Klominal

Overdose

Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as possible.

In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Klominal either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. The 10 nonfatal cases involved doses of up to 5000 mg, accompanied by plasma levels of up to 1010 ng/mL. All 10 patients completely recovered. Among reports from other countries of Klominal overdose, the lowest dose associated with a fatality was 750 mg. Based upon postmarketing reports in the United Kingdom, CMI’s lethality in overdose is considered to be similar to that reported for closely related tricyclic compounds marketed as antidepressants.

Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness, agitation, delirium, severe perspiration, hyperactive reflexes, muscle rigidity, and athetoid and choreiform movements. Cardiac abnormalities may include tachycardia, signs of congestive heart failure, and in very rare cases, cardiac arrest. Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and oliguria or anuria may also be present.

Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary.

If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.

All patients suspected of tricyclic overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.

A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).

In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic poisoning.

In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.

Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.

The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

The signs and symptoms of overdose with Klominal 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, athetoid and choreoathetoid movements, convulsions, serotonin syndrome (e.g. hypertensive crisis, hyperpyrexia, myoclonus, delirium and coma).

Cardiovascular system

Hypotension, tachycardia, QTc prolongation and arrhythmia 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 Klominal, 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 has impaired consciousness, 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:

For respiratory failure:

- intubation and artificial respiration.

For cardiovascular symptoms:

- in severe hypotension the patient should be placed in an appropriate position and be given a plasma expander, dopamine, or dobutamine by intravenous drip.

- cardiac arrhythmias must be treated according to the requirements of the case.

- implantation of a cardiac pacemaker should be considered.

- low potassium values and acidosis should be corrected.

In all patients with ECG abnormalities, cardiac function should - even after the ECG tracings have reverted to normal - be kept under close observation for at least another 48 hours because relapses may occur.

Treatment of torsades de pointes:

If torsades de pointes should occur during treatment with Klominal, the drug should be discontinued and hypoxia, electrolyte abnormalities and acid base disturbances should be corrected. Persistent torsades de pointes may be treated with magnesium sulphate 2 g (20 ml 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 per minute. Torsades 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 Klominal. Haemodialysis or peritoneal dialysis are ineffective because of the low plasma concentrations of Klominal.

For convulsions:

Diazepam should be given iv or other anticonvulsants such as phenobarbitone or paraldehyde (these substances may exacerbate existing respiratory failure, hypotension, or coma).

Contraindications

Klominal is contraindicated in patients with a history of hypersensitivity to Klominal or other tricyclic antidepressants.

The use of MAOIs intended to treat psychiatric disorders with Klominal or within 14 days of stopping treatment with Klominal is contraindicated because of an increased risk of serotonin syndrome. The use of Klominal within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION).

Starting Klominal in a patient who is being treated with linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).

Klominal is contraindicated during the acute recovery period after a myocardial infarction.

- recent myocardial infarction, any degree of heart block or other cardiac arrhythmias

- severe liver disease

- concurrent administration with monoamine oxidase inhibitors or within 3 weeks of start or cessation of therapy

- concomitant treatment with selective, reversible MAO-A inhibitors, such as moclobemide

- narrow-angle glaucoma

- retention of urine

- mania.

Incompatibilities

Not applicable

Undesirable effects

The most commonly observed adverse events associated with the use of Klominal and not seen at an equivalent incidence among placebo-treated patients were gastrointestinal complaints, including dry mouth, constipation, nausea, dyspepsia, and anorexia; nervous system complaints, including somnolence, tremor, dizziness, nervousness, and myoclonus; genitourinary complaints, including changed libido, ejaculatory failure, impotence, and micturition disorder; and other miscellaneous complaints, including fatigue, sweating, increased appetite, weight gain, and visual changes.

Approximately 20% of 3616 patients who received Klominal in U.S. premarketing clinical trials discontinued treatment because of an adverse event. Approximately one-half of the patients who discontinued (9% of the total) had multiple complaints, none of which could be classified as primary. Where a primary reason for discontinuation could be identified, most patients discontinued because of nervous system complaints (5.4%), primarily somnolence. The second-most-frequent reason for discontinuation was digestive system complaints (1.3%), primarily vomiting and nausea.

There was no apparent relationship between the adverse events and elevated plasma drug concentrations.

The following table enumerates adverse events that occurred at an incidence of 1% or greater among patients with OCD who received Klominal in adult or pediatric placebo-controlled clinical trials. The frequencies were obtained from pooled data of clinical trials involving either adults receiving Klominal (N=322) or placebo (N=319) or children treated with Klominal (N=46) or placebo (N=44). The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the populations studied.

