Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In China, Europe, Japan, and US.

European Pharmacopoeia, 6th ed. (Clomipramine Hydrochloride). A white or slightly yellow, slightly hygroscopic, crystalline powder. Freely soluble in water and in dichloromethane soluble in alcohol. A 10% solution in water has apH of 3.5 to 5.0. Protect from light.

The United States Pharmacopeia 31, 2008 (Clomipramine Hydrochloride). A white to faintly yellow crystalline powder. Very soluble in water. pH of a 10% solution in water is between 3.5 and 5.0.

Adverse Effects, Treatment, and Precautions

As for tricyclic antidepressants in general (see amitriptyline“>Amitriptyline).

Breast feeding. For comments on the use of tricyclic antidepressants in breast feeding patients, see under Precautions for Amitriptyline.

Porphyria. Clomipramine is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in in-vitro systems, although there is conflicting evidence of porphyrinogenicity.

Interactions

For interactions associated with tricyclic antidepressants, see Amitriptyline.

MAOIs. The combination of clomipramine and tranylcypromine is considered particularly hazardous. The serotonin syndrome has occurred in patients receiving clomipramine and moclobemide (see under Interactions of Antidepressants in Phenelzine).

Pharmacokinetics

Clomipramine is readily absorbed from the gastrointestinal tract, and extensively demethylated during first-pass metabolism in the liver to its primary active metabolite, desmethylclomipramine. Clomipramine and desmethylclomipramine are widely distributed throughout the body and are extensively bound to plasma and tissue protein. Clomipramine has been estimated to have a plasma elimination half-life of about 21 hours, which may be considerably extended in overdosage that of desmethylclomipramine is longer (about 36 hours).

Paths of metabolism of both clomipramine and desmethylclomipramine include hydroxylation and N-oxidation. About two-thirds of a single dose of clomipramine is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form the remainder of the dose is excreted in the faeces. Clomipramine crosses the placenta and is distributed into breast milk.

Uses and Administration

Clomipramine is a dibenzazepine tricyclic antidepressant with actions and uses similar to those of amitriptyline. It has antimuscarinic properties and is also a potent serotonin reuptake inhibitor. Clomipramine is one of the more sedating tricyclics. It is used as the hydrochloride.

In the treatment of depression in adults, clomipramine hydrochloride is given in oral doses of 10 mg daily initially, increasing gradually to 30 to 150 mg daily if required up to 250 mg daily or higher may be given in severe cases. A suggested initial dose for the elderly is 10 mg daily increasing gradually over 10 days to 30 to 75 mg daily if required. Clomipramine may be given in divided doses throughout the day, but since it has a prolonged half-life, once-daily dosage regimens are also suitable, usually given at night.

In the treatment of obsessive-compulsive disorder and phobias, clomipramine hydrochloride may be given in an initial oral dose of 25 mg daily (or 10 mg daily for elderly patients or those sensitive to tricyclics) increased gradually over two weeks to 100 to 150 mg daily. In some countries, maximum doses of 250 mg daily have been used. Similar doses have also been used in the management of panic disorder. In some countries clomipramine hydrochloride is also used for the treatment of obsessive-compulsive disorder in children and adolescents aged 10 years and over (see below for doses).

In some countries clomipramine may be given for depression or obsessive-compulsive disorder by the intramuscular or intravenous routes if giving it orally is impracticable or inadvisable. The initial dose of clomipramine hydrochloride by intramuscular injection is 25 to 50 mg daily, increasing to a maximum of 100 to 150 mg daily oral dosage should be substituted as soon as possible. Clomipramine hydrochloride may also be given by intravenous infusion in doses of 50 to 75 mg daily diluted in 250 to 500 mL of sodium chloride 0.9% or glucose 5% and infused over 1.5 to 3 hours. When a satisfactory response to parenteral doses has been obtained oral therapy should be substituted, initially giving double the parenteral dose by mouth and subsequently adjusting if necessary. Patients must be carefully supervised during intravenous infusion of clomipramine hydrochloride and the blood pressure carefully monitored owing to the risk of hypotension.

In the adjunctive treatment of cataplexy associated with narcolepsy, clomipramine hydrochloride is given in an initial oral dose of 10 mg daily and gradually increased until a satisfactory response occurs, usually within the range of 10 to 75 mg daily.

