Anafranil

Anafranil

clomipramine

Manufacturer:

Sandoz

Distributor:

Zuellig
Full Prescribing Info
Contents
Clomipramine hydrochloride.
Description
One coated tablet contains 10 mg or 25 mg clomipramine hydrochloride.
The active ingredient is 3-Chloro-5-[3-(dimethylamino)-propyl] 10, 11-dihydro-5H-dibenz-[b,f]azepine hydrochloride (clomipramine hydrochloride).
Excipients/Inactive Ingredients: Lactose monohydrate, maize starch, hypromellose (hydroxypropyl methylcellulose), magnesium stearate, silica colloidal anhydrous, talc, copovidone (vinylpyrrolidone/vinylacetate copolymer), titanium dioxide (E171), sucrose, povidone (polyvinylpyrrolidone), iron oxide, yellow (E172), macrogol 8000 (polyethylene glycol 8000), cellulose microcrystalline.
The 25 mg Coated tablets also contain Stearic acid and Glycerol (85%).
Action
Tricyclic antidepressant, noradrenaline and preferential serotonin re-uptake inhibitor.
Pharmacology: Pharmacodynamics: Mechanism of action: The therapeutic activity of Anafranil is believed to be based on its ability to inhibit the neuronal reuptake of noradrenaline (NA) and serotonin (5-HT) released in the synaptic cleft, with inhibition of 5-HT reuptake being the more important of these activities.
Anafranil also has a wide pharmacological spectrum of action, which includes alpha1-adrenolytic, anticholinergic, antihistaminic, and antiserotonergic (5-HT-receptor blocking) properties.
Pharmacodynamic effects: Anafranil acts on the depressive syndrome as a whole, including in particular typical features such as psychomotor retardation, depressed mood, and anxiety. The clinical response usually sets in after 2-3 weeks of treatment.
Anafranil also exerts a specific effect on obsessive-compulsive disorder distinct from its antidepressant effects.
In chronic pain with or without somatic causes, Anafranil acts presumably by facilitating serotonin and noradrenaline neurotransmission.
Clinical Studies: No recent clinical trials have been conducted with Anafranil.
Pharmacokinetics: Absorption: Following oral administration, clomipramine is completely absorbed from the gastrointestinal tract. The systemic bioavailability of unchanged clomipramine is reduced to about 50% by hepatic first-pass metabolism to the active metabolite, N-desmethylclomipramine.
Following single dose administration 25 mg coated tablet and 75 mg sustained release tablet, the mean maximum plasma concentration (Cmax) of clomipramine were 63.37 ± 12.71 ng/mL (Tmax 4.83 ± 0.39 hr) and 32.55 ± 8.10 (Tmax 9.00 ± 1.81 hr), respectively. The dose of 75 mg daily, administered either as coated tablets of 25 mg t.i.d. or as a sustained-release tablet of 75 mg once daily, produces steady-state plasma concentrations ranging from about 20 to 175 ng/mL.
The steady-state plasma concentrations of the active metabolite N-desmethylclomipramine follow a similar pattern. However, at a dose of 75 mg Anafranil per day, the metabolite levels are 40-85% higher than those of clomipramine.
Distribution: Clomipramine is 97.6% bound to plasma proteins. Clomipramine is extensively distributed throughout the body with the apparent distribution volume is about 12 to 17 L/kg bodyweight. Concentrations in cerebrospinal fluid are about 2% of the plasma concentration. Clomipramine passes into maternal milk in concentrations similar to those in plasma and crosses the placenta.
