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Anafranil tablets

2014 ‫פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר על ידו בדצמבר‬

ANAFRANIL®

25 mg Coated tablets, 75 mg Slow-release tablets

Prescribing Information

1. Trade name
ANAFRANIL 25 mg coated tablets
ANAFRANIL 75 mg slow-release tablets

2. Description and composition

Pharmaceutical form
Coated tablets (Anafranil 25 mg)
Slow-release tablets, divisible (Anafranil SR 75 mg Divitabs)

Active substance
The active ingredient is 3-Chloro-5-[3-(dimethylamino)-propyl]10,11-dihydro-5H-dibenz-
[b,f]azepine hydrochloride (clomipramine hydrochloride).
One coated tablet contains 25 mg clomipramine hydrochloride.
One slow-release tablet (divisible) contains 75 mg clomipramine hydrochloride.

Active moiety
Clomipramine

Excipients
25mg Coated tablets: lactose monohydrate, maize starch, silica colloidal anhydrous, stearic
acid, talc, magnesium stearate, glycerol 85%, hydroxypropyl methylcellulose,
vinylpyrrolidone/vinylacetate copolymer, titanium dioxide, sucrose cryst.,
polyvinylpirrolidone K30, dispersed yellow 15093 anstead 5% EEC172+95% EEC171,
polyethylene glycol 8000, cellulose microcrystalline (avicel PH 101).
75mg Slow-release, divisible tablets: calcium hydrogen phosphate dihydrate, polyacrylate
dispersion 30%, calcium stearate, silica colloydalis anhydrica, hydroxypropyl
methylcellulose, talc, titanium dioxide, polyoxyl 40 hydrogenated castor oil, red iron oxide.

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3. Indications
Depression of varying origin
In children and adolescents, there is not sufficient evidence of safety and efficacy of Anafranil
in the treatment of depressive states of varying aetiology and symptomatology. The use of
Anafranil in children and adolescents (0-17 years of age) in this indication is therefore not
recommended.
Obsessive-compulsive syndromes
No experience is available in children younger than 5 years of age.

4. Dosage and administration

Before initiating treatment with Anafranil, hypokalemia should be treated (see section 6
Warnings and precautions).
The dosage should be adapted to the individual patient's condition. The aim is to achieve an
optimum effect while keeping the doses as low as possible and increasing them cautiously.
After a response has been obtained, maintenance therapy should be continued at the optimum
dose to avoid relapse. Patients with a history of recurrent depression require maintenance
treatment for a longer duration. Duration of maintenance treatment and need for further
treatment should be reviewed periodically.
As a precaution against possible QTc prolongation and serotonergic toxicity, adherence to the
recommended doses of Anafranil is advised and any increase in dose should be made with
caution if drugs that prolong QT interval or other serotonergic agents are co-administered (see
sections 6 Warnings and precautions and 8 Interactions).
Abrupt discontinuation of Anafranil therapy should be avoided because of possible
withdrawal symptoms. Therefore, dosage should be stopped gradually after regular use for
long duration and the patient should be monitored carefully when Anafranil therapy is
discontinued.
Immediate release formulations (coated tablets) and slow-release tablets can be used inter-
changeably in equivalent doses.

Depression and obsessive-compulsive syndromes

Start treatment with 50-75 mg/day (1 coated tablet of 25 mg 2-3 times daily or 1 slow-release
tablet of 75 mg once daily [preferably in the evening]). Raise the daily dosage stepwise, e.g.
25 mg every few days, (depending on how the medication is tolerated) to 100-150 mg, during
the first week of treatment. In severe cases this dosage can be increased up to a maximum of
250 mg daily. Once there is a distinct improvement, adjust the daily dosage to a maintenance
level of about 50-100 mg.

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Dosage and administration in special populations

Geriatric population
Elderly patients generally show a stronger response to Anafranil than patients of intermediate
age groups, Anafranil should be used with caution in elderly patients and doses should be
increased cautiously. Start treatment with 10 mg daily. Gradually raise the dosage to an
optimum level of 30-50 mg daily, which should be reached after about 10 days and then
maintained until the end of treatment.

