Clomipramine Hydrochloride

Anafranil ™ (clomipramine hydrochloride) Capsules USP is indicated for the treatment of obsessions and compulsions in patients with Obsessive-Compulsive Disorder (OCD). The obsessions or compulsions must cause marked distress, be time-consuming, or significantly interfere with social or occupational functioning, in order to meet the DSM-III-R (circa 1989) diagnosis of OCD. Obsessions are recurrent, persistent ideas, thoughts, images, or impulses that are ego-dystonic. Compulsions are repetitive, purposeful, and intentional behaviors performed in response to an obsession or in a stereotyped fashion, and are recognized by the person as excessive or unreasonable. The effectiveness of Anafranil for the treatment of OCD was demonstrated in multicenter, placebo-controlled, parallel-group studies, including two 10-week studies in adults and one 8-week study in children and adolescents 10 to 17 years of age. Patients in all studies had moderate-to-severe OCD (DSM-III), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS) ranging from 26 to 28 and a mean baseline rating of 10 on the NIMH Clinical Global Obsessive Compulsive Scale (NIMH-OC). Patients taking CMI experienced a mean reduction of approximately 10 on the YBOCS, representing an average improvement on this scale of 35% to 42% among adults and 37% among children and adolescents. CMI-treated patients experienced a 3.5 unit decrement on the NIMH-OC. Patients on placebo showed no important clinical response on either scale. The maximum dose was 250 mg/day for most adults and 3 mg/kg/day (up to 200 mg) for all children and adolescents. The effectiveness of Anafranil for long-term use (i.e., for more than 10 weeks) has not been systematically evaluated in placebo-controlled trials. The physician who elects to use Anafranil for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient ( see DOSAGE AND ADMINISTRATION ).

Anafranil is contraindicated in patients with a history of hypersensitivity to Anafranil or other tricyclic antidepressants. Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with Anafranil or within 14 days of stopping treatment with Anafranil is contraindicated because of an increased risk of serotonin syndrome. The use of Anafranil within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated ( see WARNINGS and DOSAGE AND ADMINISTRATION ). Starting Anafranil 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 Anafranil is contraindicated during the acute recovery period after a myocardial infarction.

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 . 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 18-24 5 additional cases Decreases Compared to Placebo 25-64 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 Anafranil, 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 Anafranil with MAOIs intended to treat psychiatric disorders is contraindicated. Anafranil 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 Anafranil. Anafranil should be discontinued before initiating treatment with the MAOI ( see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION ) . If concomitant use of Anafranil with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. […]

