Clomipramine: Difference between revisions

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|alcohol=Alcohol-Clomipramine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=Alcohol-Clomipramine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
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{{Drugbox|
|IUPAC_name = ?
| image=Clomipramine.svg
| width=150
| CAS_number=303-49-1
| ATC_prefix=N06
| ATC_suffix=AA04
| ATC_supplemental=
| PubChem=2801
| DrugBank=APRD00253
| C=19 | H=23 | Cl=1 | N=2
| molecular_weight = 314.9
| bioavailability= Oral ~50%
| metabolism = [[Hepatic]]
| elimination_half-life= Clomipramine ~35 hours <br>Desmethylclomipramine (main active metabolite) ~50 hours
| excretion = [[Renal]]
| pregnancy_category = C (U.S.)<ref>http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1895</ref><br> May cause withdrawal symptoms in newborn.
| legal_status = Rx only, unscheduled
| routes_of_administration= Oral, I.M., I.V.
}}
'''Clomipramine''' (brand-name '''Anafranil'''®) is a [[tricyclic antidepressant]]. It was developed in the 1960s by the Swiss drug manufacturer Geigy (now known as [[Novartis]]) and has been in clinical use worldwide for decades.
==Indications==
*[[clinical depression|Depression]] with lack of energy or '''mild''' agitation
*[[Obsessive compulsive disorder]] (OCD)
*[[Panic attacks]] with or without [[agoraphobia]]
*[[Narcolepsy]]
*[[Chronic pain]] with or without organic disease, particular headache of the tension type
*[[Bedwetting|enuresis]] (involuntary nightly urinating in sleep) in children and adolescents
*Off label: sometimes antidepressants of this type have been found helpful in reducing relapses in cocaine addicts and to help repair cocaine-caused [[neurotransmitter]] imbalances and early brain damage. Further studies are needed for clomipramine in this regard.
It may take 2 to 3 weeks before the full effects of this medication are noticed in all indications.
Along with [[SSRIs]], clomipramine is a frequently prescribed drug for the treatment of OCD.  As is typical with the older tricyclic antidepressants, it has more side effects than SSRIs, so some authorities regard it as a second-line treatment to be used if treatment with SSRIs fails.  However, disregarding side effects, it may be slightly more effective in combatting the symptoms of OCD.  It is not commonly used for treating depression, and usually another tricyclic (or drug from a different class) would be used. Clomipramine and the SSRIs (specifically Paroxetine) have also been used to treat premature ejaculation.
==Contraindications==
*Concomitant therapy with an (irreversible) [[Monoamine oxidase inhibitor|MAO inhibitor]] (e.g. [[tranylcypromine]], [[phenelzine]])
*Acute intoxication with central depressants (alcohol, psychoactive drugs, narcotics)
*States of confusion (caution), absolutely contraindicated in patients with coma and [[delirium tremens]]
*Patients with severe agitation or anxiety (give sedative drugs concomitantly)
*Hypersensitivity/allergy against clomipramine or other related tricyclic compounds
*Hypertrophy of the prostate with [[urinary retention|urine retention]] (=difficulty in urinating)
*Caution: hypertrophy of the prostate without urine retention
*Preexisting [[glaucoma|closed angle glaucoma]]
*Epilepsy and other conditions which lower the seizure threshold (alcohol-withdrawal, active brain tumors)
*Serious liver disease (elimination is decreased), if clomipramine is given consider dose reduction
*Serious kidney disease (elimination is decreased), if clomipramine is given consider dose reduction
*Severe [[hypotension]], shock, serious cardiovascular dysfunction (postinfarctous states, heart insufficience, arrhythmias), avoid high oral doses or injections/infusions
*Preexisting bone marrow depression ([[leukopenia]], [[thrombocytopenia]], [[anemia]], [[pancytopenia]]), can be worsened by clomipramine
*[[Hyperthyroidism]] (overfunction of the thyroid gland) makes the patient more sensitive to side effects of clomipramine. Cautious doses should be used and the overfunction should be treated.
*Caution should be exerted when treating pediatric patients under 18 years of age
==Pharmacology==
