|
This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(kloe MI pra meen)
Generic Available (U.S.)
Yes
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm085910.pdf, must be dispensed with this medication.
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of obsessive-compulsive disorder (OCD)
Use: Unlabeled/Investigational
Depression, panic attacks, chronic pain
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events were observed in some animal reproduction studies. Withdrawal symptoms (including jitteriness, tremor, and seizures) have been observed in neonates whose mothers took clomipramine up to delivery.
Lactation
Enters breast milk/not recommended (AAP rates “of concern”; AAP 2001 update pending)
Breast-Feeding Considerations
Based on information from three mother-infant pairs, following maternal use of clomipramine 75-150 mg/day, the estimated exposure to the breast-feeding infant would be 0.4% to 4% of the weight-adjusted maternal dose. Adverse events have not been reported in nursing infants (information from seven cases). Infants should be monitored for signs of adverse events; routine monitoring of infant serum concentrations is not recommended.
Contraindications
Hypersensitivity to clomipramine, other tricyclic agents, or any component of the formulation; use of MAO inhibitors within 14 days; use in a patient during the acute recovery phase of MI
Warnings/Precautions
Boxed warnings:
• Suicidal thinking/behavior: See “Major psychiatric warnings” below.
Major psychiatric warnings:
• [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Clomipramine is FDA approved for the treatment of OCD in children ≥10 years of age.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.
• May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Clomipramine is not FDA approved for the treatment of bipolar depression.
Concerns related to adverse effects:
• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is very high relative to other antidepressants.
• Hematologic effects: TCAs may rarely cause bone marrow suppression; monitor for any signs of infection and obtain CBC if symptoms (eg, fever, sore throat) evident.
• Orthostatic hypotension: May cause orthostatic hypotension (risk is moderate relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
• Sedation: May cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is very high relative to other antidepressants.
• Seizures: May cause seizures (relationship to dose and/or duration of therapy); do not exceed maximum doses. Use with caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold.
• Sexual dysfunction: Has been associated with a high incidence of male sexual dysfunction.
• Weight gain: May cause weight gain.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk of conduction abnormalities with this agent is high relative to other antidepressants.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment.
• Thyroid dysfunction: Use with caution in patients with hyperthyroidism or those receiving thyroid supplementation due to concerns of pro-arrhythmogenesis.
Concurrent drug therapy issues:
• Anticholinergic and/or neuroleptic agents: Hyperpyrexia has been observed with TCAs in combination with anticholinergics and/or neuroleptics, particularly during hot weather.
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
• Elderly: Use with caution in the elderly.
Other warnings/precautions:
• Discontinuation of therapy: Recommended to discontinue prior to elective surgery requiring general anesthesia. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.
• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.
Adverse Reactions
Data shown for children reflects both children and adolescents studied in clinical trials.
>10%:
Central nervous system: Dizziness (54%), somnolence (54%), drowsiness, headache (52%; children 28%), fatigue (39%), insomnia (25%; children 11%), malaise, nervousness (18%; children 4%)
Endocrine & metabolic: Libido changes (21%), hot flushes (5%)
Gastrointestinal: Xerostomia (84%, children 63%) constipation (47%; children 22%), nausea (33%; children 9%), dyspepsia (22%; children 13%), weight gain (18%; children 2%), diarrhea (13%; children 7%), anorexia (12%; children 22%), abdominal pain (11%), appetite increased (11%)
Genitourinary: Ejaculation failure (42%), impotence (20%), micturition disorder (14%; children 4%)
Neuromuscular & skeletal: Tremor (54%), myoclonus (13%; children 2%), myalgia (13%)
Ocular: Abnormal vision (18%; children 7%)
Respiratory: Pharyngitis (14%), rhinitis (12%)
Miscellaneous: Diaphoresis increased (29%; children 9%)
1% to 10%:
Cardiovascular: Flushing (8%), postural hypotension (6%), palpitation (4%), tachycardia (4%; children 2%), chest pain (4%), edema (2%)
