Anafranil

Name: Anafranil

What side effects can this medication cause?

Clomipramine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • drowsiness
  • dry mouth
  • nausea
  • vomiting
  • diarrhea
  • constipation
  • nervousness
  • decreased sexual ability
  • decreased memory or concentration
  • headache
  • stuffy nose
  • change in appetite or weight

Some side effects may be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING or SPECIAL PRECAUTIONS sections, call your doctor immediately or get emergency medical treatment:

  • uncontrollable shaking of a part of the body
  • seizures
  • fast, irregular, or pounding heartbeat
  • difficulty urinating or loss of bladder control
  • believing things that are not true
  • hallucinations (seeing things or hearing voices that do not exist)
  • shakiness
  • difficulty breathing or fast breathing
  • severe muscle stiffness
  • unusual tiredness or weakness
  • sore throat, fever, and other signs of infection

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Anafranil Overview

Anafranil is a prescription medication used to treat symptoms of obsessive-compulsive disorder (OCD). Anafranil belongs to a class of drugs called tricyclic antidepressants. These work by increasing the amount of serotonin in your brain, a naturally occurring chemical that is involved in mental balance.

This medication comes in an oral (by mouth) capsule form and is usually taken once a day, at bedtime. At the beginning of treatment with Anafranil, it is usually given in divided doses, with food.

Common side effects of Anafranil include dry mouth, headache, constipation, and uncontrollable shaking in a part of the body.

Anafranil can also cause drowsiness and dizziness. Do not drive or operate heavy machinery until you know how Anafranil affects you.

Side Effects of Anafranil

Serious side effects have been reported with Anafranil. See the "Anafranil Precautions" section.

Common side effects of Anafranil include the following:

  • dry mouth
  • constipation
  • nausea
  • vomiting
  • diarrhea
  • dyspepsia (indigestion)
  • drowsiness
  • dizziness
  • nervousness
  • headache
  • changes in weight or eating habits
  • changes in sexual desire

This is not a complete list of Anafranil side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Anafranil Precautions

Serious side effects have been reported with Anafranil, including the following:

  • uncontrollable shaking
  • fast, irregular, or pounding heartbeat
  • difficulty urinating or loss of bladder control
  • believing things that are not true
  • hallucinations
  • difficulty breathing or fast breathing
  • severe muscle stiffness
  • unusual tiredness or weakness
  • sore throat, fever, and other signs of infection

Anafranil can also cause drowsiness and dizziness. Do not drive or operate heavy machinery until you know how Anafranil affects you.

Do not take Anafranil if you:

  • are allergic to Anafranil or to any of its ingredients
  • have taken a monoamine oxidase inhibitor in the last 14 days
  • are taking linezolid
  • are taking methylene blue
  • have recently had a heart attack

Anafranil and Pregnancy

Tell your doctor if yo are pregnant or plan to become pregnant. 

The FDA categorizes medication based on safety for use during pregnancy. Five categories - A, B, C, D, and X - are used to classify the possibel risks to an unborn baby when a medication is taken during pregnancy.

Anafranil falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Anafranil and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

Anafranil has been detected in human breast milk. Because of the possibility for adverse reactions in nursing infants from Anafranil, a choice should be made whether to stop nursing or to stop use of this medication. The importance of the drug to the mother should be considered.

Anafranil Overdose

If you take too much Anafranil, call your healthcare provider or local Poison Control Center or seek emergency medical attention right away.

If Anafranil is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Anafranil Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration,2 3 4 5 10 55 with peak plasma concentrations usually attained within 2–6 hours (mean: 4.7 hours).1 10 11 12 25 29

Oral bioavailability is about 50% because of extensive first-pass metabolism.1 2 25 55

Onset

Therapeutic response in OCD generally occurs within 2–6 weeks, with maximal effects after 3–4 months.33 66 99 103

Food

Food does not appear to substantially affect bioavailability from capsules.1 29

Special Populations

In geriatric patients, plasma concentrations of clomipramine and its major active metabolite (desmethylclomipramine) are substantially higher than those in younger adults (18–40 years of age).1 41 60

In children <15 years of age, plasma concentration-dose ratios of clomipramine are substantially lower than those of adults.1 43

In smokers, steady-state plasma clomipramine concentrations are substantially lower than in nonsmokers;1 41 55 60 smoking appears to have less effect on plasma concentrations of desmethylclomipramine.60

Distribution

Extent

Clomipramine and desmethylclomipramine widely distributed in body tissues, with moderate to high concentrations occurring in organs such as the lungs, adrenals, kidneys, heart, and brain.1 3 5 10 53

Crosses the blood-brain barrier; desmethylclomipramine concentration in CSF is about 2.6 times higher than in plasma.1