Clomipramine is the 3-chloro derivative of [[imipramine]].  Clomipramine is a strong, but not completely [[selective serotonin reuptake inhibitor]] (SSRI), as the primary active metabolite desmethylclomipramine acts preferably as [[norepinephrine reuptake inhibitor]].  Other hydroxy-metabolites are also active. [[Adrenergic receptor|α<sub>1</sub> receptor]] blockage and beta receptor downregulation as well as postsynaptic [[receptor antagonist|antagonism]] on [[H1 receptor]]s have been noted.
As with other tricyclics, downregulation of [[NMDA receptor]]s may also account for its effects.
Clomipramine has the disadvantage of a higher incidence of [[seizures]] than seen with other tricyclic antidepressants (up to a dose of 250mg daily in 0,5%, more than 300 mg in 2%). {{Fact|date=February 2007}}
Some studies have indicated that clomipramine is slightly more effective in the treatment of depression than other tricyclics {{Fact|date=February 2007}}.
==Side effects==
Clomipramine may have a broad range of side effects:
*central nervous system: Often, fatigue, dizziness, lightheadedness, headaches, confusion, agitation, [[insomnia]], nightmares, increased anxiety, seizures (0,5% to 2%, see above), rarely [[hypomania]] or induction of [[schizophrenia]] (immediate termination of therapy required), and [[Extrapyramidal system|extrapyramidal]] side-effects (pseudoparkinsonism, [[dyskinesia]], rarely [[tardive dyskinesia]]) are noted.
*[[Anticholinergic]] side effects in different grades of severity are quite common: dry mouth, constipation, rarely [[ileus]] (paralysis of the large intestine, life-threatening), difficulties in urinating, sweating, precipitation of glaucoma (may lead to permanent eye-damage or even blindness, if untreated). The incidence of dental [[caries]] may be increased due to dry mouth.
*[[adrenergic|antiadrenergic]] side effects occur very frequently due to strong central and peripheral blockage of alpha receptors: hypotension, postural collapse (when patient is rising too fast from lying or sitting position to standing), arrhythmias ([[sinus tachycardia]], [[bradycardia]], AV block, rarely other forms of cardiac problems). Preexisting heart insufficiency can be worsened.
Most of these side-effects are dose related and/or tolerance will develop with continued use.
*Allergic/toxic: skin reactions and [[photosensitivity]] with increased frequency of sunburns are seen in a few percentage of cases. Rarely liver damage of the cholostatic type, [[hepatitis]], and leukopenia or other forms of blood dyskrasia are seen, also severe acute allergy including difficulties in breathing, skin reaction, chest pain etc.
*Other side effects may include [[heartburn]], weight gain, but also nausea and [[bruxism]] - teeth-grinding while asleep - (the latter due to the strong inhibition of reuptake of [[serotonin]]).
*The drug often causes sexual problems in men (e.g. impotence, ejaculation difficulties). In about 5% of patients, it can instead cause inadvertent orgasms when yawning.<ref>[http://www.snopes.com/risque/aphrodisiacs/yawn.asp "Yin, Yang and Yawn"] - Snopes article on Clomipramine</ref>
==Drug abuse and dependence==
Clomipramine has no known potential for abuse and dependence. It is not a controlled substance.
Withdrawal symptoms occurring when clomipramine is stopped abruptly (agitation, fatigue, nausea, headaches, insomnia, sometimes activation of mania and rebound of depression or anxiety) is not indicative of dependence and can be avoided, if clomipramine is gradually withdrawn by reducing the daily dose by approximately 25% weekly. If medical reasons dictate an immediate termination of treatment, a short-term course of [[benzodiazepine]]s (up to four weeks as needed) will usually suppress the unpleasant withdrawal symptoms.
==Other reasons for caution==
Depression itself can lead to thoughts or attempts of suicide. Emotionally unstable patients or those with suicidal thoughts should receive the smallest amount of the drug feasible. Often cotreatment with a sedative drug (e.g. a benzodiazepine or [[chlorprothixene]]) is necessary until remission of depression is evident.
Caution is advised when using clomipramine in the elderly, because they may be more sensitive to the effects of the drug (e.g., confusion may occur or worsen). Clomipramine should be used during pregnancy only if clearly needed. It is excreted into breast milk. The effects on the infant are not known at this time.
==Drug interactions==