Metabolism: The primary route of clomipramine metabolism is demethylation to form the active metabolite, N-desmethylclomipramine. N-desmethylclomipramine can be formed by several P450 enzymes, primary CYP3A4, CYP2C19, and CYP1A2. Clomipramine and Ndesmethylclomipramine are hydroxylated to form 8-hydroxyclomipramine or 8-hydroxy-Ndesmethylclomipramine. Clomipramine is also hydroxylated at the 2-position and Ndesmethylclomipramine can be further demethylated to form didesmethylclomipramine. The 2- and 8- hydroxy metabolites are excreted primarily as glucuronides in the urine. Elimination of the active components, clomipramine and N-desmethylclomipramine, by formation of 2- and 8-hydroxy clomipramine is catalysed by CYP2D6.
Elimination: Clomipramine is eliminated from the blood with a mean half-life of 21 h (range: 12-36 h), and desmethylclomipramine with a mean half-life of 36 h.
About two thirds of a single dose of clomipramine are excreted in the form of water-soluble conjugates in the urine and approximately one third in the faeces. The quantity of unchanged clomipramine and desmethylclomipramine excreted in the urine is about 2% and 0.5% of the dose administered, respectively.
Food effect: Food has no significant impact on the pharmacokinetics of clomipramine. A slight delay in the onset of absorption may be observed with the administration of Anafranil with food.
Dose proportionality: The drug follows dose-proportionate pharmacokinetics over a dose range of 25 to 150 mg.
Effect of age: In elderly patients, clomipramine has relatively low clearance in comparison to younger adult patients. It is reported to reach a therapeutic steady state at doses lower than that reported formiddle-age patients.
Clomipramine should be used with caution in elderly patients.
Renal impairment: There are no specific reports describing the pharmacokinetic of the drug in patients with renal impairment. Although the drug is excreted as inactive metabolites in the urine and feces, the accumulation of inactive metabolites may subsequently result in the accumulation of the parent drug and its active metabolite. In moderate and severe renal impairment, it is recommended to monitor the patient during the treatment.
Hepatic impairment: Clomipramine is extensively metabolized in the liver by CYP2D6, CYP3A4, CYP2C19 and CYP1A2, hepatic impairment may impact on its pharmacokinetics. In patients with liver impairment, clomipramine should be administered with caution.
Ethnic sensitivity: Although the impact of ethnic sensitivity and race on the pharmacokinetics of clomipramine has not been studied extensively, the metabolism of clomipramine and its active metabolite is governed by genetic factors leading to poor and extensive metabolism of the drug and its metabolite. The metabolism of clomipramine in Caucasians population may not be extrapolated to Asians, in particular, Japanese and Chinese because of the pronounced differences of metabolism of clomipramine between these two ethnic groups.
Toxicology: Non-clinical Safety Data: Repeat-dose toxicity: Phospholipidosis and testicular changes, commonly associated with tricyclic compounds, have been observed with clomipramine hydrochloride at doses >10 fold greater than the maximum recommended human daily dose (MRHD).
Reproductive toxicity: No adverse effects on reproductive performance, including male and female fertility, were observed in rats at oral doses up to 24 mg/kg.
No teratogenic effects were detected in mice, rats, and rabbits at doses up to 100, 50, and 60 mg/kg, respectively.
Mutagenicity: Various in vitro and in vivo mutagenicity tests were performed and did not reveal any mutagenic activity of clomipramine hydrochloride.
Carcinogenicity: There was no evidence of carcinogenicity in mice and rats after 104 weeks of treatment with clomipramine hydrochloride.
Indications/Uses
Adult: Treatment of depressive states of varying aetiology and symptomatology: Endogenous, reactive, neurotic, organic, masked and involutional depression; depression associated with schizophrenia and psychopathy; depressive syndromes due to presenility or senility, chronic painful conditions and to chronic somatic diseases; depressive mood disorders of a reactive, neurotic or psychopathic nature.
Additional uses: Phobias and panic attacks, obsessive-compulsive syndromes, cataplexy accompanying narcolepsy, chronic painful conditions (in particular cancer pain, neuropathic pain and idiopathic pain syndrome).
Children and adolescents: Obsessive-compulsive syndromes: Nocturnal enuresis in patients 6 years of age and older, once organic causes have been ruled out. Cautious assessment of benefits and risks. Potential alternative therapies should be considered. No data are available in children under 5 years of age.
