Clofranil

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLOFRANIL (CLOFRANIL)

Composition:

Active substance: clomipramine;

1 tablet contains clomipramine hydrochloride 25 mg;

Excipients: lactose monohydrate; maize starch; microcrystalline cellulose; talc; magnesium stearate; colloidal anhydrous silicon dioxide; sodium starch glycolate; hypromellose; titanium dioxide (E 117); polyethylene glycol 6000; brilliant blue (E 133).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, film-coated tablets, blue in colour, with a break line on one side and smooth on the other.

Pharmacotherapeutic group.

Antidepressants. Non-selective inhibitors of neuronal reuptake of monoamines.

ATC code N06A A04.

Pharmacological Properties

Pharmacodynamics

The therapeutic effect of clomipramine is due to its ability to inhibit neuronal reuptake of norepinephrine (NE) and serotonin (5-HT), with the most significant action being the inhibition of serotonin reuptake.

Clomipramine also exhibits a broad spectrum of other pharmacological effects: α1-adrenergic blockade, anticholinergic, antihistaminic, and antiserotonergic activity (blockade of 5-HT receptors).

Clomipramine affects the overall depressive syndrome, particularly its typical manifestations such as psychomotor retardation, depressed mood, and anxiety. Clinical effects are usually observed after 2–3 weeks of treatment.

Clomipramine also has a specific effect in obsessive-compulsive disorders, which is distinct from its antidepressant action.

The effect of clomipramine in chronic pain syndromes, whether associated with or independent of somatic diseases, is related to the facilitation of nerve impulse transmission mediated by serotonin and norepinephrine.

Pharmacokinetics

Absorption. Clomipramine is completely absorbed from the gastrointestinal tract. The systemic bioavailability of unchanged drug is approximately 50%, due to extensive first-pass metabolism in the liver, resulting in the formation of the active metabolite, N-desmethylclomipramine.

After repeated oral dosing, steady-state plasma concentrations of clomipramine vary considerably among individual patients. With daily administration of 75 mg, the steady-state plasma concentration ranges between 20 and 175 ng/mL.

Steady-state plasma concentrations of the active metabolite N-desmethylclomipramine fall within a similar range. However, when clomipramine is administered at 75 mg/day, concentrations of the metabolite are 40–85% higher than those of the parent compound.

Distribution. Plasma protein binding of clomipramine is up to 97.6%. The apparent volume of distribution is approximately 12–17 L/kg body weight. Drug concentrations in cerebrospinal fluid are about 2% of plasma levels. Clomipramine penetrates into breast milk, where concentrations are similar to those in plasma.

Metabolism. The primary metabolic pathway of clomipramine is demethylation, forming the active metabolite N-desmethylclomipramine. N-Desmethylclomipramine can be formed by several P450 enzymes, primarily CYP3A4, CYP2C19, and CYP1A2. Clomipramine and N-desmethylclomipramine undergo hydroxylation to form 8-hydroxyclomipramine or 8-hydroxy-N-desmethylclomipramine. The in vivo activity of these 8-hydroxy metabolites has not been established. Clomipramine is also hydroxylated at the 2-position, and N-desmethylclomipramine may undergo further demethylation to form didesmethylclomipramine. The 2- and 8-hydroxy metabolites are excreted as glucuronides in urine. The elimination of active components—clomipramine and N-desmethylclomipramine—forming 2- and 8-hydroxyclomipramine, is catalyzed by CYP2D6.

Elimination. After oral administration, the mean elimination half-life of clomipramine from plasma is approximately 21 hours (range: 12–36 hours), while that of desmethylclomipramine is on average 36 hours.

Approximately two-thirds of a single dose of clomipramine is excreted in urine as water-soluble conjugates, and about one-third is excreted in feces. Approximately 2% of the administered dose is excreted unchanged in urine, and about 0.5% of desmethylclomipramine.

Pharmacokinetics in Specific Patient Populations. In elderly patients, regardless of the administered dose of clomipramine, plasma concentrations are higher than in younger patients due to reduced metabolic capacity. The impact of hepatic or renal impairment on the pharmacokinetics of clomipramine has not been fully studied.

Clinical characteristics.

Indications.

Adults.