Crosses the placenta and distributes into milk.1 4 22 55 60 62 71

Plasma Protein Binding

Approximately 97–98%, principally to albumin and possibly to α1-acid glycoprotein (α1-AGP).1 2 4 29 55 56

Elimination

Metabolism

Extensively metabolized to active metabolites1 2 3 4 5 19 20 55 61 72 73 by various CYP isoenzymes (e.g., CYP1A2,346 CYP2C,73 CYP2D6,72 73 CYP3A4).c

Exhibits nonlinear pharmacokinetics at dosages >150 mg daily.1 8 Metabolism of clomipramine and desmethylclomipramine may be capacity limited (saturable).1 8 55

Elimination Route

Clomipramine and metabolites excreted in urine and in feces (via biliary elimination).1 4 5 11 21 29 55 73

Half-life

Elimination half-lives of clomipramine and desmethylclomipramine are approximately 32 hours (range: 19–37 hours) and 69 hours (range: 54–77 hours), respectively, after a 150-mg oral dose.1 2

Elimination half-lives may be considerably prolonged at dosages near upper limit of recommended dosage range (i.e., 200–250 mg daily).1 8

Special Populations

Effects of renal and hepatic impairment on the disposition of clomipramine have not been fully elucidated.1 60

Hemodialysis, peritoneal dialysis, forced diuresis, and/or exchange transfusion are unlikely to remove clomipramine and desmethylclomipramine substantially because of the drug’s rapid distribution into body tissues.1

Stability

Storage

Oral

Capsules

Tightly closed container at ≤30°C.1 Protect from moisture.1

Uses of Anafranil

  • It is used to treat obsessive-compulsive problems.
  • It may be given to you for other reasons. Talk with the doctor.

What do I need to tell my doctor BEFORE I take Anafranil?

  • If you have an allergy to clomipramine or any other part of Anafranil.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have had a recent heart attack.
  • If you are taking any of these drugs: Linezolid or methylene blue.
  • If you have taken certain drugs used for low mood (depression) like isocarboxazid, phenelzine, or tranylcypromine or drugs used for Parkinson's disease like selegiline or rasagiline in the last 14 days. Taking this medicine within 14 days of those drugs can cause very bad high blood pressure.
  • If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with Anafranil.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

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.

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. 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 Anafranil 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 Anafranil 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 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 (see DOSAGE AND ADMINISTRATION).

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.

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.

Medication Guide - Anafranil™ (clomipramine hydrochloride) Capsules USP Antidepressant 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. Talk to your, or your family member's, healthcare provider about:

  • all risks and benefits of treatment with antidepressant medicines
  • all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?

  1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
  2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
  3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?

    • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
    • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
    • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling very agitated or restless
  • panic attacks
  • trouble sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking (mania)
  • other unusual changes in behavior or mood

Visual problems

  • eye pain
  • changes in vision
  • swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

Who should not take Anafranil?

Do not take Anafranil if you:

  • take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
    • Do not take an MAOI within 2 weeks of stopping Anafranil unless directed to do so by your physician.
    • Do not start Anafranil if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

What else do I need to know about antidepressant medicines?

  • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
  • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
  • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
  • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
  • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information.

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.

Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company.

© 2017 Mallinckrodt.

Manufactured by                                                                             
Patheon Inc.                                                                                    
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L1N 5Z5
for Mallinckrodt Inc.
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Rev 04/2017

Mallinckrodt™
Pharmaceuticals

Adverse Effects

>10%

Xerostomia (84%)

Headache (50-55%)

Constipation (47%)

Ejaculation failure (42%)

Fatigue (35-40%)

Nausea (30-35%)

Impotence (20-25%)

Weight gain (18%)

1-10%

Weight loss (5%)

Hepatotoxicity (1-3%)

Frequency Not Defined

Common

  • Dizziness, mainia, somnolence, tremor
  • Dyspepsia
  • Blurred vision
  • Urinary retention
  • Orgasm incapacity, libido change

Rare

  • Myocardial infarction, orthostatic hypotension
  • Depression worsening, suicidal thoughts suicide, seizure
  • Hyperglycemia
  • Agranulocytosis, leukopenia, pancytopenia, thrombocytopenia
  • Body temperature above normal
  • Drug rash with eosinophilia and systemic symptoms (DRESS)

Clomipramine Pregnancy Warnings

AU, US: This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus. UK: Use is not recommended. AU TGA pregnancy category: C US FDA pregnancy category: C Comments: -Withdrawal symptoms, including jitteriness, tremor, and seizures, have been reported in neonates whose mothers had taken this drug until delivery.

Animal studies have shown reproductive toxicity. There are no controlled data in human pregnancy. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Clomipramine Breastfeeding Warnings

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. Excreted into human milk: Yes Comments: The effects in the nursing infant are unknown.

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