Clomipramine should be withdrawn gradually to reduce the risk of withdrawal symptoms.

Administration in children. In the UK, the use of clomipramine in children under 18 years is not recommended in the treatment of depressive states, phobias, or cataplexy associated with narcolepsy. However, in some countries clomipramine hydrochloride is used for the treatment of obsessive-compulsive disorder in children and adolescents aged 10 years and over. Initial oral doses are 25 mg daily, increased gradually during the first 2 weeks to a maximum daily dose of 3 mg/kg or 100 mg, whichever is smaller, and given in divided doses. Further increases are permitted, over several weeks to a maximum daily dose of 3 mg/kg or 200 mg, whichever is smaller. Once titration has been achieved the dose may be given as a single dose at bedtime.

Clomipramine hydrochloride is also licensed for oral use in the management of nocturnal enuresis in some countries (for a discussion of tricyclic use in nocturnal enuresis see Micturition Disorders under Amitriptyline). The age ranges and licensed doses vary somewhat from country to country, however. For example, in France, use is licensed in children over 6 years of age, at a daily dose of 10 to 30 mg, or 0.5 to 1 mg/kg, whereas in Austria and Switzerland the licensed dose is: 6 to 8 years, 20 to 30 mg 9 to 12 years, 25 to 50 mg over 12 years, 25 to 75 mg.

Anxiety disorders. Tricyclic antidepressants that inhibit serotonin reuptake, such as clomipramine and imipramine, have been given in the management of anxiety disorders including obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and trichotillomania.

Autism. Clomipramine reduced adventitious movements when tried in 5 boys with autistic disorder. However, in a small study in 7 children no improvement in symptoms was noted and adverse effects were common and serious. In another study, although clomipramine was found to be as effective as haloperidol in the treatment of some autistic symptoms, patients on clomipramine were significantly less likely to complete the trial for reasons that included the onset of adverse effects.

Micturition disorders. In some countries, clomipramine is used in children for the treatment of nocturnal enuresis for further details, see Administration in Children, above.

Pain. Antidepressants, usually amitriptyline or another tricyclic, are useful in alleviating some types of pain (see Choice of Analgesic). In a number of countries, clomipramine hydrochloride is licensed for the treatment of chronic pain oral doses range from 10 to 150 mg daily. Parenteral doses are licensed in some countries.

Premenstrual syndrome. Clomipramine reduced premenstrual irritability and depressed mood when given during the luteal phase doses of clomipramine ranged from 25 to 75 mg daily. It was postulated that the efficacy of clomipramine in relieving premenstrual symptoms is related to its serotonin reuptake inhibitor activity. For the overall management of premenstrual syndrome.

Sexual dysfunction. Clomipramine has been used for its inhibitory effect on ejaculation in the management of premature ejaculation. In some men with very short latencies (less than 1 minute) continuous therapy with a low daily dose of clomipramine, typically 20 or 30 mg, may be more effective than taking 25 mg as required. Any benefits may relate to its effect as a serotonin reuptake inhibitor other antidepressants with serotonin reuptake inhibiting actions, such as fluoxetine and sertraline, have also been tried in this condition.

Stuttering. Clomipramine was of modest success in a controlled study of 17 patients with developmental stuttering. It was suggested that its efficacy may be related to its serotonin reuptake inhibitor activity.

Preparations

British Pharmacopoeia 2008: Clomipramine Capsules

The United States Pharmacopeia 31, 2008: Clomipramine Hydrochloride Capsules.