Children and Adolescents

Adolescents generally show a stronger response to Anafranil than patients of intermediate age
groups, Anafranil should be used with caution in adolescents and doses should be increased
cautiously.
Obsessive-compulsive syndromes
The starting dose is 25 mg daily and should be gradually increased (also given in divided
doses) during the first 2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg,
whichever is smaller. Thereafter, the dosage may be increased gradually over the next several
weeks up to a daily maximum of 3 mg/kg or 200 mg, whichever is smaller.
No experience is available in children under 5 years.

Renal impairment
Anafranil should be given with caution in patients with renal impairment (see section 6
Warnings and precautions and 11 Clinical pharmacology).

Hepatic impairment
Anafranil should be given with caution in patients with hepatic impairment (see section 6
Warnings and precautions and 11 Clinical pharmacology).

Method of administration
The method of administration should be adapted to the individual patient's condition. The
Divitabs (slow-release tablets divisible) can be halved, allowing the dosage to be adapted
individually, but they should not be chewed (see section 14 Pharmaceutical information).
Anafranil can be administered with or without food.

5. 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 section 8 Interactions). The concomitant treatment with selective,
reversible MAO-A inhibitors, such as moclobemide, is also contraindicated.
Recent myocardial infarction.
Congenital long QT syndrome.

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6. Warnings and 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.
Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide.
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.
Short-term studies did not show an increase in the risk of suicidality with antidepressants
compared to placebo in adults beyond age 25; there was a reduction with antidepressants
compared to placebo in adults aged 65 and older.
All patients being treated with Anafranil for any indication should be observed closely for
clinical worsening, suicidality and other psychiatric symptoms (see section 7 Adverse drug
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 in section 6
Warnings and precautions).
Families and caregivers of both paediatric and adult patients being treated with
antidepressants for both psychiatric and nonpsychiatric indications, should be alerted about
the need to monitor patients for the emergence of other psychiatric symptoms (see section 7
Adverse drug 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 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 section 4 Dosage and 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.

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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 supra-
therapeutic 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 sections 4
Dosage and administration and 8 Interactions). It is established that hypokalemia is a risk-
factor of QTc prolongation and torsades de pointes. Therefore, hypokalemia should be treated
before initiating treatment with Anafranil (see sections 4 Dosage and administration and 8
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
co-medications such as SSRIs, SNaRIs, tricyclic antidepressants or lithium (see sections 4
Dosage and administration and 8 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.

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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 section 8 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 section 7 Adverse drug reactions, for a description of the risks of
discontinuation of Anafranil).

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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 section 7 Adverse drug
rections) 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 section 8 Interactions).

7. Adverse drug 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 below are based on clinical trial results as well as post-marketing
reports.

Table 7-1 Tabulated summary of adverse drug reactions

Blood and lymphatic system disorders
Very rare Leucopenia, agranulocytosis, thrombocytopenia, eosinophilia
Cardiac disorders
Common Sinus tachycardia, palpitation, orthostatic hypotension, clinically
irrelevant ECG changes (e.g. ST and T changes) in patients of normal
cardiac status
Uncommon Arrhythmias, blood pressure increased
Very rare Conduction disorders (e.g. widening of QRS complex, prolonged QT
interval, PQ changes, bundle-branch block, torsade de pointes,
particularly in patients with hypokalaemia)
Ear and labyrinth disorders
Common Tinnitus
Endocrine disorders
Very rare SIADH (inappropriate antidiuretic hormone secretion syndrome)
Eye disorders
Very common Accommodation disorder, vision blurred
Common Mydriasis