Clomipramine shows a number of clinical significant interactions, either due to central depressant or stimulant activity of the other drug or due to interference of the other drug with the metabolization and elimination of clomipramine or vice versa. Some examples are:
*MAO inhibitors (e.g., [[furazolidone]], [[linezolid]], [[phenelzine]], [[selegiline]], [[tranylcypromine]]): severe reactions including central excitation, [[hypertensive crisis]], bizarre behaviour, psychosis, seizures, coma and death are possible. [[Serotonin syndrome]] is likely.
*Central stimulants: Potentially dangerous central excitation with agitation and anxiety may be encountered.
*[[SSRI]] type antidepressants (eg. [[fluoxetine]]): Side effects of clomipramine are increased.
*Drugs with central depressant activity (tranquilizers, alcohol, narcotics): Increased central depression (dizziness, drowsiness etc.) is frequently noted.
*Antihypertensive drugs: The risk of hypotension, collapse, and tachycardia is increased.
*Interactions with [[Over-the-counter drug|OTC]] medications against colds and sleeping aids with [[diphenhydramine]], [[doxylamine]] and [[St. John's wort]] may occur.
==Dosage==
Initial doses are usually 25 mg 2 or 3 times daily or 75 mg once daily in slow released form. The dose may be increased in regular intervals (the usual dose per day is 100 to 225 mg). Doses up to 300 mg may be used, but these are associated with an increased risk of seizures. This medication may be taken with food to prevent stomach upset.
In hospitalized patients initial [[intramuscular]] injections and very slow [[intravenous]] infusions can be used, but the risk of hypotension and seizures may be increased with parental drug use. The advantage is that the onset of action may be faster.
Usually, clomipramine needs some weeks to reach its maximum effects and needs to be given as longterm treatment, sometimes for life (narcolepsy). Sometimes, in patients with narcolepsy the full effect of clomipramine is not sufficient. In these cases treatment with clomipramine should be terminated gradually and a commonly used central stimulant (e.g. [[modafinil]], [[methylphenidate]] or [[methamphetamine]]) tried instead.
Clomipramine is not able to elevate the mood of non-depressive persons and any unindicated use may be dangerous.
==Overdose==
{{main|Tricyclic antidepressant}}
If overdose is suspected, contact your local [[poison control center]] or emergency room immediately. [[United States]] residents can call the US national poison hotline at 1-800-222-1222. Other worldwide poison centers can be found at the [http://www.who.int/ipcs/poisons/centre/directory/en/ World directory of poisons centers]
Ten out of 12 patients presenting with manifest clomipramine overdose survived with appropriate treatment. These 10 patients took clomipramine doses of up to 5 grams. The 2 patients who died ingested 5.75 and 7 grams, respectively. Outside the US one patient died who took only 0.75 grams. Lethal doses may be lower, if other drugs have been taken in an overdose, too, particular central nervous depressants.{{Fact|date=February 2007}}
The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.
==Veterinary uses==
Clomipramine is widely used for the treatment of disturbed behaviour of dogs, cats, and horses.  Marketed by Novartis for veterinary use under the name 'Clomicalm', clomipramine is given orally and is indicated for:
"Treatment of stereotypic behaviours (obsessive-compulsive disorders) in dogs such as acral lick dermatitis, excessive grooming and tail chasing. An aid in the treatment of anxiety disorders in dogs such as destructiveness, excessive vocalisation, loss of toilet control, associated with separation anxiety. An aid in the treatment of urine spraying in desexed and female cats." (Product Information for Clomicalm, Novartis Animal Health Australasia Pty Limited).
==Brands==
*Anafranil® registered TM of [[Mallinckrodt]] in the United States
*Anafranil® registered TM of Novartis, sold worldwide
*generics
==References==
<references/>
{{Antidepressants}}
[[Category:Tricyclic antidepressants]]
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[[ja:塩酸クロミプラミン]]
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[[sv:Klomipramin]]
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Revision as of 14:05, 14 May 2014