Depressive states of various etiologies, presenting with diverse symptomatology:

• endogenous, reactive, neurotic, organic, masked, involutional forms of depression;
• depression in patients with schizophrenia and psychopathy;
• depressive syndromes occurring in elderly individuals; depressive states associated with chronic pain syndrome or chronic somatic diseases;
• mood disturbances of depressive nature of reactive, neurotic, or psychopathic origin.
  • Phobias and panic disorders (attacks).
  • Obsessive-compulsive disorders.
  • Cataplexy associated with narcolepsy.
  • Chronic pain syndrome (specific pain syndrome in cancer patients, neuropathic and idiopathic pain syndromes).

There is currently insufficient evidence regarding the safety and efficacy of Clomipramine in treating children for depressive states of various etiologies, phobias, panic disorders, cataplexy associated with narcolepsy, and chronic pain syndrome. Therefore, Clomipramine should not be used in children and adolescents under 18 years of age for these indications.

Contraindications.

• Hypersensitivity to clomipramine or to any of the other components of the drug, cross-hypersensitivity to tricyclic antidepressants of the dibenzazepine group.
• Antiarrhythmic drugs, such as quinidine and propafenone, which are potent inhibitors of CYP2D6, should not be co-administered with tricyclic antidepressants.
• Concomitant use of monoamine oxidase inhibitors (MAOIs), as well as within 14 days before and after their administration. Concurrent use of selective reversible MAO-A inhibitors (e.g., moclobemide) or non-selective reversible MAO inhibitors (e.g., linezolid) is also contraindicated.
  • Recent myocardial infarction.
  • Congenital long QT syndrome.
  • Acute intoxication with central nervous system (CNS) depressants (e.g., hypnotics, analgesics, or psychotropic agents) or alcohol.
  • Acute urinary retention.
  • Acute delirium;
  • Untreated closed-angle glaucoma.
  • Prostatic hypertrophy with residual urinary retention.
  • Pyloric stenosis.
  • Paralytic ileus.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

MAO inhibitors. Clomipramine should not be administered within at least 2 weeks after discontinuation of MAO inhibitors (due to the risk of developing severe symptoms and conditions such as hypertensive crisis, hyperpyrexia, myoclonus, agitation, generalized seizures, delirium, and coma). The same rule applies when initiating an MAOI after prior treatment with Clomipramine. In either case, initial doses of Clomipramine or MAOIs should be low and gradually increased under continuous monitoring of drug effects.

The existing risk indicates that Clomipramine may be used no earlier than 24 hours after discontinuation of reversible MAO-A inhibitors such as moclobemide. However, if such a drug is to be administered after discontinuation of Clomipramine, the washout period should be at least 2 weeks.

Since the antibiotic linezolid is a non-selective reversible MAO inhibitor, it should not be prescribed to patients receiving clomipramine.

Selective serotonin reuptake inhibitors (SSRIs). Concomitant use of Clomipramine with these agents may potentiate effects on the serotonergic system.

Serotonergic agents. Serotonin syndrome may occur when clomipramine is used concomitantly with serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, or lithium salts. Clomipramine should not be used for 2–3 weeks before or after treatment with fluoxetine.

Antiadrenergic agents affecting neuronal excitation transmission. Clomipramine may reduce or completely abolish the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine, and alpha-methyldopa. Therefore, when antihypertensive therapy is required concomitantly with Clomipramine, drugs of a different class (e.g., vasodilators or beta-blockers) should be used.

Sympathomimetic agents. Clomipramine may enhance the cardiovascular effects of adrenaline, noradrenaline, isoprenaline, ephedrine, and phenylephrine (including when these substances are components of local anesthetics).

CNS depressants. Tricyclic antidepressants may potentiate the effects of alcohol and other agents that depress the CNS (e.g., opioids, barbiturates, benzodiazepines, or general anesthetics).

Anticholinergic agents. Tricyclic antidepressants may enhance the anticholinergic effects of certain drugs (e.g., phenothiazines, antiparkinsonian agents, antihistamines, atropine, biperiden) on the eye, CNS, gastrointestinal tract, and urinary bladder. There is a risk of hyperthermia.

Diuretics. Concomitant use of Clomipramine with diuretics may lead to hypokalemia, which in turn increases the risk of QTc prolongation and bidirectional ventricular tachycardia. Hypokalemia should be corrected prior to initiating Clomipramine.

