Anafranil™ (clomipramine hydrochloride) Capsules, USP 25 mg

IMPORTANT SAFETY INFORMATION

WARNINGS and PRECAUTIONS

·        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.

·        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.

·        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. Clomipramine hydrochloride is not approved for use in treating bipolar depression.

·        The development of life-threatening serotonin syndrome has been reported with use of serotonin/norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), including Anafranil, alone but particularly with concomitant use of other serotonergic drugs (triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, busiprone, and St. John's Wort) or medications that impair metabolism of serotonin (e.g. MAOIs, including linezolid and intravenous methylene blue).

·        The pupillary dilation that occurs following use of many antidepressant drugs including Anafranil may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

·        Seizure was identified as the most significant risk of Anafranil use in premarket evaluation. Caution should be used in administering Anafranil 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 cases of drug rash with eosinophilia and systemic symptoms (DRESS) have been reported with the use of clomipramine. In such an event, discontinue clomipramine therapy immediately and institute appropriate treatment.

·        The risk of suicide must be considered since depression is a commonly associated feature of OCD. Prescriptions for Anafranil should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce risk of overdose.

·        Caution is necessary in treating patients with known cardiovascular disease, and gradual dose titration is recommended due to potential cardiovascular effects (e.g. orthostatic decreases in blood pressure, tachycardia, changes in ECGs, etc.).

·        Patients treated with Anafranil have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychotic episodes, confusion, and paranoia. Treatment may precipitate an acute psychotic episode in patients with unrecognized schizophrenia.

·        Precipitation of hypomania and mania has been reported in patients receiving Anafranil for the treatment of affective disorders. Activation of mania or hypomania has been reported in a small proportion of patients receiving other tricyclic antidepressants.

·        Anafranil has been associated with elevations in SGOT and SGPT of potential clinical importance (i.e., values greater than 3 times the upper limit of normal). Use with caution in patients with known liver disease, and periodic monitoring of hepatic enzyme levels is recommended in such patients.

·        Leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia have been reported with use of Anafranil.

·        Hyperthermia has been reported in patients receiving Anafranil. Most cases were in combination with other drugs, including neuroleptic agents.

·        Sexual dysfunction, including ejaculatory failure and impotence, has been reported in males treated with Anafranil.

·        Hyponatremia has occurred as a result of treatment with clomipramine. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Elderly patients may be at greater risk as well as patients taking diuretics or who are otherwise volume-depleted. Anafranil should be discontinued in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

·        Increases and decreases in weight can occur with use of Anafranil.

·        Concurrent administration of Anafranil with electroconvulsive therapy may increase the risks.

·        Prior to elective surgery with general anesthetics, therapy with Anafranil should be discontinued for as long as is clinically feasible, and the anesthetist should be advised.

·        Use with caution in patients with the following concomitant illnesses:

o   hyperthyroidism or in patients receiving thyroid medications due to possible cardiac toxicity.

o   increased intraocular pressure, history of narrow-angle glaucoma or urinary retention due to anticholinergic properties of the drug.

o   tumors of the adrenal medulla (e.g. pheochromocytoma, neuroblastoma) in whom the drug may provoke hypertensive crises.

o   significant renal impairment.

·        Withdrawal symptoms have been reported in association with abrupt discontinuation of Anafranil. It is recommended that the dosage be tapered gradually and the patient monitored carefully during discontinuation.

·        Given the primary CNS effects of Anafranil, caution is advised in using them concomitantly with other CNS-active drugs.

·        Due to potential impact on drug metabolism, use caution when administering with drugs that impact CYP450 2D6 or in individuals who have altered CYP450 2D6 metabolism.

·        Anafranil should be used with caution with drugs that are highly bound to serum protein (e.g. warfarin, digoxin, etc.).

ADVERSE REACTIONS 

The most commonly observed adverse events associated with the use of Anafranil and not seen at an equivalent incidence among placebo-treated patients were gastrointestinal complaints, including dry mouth, constipation, nausea, dyspepsia, and anorexia; nervous system complaints, including somnolence, tremor, dizziness, nervousness, and myoclonus; genitourinary complaints, including changed libido, ejaculatory failure, impotence, and micturition disorder; and other miscellaneous complaints, including fatigue, sweating, increased appetite, weight gain, and visual changes.

This is not a complete list of potential adverse events associated with Anafranil. Please see Full Prescribing Information for a complete list.