Incidence of Treatment-Emergent Adverse Experience in Placebo-Controlled Clinical Trials (Percentage of Patients Reporting Event)

During clinical testing in the U.S., multiple doses of Klominal were administered to approximately 3600 subjects. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, a modified World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the 3525 individuals exposed to Klominal who experienced an event of the type cited on at least one occasion while receiving Klominal. All events are included except those already listed in the previous table, those reported in terms so general as to be uninformative, and those in which an association with the drug was remote. It is important to emphasize that although the events reported occurred during treatment with Klominal, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients.

Body as a Whole – Infrequent -general edema, increased susceptibility to infection, malaise. Rare -dependent edema, withdrawal syndrome.

Cardiovascular System – Infrequent -abnormal ECG, arrhythmia, bradycardia, cardiac arrest, extrasystoles, pallor. Rare -aneurysm, atrial flutter, bundle branch block, cardiac failure, cerebral hemorrhage, heart block, myocardial infarction, myocardial ischemia, peripheral ischemia, thrombophlebitis, vasospasm, ventricular tachycardia.

Digestive System – Infrequent -abnormal hepatic function, blood in stool, colitis, duodenitis, gastric ulcer, gastritis, gastroesophageal reflux, gingivitis, glossitis, hemorrhoids, hepatitis, increased saliva, irritable bowel syndrome, peptic ulcer, rectal hemorrhage, tongue ulceration, tooth caries. Rare -cheilitis, chronic enteritis, discolored feces, gastric dilatation, gingival bleeding, hiccup, intestinal obstruction, oral/pharyngeal edema, paralytic ileus, salivary gland enlargement.

Endocrine System – Infrequent -hypothyroidism. Rare -goiter, gynecomastia, hyperthyroidism.

Hemic and Lymphatic System – Infrequent -lymphadenopathy. Rare -leukemoid reaction, lymphoma-like disorder, marrow depression.

Metabolic and Nutritional Disorder – Infrequent -dehydration, diabetes mellitus, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypokalemia. Rare -fat intolerance, glycosuria.

Musculoskeletal System – Infrequent -arthrosis. Rare -dystonia, exostosis, lupus erythematosus rash, bruising, myopathy, myositis, polyarteritis nodosa, torticollis.

Nervous System – Frequent -abnormal thinking, vertigo. Infrequent -abnormal coordination, abnormal EEG, abnormal gait, apathy, ataxia, coma, convulsions, delirium, delusion, dyskinesia, dysphonia, encephalopathy, euphoria, extrapyramidal disorder, hallucinations, hostility, hyperkinesia, hypnagogic hallucinations, hypokinesia, leg cramps, manic reaction, neuralgia, paranoia, phobic disorder, psychosis, sensory disturbance, somnambulism, stimulation, suicidal ideation, suicide attempt, teeth-grinding. Rare -anticholinergic syndrome, aphasia, apraxia, catalepsy, cholinergic syndrome, choreoathetosis, generalized spasm, hemiparesis, hyperesthesia, hyperreflexia, hypoesthesia, illusion, impaired impulse control, indecisiveness, mutism, neuropathy, nystagmus, oculogyric crisis, oculomotor nerve paralysis, schizophrenic reaction, stupor, suicide.

Respiratory System – Infrequent -bronchitis, hyperventilation, increased sputum, pneumonia. Rare -cyanosis, hemoptysis, hypoventilation, laryngismus.

Skin and Appendages – Infrequent -alopecia, cellulitis, cyst, eczema, erythematous rash, genital pruritus, maculopapular rash, photosensitivity reaction, psoriasis, pustular rash, skin discoloration. Rare -chloasma, folliculitis, hypertrichosis, piloerection, seborrhea, skin hypertrophy, skin ulceration.

Special Senses – Infrequent -abnormal accommodation, deafness, diplopia, earache, eye pain, foreign body sensation, hyperacusis, parosmia, photophobia, scleritis, taste loss. Rare -blepharitis, chromatopsia, conjunctival hemorrhage, exophthalmos, glaucoma, keratitis, labyrinth disorder, night blindness, retinal disorder, strabismus, visual field defect.

Urogenital System – Infrequent -endometriosis, epididymitis, hematuria, nocturia, oliguria, ovarian cyst, perineal pain, polyuria, prostatic disorder, renal calculus, renal pain, urethral disorder, urinary incontinence, uterine hemorrhage, vaginal hemorrhage. Rare -albuminuria, anorgasmy, breast engorgement, breast fibroadenosis, cervical dysplasia, endometrial hyperplasia, premature ejaculation, pyelonephritis, pyuria, renal cyst, uterine inflammation, vulvar disorder.