Central nervous system: Anxiety (9%), memory impairment (9%), twitching (7%), depression (5%), concentration impaired (5%), fever (4%), hypertonia (4%), abnormal dreaming (3%), agitation (3%), confusion (3%), migraine (3%), pain (3%), psychosomatic disorder (3%), speech disorder (3%), yawning (3%), aggressiveness (children 2%), chills (2%), depersonalization (2%), emotional lability (2%), irritability (2%), panic reaction (1%)
Dermatologic: Rash (8%), pruritus (6%), purpura (3%), dermatitis (2%), acne (2%), dry skin (2%), urticaria (1%)
Endocrine & metabolic: Amenorrhea (1%), breast enlargement (2%), breast pain (1%), hot flashes (5%), lactation (nonpuerperal) (4%)
Gastrointestinal: Taste disturbance (8%), vomiting (7%), flatulence (6%), tooth disorder (5%), dysphagia (2%), esophagitis (1%)
Genitourinary: UTI (2% to 6%), micturition frequency (5%), dysuria (2%), leucorrhea (2%), vaginitis (2%), urinary retention (2%)
Neuromuscular & skeletal: Paresthesia (9%), back pain (6%), arthralgia (3%), paresis (children 2%), weakness (1%)
Ocular: Lacrimation abnormal (3%), mydriasis (2%), conjunctivitis (1%)
Otic: Tinnitus (6%)
Respiratory: Sinusitis (6%), coughing (6%), bronchospasm (2%; children 7%), epistaxis (2%)
<1% (Limited to important or life-threatening): Accommodation abnormal, albuminuria, aneurysm, anticholinergic syndrome, aphasia, apraxia, arrhythmia, ataxia, atrial flutter, blepharitis, blood in stool, bradycardia, breast fibroadenosis, bronchitis, bundle branch block, cardiac arrest, cardiac failure, catalepsy, cellulitis, cerebral hemorrhage, cervical dysplasia, cheilitis, cholinergic syndrome, choreoathetosis, chromatopsia, chronic enteritis, coma, conjunctival hemorrhage, cyanosis, deafness, dehydration, delirium, delusion, diabetes mellitus, diplopia, dyskinesia, dysphonia, dystonia, EEG abnormal, encephalopathy, endometrial hyperplasia, endometriosis, epididymitis, erythematous rash, exophthalmos, extrapyramidal disorder, extrasystoles, gastric ulcer, generalized spasm, glaucoma, glycosuria, goiter, gynecomastia, hallucinations, heart block, hematuria, hemiparesis, hemoptysis, hepatitis, hostility, hyperacusis, hypercholesterolemia, hyper-/hypoesthesia, hyperglycemia, hyper-/hypokinesia, hyper-reflexia, hyper-/hypothyroidism, hyperuricemia, hyper-/hypoventilation, hypnagogic hallucination, hypokalemia, ideation, intestinal obstruction, irritable bowel syndrome, keratitis, laryngismus, leukemoid reaction, lupus erythematosus rash, lymphadenopathy, lymphoma-like disorder, maculopapular rash, manic reaction, marrow depression, myocardial infarction, myocardial ischemia, myopathy, myositis, neuralgia, neuropathy, oculogyric crisis, oculomotor nerve paralysis, oral/pharyngeal edema, ovarian cyst, paralytic ileus, paranoia, parosmia, peptic ulcer, peripheral ischemia, phobic disorder, photophobia, photosensitivity reaction, pneumonia, polyarteritis nodosa, premature ejaculation, psychosis, pyelonephritis, pyuria, rectal hemorrhage, renal calculus, renal cyst, schizophrenic reaction, scleritis, seizure, sensory disturbance, skin ulceration, strabismus, stupor, suicidal ideation, suicide, suicide attempt, thrombophlebitis, tongue ulceration, tooth caries, torticollis, urinary incontinence, uterine hemorrhage, uterine inflammation, vaginal hemorrhage, vasospasm, ventricular tachycardia, visual field defect, withdrawal syndrome
Metabolism/Transport Effects
Substrate of CYP1A2 (major), 2C19 (major), 2D6 (major), 3A4 (minor); Inhibits CYP2D6 (moderate)
Drug Interactions
Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification
Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Alpha-/Beta-Agonists (Direct-Acting): Tricyclic Antidepressants may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Exceptions: Dipivefrin. Risk D: Consider therapy modification
Alpha1-Agonists: Tricyclic Antidepressants may enhance the vasopressor effect of Alpha1-Agonists. Risk D: Consider therapy modification
Alpha2-Agonists: Tricyclic Antidepressants may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine; Brimonidine. Risk D: Consider therapy modification
Altretamine: May enhance the orthostatic hypotensive effect of Tricyclic Antidepressants. Risk C: Monitor therapy
Amphetamines: Tricyclic Antidepressants may enhance the stimulatory effect of Amphetamines. Tricyclic Antidepressants may also potentiate the cardiovascular effects of Amphetamines. Risk C: Monitor therapy
Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Levocabastine (Nasal); Paliperidone. Risk C: Monitor therapy
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Aspirin: Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy
Barbiturates: May increase the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification
Beta2-Agonists: Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy
BuPROPion: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy
CarBAMazepine: May increase the serum concentration of ClomiPRAMINE. Risk C: Monitor therapy
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Cimetidine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy
