Clomipramine Hydrochloride , ANAFRANIL®

• ANAFRANIL®

1. Tricyclic anti-depressant

2. Anti-Obsessional

• Tablets 10 mg, 25 mg and 50 mg

• Obsessive Compulsive Disorder
• Major Depressive Disorder

• Inhibits norepinephrine and serotonin uptake into central nerve terminals >>> blocking the membrane-pump of neurons
• Weak antihistamine
• Potentiates the effect of norepinephrine and other drugs acting on the central nervous system

• Absorption: Completely orally >>> Peak plasma levels >>> 2 hours >>> Plasma half-life ~ 21 hours.
• Distribution: binding to serum proteins is very high -96 to 97%-
• Metabolism: Hydroxylation, Demethylation and N-oxidation.
• Excretion: 2/3 Urine, 1/3 Feces.

1. Depression:

Adults:

• Initial Dosage: 25mg/day >>> 150 mg by the end of two weeks (Gradual increase) >>> over a period of several weeks to 200 mg (Gradual Increase)
• Maintenance dose: lowest effective level
• Max Dose: 300 mg/day

Elderly And Debilitated Patients:

• Initial Dosage: 20 to 30 mg daily (Divided suggested) >>> very gradual increments, depending on tolerance and response
• Maintenance dose: lowest effective level

2. Obsessive Compulsive Disorders:

Adults:

• Initial Dosage: 25 mg/day >>> 100 or 150 mg by the end of 2 weeks (Gradual Increase) >>> over a period of several weeks to 200 mg (Gradual Increase)
• Maintenance dose: lowest effective level
• Max Dose: 250 mg/day

Children And Adolescents:

• Aged 10 to 17 years>>> Initial Dose: 25 mg per day >>> Increase within 3 to 4 day intervals >>> in 2 weeks, titrate up to 100-150 mg per day or 3 mg/kg
• Maintenance dose: Lowest effective dose
• Max Dose: 200 mg/day

Elderly And Debilitated Patients:

• Initial Dose: 20-30 mg/day >>> very gradual increments, depending on tolerance and response
• Maintenance dose: Lowest effective dose

1. Major Depressive Disorder: (MDD)

2. Obsessive Compulsive Disorder: (OCD)

3. Alcoholic beverages

4. CNS depressants, eg:

• Barbiturates
• Benzodiazepines
• General anaesthetics

5. Guanethidine

6. Bethanidine

7. Clonidine

8. Reserpine

9. Alpha-methyldopa

10. Isoprinosine

11. Ephedrine

12. Phenylephrine

13. Noradrenaline

14. Adrenaline

15. Amphetamine (methylphenidate)

16. Selective serotonin reuptake inhibitors (SSRIs)

17. Enzyme inhibitor medications such as: Cimetidine

18. Enzyme inducer Medications: Barbiturates, Carbamazepine, Phenytoin, Nicotine & Oral contraceptives.

19. Neuroleptic agents: (e.g., phenothiazines and butyrophenones, thioridazine )

20. Alprazolam

21. Disulfiram

Frequent: (> 10 %)

• Mild sedation
• Mania
• Somnolence
• Tremor
• Sexual Dysfunction: (Libido change, Impotence, Ejaculation Failure)
• Urinary Retention
• Blurred Vision
• Dyspepsia
• Dry Mouth, Nausea, Vomiting, Constipation

< 10%:

• Orthostatic Hypotension
• Suicidal thoughts/ Ideation
• Myocardial Infarction
• Thrombocytopenia & Agranulocytosis: (Bone Marrow Failure)

• Hypersensitivity to medication.
• Monoamine oxidase inhibitor (MAOIs).
• Acute recovery phase following myocardial infarction.
• Acute congestive heart failure.
• Liver or kidney
• Blood dyscrasias.
• Narrow angle Glaucoma
• Paralytic ileus
• Pheochromocytoma
• Neuroblastoma

• Pregnancy: Category C
• Lactation: Do not use in nursing mother

1. Mild sedative effect >>> Alleviating the anxiety accompanying depression >>> difficulty in concentrating and thinking >>> Avoid Driving! Using complex machineries, swimming, climbing.