There is a lack of sufficient evidence of the safety and efficacy of Anafranil in the treatment of children and adolescents with depressive states of varying aetiology, phobias, panic attacks, cataplexy accompanying narcolepsy and chronic painful conditions. Therefore, Anafranil should not be used in these indications in children and adolescents under 18 years of age.
Dosage/Direction for Use
Before initiating treatment with Anafranil, hypokalaemia, if present, must be treated (see Precautions).
The dosage and method of administration should be determined individually and adapted to the patient's condition. The aim is to achieve an optimum effect while keeping doses as low as possible and increasing them cautiously, particularly in elderly patients and adolescents, who generally show greater response to Anafranil than patients in the intervening age groups. The sustained-release tablets may be halved, but should not be chewed. They are divisible into two equal halves, enabling the dosage to be closely adapted to the patient's individual requirements.
As a precaution against possible QT prolongation and serotonergic toxicity, the recommended doses of Anafranil should not be exceeded. Any increase in the dose of Anafranil should be made with caution if other serotonergic agents or medicinal products that prolong the QT interval are coadministered (see Precautions and Interactions).
Depressions, obsessive-compulsive syndromes and phobias: Oral forms: Start treatment with one 25 mg tablet 2-3 times daily.
Increase stepwise during the first week of treatment (e.g. by 25 mg every few days, depending on tolerability) to 4-6 tablets of 25 mg daily. In severe cases the dose can be increased to a maximum of 250 mg/day.
Once there is a distinct improvement reduce to a maintenance dose of about 2-4 tablets of 25 mg daily.
Panic attacks, agoraphobia: Start with one 10 mg tablet daily. Depending on tolerability, increase the dosage until the desired response is obtained. The required daily dosage varies considerably from patient to patient within the range 25-100 mg, but as much as 150 mg may be given if necessary. It is recommended that treatment be given for at least six months and that the maintenance dose be gradually reduced during this time.
Cataplexy accompanying narcolepsy: An oral dose of 25-75 mg/day.
Chronic painful conditions: The dosage must be individualized in patients with chronic painful conditions (10-150 mg/day), taking into account (and, as appropriate, reducing the dose of) any concomitant analgesic medication.
Elderly patients: Initiate treatment with one tab of 10 mg daily. Gradually increase the dosage to an optimum level of 30-50 mg daily, which should be reached after about 10 days. The optimum daily dosage is maintained until the end of treatment.
Children and adolescents: Obsessive-compulsive syndromes: As in adults, the starting dose is 25 mg per day. During the first 2 weeks, the dose should be divided into several sub-doses, as appropriate, and depending on tolerability should gradually be increased to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller.
Thereafter, the dosage may gradually be increased in the following weeks up to a daily maximum of 3 mg/kg or 200 mg, whichever is smaller.
Nocturnal enuresis (only in children aged 6 years or older): Initial daily dose: Children 6-8 years of age: 2-3 tablets of 10 mg.
Children 9-12 years of age: 1-2 tablets of 25 mg.
Children over 12 years of age: 1-3 tablets of 25 mg.
The higher doses are for patients who do not respond fully to treatment within one week, and should not be exceeded.
Treatment (including time needed for gradual withdrawal) should not be given for more than three months.
The tablets should be given in a single dose after the evening meal, but children who wet the bed early in the night should be given part of the dose earlier, at 16:00 (4 p.m.).
When treating children and adolescents, particular attention must be paid to warnings and precautions relating to the risk of suicide (see Precautions).
No data are available on the treatment of children under 6 years of age.
Overdosage
The signs and symptoms of overdose with Anafranil are similar to those reported with other tricyclic antidepressants. Cardiac abnormalities and neurological disturbances are the main complications. In children, accidental ingestion of any amount should be regarded as serious and potentially fatal.