General Suicide – Since depression is a commonly associated feature of OCD, the risk of suicide must be considered. Prescriptions for Anafranil should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Cardiovascular Effects – Modest orthostatic decreases in blood pressure and modest tachycardia were each seen in approximately 20% of patients taking Anafranil in clinical trials; but patients were frequently asymptomatic. Among approximately 1400 patients treated with CMI in the premarketing experience who had ECGs, 1.5% developed abnormalities during treatment, compared with 3.1% of patients receiving active control drugs and 0.7% of patients receiving placebo. The most common ECG changes were PVCs, ST-T wave changes, and intraventricular conduction abnormalities. These changes were rarely associated with significant clinical symptoms. Nevertheless, caution is necessary in treating patients with known cardiovascular disease, and gradual dose titration is recommended. Psychosis, Confusion, and Other Neuropsychiatric Phenomena – Patients treated with Anafranil have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychotic episodes, confusion, and paranoia. Because of the uncontrolled nature of many of the studies, it is impossible to provide a precise estimate of the extent of risk imposed by treatment with Anafranil. As with tricyclic antidepressants to which it is closely related, Anafranil may precipitate an acute psychotic episode in patients with unrecognized schizophrenia. Mania/Hypomania – During premarketing testing of Anafranil in patients with affective disorder, hypomania or mania was precipitated in several patients. Activation of mania or hypomania has also been reported in a small proportion of patients with affective disorder treated with marketed tricyclic antidepressants, which are closely related to Anafranil. Hepatic Changes – During premarketing testing, Anafranil was occasionally associated with elevations in SGOT and SGPT (pooled incidence of approximately 1% and 3%, respectively) of potential clinical importance (i.e., values greater than 3 times the upper limit of normal). In the vast majority of instances, these enzyme increases were not associated with other clinical findings suggestive of hepatic injury; moreover, none were jaundiced. Rare reports of more severe liver injury, some fatal, have been recorded in foreign postmarketing experience. Caution is indicated in treating patients with known liver disease, and periodic monitoring of hepatic enzyme levels is recommended in such patients. Hematologic Changes – Although no instances of severe hematologic toxicity were seen in the premarketing experience with Anafranil, there have been postmarketing reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in association with Anafranil use. As is the case with tricyclic antidepressants to which Anafranil is closely related, leukocyte and differential blood counts should be obtained in patients who develop fever and sore throat during treatment with Anafranil. Central Nervous System – More than 30 cases of hyperthermia have been recorded by nondomestic postmarketing surveillance systems. Most cases occurred when Anafranil was used in combination with other drugs. When Anafranil and a neuroleptic were used concomitantly, the cases were sometimes considered to be examples of a neuroleptic malignant syndrome. Sexual Dysfunction – The rate of sexual dysfunction in male patients with OCD who were treated with Anafranil in the premarketing experience was markedly increased compared with placebo controls (i.e., 42% experienced ejaculatory failure and 20% experienced impotence, compared with 2.0% and 2.6%, respectively, in the placebo group). Approximately 85% of males with sexual dysfunction chose to continue treatment. Hyponatremia – 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 of developing hyponatremia with a serotonergic antidepressant. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of Anafranil in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Weight Changes – In controlled studies of OCD, weight gain was reported in 18% of patients receiving Anafranil, compared with 1% of patients receiving placebo. In these studies, 28% of patients receiving Anafranil had a weight gain of at least 7% of their initial body weight, compared with 4% of patients receiving placebo. Several patients had weight gains in excess of 25% of their initial body weight. Conversely, 5% of patients receiving Anafranil and 1% receiving placebo had weight losses of at least 7% of their initial body weight. Electroconvulsive Therapy – As with closely related tricyclic antidepressants, concurrent administration of Anafranil with electroconvulsive therapy may increase the risks; such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience. Surgery – 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 in Concomitant Illness – As with closely related tricyclic antidepressants, Anafranil should be used with caution in the following: Hyperthyroid patients or patients receiving thyroid medication, because of the possibility of cardiac toxicity; Patients with increased intraocular pressure, a history of narrow-angle glaucoma, or urinary retention, because of the anticholinergic properties of the drug; Patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma) in whom the drug may provoke hypertensive crises; Patients with significantly impaired renal function. Withdrawal Symptoms – A variety of withdrawal symptoms have been reported in association with abrupt discontinuation of Anafranil, including dizziness, nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia, and irritability. In addition, such patients may experience a worsening of psychiatric status. While the withdrawal effects of Anafranil have not been systematically evaluated in controlled trials, they are well known with closely related tricyclic antidepressants, and it is recommended that the dosage be tapered gradually and the patient monitored carefully during discontinuation ( see DRUG ABUSE AND DEPENDENCE ). Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with clomipramine hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for clomipramine hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. […]