Cinacalcet: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Management: Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates. Risk D: Consider therapy modification
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification
CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Risk C: Monitor therapy
Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Desmopressin: Tricyclic Antidepressants may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy
Dexmethylphenidate: May enhance the adverse/toxic effect of Tricyclic Antidepressants. Dexmethylphenidate may increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
Divalproex: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
DULoxetine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy
Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Grapefruit Juice: May increase the serum concentration of ClomiPRAMINE. Risk C: Monitor therapy
Iobenguane I 123: Tricyclic Antidepressants may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination
Lithium: May enhance the neurotoxic effect of Tricyclic Antidepressants. Risk C: Monitor therapy
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
MAO Inhibitors: May enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. Risk X: Avoid combination
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylene Blue: Tricyclic Antidepressants may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Methylphenidate: May enhance the adverse/toxic effect of Tricyclic Antidepressants. Methylphenidate may increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
Metoclopramide: May enhance the adverse/toxic effect of Tricyclic Antidepressants. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with tricyclic antidepressants for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Risk D: Consider therapy modification
Milnacipran: ClomiPRAMINE may enhance the adverse/toxic effect of Milnacipran. Specifically, the incidence of euphoria and postural hypotension were higher in patients changing from clomipramine to milnacipran. Risk C: Monitor therapy
Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
NSAID (COX-2 Inhibitor): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). Risk C: Monitor therapy
NSAID (Nonselective): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (Nonselective). Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification
Propoxyphene: May enhance the CNS depressant effect of Tricyclic Antidepressants. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QuiNIDine: Tricyclic Antidepressants may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may increase the serum concentration of Tricyclic Antidepressants. Risk D: Consider therapy modification
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination
Sodium Phosphates: Tricyclic Antidepressants may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure and/or loss of consciousness may be increased in patients with significant sodium phosphate induced fluid/electrolyte abnormalities. Risk C: Monitor therapy
St Johns Wort: May increase the metabolism of Tricyclic Antidepressants. The risk of serotonin syndrome may theoretically be increased. Risk D: Consider therapy modification
Sulfonylureas: Cyclic Antidepressants may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Risk D: Consider therapy modification
Terbinafine: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification
Terbinafine (Systemic): May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Toremifene: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Toremifene. The risk for potentially dangerous arrhythmias may be increased. Risk X: Avoid combination
TraMADol: Tricyclic Antidepressants may enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. Risk C: Monitor therapy
Valproic Acid: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
Vandetanib: QTc-Prolonging Agents may enhance the arrhythmogenic effect of Vandetanib. Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): Tricyclic Antidepressants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Yohimbine: Tricyclic Antidepressants may increase the serum concentration of Yohimbine. Risk C: Monitor therapy
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Food: Serum concentrations/toxicity may be increased by grapefruit juice.
Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava.
Mechanism of Action
Clomipramine appears to affect serotonin uptake while its active metabolite, desmethylclomipramine, affects norepinephrine uptake
Pharmacodynamics/Kinetics
Absorption: Rapid
Protein binding: 97%, primarily to albumin
Metabolism: Hepatic to desmethylclomipramine (DMI; active); extensive first-pass effect
Half-life elimination: Clomipramine: mean 32 hours (19-37 hours); DMI: mean 69 hours (range 54-77 hours)
Time to peak, plasma: 2-6 hours
Excretion: Urine and feces
Dosage
Oral:
Children:
<10 years: Safety and efficacy have not been established.