Signs and symptoms: Symptoms generally appear within 4 hours of ingestion and reach maximum severity after 24 hours. Owing to delayed absorption (anticholinergic effect), long half-life, and enterohepatic recycling of the drug, the patient may be at risk for up to 4-6 days. The following signs and symptoms may be seen: Central nervous system: Drowsiness, stupor, coma, ataxia, restlessness, agitation, enhanced reflexes, muscular rigidity and choreoathetoid movements, convulsions. In addition, symptoms consistent with serotonin syndrome (e.g. hyperpyrexia, myoclonus, delirium and coma) may be observed.
Cardiovascular system: Hypotension, tachycardia, arrhythmias, QTc prolongation and arrhythmias including torsades de pointes, conduction disorders, shock, heart failure; in very rare cases cardiac arrest.
Respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, and oliguria or anuria may also occur.
Treatment: There is no specific antidote, and treatment is essentially symptomatic and supportive.
Anyone suspected of receiving an overdose of Anafranil, particularly children, should be hospitalised and kept under close surveillance for at least 72 hours.
Perform gastric lavage or induce vomiting as soon as possible if the patient is alert. If the patient is not alert, secure the airway with a cuffed endotracheal tube before beginning lavage, and do not induce vomiting. These measures are recommended for up to 12 hours or even longer after the overdose, since the anticholinergic effect of the drug may delay gastric emptying. Administration of activated charcoal may help to reduce drug absorption.
Since it has been reported that physostigmine may cause severe bradycardia, asystole and seizures it is not recommended in cases of overdosage with Anafranil. Haemodialyses or peritoneal dialyses are ineffective because of the low plasma concentrations of clomipramine.
Contraindications
Known hypersensitivity to clomipramine or any of the excipients or cross-sensitivity to tricyclic antidepressants of the dibenzazepine group.
Anafranil must not be given in combination, or within 14 days before or after treatment, with a MAO inhibitor (see Interactions). The concomitant treatment with selective, reversible MAO-A inhibitors, such as moclobemide is also contraindicated.
Recent myocardial infarction.
Congenital long QT syndrome.
Special Precautions
Risk of suicide: Risk of suicide is inherent to severe depression and may persist until significant remission occurs. Patients with depressive disorders, both adult and paediatric, may experience worsening of depression and/or suicidality or other psychiatric symptoms, whether or not they are taking antidepressant medication. Antidepressants increased the risk of suicidal thinking and behaviour (suicidality) in short-term studies in children, adolescents and young adults less than 25 years old with depressive disorders and other psychiatric disorders.
All patients being treated with Anafranil for any indication should be observed closely for clinical worsening, suicidality and other psychiatric symptoms (see Adverse Reactions), especially during the initial phase of therapy or at times of dose changes.
Modifying the therapeutic regimen, including possibly discontinuing the medication, should be considered in these patients, especially if these changes are severe, abrupt in onset, or were not part of the patient's presenting symptoms (see also Treatment discontinuation as follows).
Families and caregivers of both paediatric and adult patients being treated with antidepressants for both psychiatric and non-psychiatric indications, should be alerted about the need to monitor patients for the emergence of other psychiatric symptoms (see Adverse Reactions) as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.
Prescriptions for Anafranil should be written for the smallest quantity of tablets or capsules consistent with good patient management, in order to reduce the risk of overdose. Anafranil has been reported to be associated with fewer deaths following overdose than other tricyclic antidepressants.
Other psychiatric effects: Many patients with panic disorder experience more marked anxiety at the start of the treatment with Anafranil (see Dosage & Administration). This paradoxical initial increase in anxiety is most pronounced during the first few days of treatment and generally subsides within two weeks.
Activation of psychosis has occasionally been observed in patients with schizophrenia receiving tricyclic antidepressants.
Hypomanic or manic episodes have also been reported during a depressive phase in patients with cyclic affective disorders receiving treatment with a tricyclic antidepressant.