Commonly Observed 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. Leading to Discontinuation of Treatment Approximately 20% of 3616 patients who received Anafranil in U.S. premarketing clinical trials discontinued treatment because of an adverse event. Approximately one-half of the patients who discontinued (9% of the total) had multiple complaints, none of which could be classified as primary. Where a primary reason for discontinuation could be identified, most patients discontinued because of nervous system complaints (5.4%), primarily somnolence. The second-most-frequent reason for discontinuation was digestive system complaints (1.3%), primarily vomiting and nausea. There was no apparent relationship between the adverse events and elevated plasma drug concentrations. Incidence in Controlled Clinical Trials The following table enumerates adverse events that occurred at an incidence of 1% or greater among patients with OCD who received Anafranil in adult or pediatric placebo-controlled clinical trials. The frequencies were obtained from pooled data of clinical trials involving either adults receiving Anafranil (N=322) or placebo (N=319) or children treated with Anafranil (N=46) or placebo (N=44). The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the populations studied. Incidence of Treatment-Emergent Adverse Experience in Placebo-Controlled Clinical Trials (Percentage of Patients Reporting Event) *Events reported by at least 1% of Anafranil patients are included. Adults Children and Adolescents Body System/ Adverse Event* Anafranil (N=322) Placebo (N=319) Anafranil (N=46) Placebo (N=44) Nervous System Somnolence 54 16 46 11 Tremor 54 2 33 2 Dizziness 54 14 41 14 Headache 52 41 28 34 Insomnia 25 15 11 7 Libido change 21 3 – – Nervousness 18 2 4 2 Myoclonus 13 – 2 – Increased appetite 11 2 – 2 Paresthesia 9 3 2 2 Memory impairment 9 1 7 2 Anxiety 9 4 2 – Twitching 7 1 4 5 Impaired concentration 5 2 – – Depression 5 1 – – Hypertonia 4 1 2 – Sleep disorder 4 – 9 5 Psychosomatic disorder 3 – – – Yawning 3 – – – Confusion 3 – 2 – Speech disorder 3 – – – Abnormal dreaming 3 – – 2 Agitation 3 – – – Migraine 3 – – – Depersonalization 2 – 2 – Irritability 2 2 2 – Emotional lability 2 – – 2 Panic reaction 1 – 2 – Aggressive reaction – – 2 – Paresis – – 2 – Skin and Appendages Increased sweating 29 3 9 – Rash 8 1 4 2 Pruritus 6 – 2 2 Dermatitis 2 – – 2 Acne 2 2 – 5 Dry skin 2 – – 5 Urticaria 1 – – – Abnormal skin odor – – 2 – Digestive System Dry mouth 84 17 63 16 Constipation 47 11 22 9 Nausea 33 14 9 11 Dyspepsia 22 10 13 2 Diarrhea 13 9 7 5 Anorexia 12 – 22 2 Abdominal pain 11 9 13 16 Vomiting 7 2 7 – Flatulence 6 3 – 2 Tooth disorder 5 – – – Gastrointestinal disorder 2 – – 2 Dysphagia 2 – – – Esophagitis 1 – – – Eructation – – 2 2 Ulcerative stomatitis – – 2 – Body as a Whole Fatigue 39 18 35 9 Weight increase 18 1 2 – Flushing 8 – 7 – Hot flushes 5 – 2 – Chest pain 4 4 7 – Fever 4 – 2 7 Allergy 3 3 7 5 Pain 3 2 4 2 Local edema 2 4 – – Chills 2 1 – – Weight decrease – – 7 – Otitis media – – 4 5 Asthenia – – 2 – Halitosis – – 2 – Cardiovascular System Postural hypotension 6 – 4 – Palpitation 4 2 4 – Tachycardia 4 – 2 – Syncope – – 2 – Respiratory System Pharyngitis 14 9 – 5 Rhinitis 12 10 7 9 Sinusitis 6 4 2 5 Coughing 6 6 4 5 Bronchospasm 2 – 7 2 Epistaxis 2 – – 2 Dyspnea – – 2 – Laryngitis – 1 2 – Urogenital System Male and Female Patients Combined Micturition disorder 14 2 4 2 Urinary tract infection 6 1 – – Micturition frequency 5 3 – – Urinary retention 2 – 7 – Dysuria 2 2 – – Cystitis 2 – – – Female Patients Only (N=182) (N=167) (N=10) (N=21) Dysmenorrhea 12 14 10 10 Lactation (nonpuerperal) 4 – – – Menstrual disorder 4 2 – – Vaginitis 2 – – – Leukorrhea 2 – – – Breast enlargement 2 – – – Breast pain 1 – – – Amenorrhea 1 – – – Male Patients Only (N=140) (N=152) (N=36) (N=23) Ejaculation failure 42 2 6 – Impotence 20 3 – – Special Senses Abnormal vision 18 4 7 2 Taste perversion 8 – 4 – Tinnitus 6 – 4 – Abnormal lacrimation 3 2 – – Mydriasis 2 – – – Conjunctivitis 1 – – – Anisocoria – – 2 – Blepharospasm – – 2 – Ocular allergy – – 2 – Vestibular disorder – – 2 2 Musculoskeletal Myalgia 13 9 – – Back pain 6 6 – – Arthralgia 3 5 – – Muscle weakness 1 – 2 – Hemic and Lymphatic Purpura 3 – – – Anemia – – 2 2 Metabolic and Nutritional Thirst 2 2 – 2 Other Events Observed During the Premarketing Evaluation of Anafranil During clinical testing in the U.S., multiple doses of Anafranil were administered to approximately 3600 subjects. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, a modified World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the 3525 individuals exposed to Anafranil who experienced an event of the type cited on at least one occasion while receiving Anafranil. All events are included except those already listed in the previous table, those reported in terms so general as to be uninformative, and those in which an association with the drug was remote. It is important to emphasize that although the events reported occurred during treatment with Anafranil, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients. Body as a Whole – Infrequent – general edema, increased susceptibility to infection, malaise. Rare – dependent edema, withdrawal syndrome. Cardiovascular System – Infrequent – abnormal ECG, arrhythmia, bradycardia, cardiac arrest, extrasystoles, pallor. Rare – aneurysm, atrial flutter, bundle branch block, cardiac failure, cerebral hemorrhage, heart block, myocardial infarction, myocardial ischemia, peripheral ischemia, thrombophlebitis, vasospasm, ventricular tachycardia. Digestive System – Infrequent – abnormal hepatic function, blood in stool, colitis, duodenitis, gastric ulcer, gastritis, gastroesophageal reflux, gingivitis, glossitis, hemorrhoids, hepatitis, increased saliva, irritable bowel syndrome, peptic ulcer, rectal hemorrhage, tongue ulceration, tooth caries. Rare – cheilitis, chronic enteritis, discolored feces, gastric dilatation, gingival bleeding, hiccup, intestinal obstruction, oral/pharyngeal edema, paralytic ileus, salivary gland enlargement. […]