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Very rare Glaucoma

Gastrointestinal disorders
Very common Nausea, dry mouth, constipation
Common Vomiting, abdominal disorders, diarrhea
General disorders and administration site conditions
Very common Fatigue
Very rare Oedema (local or generalised), alopecia, hyperpyrexia
Hepatobiliary disorders
Very rare Hepatitis with or without jaundice
Immune system disorders
Very rare Anaphylactic and anaphylactoid reactions including hypotension
Investigations
Very common Weight increased
Common Transaminases increased
Very rare Electroencephalogram abnormal
Metabolism and nutrition disorders
Very common Increased appetite
Common Decreased appetite
Musculoskeletal and connective tissue disorders
Common Muscular weakness
Nervous system disorders
Very common Dizziness, tremor, headache, myoclonus, somnolence
Common Speech disorder, paraesthesias, muscle hypertonia, dysgeusia,
memory impairment, disturbance in attention
Uncommon Convulsions, ataxia
Very rare Neuroleptic malignant syndrome
Psychiatric disorders
Very common Restlessness
Common Confusional state, disorientation, hallucinations (particularly in elderly
patients and patients with Parkinson's disease), anxiety, agitation,
sleep disorder, mania, hypomania, aggression, depersonalisation,
aggravation of depression, insomnia, nightmares, delirium
Uncommon Activation of psychotic symptoms
Renal and urinary disorders
Very common Micturition disorder
Very rare Urinary retention
Reproductive system and breast disorders
Very common Libido disorder, erectile dysfunction
Common Galactorrhoea, breast enlargement
Respiratory, thoracic, and mediastinal disorders
Common Yawning
Very rare Alveolitis allergic (pneumonitis) with or without eosinophilia
Skin and subcutaneous tissue disorders
Very common Hyperhidrosis
Common Dermatitis allergic (skin rash, urticaria), photosensitivity reaction,
pruritus

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Very rare Purpura

Vascular disorders
Common Hot flush

Additional adverse drug reactions from post-marketing spontaneous reports

The following additional adverse drug reactions have been identified with Anafranil oral or
IM/IV dosage forms 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 section 6 Warnings and 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.

8. 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). MAO inhibitors, which are also potent CYP2D6 inhibitors in vivo, such as
moclobemide, are contraindicated for coadministration with clomipramine (see section
5 Contraindications). The same applies when giving a MAO inhibitor after previous treatment

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with Anafranil. In both instances Anafranil or the MAO inhibitor should initially be given in
small, gradually increasing doses and its effects monitored (see section 5 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.

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 hypokalemia, which in turn increases the risk of QTc prolongation and
torsades de pointes. Hypokalemia should therefore be treated prior to administration of
Anafranil (see sections 4 Dosage and administration and 6 Warnings and precautions).
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs which are inhibitors of CYP2D6, such as flouxetine, 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 (N-
desmethylclomipramine decreased ~2-fold). In addition, comedication with SSRIs may lead
to additive effects on the serotonergic system (see serotonergic agents). See sections 4 Dosage
and administration and 6 Warnings and precautions.
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 sections 4
Dosage and administration and 6 Warnings and precautions). For fluoxetine, a washout period
of two to three weeks is advised before and after treatment with flouxetine.

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.

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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) e.g. 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.

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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 N-
desmethylclomipramine).
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 adrenergic neuron blockers
such as 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 beta-blockers).
CNS depressants
Tricyclic antidepressants may potentiate the effects of alcohol and other central depressant
substances (e.g. barbiturates, benzodiazepines, or general anaesthetics).
Sympathomimetic drugs
Anafranil may potentiate the cardiovascular effects of sympathomimetics such as 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.

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9. Pregnancy and breast-feeding

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 should 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 section 13 Non clinical safety data).
No interaction between chronic oral contraceptive use (15 or 30 micrograms ethinyl estradiol
daily) and Anafranil (25 mg daily) has been documented (see section 8 Interactions).

10. 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.
Rare cases of pharmacobezoar, of varying severity including fatal outcome, have been
reported in association with overdose of slow release Anafranil. The pharmacobezoar may be
radiopaque, facilitating radiologic (X-ray or CT scan) confirmation but cannot exclude the
diagnosis. The formation of pharmacobezoar may cause slow but continual release and
absorption of Anafranil which may lead to overdose complications, including death, hours
after drug ingestion and initial treatment with gastric lavage and activated charcoal. Since
gastric lavage may be ineffective and could further increase systemic drug levels,
consideration should be given to physical removal of the pharmacobezoar by endoscopy or
surgery in selected patients. Since these cases are rare, there is insufficient clinical data
regarding optimal treatment which should take into account the size and location of the
pharmacobezoar, patient symptoms and condition and drug levels.