In such cases it may be necessary to reduce the dosage of Anafranil or to withdraw it and administer an antipsychotic agent. After such episodes have subsided, low dose therapy with Anafranil may be resumed if required.
In predisposed patients, tricyclic antidepressants may provoke pharmacogenic (delirious) psychoses, particularly at night. These disappear within a few days of withdrawing the drug.
Cardiac and vascular disorders: Anafranil should be administered with particular caution in patients with cardiovascular disorders, especially those with cardiovascular insufficiency, conduction disorders, (e.g. atrioventricular block grades I to III), or arrhythmias. Monitoring of cardiac function and the ECG is indicated in such patients.
There may be a risk of QTc prolongation and torsades de pointes, particularly at supratherapeutic doses or supra-therapeutic plasma concentrations of clomipramine, as occur in the case of co-medication with selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenergic reuptake inhibitors (SNaRIs). Therefore, concomitant administration of drugs that can cause accumulation of clomipramine should be avoided. Equally, concomitant administration of drugs that can prolong the QTc interval should be avoided (see Dosage & Administration and Interactions). It is established that hypokalaemia is a risk-factor of QTc prolongation and torsades de pointes. Therefore, hypokalaemia should be treated before initiating treatment with Anafranil (see Dosage & Administration and Interactions).
Before starting treatment with Anafranil, it is advisable to check blood pressure because patients with postural hypotension or a labile circulation may experience a fall in blood pressure.
Serotonin syndrome: Due to the risk of serotonergic toxicity, it is advisable to adhere to recommended doses. Serotonin syndrome, with symptoms such as hyperpyrexia, myoclonus, agitation, seizures, delirium and coma, can possibly occur when clomipramine is administered with serotonergic comedications such as SSRIs, SNaRIs, tricyclic antidepressants or lithium (see Dosage & Administration and Interactions). For fluoxetine, a washout period of two to three weeks is advised before and after treatment with fluoxetine.
Convulsions: Tricyclic antidepressants are known to lower the convulsion threshold and Anafranil should, therefore, be used with extreme caution in patients with epilepsy and other predisposing factors, e.g. brain damage of varying aetiology, concomitant use of neuroleptics, withdrawal from alcohol or drugs with anticonvulsive properties (e.g. benzodiazepines).
It appears that the occurrence of seizures is dose dependent. Therefore, the recommended total daily dose of Anafranil should not be exceeded.
Like related tricyclic antidepressants, Anafranil should be given with electroconvulsive therapy only under careful supervision.
Anticholinergic effects: Because of its anticholinergic properties, Anafranil should be used with caution in patients with a history of increased intraocular pressure, narrow-angle glaucoma, or urinary retention (e.g. diseases of the prostate).
Decreased lacrimation and accumulation of mucoid secretions due to the anticholinergic properties of tricyclic antidepressants may cause damage to the corneal epithelium in patients with contact lenses.
Specific treatment populations: Caution is called for when giving tricyclic antidepressants to patients with severe hepatic disease and tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), in whom they may provoke hypertensive crises.
Caution is indicated in patients with hyperthyroidism or patients receiving thyroid preparations, owing to the possibility of cardiac toxicity.
In patients with hepatic and renal disease, periodic monitoring of the hepatic enzyme levels and renal function is recommended.
Caution is called for in patients with chronic constipation. Tricyclic antidepressants may cause paralytic ileus, particularly in elderly and in bedridden patients.
In elderly patients, tricyclic antidepressants may provoke pharmacogenic (delirious) psychoses. Particularly at night. These disappear within a few days of withdrawing the drug.
Monitoring of cardiac function and the ECG is indicated in elderly patients.
An increase in dental caries has been reported during long-term treatment with tricyclic antidepressants. Regular dental check-ups are therefore advisable during long-term treatment.
Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are not available.