The following adverse drug reaction has been reported during post-approval use of Klominal. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency.

Eye Disorders – angle-closure glaucoma.

Immune System Disorders – Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)

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, Klominal 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 to <1/10); uncommon (>1/1,000 to < 1/100); rare (>1/10,000 to < 1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

1 In post-marketing experience very rarely malignant neuroleptic syndrome has been reported although a causal relationship has not been confirmed.

2 Cases of suicidal ideation and suicidal behaviours have been reported during Klominal therapy or early after treatment discontinuation.

3 These adverse events were reported in patients treated with Klominal based on post marketing reports.

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.

Class effects

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

Elderly 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

Preclinical safety data

Repeat-dose toxicity

Phospholipidosis and testicular changes considered to be secondary to the phospholipidosis, commonly associated with tricyclic compounds, have been observed with Klominal hydrochloride at doses >4 fold greater than the maximum recommended human daily dose (MRHD). The clinical relevance of these findings is unknown.

Reproductive toxicity

Klominal hydrochloride demonstrated evidence of embryotoxicity e.g. increased embryolethality and growth retardation, in the rat and mouse studies (at doses which are 5 to 10 times the estimated oral MRHD of 5 mg/kg on a mg/kg basis), but not in the rabbit study. The safety margin for increased embryolethality based on the administered dose is 2.5 times the oral MHRD.

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 Klominal hydrochloride.

Carcinogenicity

The administration of Klominal hydrochloride to mice and rats for 104 weeks did not show any evidence of carcinogenicity at dose levels representing 16 - 20 times the estimated oral MRHD of 5 mg/kg on a mg/kg basis.

Therapeutic indications

Klominal™ (clomipramine hydrochloride) Capsules USP is indicated for the treatment of obsessions and compulsions in patients with Obsessive-Compulsive Disorder (OCD). The obsessions or compulsions must cause marked distress, be time-consuming, or significantly interfere with social or occupational functioning, in order to meet the DSM-III-R (circa 1989) diagnosis of OCD.

Obsessions are recurrent, persistent ideas, thoughts, images, or impulses that are egodystonic. Compulsions are repetitive, purposeful, and intentional behaviors performed in response to an obsession or in a stereotyped fashion, and are recognized by the person as excessive or unreasonable.

The effectiveness of Klominal for the treatment of OCD was demonstrated in multicenter, placebo-controlled, parallel-group studies, including two 10-week studies in adults and one 8-week study in children and adolescents 10 to 17 years of age. Patients in all studies had moderate-to-severe OCD (DSM-III), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS) ranging from 26 to 28 and a mean baseline rating of 10 on the NIMH Clinical Global Obsessive Compulsive Scale (NIMH-OC). Patients taking CMI experienced a mean reduction of approximately 10 on the YBOCS, representing an average improvement on this scale of 35% to 42% among adults and 37% among children and adolescents. CMI-treated patients experienced a 3.5 unit decrement on the NIMH-OC. Patients on placebo showed no important clinical response on either scale. The maximum dose was 250 mg/day for most adults and 3 mg/kg/day (up to 200 mg) for all children and adolescents.

The effectiveness of Klominal for long-term use (i.e., for more than 10 weeks) has not been systematically evaluated in placebo-controlled trials. The physician who elects to use Klominal for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Adults

Klominal capsules are indicated for the treatment of:

- the symptoms of depressive illness especially where sedation is required

- obsessional and phobic states

- adjunctive treatment of cataplexy associated with narcolepsy.

Children and adolescents

In children and adolescents, there is not sufficient evidence of safety and efficacy of Klominal in the treatment of depressive states, phobias and cataplexy associated with narcolepsy. The use of Klominal in children and adolescents (0-17 years of age) in these indications is therefore not recommended.

Pharmacotherapeutic group

Pharmacodynamic properties

Clomipramine (CMI) is presumed to influence obsessive and compulsive behaviors through its effects on serotonergic neuronal transmission. The actual neurochemical mechanism is unknown, but CMI’s capacity to inhibit the reuptake of serotonin (5-HT) is thought to be important.

Pharmacotherapeutic group: Antidepressants, Non-selective monoamine reuptake inhibitors, ATC code: N06AA04.

Mechanism of action

The therapeutic activity of Klominal 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.