Pharmacokinetic interactions

Clomipramine is primarily eliminated via metabolism. The main metabolic pathway is demethylation, forming the active metabolite N-desmethylclomipramine, followed by hydroxylation and subsequent conjugation of N-desmethylclomipramine and the parent drug. Several cytochrome P450 enzymes are involved in demethylation, predominantly CYP3A4, CYP2C19, and CYP1A2. Elimination of both active components occurs via hydroxylation, catalyzed by CYP2D6.

Concomitant use of CYP2D6 inhibitors may increase plasma concentrations of both active substances up to threefold in patients with the rapid metabolizer phenotype for debrisoquine/sparteine, effectively converting them to a slow metabolizer phenotype. Concomitant use of CYP1A2, CYP2C19, and CYP3A4 inhibitors increases clomipramine concentration while decreasing N-desmethylclomipramine concentration; thus, such combinations do not necessarily affect overall pharmacology.

• MAO inhibitors that are also potent in vivo CYP2D6 inhibitors, such as moclobemide, are contraindicated for concomitant use with clomipramine.
• Antiarrhythmic drugs (e.g., quinidine and propafenone), which are potent CYP2D6 inhibitors, should not be used in combination with tricyclic antidepressants.
• Selective serotonin reuptake inhibitors that are CYP2D6 inhibitors, such as fluoxetine, paroxetine, sertraline, and fluvoxamine (which inhibits other CYPs, including CYP1F2 and CYP2C19), also increase plasma clomipramine concentrations with corresponding adverse effects. Steady-state clomipramine levels increase approximately fourfold when co-administered with fluvoxamine (N-desmethylclomipramine levels decrease by about half).

Concomitant treatment with neuroleptics (e.g., phenothiazines) may increase plasma levels of tricyclic antidepressants, lower seizure threshold, and provoke seizures. Combination with thioridazine may lead to severe cardiac arrhythmias.

• Concomitant use with terbinafine, a potent CYP2D6 inhibitor, may increase exposure and accumulation of clomipramine and its N-demethylated metabolites. Consequently, dose adjustment of Clomipramine is required when used concomitantly.
• Concomitant use with histamine H2-receptor antagonists, such as cimetidine (an inhibitor of several P450 enzymes, including CYP2D6 and CYP3A4), may increase plasma concentrations of tricyclic antidepressants; therefore, their dosage should be reduced.
• No interaction has been established between continuous use of oral contraceptives (15 or 30 mg ethinylestradiol daily) and Clomipramine (25 mg daily). There is no evidence that estrogens act as inhibitors of CYP2D6, the primary enzyme involved in clomipramine clearance; thus, interaction is not expected. Although in some cases increased adverse reactions and therapeutic effects have been observed with high-dose estrogen (50 mg daily) and the tricyclic antidepressant imipramine, there is no evidence of such a relationship for clomipramine or need to reduce estrogen doses during concomitant use. Monitoring of tricyclic antidepressant efficacy is recommended.
• Methylphenidate may increase tricyclic antidepressant concentrations by inhibiting their metabolism; therefore, Clomipramine dosage adjustment is necessary.
• Concomitant use of valproate with clomipramine may inhibit CYP2C and/or UGT enzyme activity, thereby increasing plasma levels of clomipramine and desmethylclomipramine.
• Concomitant use of Clomipramine with grapefruit, grapefruit juice, or cranberry juice may alter clomipramine plasma concentrations.
• Some tricyclic antidepressants may potentiate the anticoagulant effect of coumarins (e.g., warfarin), possibly by inhibiting their metabolism (CYP2C9). Monitoring of plasma prothrombin time is recommended. Concomitant use of Clomipramine with cytochrome P450 inducers, particularly CYP3A4, CYP2C19, and/or CYP1A2, may enhance metabolism and reduce Clomipramine efficacy.
• Inducers of CYP3A4 and CYP2C19, such as rifampicin or anticonvulsants (e.g., barbiturates, carbamazepine, phenobarbital, and phenytoin), may reduce clomipramine plasma concentrations.
• Known inducers of CYP1A2 (e.g., nicotine/other cigarette smoke components) reduce tricyclic antidepressant concentrations. Steady-state clomipramine concentration is approximately two-fold lower in smokers compared to non-smokers (no changes in N-desmethylclomipramine concentrations). Clomipramine inhibits CYP2D6 activity (sparteine oxidation) both in vivo and in vitro, and thus may increase plasma concentrations of concurrently administered drugs metabolized primarily by CYP2D6 in rapid metabolizers.
• Concomitant use with ion-exchange resins such as cholestyramine or colestipol may reduce clomipramine plasma concentrations. If concomitant use is necessary, clomipramine should be administered at least 2 hours before or 4–6 hours after resin administration.
• Concomitant use of Clomipramine and St. John’s wort (Hypericum perforatum) may reduce clomipramine plasma concentrations.