White blood cell count: Although changes in the white blood cell count have been reported with Anafranil only in isolated cases, periodic blood cell counts and monitoring for symptoms such as fever and sore throat are called for, particularly during the first few months of therapy and during prolonged treatment.
Anaesthesia: Before general or local anaesthesia, the anaesthetist should be told that the patient has been receiving Anafranil (see Interactions).
Treatment discontinuation: Abrupt withdrawal should be avoided because of possible adverse reactions. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see Adverse Reactions, for a description of the risks of discontinuation of Anafranil).
Lactose and sucrose: Anafranil coated tablets contain lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, severe lactase deficiency, sucrase-isomaltase insufficiency or glucose-galactose malabsorption should not take Anafranil coated tablets.
Driving and using machines: Patients receiving Anafranil should be warned that blurred vision, drowsiness and other nervous system and psychiatric related disorders such as somnolence, disturbance in attention, confusion, disorientation, aggravation of depression, delirium etc. (see Adverse Reactions) have been observed. In the presence of such effects, patients should not drive, operate machinery, or do anything else requiring alertness. Patients should also be warned that alcohol or other drugs may potentiate these effects (see Interactions).
Use In Pregnancy & Lactation
Pregnancy: There is limited amount of data from the use of Anafranil in pregnant women that indicates a potential to harm the foetus or cause congenital malformation. Anafranil should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus.
Neonates whose mothers had taken tricyclic antidepressants until delivery showed drug withdrawal symptoms, such as dyspnoea, lethargy, colic, irritability, hypotension or hypertension, and tremor/spasms/convulsions, during the first few hours or days. To avoid such symptoms, Anafranil, if possible, be gradually withdrawn at least 7 weeks before the calculated date of confinement.
Breast-feeding: Since the active substance passes into the breast milk, Anafranil should be gradually withdrawn or the infant weaned if the patient is breast-feeding.
Fertility: No adverse effects on reproductive performance, including male and female fertility, were observed in rats at oral doses up to 24 mg/kg.
No teratogenic effects were detected in mice, rats, and rabbits at doses up to 100, 50, and 60 mg/kg, respectively (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
No interaction between chronic oral contraceptive use (15 or 30 micrograms ethinyl estradiol daily) and Anafranil (25 mg daily) has been documented (see Interactions).
Adverse Reactions
Summary of the safety profile: Unwanted effects are usually mild and transient, disappearing under continued treatment or with a reduction in the dosage. They do not always correlate with plasma drug levels or dose. It is often difficult to distinguish certain undesirable effects from symptoms of depression such as fatigue, sleep disturbances, agitation, anxiety, constipation, and dry mouth. If severe neurological or psychiatric reactions occur, Anafranil should be withdrawn.
Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports. The ADRs tabulated as follows are based on clinical trial results as well as post-marketing reports. (See Table.)

Click on icon to see table/diagram/image

Additional adverse drug reactions from post-marketing spontaneous reports: The following additional adverse drug reactions have been identified with Anafranil based on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
Nervous system disorders: Frequency unknown: Serotonin syndrome, extrapyramidal symptoms (including akathisia and tardive dyskinesia).
Musculoskeletal and connective tissue disorders: Frequency unknown: Rhabdomyolysis (as a complication of neuroleptic malignant syndrome).
Investigations: Frequency unknown: Blood prolactin increased.
Withdrawal symptoms: The following symptoms commonly occur after abrupt withdrawal or reduction of the dose: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, and anxiety (see Precautions).
Bone fractures: Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and tricyclic antidepressants. The mechanism leading to this risk is unknown.
Geriatric population: Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric, or cardiovascular effects. Their ability to metabolise and eliminate drugs may be reduced, leading to a risk of elevated plasma concentrations at therapeutic doses.