Klominal also has a wide pharmacological spectrum of action, which includes alpha1- adrenolytic, anticholinergic, antihistaminic, and antiserotonergic (5-HT-receptor blocking) properties.

Pharmacokinetic properties

CMI from Klominal capsules is as bioavailable as CMI from a solution. The bioavailability of CMI from capsules is not significantly affected by food.

In a dose proportionality study involving multiple CMI doses, steady-state plasma concentrations (Css) and area-under-plasma-concentration-time curves (AUC) of CMI and CMI’s major active metabolite, desmethylclomipramine (DMI), were not proportional to dose over the ranges evaluated, i.e., between 25 to 100 mg/day and between 25 to 150 mg/day, although Css and AUC are approximately linearly related to dose between 100 to 150 mg/day. The relationship between dose and CMI/DMI concentrations at higher daily doses has not been systematically assessed, but if there is significant dose dependency at doses above 150 mg/day, there is the potential for dramatically higher Css and AUC even for patients dosed within the recommended range. This may pose a potential risk to some patients (see WARNINGS and DRUG INTERACTIONS).

After a single 50 mg oral dose, maximum plasma concentrations of CMI occur within 2 to 6 hours (mean, 4.7 hr) and range from 56 ng/mL to 154 ng/mL (mean, 92 ng/mL). After multiple daily doses of 150 mg of Klominal, steady-state maximum plasma concentrations range from 94 ng/mL to 339 ng/mL (mean, 218 ng/mL) for CMI and from 134 ng/mL to 532 ng/mL (mean, 274 ng/mL) for DMI. Additional information from a rising dose study of doses up to 250 mg suggests that DMI may exhibit nonlinear pharmacokinetics over the usual dosing range. At a dose of Klominal 200 mg, subjects who had a single blood sample taken approximately 9 to 22 hours, (median 16 hours), after the dose had plasma concentrations of up to 605 ng/mL for CMI, 781 ng/mL for DMI, and 1386 ng/mL for both.

CMI distributes into cerebrospinal fluid (CSF) and brain and into breast milk. DMI also distributes into CSF, with a mean CSF/plasma ratio of 2.6. The protein binding of CMI is approximately 97%, principally to albumin, and is independent of CMI concentration. The interaction between CMI and other highly protein-bound drugs has not been fully evaluated, but may be important (see DRUG INTERACTIONS).

CMI is extensively biotransformed to DMI and other metabolites and their glucuronide conjugates. DMI is pharmacologically active, but its effects on OCD behaviors are unknown. These metabolites are excreted in urine and feces, following biliary elimination. After a 25 mg radiolabeled dose of CMI in two subjects, 60% and 51%, respectively, of the dose were recovered in the urine and 32% and 24%, respectively, in feces. In the same study, the combined urinary recoveries of CMI and DMI were only about 0.8% to 1.3% of the dose administered. CMI does not induce drug-metabolizing enzymes, as measured by antipyrine half-life.

Evidence that the Css and AUC for CMI and DMI may increase disproportionately with increasing oral doses suggests that the metabolism of CMI and DMI may be capacity limited. This fact must be considered in assessing the estimates of the pharmacokinetic parameters presented below, as these were obtained in individuals exposed to doses of 150 mg. If the pharmacokinetics of CMI and DMI are nonlinear at doses above 150 mg, their elimination half-lives may be considerably lengthened at doses near the upper end of the recommended dosing range (i.e., 200 mg/day to 250 mg/day). Consequently, CMI and DMI may accumulate, and this accumulation may increase the incidence of any dose-or plasma-concentration-dependent adverse reactions, in particular seizures (see WARNINGS).

After a 150 mg dose, the half-life of CMI ranges from 19 hours to 37 hours (mean, 32 hr) and that of DMI ranges from 54 hours to 77 hours (mean, 69 hr). Steady-state levels after multiple dosing are typically reached within 7 to 14 days for CMI. Plasma concentrations of the metabolite exceed the parent drug on multiple dosing. After multiple dosing with 150 mg/day, the accumulation factor for CMI is approximately 2.5 and for DMI is 4.6. Importantly, it may take two weeks or longer to achieve this extent of accumulation at constant dosing because of the relatively long elimination half-lives of CMI and DMI (see DOSAGE AND ADMINISTRATION). The effects of hepatic and renal impairment on the disposition of Klominal have not been determined.