Special precautions for use.

Suicide risk.

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide. Worsening of suicidal ideation and suicidal behavior may occur in patients receiving antidepressant therapy.

Clomipramine should not be used for the treatment of depression in children and adolescents under 18 years of age. In clinical trials evaluating the efficacy of antidepressants in this age group, therapeutic efficacy of tricyclic antidepressants has not been demonstrated.

Published data from clinical trials with selective serotonin reuptake inhibitors (SSRIs) and similar medicinal products indicate an increased risk of suicidal behavior in children, adolescents, and young adults (up to 25 years of age) treated for depression. A similar effect cannot be excluded for other antidepressants (including Clomipramine), for which relevant data are lacking.

Therefore, patients receiving antidepressants require close monitoring for signs of worsening depression, including suicidal behavior and/or akathisia (inner restlessness, psychomotor agitation), particularly at the beginning of treatment and when the dose is changed. Additionally, close monitoring is required during discontinuation of treatment, as such symptoms may occur upon withdrawal or in the early phase of relapse.

Besides depressive disorders, other psychiatric conditions may also be associated with an increased risk of suicidal behavior; therefore, the same precautions should be observed as with antidepressant therapy.

Patients' family members and caregivers should be informed that they need to be vigilant for the development of other psychiatric symptoms (see "Side effects") and suicidal behavior, and to immediately report these to the physician providing medical care.

Antidepressant therapy is not a complete substitute for hospitalization, which is necessary if the patient poses a threat to themselves. The physician should prescribe the smallest available dose of the medicinal product, especially at the beginning of treatment, to minimize the risk of such situations.

Regarding the risk of fatal overdose, fewer fatal cases have been reported with Clomipramine compared to other tricyclic antidepressants. To reduce the risk of overdose, the lowest possible dose of Clomipramine should be prescribed to achieve optimal therapeutic effect.

Psychiatric effects.

In many patients with panic attacks, anxiety may increase at the beginning of Clomipramine treatment. This paradoxical increase in anxiety is most pronounced during the first days of treatment and usually subsides within 2 weeks.

In patients with schizophrenia receiving tricyclic antidepressants, psychosis may occasionally be activated. Due to the activating effect of tricyclic antidepressants, increased anxiety, inner restlessness, and agitation may occur in patients with agitation or concomitant schizophrenic symptoms.

It is known that in patients with bipolar affective disorders taking tricyclic antidepressants, manic or hypomanic episodes may develop during the depressive phase. In such cases, it may be necessary to reduce the dose of Clomipramine or discontinue it and initiate an antipsychotic agent. After resolution of these conditions, if indicated, Clomipramine treatment at low doses may be resumed.

In patients predisposed to mental disorders and in elderly patients, tricyclic antidepressants may provoke pharmacogenetic psychosis (delirium), predominantly at night. These disorders usually resolve within a few days after discontinuation of the drug.

Seizures.

Tricyclic antidepressants are known to lower the seizure threshold; therefore, Clomipramine should be administered with particular caution in patients with epilepsy and in those with other factors predisposing to seizure development, such as brain injury of any etiology, concomitant use of neuroleptic agents, during alcohol withdrawal, or when discontinuing anticonvulsant medications (e.g., benzodiazepines). Seizures during Clomipramine treatment are considered to be dose-dependent. Therefore, the recommended daily dose of Clomipramine should not be exceeded.

Clomipramine, like other tricyclic antidepressants, should be used in combination with electroconvulsive therapy only under strict medical supervision.

Anticholinergic effects.

Since the drug has anticholinergic properties, it should be used with particular caution in patients with a history of elevated intraocular pressure, narrow-angle glaucoma, or urinary retention (e.g., due to prostate disorders).