2. Persistent increase in the frequency of shifts into stage I sleep >>> produces marked reduction or suppression of rapid eye movement sleep

3. Elderly patients require lower doses of ANAFRANIL.

4. Practically concentration-independent within the therapeutic range. (Low Therapeutic index)

5. Should not be given in conjunction with monoamine oxidase inhibitor >>> Caution for Serotonin Syndrome: Hypertensive crises, hyperactivity, hyperpyrexia, spasticity, severe convulsions / coma / death >>> Wait for least 14 days!

6. Anti- Cholinergic effects : Do not use in Glaucoma & urinary retention (prostatic hypertrophy) >>> aggravated condition >>> atropine-like effects.

7. Seizures: extreme caution in patients with a history of convulsive disorders/ predisposing factors: brain damage, alcoholism, drugs lower the seizure threshold.

8. Cardiovascular: particularly in high doses, sinus tachycardia, changes in conduction time (AV block 1-2-3) + arrhythmias (premature ventricular contractions, ST-T wave changes = Most common) >>> Use with caution!

•  Check the patient’s blood pressure before stating Clomipramine
• Do regular ECGs & Blood pressure. (Postural Hypotension > Diminish the dose)
• QTc prolongation & Torsades de points at supra-therapeutic doses
• Hyperthyroid patients/ patients receiving thyroid medication: Transient cardiac arrhythmias.
• Caution in concomitant use with: Guanethidine, Bethanidine, Clonidine, Reserpine /alpha-methyldopa.
• Potentiate the cardiovascular effects of noradrenaline / adrenaline, amphetamine, nasal drops & sympathomimetic, local anaestheticsg. >>> Isoprenaline, Ephedrine, Phenylephrine.

9.  Paralytic ileus: Ederly & hospitalized patients >>> Use with caution!

10. Tumors of the adrenal medulla: Pheochromocytoma, Neuroblastoma >>> Use with caution!

11. Suicidal abuse risk: Prescribe ANAFRANIL for the smallest possible quantity of the drug consistent with good patient management.

12. Psychosis, Mania-Hypomania:

Patients treated with TCAs >>> May Occur:

• Activation of latent schizophrenia/
• Aggravation of existing psychotic manifestations
• Over-stimulation of agitated patients
• In predisposed & elderly patients >>> Provoke delirium. (Especially with night use)

13. Hepatic Changes: elevations in SGOT and SGPT >>> Caution is considered!

14. Hematologic Changes: bone marrow depression with agranulocytosis >>> Use with caution in hematologic disorder patients!

15. Withdrawal Symptoms: Do not do abrupt discontinuation! >>> Taper gradually

16. Metabolic Effects: Tricyclic antidepressants have been associated with porphyrinogenicity in susceptible patients.

17. Renal Function: monitor renal function during long-term therapy (BUN, Cr)

18. Dental Effects: Lengthy treatment >>> increased incidence of dental caries.

19. Decreased lacrimation: may cause damage to the corneal epithelium in patients with contact lenses.

20. Endocrine Effects: ANAFRANIL elevates prolactin levels

21. ANAFRANIL has not been studied in patients under 10 y/o

22. Diuretics: Concomitant use may lead to hypokalemia

23. Co-medication with Selective serotonin reuptake inhibitors (SSRIs) may lead to additive effects on the serotonergic system. >>> Caution!

24. ANAFRANIL should be discontinued prior to elective surgery.

25. Concomitant treatment with neuroleptic agents: (e.g., phenothiazines and butyrophenones) >>> Enzyme inhibitor effect >>> increased plasma concentrations of ANAFRANIL >>> lowered convulsion threshold.

26. Lower the dosage of ANAFRANIL if administered concomitantly with Alprazolam or Disulfiram.

27. Tricyclic antidepressants may potentiate the anticoagulant effect of Coumarin drugs (eg: Warfarin) by inhibiting hepatic metabolism of these drugs. Careful monitoring of Protrombine time + INR.

28. Over-dosage: (General treatment overview):

• Symptoms: drowsiness, stupor, ataxia, vomiting, cyanosis, restlessness, muscle rigidity, athetoid and choreiform movements, & convulsions, Cardiac Shock, Coma.
• Admit to hospital without delay > Gastric lavage up to 12 hours> Heart Monitoring > activated charcoal > peritoneal dialysis and hemodialysis.
• Goal: insure maintenance of the vital functions