CLOMIPRAMINE Drug Interactions: What You Need to Know

Drug Interactions The risks of using clomipramine hydrochloride in combination with other drugs have not been systematically evaluated. Given the primary CNS effects of clomipramine hydrochloride, caution is advised in using it concomitantly with other CNS-active drugs ( see Information for Patients ). Clomipramine hydrochloride should not be used with MAO inhibitors ( see CONTRAINDICATIONS ). Close supervision and careful adjustment of dosage are required when clomipramine hydrochloride is administered with anticholinergic or sympathomimetic drugs. Several tricyclic antidepressants have been reported to block the pharmacologic effects of guanethidine, clonidine, or similar agents, and such an effect may be anticipated with CMI because of its structural similarity to other tricyclic antidepressants. The plasma concentration of CMI has been reported to be increased by the concomitant administration of haloperidol; plasma levels of several closely related tricyclic antidepressants have been reported to be increased by the concomitant administration of methylphenidate or hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decreased by the concomitant administration of hepatic enzyme inducers (e.g., barbiturates, phenytoin), and such an effect may be anticipated with CMI as well. Administration of CMI has been reported to increase the plasma levels of phenobarbital, if given concomitantly ( see CLINICAL PHARMACOLOGY , Interactions ).

Drugs

Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, paroxetine, and fluvoxamine, inhibit P450 2D6, they may vary in the extent of inhibition. Fluvoxamine has also been shown to inhibit P450 1A2, an isoform also involved in TCA metabolism. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of agents in the tricyclic antidepressant class (which includes clomipramine hydrochloride) with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant agent or the other drug. Furthermore, whenever one of these drugs is withdrawn from co therapy, an increased dose of tricyclic antidepressant agent may be required. It is desirable to monitor TCA plasma levels whenever an agent of the tricyclic antidepressant class including clomipramine hydrochloride is going to be co-administered with another drug known to be an inhibitor of P450 2D6 (and/or P450 1A2). Because clomipramine hydrochloride is highly bound to serum protein, the administration of clomipramine hydrochloride to patients taking other drugs that are highly bound to protein (e.g., warfarin, digoxin) may cause an increase in plasma concentrations of these drugs, potentially resulting in adverse effects. Conversely, adverse effects may result from displacement of protein- bound clomipramine hydrochloride by other highly bound drugs ( see CLINICAL PHARMACOLOGY , Distribution ).

Monoamine Oxidase

Inhibitors (MAOIs) ( See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .)

Serotonergic

Drugs ( See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .) Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenicity was found in two 2-year bioassays in rats at doses up to 100 mg/kg, which is 24 and 4 times the maximum recommended human daily dose (MRHD) on a mg/kg and mg/m2 basis, respectively, or in a 2-year bioassay in mice at doses up to 80 mg/kg, which is 20 and 1.5 times the MRHD on a mg/kg and mg/m 2 basis, respectively. In reproduction studies, no effects on fertility were found in rats given up to 24 mg/kg, which is 6 times, and approximately equal to, the MRHD on a mg/kg and mg/m 2 basis, respectively.

CONTRAINDICATIONS Clomipramine hydrochloride capsules, USP are contraindicated in patients with a history of hypersensitivity to clomipramine hydrochloride capsules, USP or other tricyclic antidepressants.

Monoamine Oxidase

Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with clomipramine hydrochloride capsules, USP or within 14 days of stopping treatment with clomipramine hydrochloride capsules, USP are contraindicated because of an increased risk of serotonin syndrome. The use of clomipramine hydrochloride capsules, USP within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated ( see WARNINGS and DOSAGE AND ADMINISTRATION ). Starting clomipramine hydrochloride capsules, USP in a patient who is being treated with linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome ( see WARNINGS and DOSAGE AND ADMINISTRATION ).

Myocardial Infarction

Clomipramine hydrochloride capsules, USP are contraindicated during the acute recovery period after a myocardial infarction.

WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long­-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. 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 with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table-1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for clomipramine hydrochloride should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Screening

Patients for Bipolar Disorder – A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that clomipramine hydrochloride is not approved for use in treating bipolar depression.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including clomipramine hydrochloride capsules, USP alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of clomipramine hydrochloride capsules, USP with MAOIs intended to treat psychiatric disorders is contraindicated. Clomipramine hydrochloride capsules, USP should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking clomipramine hydrochloride capsules, USP. Clomipramine hydrochloride capsules, USP should be discontinued before initiating treatment with the MAOI ( see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION ) . If concomitant use of clomipramine hydrochloride capsules, USP with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with clomipramine hydrochloride capsules, USP and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including clomipramine hydrochloride capsules, USP may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Seizures

During premarket evaluation, seizure was identified as the most significant risk of clomipramine hydrochloride capsules, USP use. The observed cumulative incidence of seizures among patients exposed to clomipramine hydrochloride capsules, USP at doses up to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, and 1.45% at 365 days. The cumulative rates correct the crude rate of 0.7% (25 of 3519 patients) for the variable duration of exposure in clinical trials. Although dose appears to be a predictor of seizure, there is a confounding of dose and duration of exposure, making it difficult to assess independently the effect of either factor alone. The ability to predict the occurrence of seizures in subjects exposed to doses of CMI greater than 250 mg is limited, given that the plasma concentration of CMI may be dose-dependent and may vary among subjects given the same dose. Nevertheless, prescribers are advised to limit the daily dose to a maximum of 250 mg in adults and 3 mg/kg (or 200 mg) in children and adolescents ( see DOSAGE AND ADMINISTRATION ). Caution should be used in administering clomipramine hydrochloride capsules, USP to patients with a history of seizures or other predisposing factors, e.g., brain damage of varying etiology, alcoholism, and concomitant use with other drugs that lower the seizure threshold. Rare reports of fatalities in association with seizures have been reported by foreign postmarketing surveillance, but not in U.S. clinical trials. In some of these cases, clomipramine hydrochloride capsules, USP had been administered with other epileptogenic agents; in others, the patients involved had possibly predisposing medical conditions. Thus a causal association between clomipramine hydrochloride capsules, USP treatment and these fatalities has not been established. Physicians should discuss with patients the risk of taking clomipramine hydrochloride capsules, USP while engaging in activities in which sudden loss of consciousness could result in serious injury to the patient or others, e.g., the operation of complex machinery, driving, swimming, climbing.

Dress

Rare cases of drug rash with eosinophilia and systemic symptoms (DRESS) have been reported with the use of clomipramine. In the event of severe acute reactions such as DRESS, discontinue clomipramine therapy immediately and institute appropriate treatment.