The risks of using Anafranil in combination with other drugs have not been systematically evaluated. Given the primary CNS effects of Anafranil, caution is advised in using it concomitantly with other CNS-active drugs ( see Information for Patients ). Anafranil should not be used with MAO inhibitors ( see CONTRAINDICATIONS ). Close supervision and careful adjustment of dosage are required when Anafranil 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 Anafranil) 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 Anafranil is going to be co-administered with another drug known to be an inhibitor of P450 2D6 (and/or P450 1A2). Because Anafranil is highly bound to serum protein, the administration of Anafranil 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 Anafranil by other highly bound drugs ( see CLINICAL PHARMACOLOGY, Distribution ).

Category C No teratogenic effects were observed in studies performed in rats and mice at doses up to 100 mg/kg, which is 24 times the maximum recommended human daily dose (MRHD) on a mg/kg basis and 4 times (rats) and 2 times (mice) the MRHD on a mg/m 2 basis. Slight nonspecific embryo/fetotoxic effects were seen in the offspring of treated rats given 50 and 100 mg/kg and of treated mice given 100 mg/kg. There are no adequate or well-controlled studies in pregnant women. Withdrawal symptoms, including jitteriness, tremor, and seizures, have been reported in neonates whose mothers had taken Anafranil until delivery. Anafranil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Anafranil has been found in human milk. Because of the potential for adverse reactions, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established ( see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk ). Anyone considering the use of Anafranil in a child or adolescent must balance the potential risks with the clinical need. In a controlled clinical trial in children and adolescents (10 to 17 years of age), 46 outpatients received Anafranil for up to 8 weeks. In addition, 150 adolescent patients have received Anafranil in open-label protocols for periods of several months to several years. Of the 196 adolescents studied, 50 were 13 years of age or less and 146 were 14 to 17 years of age. The adverse reaction profile in this age group ( see ADVERSE REACTIONS ) is similar to that observed in adults. The risks, if any, that may be associated with Anafranil's extended use in children and adolescents with OCD have not been systematically assessed. The evidence supporting the conclusion that Anafranil is safe for use in children and adolescents is derived from relatively short term clinical studies and from extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long term Anafranil use on the growth, development, and maturation of children and adolescents. Although there is no evidence to suggest that Anafranil adversely affects growth, development or maturation, the absence of such findings is not adequate to rule out a potential for such effects in chronic use. The safety and effectiveness in pediatric patients below the age of 10 have not been established. Therefore, specific recommendations cannot be made for the use of Anafranil in pediatric patients under the age of 10.

Clinical studies of Anafranil did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects; 152 patients at least 60 years of age participating in various U.S. clinical trials received Anafranil for periods of several months to several years. No unusual age-related adverse events were identified in this population. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Anafranil has been associated with cases of clinically significant hyponatremia. Elderly patients may be at greater risk for this adverse reaction ( see PRECAUTIONS, Hyponatremia ).