidepressant dose reductions.
Serum concentrations of many tricyclic antidepressants can be increased in the presence of racemic methylphenidate due to inhibition of antidepressant metabolism. Increased side effects and increased serum levels of the tricyclic agent may occur, necessitating dosage adjustment. Tricyclic antidepressants may be prescribed to the narcoleptic patient for the treatment of cataplexy; however, patients on tricyclic antidepressants and a stimulant concurrently may require antidepressant dose reductions and close clinical monitoring. Similar interactions may occur with dexmethylphenidate.
Oral contraceptives and estrogens can inhibit the hepatic metabolism of tricyclic antidepressants. Occasionally, side effects of the tricyclic antidepressants may become more pronounced. However, interactions are not common.
Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects and the agent had no effect on the cardiac conduction effects of the TCAs. Such combined use is not common today. Due to their anticholinergic actions, the TCAs may antagonize the therapeutic actions of the cholinesterase-inhibitors used for the treatment of Alzheimer’s and other dementias: donepezil, galantamine, rivastigmine, or tacrine. With such uses, it may be helpful to choose an alternative antidepressant with lower propensity for anticholinergic activity.
Lithium has been used as an augmentation for antidepressant therapy in cases of refractory unipolar depression. Although cyclic antidepressants and lithium can be used together therapeutically, clinicians should be alert for possible interactions. Antidepressants may ‘switch’ a bipolar depressive patient to hypomania or mania, although data indicate this is a rare occurrence. Some data indicate that when lithium and tricyclic antidepressants are used together, the risk of neurotoxicity may be increased, despite the presence of therapeutic lithium concentrations. Serotonin syndrome and neuroleptic malignant syndrome (NMS) events have also been reported. The data are limited, and suggest that toxicity from this combination is more likely in the elderly. Events do not appear to be predictable, and the mechanism of the interactions is elusive. While tricyclic antidepressants and heterocyclic antidepressants are not precluded in patients receiving lithium, they nevertheless should be used very cautiously. Careful dosage titration is recommended. Clinicians should be alert for the presence of tremor (a common presenting symptom) or other CNS effects during concurrent use.
Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Valproic acid may reduce the metabolism of some TCAs. Barbiturates, carbamazepine, ethotoin, phenytoin or fosphenytoin may increase TCA metabolism. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. Pregabalin, a drug chemically and structurally similar to gabapentin would have additive CNS depressants effects when combined with TCAs.
Dexfenfluramine is a non-specific serotonin agonist; it enhances serotonin release from presynaptic neurons and inhibits the reuptake of serotonin into these neurons. The serotonin syndrome is possible if dexfenfluramine is used with other drugs that also potentiate serotonin. Some clinicians feel that dexfenfluramine should be used very cautiously, if at all, with other drugs that may potentiate serotonin such as tricyclic antidepressants. In response, serotonin syndrome appears to be rare, even in patients taking combinations of serotonergic drugs. Nevertheless, the manufacturer states that dexfenfluramine should not be administered with other serotonergic agents. Fenfluramine also stimulates the release of serotonin and inhibits its reuptake; similar interactions may occur with that agent as well.
Tricyclic antidepressants (TCAs) inhibit serotonin uptake and rarely cause serotonin syndrome when used alone; cases of this complication usually have involved the combination of TCAs with other serotonergic therapies. However, TCAs should be used cautiously with drugs that augment serotonin, like the serotonin-receptor agonists (’triptans’) used for the treatment of migraine. Serotonin syndrome from the use of ‘triptan’-class drugs is a rare entity with monotherapy. If it is required that ‘triptans’ be given to patients receiving a drug with potential serotonergic effects, appropriate observation of the patient is recommended; serotonin excess may be possible.
Concurrent administration of TCAs with bupropion should be undertaken only with extreme caution due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of many TCAs leading to a potential for increased TCA Cmax, AUC and T1/2; an interaction has been formally reported with desipramine. Amitriptyline is metabolized via CYP2D6. Low initial dosing and gradual dose increases of both drugs should be employed. If bupropion is added to a regimen of a patient already receiving a TCA, the need to reduce the dosage of the TCA should be considered.
Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. Pharmacokinetic interactions have been noted between disulfiram and tricyclic antidepressants, but the clinical significance is uncertain. Disulfiram is known to inhibit some of the hepatic cytochrome P450 isoenzymes involved in tricyclic antidepressant metabolism (e.g., doxepin; CYP2C9).
According to the manufacturer of amprenavir, coadministration of amprenavir in a patient on a tricyclic antidepressant (TCA) may result in increased serum concentrations of the TCA, and the two drugs should be coadministered with caution, due to the potential for serious adverse reactions resulting from increased TCA concentrations. The manufacturer of amprenavir recommends concentration monitoring of the TCA when the drugs are used concomitantly.
Atazanavir competitively inhibits the enzymes CYP3A4, CYP1A2, and CYP2C9. Concentrations of drugs that are substrates of these enzymes (e.g., tricyclic antidepressants) may be increased with concomitant atazanavir use. According to the manufacturer of atazanavir, coadministration of atazanavir in a patient on a tricyclic antidepressant (TCA) may result in increased serum concentrations of the TCA, and the two drugs should be coadministered with caution due to a potential for serious adverse events. Monitor the patient for anticholinergic effects (e.g., sedation, confusion, constipation) associated with TCA use. The manufacturer recommends TCA concentration monitoring if atazanavir is used concomitantly with a TCA.