Drug Interactions
Interactions resulting in a contraindication: MAO inhibitors: Do not give Anafranil for at least 2 weeks after discontinuation of treatment with MAO inhibitors (there is a risk of severe symptoms such as hypertensive crisis, hyperpyrexia and those consistent with serotonin syndrome, e.g. myoclonus, agitation seizures, delirium and coma). The same applies when giving a MAO inhibitor after previous treatment with Anafranil. In both instances Anafranil or the MAO inhibitor should initially be given in small, gradually increasing doses and its effects monitored (see Contraindications).
There is evidence to suggest that Anafranil may be given as little as 24 hours after a reversible MAO-A inhibitor such as moclobemide, but the two-week washout period must be observed if the MAO-A inhibitor is given after Anafranil has been used.
Serotonergic psychiatric drugs should not be started in a patient receiving linezolid. Wait until 24 hours after the last dose of linezolid before starting the serotonergic psychiatric drugs.
Interactions resulting in a concomitant use not recommended: Antiarrhythmics: Antiarrhythmics (such as quinidine and propafenone) which are potent inhibitors of CYP2D6 should not be used in combination with tricyclic antidepressants.
Diuretics: Diuretics may lead to hypokalaemia, which in turn increases the risk of QTc prolongation and torsades de pointes. Hypokalaemia should therefore be treated prior to administration of Anafranil (see Dosage & Administration and Precautions).
Selective serotonin reuptake inhibitors (SSRIs): SSRIs which are inhibitors of CYP2D6, such as fluoxetine, paroxetine, or sertraline, and of others including CYP1A2 and CYP2C19 (e.g. fluvoxamine), may also increase plasma concentrations of clomipramine, with corresponding adverse effects. Steady-state serum levels of clomipramine increased ~4-fold by co-administration of fluvoxamine (Ndesmethylclomipramine decreased ~2-fold). See Dosage & Administration and Precautions. In addition comedication with SSRIs may lead to additive effects on the serotonergic system (see serotonergic agents as follows).
Serotonergic Agents: Serotonin syndrome can possibly occur when clomipramine is administered with serotonergic co-medications such as selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenergic reuptake inhibitors (SNaRIs), tricyclic antidepressants or lithium (see Dosage & Administration and Precautions). For fluoxetine, a washout period of two to three weeks is advised before and after treatment with fluoxetine.
Interactions to be considered: Interactions resulting in increased effect of Anafranil: Concomitant administration of CYP2D6 inhibitors may lead to an increase in concentration of both active components, up to ~3-fold in patients with a debrisoquine/sparteine extensive metabolizer phenotype, converting them to a poor-metabolizer phenotype. Concomitant administration of CYP1A2, CYP2C19 and CYP3A4 inhibitors are expected to increase clomipramine concentrations and decrease N-desmethylclomipramine, thus not necessarily affecting the overall pharmacology.
Terbinafine: Coadministration of Anafranil with oral antifungal terbinafine, a strong inhibitor of CYP2D6, may result in increased exposure and accumulation of clomipramine and its N-demethylated metabolite. Therefore, dose adjustments of Anafranil may be necessary when coadministered with terbinafine.
Cimetidine: Coadministration with the histamine2 (H2)-receptor antagonist, cimetidine (an inhibitor of several P450 enzymes, including CYP2D6 and CYP3A4), may increase plasma concentrations of tricyclic antidepressants, whose dosage should therefore be reduced.
Oral contraceptives: No interaction between chronic oral contraceptive use (15 or 30 micrograms ethinyl estradiol daily) and Anafranil (25 mg daily) has been documented. Estrogens are not known to be inhibitors of CYP2D6, the major enzyme involved in clomipramine clearance and, therefore, no interaction is expected. Although, in a few cases with high dose estrogen (50 micrograms daily) and the tricyclic antidepressant imipramine, increased side effects and therapeutic response were noted, it is unclear as to the relevance of these cases to clomipramine and lower dose estrogen regimens. Monitoring therapeutic response of tricyclic antidepressants at high dose estrogen regimens (50 micrograms daily) is recommended and dose adjustments may be necessary.