Due to the anticholinergic action typical of tricyclic antidepressants, reduced tear secretion and a relative increase in mucus content in tears may occur, potentially leading to corneal epithelial damage in patients wearing contact lenses.

Serotonin syndrome.

Due to the risk of serotonergic toxicity, recommended doses should be followed, and dose escalation should be cautious when another serotonergic agent is co-administered. Serotonin syndrome, characterized by symptoms such as hyperpyrexia, myoclonus, agitation, epileptic seizures, delirium, and coma, may occur when clomipramine is used concomitantly with serotonergic agents such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, or lithium, triptans, L-tryptophan, tramadol, fentanyl, or sibutramine. It is recommended to avoid using clomipramine for 2–3 weeks before and after fluoxetine treatment.

Cardiovascular effects.

Clomipramine should be prescribed with particular caution in patients with cardiovascular diseases, especially those with cardiac insufficiency, disturbances of intracardiac conduction (e.g., first- to third-degree atrioventricular block), or arrhythmias. In such patients, as well as in elderly patients, regular monitoring of cardiovascular function and ECG is required.

There is a potential risk of QT interval prolongation and development of atypical ventricular tachycardia when higher therapeutic doses of clomipramine are prescribed, or when it is used concomitantly with selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. Therefore, concomitant use of drugs that may lead to clomipramine accumulation should be avoided. Concomitant use of drugs that may prolong the QT interval should also be avoided. Hypokalemia underlies these phenomena. Therefore, serum potassium levels should be determined before initiating Clomipramine or Clomipramine in combination with serotonin inhibitors, serotonin-norepinephrine inhibitors, or diuretics, and any decrease should be corrected. Combined use of Clomipramine with selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and diuretics requires caution.

Blood pressure should be measured before initiating Clomipramine therapy, as a sharp drop in blood pressure may occur in patients with orthostatic hypotension or vascular instability.

Special patient groups.

Caution is advised when treating patients with severe liver disease and patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma), as hypertensive crisis may develop.

Caution is also advised in patients with hyperthyroidism and those receiving thyroid hormone medications, as the anticholinergic effects of tricyclic antidepressants may exacerbate unwanted cardiac effects of these drugs.

In patients with renal or hepatic impairment, continuous monitoring of liver enzymes, renal function, and plasma concentrations of the active substance and its metabolites is recommended when necessary.

Caution is required when treating patients with chronic constipation with Clomipramine. Tricyclic antidepressants may cause paralytic ileus, particularly in elderly patients or those confined to bed.

Dental caries have been reported during long-term treatment with tricyclic antidepressants. Therefore, regular dental check-ups are recommended during prolonged Clomipramine therapy.

There are no data on long-term safety in children and adolescents regarding growth, sexual maturation, and cognitive and behavioral development.

Hypersensitivity reactions.

Isolated cases of anaphylactic shock have been reported. Intravenous administration of Clomipramine requires caution.

Blood test parameter changes.

Although changes in leukocyte levels during Clomipramine treatment have been reported only rarely, periodic blood count examinations are recommended, along with vigilance for symptoms such as fever and sore throat, especially during the first months of therapy or during prolonged treatment. The drug should be discontinued if neutrophil count falls below normal.

Anesthesia.

Before general or local anesthesia, the anesthesiologist should be informed that the patient is taking Clomipramine.

Other effects.

Hyperthermia as a symptom of malignant neuroleptic syndrome has been observed in several patients receiving concomitant neuroleptic therapy with Clomipramine.

Discontinuation of the drug.

Abrupt discontinuation of Clomipramine should be avoided, as it may lead to adverse reactions. If therapy needs to be stopped, the dose should be reduced as gradually as possible, always keeping in mind that abrupt discontinuation may cause adverse reactions.

Lactose content.

The medicinal product should not be administered to patients with rare hereditary forms of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

There is clear evidence of risk to the human fetus, but this risk may be outweighed by therapeutic benefit in pregnancy. Since there are isolated reports suggesting a possible link between tricyclic antidepressant use and fetal developmental abnormalities, Clomipramine should be avoided during pregnancy except when the expected benefit to the mother clearly outweighs the potential risk to the fetus.