Proprietary Preparations

Argentina: Anafranil Clomipram †

Australia:: Anafranil Clopram Placil

Austria: Anafranil

Belgium: Anafranil

Brazil: Anafranil Clo Clomipran

Canada: Anafranil Novo-Clopamine †

Chile: Anafranil Atenual Ausentron Deprelin

Czech Republic: Anafranil Hydiphen †

Denmark: Anafranil

Finland: Anafranil

France: Anafranil

Germany: Anafranil Hydiphen †

Greece: Anafranil

Hong Kong: Anafranil Zoiral

Hungary: Anafranil

India: Anafranil

Indonesia: Anafranil

Ireland: Anafranil

Israel: Anafranil Maronil

Italy: Anafranil

Malaysia: Anafranil

Mexico: Anafranil

The Netherlands: Anafranil

Norway: Anafranil

New Zealand: Anafranil Clopress

Philippines: Anafranil

Poland: Anafranil Hydiphen

Portugal: Anafranil

Russia: Anafranil Clofranil

South Africa: Anafranil Clomidep Equinorm

Singapore Anafranil

Spain: Anafranil

Sweden: Anafranil

Switzerland: Anafranil

Thailand: Anafranil Clofranil †

Turkey: Anafranil

UK: Anafranil

USA: Anafranil

Venezuela: Anafranil.

Answer. The short, no-frills answer to your question is that any of the major antidepressants or anxiolytics are probably safe, now that the most vulnerable period of organ-formation (the first trimester) has passed. I see no reason why Zoloft and/or Klonopin could not be restarted, if the clinical situation is severe enough to warrant the modest risks. An OB/GYN consult is always a reasonable precaution, but I would not necessarily be governed by it, if you believe your patient must be on a medication. If you care to read on, here is the more complicated story:

With respect to antidepressants (ADs) in pregnancy, most data come from studies of tricyclics and fluoxetine(Prozac); we have only a modicum of information about newer agents such as sertraline (Zoloft), paroxetine (Paxil), venlafaxine (Effexor) and nefazodone (Serzone). The tricyclics (e.g., desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor)) appear to have little potential for teratogenicity. Similarly, a recent study by Pastuszak and colleagues (1993) found no evidence of teratogenicity in 128 women taking fluoxetine during the first trimester, when compared to matched controls. While there was a trend toward higher miscarriage rates in the fluoxetine group compared to controls taking known non-teratogens, the risk was small (relative risk, 1.9) and comparable to that of tricyclics. (Interestingly, depression itself may also raise the risk of miscarriage). A recent study by Chambers et al. (New England Journal of Medicine 1996, vol. 335, pp. 1010-1015) found no significant differences between fluoxetine-treated pregnant women and controls in spontaneous pregnancy loss or major structural anomalies; however, the incidence of three or more minor anomalies was significantly higher in the fluoxetine cohort.

This study has been widely criticized, however, on a number of methodologic grounds. The more anticholinergic tricyclics (e.g., amitriptyline, doxepin) can occasionally induce fetal tachyarrythmias, urinary retention or intestinal obstruction. Clomipramine (Anafranil), a tricyclic used mainly in the treatment of obsessive-compulsive disorder, also has substantial anticholinergic effects, and would be expected to produce similar effects in the neonate. Wisner et al (1993) found that the doses of tricyclic antidepressant required to achieve remission actually increased during the second half of pregnancy, reaching 1.6 times the mean dose required when the patients were not pregnant. This was attributed, in part, to enhanced hepatic metabolism of antidepressants during pregnancy and to increased volume of distribution. Neonatal irritability, tachypnea, tremor and hypotonia may result from either tricyclic toxicity or withdrawal. It is therefore prudent to monitor maternal blood levels of tricyclics throughout pregnancy and gradually to reduce the dosage during the week before delivery.

Little is known about the excretion of antidepressants into breast milk or the effects of this on the nursing infant. Some studies indicate that several antidepressants or their metabolites can accumulate in breast milk, possibly peaking at about 4-6 hours after an oral dose. (See the review by Wisner et al. in the September 1996 issue of the American Journal of Psychiatry). It is not clear to what extent antidepressants accumulate in the blood of the nursing infant or whether significant adverse effects result from such accumulation. Wisner et al. (1996) conclude that sertraline is a good choice, with respect to breast-feeding. However, many clinicians feel that breast-feeding is best avoided when the mother is taking antidepressants postpartum.

Miller (1994) concluded that the tricyclics of choice during pregnancy are desipramine and nortriptyline, due to the comparative wealth of data about them, the ability to monitor serum levels and a favorable side effect profile. Alternatively, fluoxetine (Prozac) may be a reasonable choice for the pregnant patient with major depression, in light of the data from Pastuszak et al. Finally, the clinician should keep in mind that ECT appears to be a safe and effective alternative for the pregnant patient with severe depression.