Co-administration of haloperidol with CMI increases plasma concentrations of CMI. Co-administration of CMI with phenobarbital increases plasma concentrations of phenobarbital (see DRUG INTERACTIONS). Younger subjects (18 to 40 years of age) tolerated CMI better and had significantly lower steady-state plasma concentrations, compared with subjects over 65 years of age. Children under 15 years of age had significantly lower plasma concentration/dose ratios, compared with adults. Plasma concentrations of CMI were significantly lower in smokers than in nonsmokers.

Absorption

The active substance is completely absorbed following oral administration and intramuscular injection.

The systemic bioavailability of unchanged Klominal is reduced by 50% by "first-pass" metabolism to desmethylKlominal (an active metabolite). The bioavailability of Klominal is not markedly affected by the ingestion of food but the onset of absorption and therefore the time to peak may be delayed. Coated tablets and sustained release tablets are bioequivalent with respect to amount absorbed.

During oral administration of constant daily doses of Klominal the steady state plasma concentrations of Klominal and desmethylKlominal (active metabolite) and the ratio between these concentrations show a high variability between patients, e.g. 75 mg Klominal daily produces steady state concentrations of Klominal ranging from about 20 to 175 ng/ml. Levels of desmethylKlominal follow a similar pattern but are 40-85% higher.

Klominal slows gastro-intestinal transit time, absorption can, however, be delayed, particularly in overdosage.

Distribution

Klominal and desmethylKlominal are widely distributed throughout the body and is 97.6% bound to plasma and tissue protein. The apparent volume of distribution is about 12-17 l/kg body weight. Concentrations in cerebrospinal fluid are about 2% of the plasma concentration.

It is reported to have a low and variable bioavailability following oral administration (48.2% of that after intravenous administration) and this has been related to extensive first-pass hepatic metabolism. Following single oral doses of 50 mg and 100 mg in healthy volunteers peak plasma concentrations of Klominal of 28.8 ± 11.2 ng/ml range 16.5 to 53 ng/ml (at 3 to 5 hours post-dose) and 70-140 ng/ml (at 1 to 2.5 hours post-dose) respectively are reported). Peak plasma concentrations of desmethylKlominal of 5.0 ± 1.4 ng/ml (range 2.9 to 7.8 ng/ml have been reported to occur between 5 to 12 hours after a single oral dose of 50 mg.

After chronic administration in depressed patients steady state plasma concentrations of Klominal have been noted to vary 20 to 30 fold. Vandel et al reported that following repeated doses of 75 mg a day for 1 month, steady state plasma concentrations of Klominal and desmethylKlominal were 124.5 ± 94 ng/ml and 144.8 ± 113 ng/ml respectively.

Biotransformation

The major route of transformation of Klominal is demethylation to desmethylKlominal. In addition, Klominal and desmethylKlominal are hydroxylated to 8-hydroxy-Klominal and 8-hydroxy-desmethyl-Klominal but little is known about their activity in vivo. The hydroxylation of Klominal and desmethylKlominal is under genetic control similar to that of debrisoquine. In poor metabolisers of debrisoquine this may lead to high concentrations of desmethylKlominal; concentrations of Klominal are less significantly influenced.

Elimination

Oral Klominal is eliminated from the blood with a mean half-life of 21 hours (range 12-36 h), and desmethylKlominal with a half-life of 36 hours.

About two-thirds of a single dose of Klominal is excreted in the form of water-soluble conjugates in the urine, and approximately one-third in the faeces. The quantity of unchanged Klominal and desmethylKlominal excreted in the urine amounts to about 2% and 0.5% of the administered dose respectively.

Elderly

In the elderly, plasma Klominal concentrations may be higher for a given dose than would be expected in younger patients because of reduced metabolic clearance.

Hepatic and renal impairment

The effects of hepatic and renal impairment on the pharmacokinetics of Klominal have not been determined.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a longstanding concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) 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 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for clomipramine hydrochloride should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that clomipramine hydrochloride is not approved for use in treating bipolar depression.

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Klominal, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of Klominal with MAOIs intended to treat psychiatric disorders is contraindicated. Klominal should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Klominal. Klominal should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

If concomitant use of Klominal with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with Klominal and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

The pupillary dilation that occurs following use of many antidepressant drugs including Klominal may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

During premarket evaluation, seizure was identified as the most significant risk of Klominal use.

The observed cumulative incidence of seizures among patients exposed to Klominal at doses up to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, and 1.45% at 365 days. The cumulative rates correct the crude rate of 0.7% (25 of 3519 patients) for the variable duration of exposure in clinical trials.