In newborns whose mothers took tricyclic antidepressants up to delivery, symptoms such as respiratory disturbances, lethargy, colic, increased irritability, hypotonia or hypertonia, tremor, seizures, and epileptic seizures have been observed within the first hours or days after birth.

To avoid development of this syndrome, Clomipramine should be gradually discontinued approximately 7 weeks before expected delivery, based on clinical indications.

Since the active substance passes into breast milk, either breastfeeding should be discontinued or Clomipramine should be gradually discontinued.

Ability to influence reaction speed when driving or operating machinery.

Patients taking Clomipramine should be warned that they may experience blurred vision, dizziness, and other central nervous system disturbances (see section "Side effects"), and that they should refrain from driving, operating machinery, or engaging in other activities requiring heightened attention in such cases. Patients should also be warned that these effects may be enhanced by concomitant use of other medicinal products and alcohol.

Method of Administration and Dosage.

Adults.

Hypokalemia should be corrected prior to initiating treatment with Clofranil.

The dosage should be individually adjusted according to the patient's condition. The treatment strategy involves achieving optimal therapeutic effect with the lowest possible dose of the drug, as well as cautious dose escalation, particularly in elderly patients (aged 65 years and older) and adolescents, who are more sensitive to Clofranil than patients in other age groups.

After achieving maintenance therapy, the optimal dose should be maintained. Maintenance therapy may be indicated for a prolonged period in patients with a history of depressive relapses, depending on individual relapse risk. The duration and necessity of continued treatment should be periodically reviewed.

To prevent possible QT interval prolongation and the development of serotonergic toxicity, recommended Clofranil dosages should not be exceeded. Any increase in Clofranil dosage should be approached with caution when co-administering other serotonergic medicinal products that prolong the QT interval.

Abrupt discontinuation of therapy without medical justification should be avoided, as it may lead to adverse reactions. If Clofranil must be discontinued after long-term treatment, the dose should be gradually reduced, and the patient should remain under close medical supervision.

Depression, obsessive-compulsive disorders, and phobias. Treatment should be initiated with 1 coated tablet containing 25 mg of clomipramine, administered 2–3 times daily. The dose should then be gradually increased over the first week of treatment, for example by 25 mg every few days (depending on tolerability), until reaching a daily dose of 4–6 tablets of 25 mg. In severe cases, the daily dose may be increased up to the maximum of 250 mg.

Once a clear improvement is achieved, a maintenance dose of 2–4 tablets of 25 mg should be established.

Panic disorders, agoraphobia. Treatment should be initiated with 10 mg of clomipramine daily. The dose should then be gradually increased, depending on Clofranil tolerability, until the desired therapeutic effect is achieved. The required daily dose of Clofranil in these cases varies considerably among patients and ranges between 25–100 mg. If necessary, the dose may be increased up to 150 mg. Discontinuation of treatment is not recommended within 6 months; during this period, the maintenance dose should be gradually reduced.

Narcolepsy-associated cataplexy. The daily dose of Clofranil is 25–75 mg.

Chronic pain syndromes. The Clofranil dosage should be individually adjusted, taking into account concomitant use of analgesic agents (and considering the possibility of reducing their use).

Elderly patients (aged 65 years and older). Elderly patients are generally more sensitive to Clofranil than patients in other age groups. Therefore, Clofranil dosage should be increased cautiously in these patients. Treatment should be initiated with 10 mg daily. The daily dose should then be gradually increased over approximately 10 days to an optimal level of 30–50 mg, which should be maintained throughout the treatment period.

Obsessive-compulsive disorders.

Adolescents are generally more sensitive to Clofranil than patients in other age groups. Therefore, Clofranil dosage should be increased cautiously in these patients. Clinical data on short-term therapy in adolescents and children aged 10 years and older are limited.

Initial dose: 25 mg daily, with individual dose escalation up to 3 mg/kg or 100 mg within the first 2 weeks. The dose may be further increased over the following weeks up to 3 mg/kg or 200 mg, whichever is lower.

Children.

There is no experience with the use of Clofranil for the treatment of children.

Overdose.

Symptoms occurring after oral overdose of Clofranil are similar to those described following overdose of other tricyclic antidepressants. The main complications are cardiovascular disturbances and neurological disorders. Accidental ingestion of the drug by children should be considered a very serious event, potentially fatal, regardless of the ingested dose.