With respect to benzodiazepines (BZDs): In the 70s and 80s, diazepam (Valium) was found to be associated with cleft lip and palate in the fetus and other benzodiazepines were suspected of this association. More recently, one Swedish group has linked maternal use of benzodiazepines during pregnancy with both impaired intrauterine growth and various dysmorphic birth defects. A recent review concluded that the available data indicate a positive association between first-trimester in utero exposure to benzodiazepines and a specific anomaly oral cleft.

Diazepam may double the risk of oral cleft, while alprazolam may increase the risk by more than 11-fold. However, most available data suggest that BZDs do not markedly increase the absolute risk of cleft palate or other congenital abnormalities in exposed fetuses. Thus, the baseline risk of cleft palate is about 6 in 10,000. With alprazolam exposure during the first trimester, the risk may rise to 7 in 1000, still less than 1%. The teratogenicity of lorazepam (Ativan) is less clear. Clonazepam (Klonopin) has not been evaluated for teratogenesis in controlled studies of human subjects; however, based on animal data, clonazepam seems to have low teratogenic potential (Altshuler et al, 1996) . The presence of alcohol and other substance abuse in pregnant women using benzodiazepines complicates interpretation of the data. Infants exposed to BZDs either in the last trimester or at the time of parturition may show muscular hypotonicity, failure to feed, impaired temperature regulation, apnea and low Apgar scores). The data on behavioral teratogenicity and developmental delay are inconclusive.

There is also some evidence that benzodiazepines may increase duration of labor and lead to prolonged withdrawal symptoms in the neonate, when mothers have been maintained on these agents throughout pregnancy. Withdrawal effects may be more likely when high doses of short-acting benzodiazepines have been used. Benzodiazepines should not be stopped suddenly during pregnancy, rather, tapered slowly as delivery approaches. The non-benzodiazepine anxiolytic buspirone (BuSpar) has been shown to increase the number of stillbirths in rats, when given in high doses; however, there are insufficient data in humans to determine the risks of buspirone during pregnancy.

While there is evidence that several benzodiazepines (e.g., diazepam, lorazepam, oxazepam) are excreted into breast milk, the actual levels of BZDs detected in breast milk seem to be fairly low and the consequent risk to the infant, quite small. Lorazepam seems to have minimal accumulation in the fetus and the percentage of the maternal dose of lorazepam to which a nursing infant is exposed is roughly 2.2%. Thus, use of low dose lorazepam in the nursing mother – particularly on a prn, or short-term basis – is probably safe for the infant. The excretion of buspirone into human breast milk has not been adequately studied.

Given the above risks, are benzodiazepines contraindicated during pregnancy? There is no absolute contraindication. Rather, the modest risks of BZD exposure must be weighed against the severity of the patient’s condition; the risks of no medication; and the risks of alternative medications. For example, inadequately treated panic attacks may themselves pose a risk to the fetus. Tricyclic antidepressants, fluoxetine and perhaps other SSRIs, may be reasonable alternatives to benzodiazepines for the treatment of panic disorder during pregnancy . Cognitive-behavioral therapy (CBT) may also be helpful in a variety of anxiety disorders and may reduce the need for psychotropics during pregnancy.

Answer. I am providing you with a list of commonly used antidepressants, as well as their usual doses:

Maintenance Dosage and Tablet Size for Non-MAOI Antidepressants

With respect to non-addictive medications for anxiety, it is first important to realize that the term addiction is defined in many ways. The medications most commonly used in the treatment of anxiety – the benzodiazepines, such as Valium, Librium, Ativan, etc. – are not highly addictive for the vast majority of people who are prescribed them for the right reasons. These agents may be abused or become habit-forming, however, in individuals with a history of alcohol and substance abuse, and, very rarely, in individuals who do not have such problems. The antianxiety agent buspirone (BuSpar) is a good alternative, and is not habit-forming or prone to abuse; however, while buspirone is useful for generalized anxiety, it is not helpful for panic attacks or obsessive-compulsive states.

Sometimes, low doses of the older tricyclic agents, such as doxepin 15-25 mg/day, may be useful for generalized anxiety in patients who are not good candidates for benzodiazepines. If you want more details about available medications for mood and anxiety disorders, you may want to call the NIMH Depression Awareness program.