≥10 years: OCD:
Initial: 25 mg/day; may gradually increase as tolerated over the first 2 weeks to 3 mg/kg/day or 100 mg/day (whichever is less) in divided doses
Maintenance: May further increase to recommended maximum of 3 mg/kg/day or 200 mg/day (whichever is less); may give as a single daily dose at bedtime once tolerated
Adults: OCD:
Initial: 25 mg/day; may gradually increase as tolerated over the first 2 weeks to 100 mg/day in divided doses
Maintenance: May further increase to recommended maximum of 250 mg/day; may give as a single daily dose at bedtime once tolerated
Administration: Oral
During titration, may divide doses and administer with meals to decrease gastrointestinal side effects. After titration, may administer total daily dose at bedtime to decrease daytime sedation.
Monitoring Parameters
Pulse rate and blood pressure prior to and during therapy; ECG/cardiac status in older adults and patients with cardiac disease; suicidal ideation (especially at the beginning of therapy, after initiation, or when doses are increased or decreased)
Test Interactions
Increased glucose; may interfere with urine detection of methadone (false-positive)
Patient Education
Take multiple dose medication with meals to reduce side effects. Take single daily dose at bedtime to reduce daytime sedation. The effect of this drug may take several weeks to appear. Do not use alcohol. May cause weight gain, dizziness, drowsiness, headache, seizures, dry mouth or unpleasant aftertaste, constipation, or orthostatic hypotension. Report unresolved constipation or GI upset, unusual muscle weakness, palpitations, or persistent CNS disturbances (hallucinations, suicidality, seizures, delirium, insomnia, or impaired gait).
Geriatric Considerations
Not approved as an antidepressant, clomipramine's anticholinergic and hypotensive effects limit its use versus other preferred antidepressants. Elderly patients were found to have higher dose-normalized plasma concentrations as a result of decreased demethylation (decreased 50%) and hydroxylation (25%).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation). Long-term treatment with TCAs, such as clomipramine, increases the risk of caries by reducing salivation and salivary buffer capacity.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Use with caution; epinephrine and levonordefrin have been shown to have an increased pressor response in combination with TCAs. Clomipramine is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be used with caution.
Dental Comment
Clomipramine is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”). Clomipramine is considered as having a risk of causing torsade de pointes. Since it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval, a medical consult is suggested.
Mental Health: Comment
Tricyclic antidepressants may be classified as tertiary (amitriptyline, doxepin, clomipramine, imipramine, trimipramine) or secondary amines (nortriptyline, desipramine, protriptyline). The tertiary amines are not recommended to treat depression in the elderly. If a TCA is used in the elderly, it should be a secondary amine. The tertiary amines are commonly used in low dosages for various conditions associated with pain. Toxicity is generally dose dependent. Relatively small overdoses (1-week supply) can be potentially fatal.
Seizures are dose dependent. The overall cumulative incidence is 0.7%. Doses ≤250 mg/day have an incidence of 0.5% and doses ≥300 mg/day have an incidence of 2.1%.
Nursing: Physical Assessment/Monitoring
Observe for clinical worsening, suicidality, or unusual behavior changes, especially during the initial few months of therapy or during dosage changes. If history of cardiac problems, monitor cardiac status closely. Be alert to the potential of new or increased seizure activity. Instruct family or caregiver to observe the patient's behavior closely and communicate any changes to prescriber. Taper dosage slowly when discontinuing.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral, as hydrochloride: 25 mg, 50 mg, 75 mg
Anafranil®: 25 mg, 50 mg, 75 mg
Pricing: U.S. (www.drugstore.com)
Capsules (Anafranil)
25 mg (60): $789.98
50 mg (30): $380.35
Capsules (ClomiPRAMINE HCl)
50 mg (60): $33.99
References
American Academy of Pediatrics Committee on Drugs, "Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics, 2001, 108(3):776-89.
Boakes AJ, Laurence DR, Teoh PC, et al, “Interactions Between Sympathomimetic Amines and Antidepressant Agents in Man,” Br Med J, 1973, 1(849):311-5.