Antipsychotics: Comedication of Antipsychotics (e.g. phenothiazines) may result in increased plasma levels of tricyclic antidepressants, a lowered convulsion threshold, and seizures. Combination with thioridazine may produce severe cardiac arrhythmias.
Methylphenidate: Methylphenidate may also increase concentrations of tricyclic antidepressants by potentially inhibiting their metabolism and a dose reduction of the tricyclic antidepressant may be necessary.
Valproate: Concomitant administration of valproate with clomipramine may cause inhibition of CYP2C and/or UGT enzymes resulting in increased serum levels of clomipramine and desmethylclomipramine.
Grapefruit, grapefruit juice, or cranberry juice: Concomitant administration of Anafranil with grapefruit, grapefruit juice, or cranberry juice may increase the plasma concentrations of clomipramine.
Interactions resulting in decreased effect of Anafranil: Rifampicin: Rifampicin (CYP3A and CYP2C inducer), may decrease clomipramine concentrations as concomitant administration of drugs known to induce cytochrome P450 enzymes, particularly CYP3A4, CYP2C19 may accelerate the metabolism and decrease the efficacy of Anafranil.
Anticonvulsants: Anticonvulsants (CYP3A and CYP2C inducer) eg, barbiturates, carbamazepine, phenobarbital and phenytoin, may decrease clomipramine concentrations as concomitant administration of drugs known to induce cytochrome P450 enzymes, particularly CYP3A4, CYP2C19 may accelerate the metabolism and decrease the efficacy of Anafranil.
Cigarette smoking: Known inducers of CYP1A2 (e.g. nicotine/components in cigarette smoke), decrease plasma concentrations of tricyclic drugs. In cigarette smokers, clomipramine steady-state plasma concentrations were decreased 2-fold compared to non-smokers (no change in Ndesmethylclomipramine).
Colestipol and cholestyramine: Concomitant administration of ion exchange resins such as cholestyramine or colestipol may reduce the plasma levels of clomipramine. Staggering the dosage of clomipramine and resins, such that the drug is administered at least 2 h before or 4-6 h after the administration of resins, is recommended.
St. John's wort: Concomitant administration of Anafranil with St. John's wort during the treatment may decrease the plasma concentrations of clomipramine.
Interactions affecting other drugs: Anticholinergic agents: Tricyclic antidepressants may potentiate the effects of these drugs (e.g. phenothiazine, antiparkinsonian agents, antihistamines, atropine, biperiden) on the eye, central nervous system, bowel and bladder.
Antiadrenergic agents: Anafranil may diminish or abolish the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine and alpha-methyldopa. Patients requiring comedication for hypertension should therefore be given antihypertensives of a different type (e.g. vasodilators, or betablockers).
CNS depressants: Tricyclic antidepressants may potentiate the effects of alcohol and other central depressant substances (eg, barbiturates, benzodiazepines, or general anaesthetics).
Sympathomimetic drugs: Anafranil may potentiate the cardiovascular effects of adrenaline, noradrenaline, isoprenaline, ephedrine and phenylephrine (e.g. local anaesthetics).
Anticoagulants: Some tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs, such as warfarin, and this may be through inhibition of their metabolism (CYP2C9). There is no evidence for the ability of clomipramine to inhibit the metabolism of anticoagulants, such as warfarin, however, careful monitoring of plasma prothrombin has been advised for this class of drug.
Clomipramine is also an in vitro (Ki=2.2 microM) and in vivo inhibitor of CYP2D6 activity (sparteine oxidation) and therefore, may cause increased concentrations of co-administered compounds that are primarily cleared by CYP2D6 in extensive metabolizers.
Caution For Usage
Incompatibilities: Not applicable.
MIMS Class
ATC Classification
N06AA04 - clomipramine ; Belongs to the class of non-selective monoamine reuptake inhibitors. Used in the management of depression.
Presentation/Packing
Tab (coated) 10 mg x 30's. 25 mg x 200's.
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