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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.
Treatment of symptoms is based on modern methods of intensive care, with continuous
monitoring of cardiac function, blood gases, and electrolytes, and if necessary emergency
measures such as anticonvulsive therapy, artificial respiration, and resuscitation.
Treatment of Torsade de Pointes.
If Torsade de Pointes should occur during treatment with Anafranil, the drug should be
discontinued and hypoxia, electrolyte abnormalities and acid base disturbances should be
corrected. Persistent Torsade de Pointes may be treated with magnesium sulphate 2g (20ml of
10% solution) intravenously over 30-120 seconds, repeated twice at intervals of 5-15 minutes
if necessary. Alternatively, if these measures fail, the arrhythmia may be abolished by
increasing the underlying heart rate. This can be achieved by atrial and ventricular pacing or
by isoprenaline (isproterenol) infusion to achieve a heart rate of 90-110 beats/minute. Torsade
de Pointes is usually not helped by antiarrhythmic drugs and those which prolong the QTc
interval (e.g. amiodarone, quinidine) may make it worse.
Since it has been reported that physostigmine may cause severe bradycardia, asystole and
seizures, its use is not recommended in cases of overdosage with Anafranil. Haemodialysis or
peritoneal dialysis are ineffective because of the low plasma concentrations of clomipramine.

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11. Clinical pharmacology

Pharmacodynamic properties (PD)
Pharmacotherapeutic group: Tricyclic antidepressant. Noradrenaline and preferential
serotonin-reuptake inhibitor (non selective monoamine reuptake inhibitors), ATC code: N06A
A04.
Mechanism of action
The therapeutic activity of Anafranil is believed to be based on its ability to inhibit the
neuronal re-uptake 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.

Pharmacokinetic properties (PK)

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 slow 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 slow-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 of 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.

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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 N-
desmethylclomipramine are hydroxylated to form 8-hydroxyclomipramine or 8-hydroxy-N-
desmethylclomipramine. Clomipramine is also hydroxylated at the 2-position and N-
desmethylclomipramine 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 for
middle-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

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extrapolated to Asians, in particular, Japanese and Chinese because of the pronounced

differences of metabolism of clomipramine between these two ethnic groups.
Slow release formulation
Slow release of clomipramine from Anafranil slow release formulation provides a smoother
pharmacokinetic profile by maintaining therapeutic plasma concentrations over 24 hours.
Maximum mean plasma concentrations are reached within about 9 hours post-dose. Following
administration of 75 mg clomipramine as slow release formulation, observed Cmax is half the
maximum concentration levels reached after administration of 25 mg tablets three times a
day. Nevertheless, the total exposure remains unchanged. Following multiple administration
of slow release formulation, Cmin and Cmax levels attained at steady state are within the
therapeutic range. Slow-release tablets are bioequivalent with coated tablets and capsules.

12. Clinical studies

No recent clinical trials have been conducted with Anafranil.

13. 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.

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14. Pharmaceutical information

Incompatibilities
Not applicable.

Special precautions for storage

25mg Coated tablets: Store below 25°C, protect from moisture.
75mg Slow release tablets: Store below 25°C, protect from moisture.
Anafranil must be kept out of the reach and sight of children.

Instructions for use and handling

The slow-release tablets should be swallowed whole. The Divitabs (slow-release tablets
divisible) can be halved, allowing the dosage to be adapted individually, but they should not
be chewed.

Manufacturer:
Novartis Pharma S.p.A., Torre Annunziata, Italy
For: Novartis Pharma AG, Basel, Switzerland.

Registration Holder:
Novartis Israel Ltd.,
36 Shacham St.,
Petach-Tikva.

The format of this leaflet was determined by the Israeli Ministry of Health (MOH) and its
content was checked and approved by the Israeli MOH in December 2014.

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