Bocksberger JP, Gex-Fabry M, Gauthey L, et al, “Clomipramine Therapy in the Geriatric Hospital: Experience With Therapeutic Drug Monitoring,” Ther Drug Monit, 1994, 16(2):113-9.
Cano-Munoz JL, Montejo-Iglesias ML, Yanez-Saez RM, et al, “Possible Serotonin Syndrome Following the Combined Administration of Clomipramine and Alprazolam,” J Clin Psychiatry, 1995, 56(3):122.
Dale O and Hole A, “Biphasic Time-Course of Serum Concentrations of Clomipramine and Desmethylclomipramine After a Near-Fatal Overdose,” Vet Hum Toxicol, 1994, 36(4):309-10.
Fortinguerra F, Clavenna A, and Bonati M, "Psychotropic Drug Use During Breastfeeding: A Review of the Evidence," Pediatrics, 2009, 124(4):547-56.
Hernandez AF, Montero MN, Pla A, et al, “Fatal Moclobemide Overdose or Death Caused by Serotonin Syndrome?” J Forensic Sci, 1995, 40(1):128-30.
Jastak JT and Yagiela JA, “Vasoconstrictors and Local Anesthesia: A Review and Rationale for Use,” J Am Dent Assoc, 1983, 107(4):623-30.
Kuisma MJ, “Fatal Serotonin Syndrome With Trismus,” Ann Emerg Med, 1995, 26(1):108.
Lancelin F, Kraoul L, Flatischler N, et al, “False-Positive Results in the Detection of Methadone in Urines of Patients Treated With Psychotropic Substances,” Clin Chem, 2005, 51(11):2176-7.
Larochelle P, Hamet P, and Enjalbert M, “Responses to Tyramine and Norepinephrine After Imipramine and Trazodone,” Clin Pharmacol Ther, 1979, 26(1):24-30.
Larrey D, Rueff B, Pessayre D, et al, “Cross Hepatotoxicity Between Tricyclic Antidepressants,” Gut, 1986, 27(6):726-7.
Lejoyeux M, et al, “Serotonin Syndrome: Incidence, Symptoms, and Treatment,” CNS Drugs, 1994, 2:132-43.
Ljungren B and Bojs G, “A Case of Photosensitivity and Contact Allergy to Systemic Tricyclic Drugs, With Unusual Features,” Contact Dermatitis, 1991, 24(4):259-65.
Mitchell JR, “Guanethidine and Related Agents. III Antagonism by Drugs Which Inhibit the Norepinephrine Pump in Man,” J Clin Invest, 1970, 49(8):1596-604.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
Pass SE and Simpson RW, “Discontinuation and Reinstitution of Medications During the Perioperative Period,” Am J Health Syst Pharm, 2004, 61(9):899-912.
Roberge RJ, Martin TG, Hodgman M, et al, “Acute Chemical Pancreatitis Associated With a Tricyclic Antidepressant (Clomipramine) Overdose,” J Toxicol Clin Toxicol, 1994, 32(4):425-9.
Rundegren J, van Dijken J, Mörnstad H, et al, “Oral Conditions in Patients Receiving Long-Term Treatment With Cyclic Antidepressant Drugs,” Swed Dent J, 1985, 9(2):55-64.
Schimmell MS, Katz E, Shaag Y, et al, “Toxic Neonatal Effects Following Maternal Clomipramine Therapy,” J Toxicol Clin Toxicol, 1991, 29(4):479-84.
Sternbach H, “Fluoxetine-Clomipramine Interaction,” J Clin Psychiatry, 1995, 56(4):171-2.
Svedmyr N, “The Influence of a Tricyclic Antidepressive Agent (Protriptyline) on Some of the Circulatory Effects of Noradrenaline and Adrenalin® in Man,” Life Sci, 1968, 7(1):77-84.
Swanson-Biearman B, Goetz CM, Dean BS, et al, “Anafranil® Overdose: A Fatal Outcome,” Vet Hum Toxicol, 1989, 31:378.
Tueth MJ, “The Serotonin Syndrome in the Emergency Department,” Ann Emerg Med, 1993, 22(8):1369.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
| 