Symptoms usually appear within 4 hours after ingestion and peak within 24 hours. Due to slow absorption (anticholinergic effect of the drug), prolonged elimination half-life, and hepatointestinal recirculation of the active substance, the period during which overdose symptoms may manifest can last up to 4–6 days.

Following overdose of hydrochloride clomipramine tablets with prolonged release, rare cases of pharmacobezoars (clumps of undigested or unabsorbed substance) of varying severity, including fatal outcomes, have been reported. A pharmacobezoar may be radiopaque, meaning that this diagnosis cannot be ruled out based on radiological confirmation (X-ray or CT scan). Formation of a pharmacobezoar may lead to slow but continuous release and absorption of clomipramine, potentially causing complications in overdose cases, including death, even hours after drug ingestion and initial treatment with gastric lavage and activated charcoal. Since gastric lavage may be ineffective and could even provoke further increase in systemic drug levels, in specifically selected patient populations, the feasibility of physical removal of the bezoar via endoscopic or surgical methods should be considered. Due to the rarity of such cases, clinical data on optimal management—taking into account both patient symptoms and condition, as well as active substance levels and size and location of the pharmacobezoar—are insufficient.

Symptoms of overdose:

Central nervous system: drowsiness, stupor, coma, ataxia, restlessness, agitation, hyperreflexia, muscle rigidity, choreoathetoid movements, seizures. Additionally, symptoms associated with serotonin syndrome may occur (e.g., hyperpyrexia, myoclonus, delirium, and coma).

Cardiovascular system: arterial hypotension, tachycardia, arrhythmias, QT interval prolongation, bidirectional ventricular tachycardia, disturbances in intracardiac conduction, shock, cardiac failure; very rarely – cardiac arrest.

Other possible symptoms include respiratory depression, depression, cyanosis, vomiting, pallor, mydriasis, increased sweating, oliguria, or anuria.

Treatment. There is no specific antidote. Treatment is primarily symptomatic and supportive.

In suspected Clofranil overdose, especially in children, the patient should be hospitalized and closely observed for 72 hours.

For management of intoxication with high doses of tricyclic antidepressants with standard release, initial decontamination with activated charcoal or gastric lavage is recommended within 1 hour after ingestion. Due to the increased risk of seizures, activated charcoal is preferred over gastric lavage. Patients with severe intoxication or partial loss of protective reflexes should undergo endotracheal intubation first. Repeated oral administration of activated charcoal may be effective in accelerating elimination (secondary decontamination) of some tricyclic antidepressants. Hemodialysis is not an effective method for secondary decontamination.

Patients with hypotension and/or ventricular arrhythmias with QRS complex widening on ECG (>100 msec) should receive intravenous sodium bicarbonate solution (1 mmol/kg) as a bolus injection or short infusion (5 minutes). This procedure may be repeated until blood pressure improves and ECG normalizes, but only up to a maximum arterial blood pH of 7.55. Intravenous lidocaine may be required. Temporary cardiac pacing is indicated in patients with bradyarrhythmias. Intravenous injection of a single dose of 0.5–1.5 g of magnesium sulfate is recommended in cases of bidirectional ventricular tachycardia.

Patients with seizures should receive intravenous benzodiazepines.

Patients with coma and/or respiratory insufficiency require intubation and mechanical ventilation.

Hyperventilation may be used to increase arterial blood pH only when sodium bicarbonate is not concurrently administered (risk of severe alkalosis).

Due to its effects on the heart, pyridostigmine and physostigmine are contraindicated in the treatment of peripheral and central anticholinergic symptoms.

Side effects

Adverse events that occur are generally mild and transient, disappearing during continued treatment or after reduction of the Clofranil dose. They are not always related to plasma levels of the active substance or to the dose of the drug. Some adverse events, such as general weakness, sleep disturbances, anxiety, restlessness, constipation, dry mouth, may be difficult to distinguish from symptoms of depression.

If serious adverse reactions affecting the nervous system or mental status occur, Clofranil should be discontinued.

Elderly patients are particularly sensitive to effects on the nervous, cardiovascular and mental systems, as well as to the anticholinergic effects of Clofranil. Drug metabolism and elimination may be slowed in this age group, leading to increased drug concentrations in plasma even when average therapeutic doses are used.