The use of erythromycin with tricyclic antidepressants is rarely problematic. Tricyclic antidepressants may prolong the QT interval, particularly in overdose, and erythromycin has also been reported to have this effect in rare circumstances. Erythromycin is sometimes used to stimulate GI motility, for example, in patients with diabetic gastroparesis. In patients requiring erythromycin to enhance GI motility, some tricyclic antidepressants with substantial antimuscarinic properties may counteract erythromycin’s effectiveness.
Ritonavir potently inhibits the CYP2D6 and CYP3A4 isozymes, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, monitor patients receiving ritonavir and TCAs concurrently closely. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Imatinib, STI-571 is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering imatinib with other CYP2D6 substrates that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions. Affected agents include tricyclic antidepressants.
Fluconazole has been reported to increase the effects of amitriptyline, perhaps through inhibition of the hepatic microsomal CYP2C19 or CYP3A4 isoenzymes. In at least one case, the interaction resulted in an increased incidence of TCA-related side effects, such as dizziness and syncope. In another case, QT-prolongation and torsades de pointes occurred. Monitor for an increased response to amitriptyline if fluconazole is co-administered. Theoretically, a similar reaction may occur with voriconazole, which is known to inhibit CYP2C19, CYP2C9, or CYP3A4 isoenzymes. Monitor for an increased response to amitriptyline if voriconazole is co-administered. Because of similar metabolic pathways, other TCAs that may be affected include clomipramine and imipramine, but specific data are lacking.
Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Tricyclic antidepressants may prolong the QT interval, particularly in overdose. The need to coadminister tricyclic antidepressants with droperidol should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA or delaying initiation of the TCA until the droperidol therapy is completed.
Documentation is not available on the concurrent use of duloxetine with many CNS agents. However, because of the potential risk and severity of the serotonin syndrome, caution should be observed when administering duloxetine with drugs that also have CNS serotonergic properties. Examples of these drugs include the tricyclic antidepressants. In addition, duloxetine is a moderate inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. It is possible that duloxetine could increase the risk of TCA-induced side effects or toxicity.
Documentation is not available on the concurrent use of venlafaxine with many CNS agents. However, because of the potential risk and severity of the serotonin syndrome, caution should be observed when administering venlafaxine with drugs that have CNS serotonergic properties. Examples of these drugs include the tricyclic antidepressants.
Many drugs, such as amitriptyline are substrates for CYP3A4 and, theoretically, plasma concentrations could be increased via CYP3A4 inhibition by aprepitant (moderate CYP3A4 inhibitor), although this interaction has not been studied.
Gefitinib may inhibit cytochrome P450 (CYP) 2D6 at clinical doses. Caution is recommended when administering gefitinib with other CYP2D6 substrates, such as amitriptyline, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
Tricyclic antidepressants may prolong the QT interval, particularly in overdose. Palonosetron may also cause QT interval prolongation, although this appears to be a rare side effect. Due to the potential for adverse cardiac effects, use palonosetron cautiously with tricyclic antidepressants and monitor the ECG if indicated.
Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes. The effect of tobacco on hepatic microsomal enzymes is not related to the nicotine component, so sudden smoking cessation may result in a reduced clearance of TCAs and increased TCA effects, despite the initiation of nicotine replacement products.
Trazodone inhibits serotonin reuptake, although, it is less potent than other serotonin reuptake inhibitors in this regard. Tricyclic antidepressants augment the activity of norepinephrine and serotonin. Because of the similarity in mechanism of action, patients receiving tricyclic antidepressants and trazodone together should be monitored for effects related to excessive serotonergic stimulation, as well as additive effects like sedation.
Delavirdine inhibits CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme; however, specific interaction studies have not been performed. Caution is recommended when administering delavirdine with CYP2D6 substrates that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions. Affected agents include tricyclic antidepressants. A dosage adjustment may be needed for TCAs when given concurrently with delavirdine.
Halofantrine is considered to have a well-established risk for QT prolongation and torsades de pointes (TdP). Halofantrine should be avoided in patients receiving drugs that may induce QT prolongation; these drugs include tricyclic antidepressants and certain related tetracyclic antidepressants (amoxapine, maprotiline).
Pharmacologic studies suggest that S-adenosyl-L-methionine, SAM-e may have additive pharmacodynamic effects with traditional antidepressant therapies such as the tricyclic antidepressants or MAOIs, but the pharmacology is poorly understood. In some trials of short duration (i.e., 2 weeks), SAM-e has been co-administered with imipramine to speed the onset of relief of depressive symptoms. An interaction of SAM-e with clomipramine has been noted and resulted in symptoms similar to those of the serotonin syndrome. Pharmacology studies indicate that SAM-e augments dopaminergic and serotonergic systems, and may have a weak inhibitory effect on MAO-B within the CNS. The routine addition of SAM-e to other conventional antidepressant medications, especially MAOIs, should be approached with caution until the mechanism of action of SAM-e with regard to neurotransmitter function or receptor activity is clarified. This dietary supplement is probably best avoided in combination with prescription antidepressants unless closely monitored by a health care professional.
Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Tricyclic antidepressants should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
[ Last revised: 2/26/2005 2:38:00 PM ]
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