D D Pramine

Uses

Body dysmorphic disorder, Cataplexy, Depression, Enuresis, Narcolepsy, Obsessive-compulsive disorder (OCD), Panic attack, Panic disorder, Phobias, Premature ejaculation, Severe anxiety disorders, Trichotillomania

D D Pramine is also used to associated treatment for these conditions: Depression, Obsessive Compulsive Disorder (OCD), Panic Disorder

How D D Pramine works

D D Pramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α₁-receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type.

Dosage

D D Pramine dosage

Adjunct in cataplexy associated with narcolepsy: Initial: 10 mg/day, up to 75 mg/day.

Obsessive-compulsive disorder; Panic disorder; Phobias: Initial: 25 mg/day, gradually increase up to 100-150 mg/day if needed. Max: 250 mg/day.

Depression: Initial: 10 mg/day, up to 30-150 mg/day if needed. ≥250 mg/day may be needed in severe cases.

Side Effects

Dryness of mouth; disturbances in micturition; drowsiness, increased sweating; sexual dysfunction; confusion, paraesthesia, ataxia, tremors; extrapyramidal symptoms; tinnitus, dizziness, fatigue, headache; wt gain esp in women; gynaecomastia and galactorrhoea.

Toxicity

Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia.

Precaution

Cardiovascular insufficiency; narrow-angle glaucoma; urinary retention; history of epilepsy; renal or hepatic dysfunction; electroconvulsive therapy; hypotension; hyperthyroidism or concomitant treatment with thyroid preparations; suicidal tendencies; surgery; pregnancy and lactation; tasks requiring mental alertness; elderly; avoid abrupt withdrawal.

Interaction

Barbiturates increase metabolism of tricyclic antidepressants; conversely cimetidine, guanethidine, haloperidol and phenothiazines block the tricyclic metabolism. CNS effects of alcohol enhanced. If clomipramine is to be substituted for MAOIs, at least 3 wk should elapse after discontinuing MAOIs. Risk of hypertension and arrhythmias if co-administered with adrenaline and noradrenaline.

Food Interaction

• Avoid alcohol.
• Avoid grapefruit products.
• Take with food. Food reduces irritation.

[Moderate] MONITOR: Limited data suggest that the administration of clomipramine with grapefruit juice or cranberry juice may significantly increase plasma drug concentrations of clomipramine.

D D Pramine is initially demethylated by CYP450 1A2, 3A3 and 3A4 before undergoing further metabolism to 8-hydroxyclomipramine.

The increase in clomipramine bioavailability may stem from inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

The precise mechanism by which cranberry juice exerts its effects is unknown, but may involve inhibition of CYP450 isoenzymes.

This interaction has occasionally been exploited in attempts to improve symptomatic control of obsessive compulsive disorder.

MANAGEMENT: Patients receiving clomipramine therapy who ingest cranberry juice, grapefruits, or grapefruit juice should be monitored for adverse effects and undue fluctuations in plasma drug levels.

D D Pramine Alcohol interaction

[Moderate] GENERALLY AVOID:

The combination of ethanol and a tricyclic antidepressant may result in additive impairment of motor skills, especially driving skills.

Also, one study has suggested that clomipramine metabolism is significantly impaired for several weeks or more following discontinuation of chronic alcohol consumption.

Patients should be warned of this interaction and advised to limit their ethanol intake while taking tricyclic antidepressants.

Monitoring for TCA toxicity (CNS depression, excessive anticholinergic effects, hypotension, arrhythmias) is recommended during alcohol withdrawal.

D D Pramine Drug Interaction

Major: duloxetine, duloxetine, escitalopram, escitalopram, fluoxetine, fluoxetineModerate: aripiprazole, aripiprazole, amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, clonazepam, clonazepam, lamotrigine, lamotrigine, quetiapine, quetiapine, lisdexamfetamine, lisdexamfetamineUnknown: cholecalciferol, cholecalciferol

D D Pramine Disease Interaction

Major: anticholinergic effects, cardiovascular disease, pheochromocytoma, acute myocardial infarction recovery, cardiovascular disease, depression, seizure disordersModerate: adrenal tumors, hypomania/mania, bone marrow suppression, diabetes, renal/liver disease, schizophrenia/bipolar disorder, tardive dyskinesia, acute alcohol intoxication, bipolar disorder screening, glaucoma, hyper/hypoglycemia, liver/renal disease, neutropenia, schizophrenia, thyroid disorders, urinary retention

Volume of Distribution

~ 17 L/kg (range: 9-25 L/kg). D D Pramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk.

Elimination Route

Well absorbed from the GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine.

Half Life

Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism).

Elimination Route

Urine (51-60%) and feces via biliary elimination (24-32%)

Pregnancy & Breastfeeding use

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Hypersensitivity. Concomitant use of MAOIs; recovery phase following MI, heartblock or other arrhythmias; mania; childn.

Acute Overdose

Symptom: Initial CNS stimulation followed by severe CNS depression. Cardiac dysrhythmias, severe hypotension, convulsions, changes in the electrocardiogram, particularly in QRS axis or width, drowsiness, stupor, ataxia, restlessness, agitation, delirium, severe sweating, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements. Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and oliguria or anuria may also be present.

Management: Treatment is symptomatic and supportive. Plasma concentrations should not guide management of the patient. Peritoneal dialysis and hemodialysis are not effective in removing the drugs as it is highly protein bound. V diazepam to be used with caution for treatment of seizures.

Storage Condition

Store below 30°C.

Innovators Monograph

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