Anafranil Information
Anafranil () Suicidality And Antidepressant Drugs
Anafranil () Description
Anafranil () ™, (clomipramine hydrochloride capsules USP), is an antiobsessional drug that belongs to the class (dibenzazepine) of pharmacologic agents known as tricyclic antidepressants. Anafranil () is available as capsules of 25, 50, and 75 mg for oral administration.
Clomipramine hydrochloride USP is 3-chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro--dibenz[]azepine monohydrochloride, and its structural formula is:
Clomipramine hydrochloride USP is a white to off-white crystalline powder. It is freely soluble in water, in methanol, and in methylene chloride, and insoluble in ethyl ether and in hexane.
Anafranil () Indications And Usage
Anafranil () ™ 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 ( ).
Anafranil () Contraindications
Anafranil () (clomipramine hydrochloride capsules USP) is contraindicated in patients with a history of hypersensitivity to Anafranil () or other tricyclic antidepressants.
Anafranil () should not be given in combination, or within 14 days before or after treatment, with a monoamine oxidase (MAO) inhibitor. Hyperpyretic crisis, seizures, coma, and death have been reported in patients receiving such combinations.
Anafranil () is contraindicated during the acute recovery period after a myocardial infarction.
Anafranil () Warnings
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 .
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 health care providers. Such monitoring should include daily observation by families and caregivers.
During premarket evaluation, seizure was identified as the most significant risk of Anafranil () use.
The observed cumulative incidence of seizures among patients exposed to Anafranil () 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 ( ).
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 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, Anafranil () had been administered with other epileptogenic agents; in others, the patients involved had possibly predisposing medical conditions. Thus a causal association between Anafranil () treatment and these fatalities has not been established.
Physicians should discuss with patients the risk of taking Anafranil () 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.
Anafranil () Precautions
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.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking clomipramine hydrochloride.
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 ( ). Anafranil () should be used with MAO inhibitors ( ).
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 ( ).
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/m 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 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 basis, respectively.
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 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.
Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established ( ). 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 ( ) 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.
Anafranil () Adverse Reactions
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.
During clinical testing in the U.S., multiple doses of Anafranil () (clomipramine hydrochloride capsules USP) 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.
Anafranil () Drug Abuse And Dependence
Anafranil () has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While a variety of withdrawal symptoms have been described in association with Anafranil () discontinuation ( ), there is no evidence for drug-seeking behavior, except for a single report of potential Anafranil () abuse by a patient with a history of dependence on codeine, benzodiazepines, and multiple psychoactive drugs. The patient received Anafranil () for depression and panic attacks and appeared to become dependent after hospital discharge.
Despite the lack of evidence suggesting an abuse liability for Anafranil () in foreign marketing, it is not possible to predict the extent to which Anafranil () might be misused or abused once marketed in the U.S. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely.
Anafranil () Overdosage
Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as possible.
Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary.
If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.
Anafranil () Dosage And Administration
The treatment regimens described below are based on those used in controlled clinical trials of Anafranil () in 520 adults, and 91 children and adolescents with OCD. During initial titration, Anafranil () should be given in divided doses with meals to reduce gastrointestinal side effects. The goal of this initial titration phase is to minimize side effects by permitting tolerance to side effects to develop or allowing the patient time to adapt if tolerance does not develop.
Because both CMI and its active metabolite, DMI, have long elimination half-lives, the prescriber should take into consideration the fact that steady-state plasma levels may not be achieved until 2 to 3 weeks after dosage change ( ). Therefore, after initial titration, it may be appropriate to wait 2 to 3 weeks between further dosage adjustments.
Anafranil () How Supplied
Anafranil ()
Anafranil () Animal Toxicology
Phospholipidosis and testicular changes, commonly associated with tricyclic compounds, have been observed with Anafranil () . In chronic rat studies, changes related to Anafranil () consisted of systemic phospholipidosis, alterations in the testes (atrophy, mineralization) and secondary changes in other tissues. In addition cardiac thrombosis and dermatitis/keratitis were observed in rats treated for 2 years at doses which were 24 and 10 times the maximum recommended human daily dose (MRHD), respectively, on a mg/kg basis, and 4 and 1.5 times the MRHD, respectively, on a mg/m basis.
Anafranil () and are trademarks of Mallinckrodt Inc.
Manufactured byPatheon Inc.Whitby, Ontario, CanadaL1N 5Z5for Mallinckrodt Inc.Hazelwood, MO 63042 USA
Anafranil () Medication Guideantidepressant Medicines, Depression And Other Serious Mental Illnesses, And Suicidal Thoughts Or Actions
Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.
Mallinckrodt Inc.Hazelwood, MO 63042 USA
[05/2009]
Rev 06/2009
Anafranil () Package Label - Principal Display Panel - Mg Bottle
NDC 0406-9906-03 Each capsule contains: Clomipramine Hydrochloride USP ... 25 mg PHARMACIST: PLEASE DISPENSE WITH ATTACHED MEDICATION GUIDE
Anafranil () Package Label - Principal Display Panel - Mg Bottle
NDC 0406-9907-03 Each capsule contains: Clomipramine Hydrochloride USP ... 50 mg PHARMACIST: PLEASE DISPENSE WITH ATTACHED MEDICATION GUIDE
Anafranil () Package Label - Principal Display Panel - Mg Bottle
NDC 0406-9908-03 Each capsule contains: Clomipramine Hydrochloride USP ... 75 mg PHARMACIST: PLEASE DISPENSE WITH ATTACHED MEDICATION GUIDE
