Does Anafranil (clomipramine) cause side effects?

Anafranil (clomipramine) is a psychotropic agent used to treat obsessive-compulsive disorder (OCD). 

Anafranil shares structural similarities with a class of antidepressants known as tricyclic antidepressants (TCAs). The exact mechanism by which Anafranil exerts its therapeutic benefits is not fully understood. However, similar to other TCAs, Anafranil is thought to enhance the actions of the neurotransmitters norepinephrine and serotonin by blocking their reuptake and prolonging their activity. 

Anafranil also has anticholinergic properties which means it blocks the action of another neurotransmitter, acetylcholine. This increases the risk for certain side effects. It also has weak antihistamine properties which appear to play a role in the mild sedative effects observed with use.

Common side effects of Anafranil include

Serious side effects of Anafranil include

Drug interactions of Anafranil include other tricyclic antidepressants or related cyclic antidepressants such as amoxapine, imipramine, and desipramine because co-administration with medications that share similar properties increases the risk for side effects.

  • Anafranil shares pharmacological properties with Class IA and Class III antiarrhythmic medications. Co-administration increases the risk for QT prolongation and life-threatening arrhythmias.
  • For this reason, use of clomipramine should be avoided with bretylium, dofetilide, dronedarone, flecainide, sotalol, quinidine, procainamide, propafenone, ranolazine, ibutilide, and others.
  • Anafranil should be avoided when possible or used cautiously with medications known to prolong the QTc interval such as thioridazine, ziprasidone, pimozide, and others.
  • Anafranil increases the levels of serotonin in the brain.
  • Co-administration with other medications that also increase serotonin levels such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and linezolid increases the risk of serotonin syndrome. Symptoms of serotonin syndrome include

Anafranil has not been adequately evaluated in pregnant women. Due to the lack of conclusive safety data, Anafranil should be used in pregnancy only if the benefit justifies the potential risk to the fetus. 

Anafranil is excreted into breast milk. Due to the lack of safety data, Anafranil is not recommended for use in females who are breastfeeding.

What are the important side effects of Anafranil (clomipramine)?

The most common side effects associated with the use of clomipramine include:

Less common but serious side effects include:

  • hypersensitivity type reactions,
  • suicidal ideation,
  • serotonin syndrome, and
  • others.

Anafranil (clomipramine) side effects list for healthcare professionals

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
  • 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

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)

Body System/ Adverse Event* Adults Children and Adolescents
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
*Events reported by at least 1% of Anafranil patients are included.

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.

Endocrine System

Infrequent - hypothyroidism.

Rare - goiter, gynecomastia, hyperthyroidism.

Hemic and Lymphatic System

Infrequent - lymphadenopathy.

Rare - leukemoid reaction, lymphoma-like disorder, marrow depression.

Metabolic and Nutritional Disorder

Infrequent - dehydration, diabetes mellitus, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypokalemia.

Rare - fat intolerance, glycosuria.

Musculoskeletal System

Infrequent - arthrosis.

Rare - dystonia, exostosis, lupus erythematosus rash, bruising, myopathy, myositis, polyarteritis nodosa, torticollis.

Nervous System

Frequent - abnormal thinking, vertigo.

Infrequent - abnormal coordination, abnormal EEG, abnormal gait, apathy, ataxia, coma, convulsions, delirium, delusion, dyskinesia, dysphonia, encephalopathy, euphoria, extrapyramidal disorder, hallucinations, hostility, hyperkinesia, hypnagogic hallucinations, hypokinesia, leg cramps, manic reaction, neuralgia, paranoia, phobic disorder, psychosis, sensory disturbance, somnambulism, stimulation, suicidal ideation, suicide attempt, teeth-grinding.

Rare - anticholinergic syndrome, aphasia, apraxia, catalepsy, cholinergic syndrome, choreoathetosis, generalized spasm, hemiparesis, hyperesthesia, hyperreflexia, hypoesthesia, illusion, impaired impulse control, indecisiveness, mutism, neuropathy, nystagmus, oculogyric crisis, oculomotor nerve paralysis, schizophrenic reaction, stupor, suicide.

Respiratory System

Infrequent - bronchitis, hyperventilation, increased sputum, pneumonia.

Rare - cyanosis, hemoptysis, hypoventilation, laryngismus.

Skin and Appendages

Infrequent - alopecia, cellulitis, cyst, eczema, erythematous rash, genital pruritus, maculopapular rash, photosensitivity reaction, psoriasis, pustular rash, skin discoloration.

Rare - chloasma, folliculitis, hypertrichosis, piloerection, seborrhea, skin hypertrophy, skin ulceration.

Special Senses

Infrequent - abnormal accommodation, deafness, diplopia, earache, eye pain, foreign body sensation, hyperacusis, parosmia, photophobia, scleritis, taste loss.

Rare - blepharitis, chromatopsia, conjunctival hemorrhage, exophthalmos, glaucoma, keratitis, labyrinth disorder, night blindness, retinal disorder, strabismus, visual field defect.

Urogenital System

Infrequent - endometriosis, epididymitis, hematuria, nocturia, oliguria, ovarian cyst, perineal pain, polyuria, prostatic disorder, renal calculus, renal pain, urethral disorder, urinary incontinence, uterine hemorrhage, vaginal hemorrhage.

Rare - albuminuria, anorgasmy, breast engorgement, breast fibroadenosis, cervical dysplasia, endometrial hyperplasia, premature ejaculation, pyelonephritis, pyuria, renal cyst, uterine inflammation, vulvar disorder.

Postmarketing Experience

The following adverse drug reaction has been reported during post-approval use of Anafranil. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency.

Eye Disorders - Angle-closure glaucoma.

Immune System Disorders - Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

Metabolism and Nutrition Disorders - Hyponatremia.

Endocrine Disorders - Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

What drugs interact with Anafranil (clomipramine)?

  • 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 not 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.

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 coadministration 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.

Monoamine Oxidase Inhibitors (MAOIs)

  • See prescribing information.

Serotonergic Drugs

  • See prescribing information.

Does Anafranil (clomipramine) cause addiction or withdrawal symptoms?

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 drugseeking 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.

Treatment & Diagnosis

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Medically Reviewed on 1/29/2021
References
FDA Prescribing Information

Professional side effects, drug interactions, and addiction sections courtesy of the U.S. Food and Drug Administration.