The frequency of adverse reactions is defined as follows: very common (> 1/10); common (from > 1/100 to < 1/10); uncommon (from > 1/1000 to < 1/100); rare (from > 1/10000 to < 1/1000); very rare (< 1/10000), including isolated cases.

Psychiatric disorders:

Very common – dizziness, transient fatigue, restlessness, increased appetite;
Common – confusion, disorientation, hallucinations (especially in elderly patients and patients with Parkinson's disease), anxiety, excitement, sleep disturbances, manic state, hypomanic state, aggression, memory impairment, depersonalization, worsening of depression, difficulty concentrating, insomnia, nightmares;
Uncommon – activation of psychotic symptoms.

Nervous system disorders:

Very common – dizziness, tremor, headache, myoclonus;
Common – delirium, speech disorders, paresthesia, muscle weakness, increased muscle tone;
Uncommon – seizures, ataxia;
Very rare – EEG changes, hyperpyrexia, extrapyramidal symptoms (including dyskinesia), drug-induced fever, neuroleptic malignant syndrome.

Cardiac disorders:

Common – sinus tachycardia, palpitations, clinically insignificant ECG changes (e.g. ST segment or T wave) in patients without heart disease;
Uncommon – arrhythmias, increased blood pressure;
Very rare – disturbances in intracardiac conduction (e.g. widened QRS complex, prolonged QT interval, changes in PQ interval, bundle branch block), bidirectional ventricular tachycardia, particularly in patients with hypokalemia.

Vascular disorders:

Common – orthostatic hypotension.

Gastrointestinal disorders:

Very common – dry mouth, constipation;
Common – nausea;
Uncommon – vomiting, abdominal discomfort, diarrhea, decreased appetite, loss of appetite, dysgeusia.

Hepatobiliary disorders:

Common – elevated transaminase levels in blood;
Very rare – hepatitis, with or without jaundice.

Skin and subcutaneous tissue disorders:

Common – allergic dermatitis (rash, urticaria), photosensitization, pruritus;
Very rare – local reactions after intravenous injections (thrombophlebitis, lymphangitis, sensation of heat and allergic skin reactions), edema (local or generalized), hair loss.

Renal and urinary disorders:

Very rare – urinary retention and fluid retention.

Reproductive system and breast disorders:

Common – libido and potency disturbances, erectile dysfunction;
Uncommon – galactorrhea, amenorrhea, breast enlargement.

Endocrine disorders:

Very common – dry mouth, increased sweating, micturition disorders;
Common – flushing, mydriasis;
Very rare – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders:

Very common – weight gain.

Immune system disorders:

Very rare – allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic/anaphylactoid reactions, including arterial hypotension.

Blood and lymphatic system disorders:

Very rare – leukopenia, agranulocytosis, thrombocytopenia, eosinophilia, purpura.

Eye disorders:

Very common – accommodation disorders, blurred vision;
Very rare – glaucoma.

Ear and labyrinth disorders:

Common – tinnitus.

Other:
After abrupt discontinuation or rapid dose reduction of Clofranil, symptoms such as nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, irritability, and anxiety may occasionally occur.

Adverse events identified from spontaneous reports during post-marketing surveillance

As the size of the affected population is unknown, the frequency of these reactions cannot be reliably determined.

Nervous system disorders:
Serotonin syndrome, extrapyramidal symptoms (including akathisia and tardive dyskinesia).

Musculoskeletal system disorders:
Rhabdomyolysis (as a complication of neuroleptic malignant syndrome).

Investigations:
Hyperprolactinemia.

Epidemiological studies, conducted mainly in patients aged ≥50 years, have indicated an increased risk of bone fractures in patients treated with SSRIs and tricyclic antidepressants. The mechanism underlying this risk is unknown.

Shelf life. 4 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per strip, 5 strips per cardboard pack.

Prescription status. Prescription only.

Manufacturer:

1. Sun Pharmaceutical Industries Ltd.
2. Sun Pharma Laboratories Limited

Manufacturer's address and place of business:

1. Survey No. 214, Plot No. 20, Gavt. Indl. Area, Phase II, Piparia, Silvassa – 396230, U.T. Dadra and Nagar Haveli, India.
2. 6-9, EPZ, Katra, Bari Brahmana, Jammu - 181133, Jammu and Kashmir, India.