Clomipramine
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2]

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Overview

Clomipramine is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

4>Obsessive-compulsive disorder
  • Monotherapy
  • Maximum, 250 mg/day[1]
  • Combination Therapy
  • Initial dose, 25 mg/day; weekly titration up to 75 mg/day; mean dose, 55 mg/day) plus fluoxetine (maximum dose, 40 mg/day), quetiapine initial dose, 50 mg/day; weekly titration up to 200 mg/day; mean dose, 142 mg/day

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition 1

  • Developed by: (Organization)
  • Class of Recommendation: (Class) (Link)
  • Strength of Evidence: (Category A/B/C) (Link)
  • Dosing Information/Recommendation
  • (Dosage)

Non–Guideline-Supported Use

Delusional disorder

  • Initial, 25 mg/day ORALLY, may increase dosage to 100 mg/day during the first 2 weeks (MAX dose 250 mg/day, mean dose 140 mg/day)

Depression

  • Initial, 75 mg/day ORALLY (3 divided doses); may increase dosage slowly as needed and tolerated to a range of 100-250 mg/day (3 divided doses)

Disorder of ejaculation

Obsessive-compulsive disorder, Intravenous therapy

  • Initial, 25 mg/day ORALLY, may increase dosage to 100 mg/day ORALLY during the first 2 weeks; MAX dose 250 mg/day

Pain, chronic

Panic disorder

  • 25-75 mg/day ORALLY

Pervasive developmental disorder

  • There is limited information about Off-Label Non–Guideline-Supported Use of Clomipramine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Obsessive-compulsive disorder

  • 10 years and older, initial, 25 mg/day ORALLY, may increase dosage to 3 mg/kg or 100 mg/day (whichever is less) ORALLY during the first 2 weeks; MAX dose 200 mg/day OR 3 mg/kg/day (whichever is less)

Off-Label Use and Dosage (Pediatric)

Non–Guideline-Supported Use

  • Safety and effectiveness in children less than 10 years of age have not been established [2]

Depression

  • 20-30 mg/day ORALLY; may increase dosage by 10 mg/day at 4-5 day intervals as needed and tolerated
  • There is limited information about Off-Label Non–Guideline-Supported Use of Clomipramine in pediatric patients.

Contraindications

  • Condition 1
  • Condition 2
  • Condition 3
  • Condition 4
  • Condition 5

Warnings

Conidition 1

(Description)

Adverse Reactions

Clinical Trials Experience

Central Nervous System

(list/description of adverse reactions)

Cardiovascular

(list/description of adverse reactions)

Respiratory

(list/description of adverse reactions)

Gastrointestinal

(list/description of adverse reactions)

Hypersensitive Reactions

(list/description of adverse reactions)

Miscellaneous

(list/description of adverse reactions)

Postmarketing Experience

Central Nervous System

(list/description of adverse reactions)

Cardiovascular

(list/description of adverse reactions)

Respiratory

(list/description of adverse reactions)

Gastrointestinal

(list/description of adverse reactions)

Hypersensitive Reactions

(list/description of adverse reactions)

Miscellaneous

(list/description of adverse reactions)

Drug Interactions

  • (Drug 1)
  • (Description)
  • (Drug 2)
  • (Description)
  • (Drug 3)
  • (Description)

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Clomipramine in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clomipramine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Clomipramine during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Clomipramine in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Clomipramine in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Clomipramine in geriatric settings.

Gender

There is no FDA guidance on the use of Clomipramine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Clomipramine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Clomipramine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Clomipramine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Clomipramine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Clomipramine in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Clomipramine Administration in the drug label.

Monitoring

There is limited information regarding Clomipramine Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Clomipramine and IV administrations.

Overdosage

There is limited information regarding Clomipramine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Clomipramine Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Clomipramine Mechanism of Action in the drug label.

Structure

There is limited information regarding Clomipramine Structure in the drug label.

Pharmacodynamics

There is limited information regarding Clomipramine Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Clomipramine Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Clomipramine Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Clomipramine Clinical Studies in the drug label.

How Supplied

There is limited information regarding Clomipramine How Supplied in the drug label.

Storage

There is limited information regarding Clomipramine Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Clomipramine |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Clomipramine |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Clomipramine Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Clomipramine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Clomipramine Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Clomipramine Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ Flament MF, Rapoport JL, Berg CJ, Sceery W, Kilts C, Mellström B et al. (1985) Clomipramine treatment of childhood obsessive-compulsive disorder. A double-blind controlled study. Arch Gen Psychiatry 42 (10):977-83. PMID: 3899048
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