Although dose appears to be a predictor of seizure, there is a confounding of dose and duration of exposure, making it difficult to assess independently the effect of either factor alone. The ability to predict the occurrence of seizures in subjects exposed to doses of CMI greater than 250 mg is limited, given that the plasma concentration of CMI may be dose-dependent and may vary among subjects given the same dose. Nevertheless, prescribers are advised to limit the daily dose to a maximum of 250 mg in adults and 3 mg/kg (or 200 mg) in children and adolescents (see DOSAGE AND ADMINISTRATION).

Caution should be used in administering Klominal to patients with a history of seizures or other predisposing factors, e.g., brain damage of varying etiology, alcoholism, and concomitant use with other drugs that lower the seizure threshold.

Rare reports of fatalities in association with seizures have been reported by foreign postmarketing surveillance, but not in U.S. clinical trials. In some of these cases, Klominal had been administered with other epileptogenic agents; in others, the patients involved had possibly predisposing medical conditions. Thus a causal association between Klominal treatment and these fatalities has not been established.

Physicians should discuss with patients the risk of taking Klominal while engaging in activities in which sudden loss of consciousness could result in serious injury to the patient or others, e.g., the operation of complex machinery, driving, swimming, climbing.

Rare cases of drug rash with eosinophilia and systemic symptoms (DRESS) have been reported with the use of clomipramine. In the event of severe acute reactions such as DRESS, discontinue clomipramine therapy immediately and institute appropriate treatment.

Since depression is a commonly associated feature of OCD, the risk of suicide must be considered. Prescriptions for Klominal should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Modest orthostatic decreases in blood pressure and modest tachycardia were each seen in approximately 20% of patients taking Klominal in clinical trials; but patients were frequently asymptomatic. Among approximately 1400 patients treated with CMI in the premarketing experience who had ECGs, 1.5% developed abnormalities during treatment, compared with 3.1% of patients receiving active control drugs and 0.7% of patients receiving placebo. The most common ECG changes were PVCs, ST-T wave changes, and intraventricular conduction abnormalities. These changes were rarely associated with significant clinical symptoms. Nevertheless, caution is necessary in treating patients with known cardiovascular disease, and gradual dose titration is recommended.

Patients treated with Klominal have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychotic episodes, confusion, and paranoia. Because of the uncontrolled nature of many of the studies, it is impossible to provide a precise estimate of the extent of risk imposed by treatment with Klominal. As with tricyclic antidepressants to which it is closely related, Klominal may precipitate an acute psychotic episode in patients with unrecognized schizophrenia.

During premarketing testing of Klominal in patients with affective disorder, hypomania or mania was precipitated in several patients. Activation of mania or hypomania has also been reported in a small proportion of patients with affective disorder treated with marketed tricyclic antidepressants, which are closely related to Klominal.

During premarketing testing, Klominal was occasionally associated with elevations in SGOT and SGPT (pooled incidence of approximately 1% and 3%, respectively) of potential clinical importance (i.e., values greater than 3 times the upper limit of normal). In the vast majority of instances, these enzyme increases were not associated with other clinical findings suggestive of hepatic injury; moreover, none were

Rare reports of more severe liver injury, some fatal, have been recorded in foreign postmarketing experience. Caution is indicated in treating patients with known liver disease, and periodic monitoring of hepatic enzyme levels is recommended in such patients.

Although no instances of severe hematologic toxicity were seen in the premarketing experience with Klominal, there have been postmarketing reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in association with Klominal use. As is the case with tricyclic antidepressants to which Klominal is closely related, leukocyte and differential blood counts should be obtained in patients who develop fever and sore throat during treatment with Klominal.

More than 30 cases of hyperthermia have been recorded by nondomestic postmarketing surveillance systems. Most cases occurred when Klominal was used in combination with other drugs. When Klominal and a neuroleptic were used concomitantly, the cases were sometimes considered to be examples of a neuroleptic malignant syndrome.

The rate of sexual dysfunction in male patients with OCD who were treated with Klominal in the premarketing experience was markedly increased compared with placebo controls (i.e., 42% experienced ejaculatory failure and 20% experienced impotence, compared with 2.0% and 2.6%, respectively, in the placebo group). Approximately 85% of males with sexual dysfunction chose to continue treatment.

In controlled studies of OCD, weight gain was reported in 18% of patients receiving Klominal, compared with 1% of patients receiving placebo. In these studies, 28% of patients receiving Klominal had a weight gain of at least 7% of their initial body weight, compared with 4% of patients receiving placebo. Several patients had weight gains in excess of 25% of their initial body weight. Conversely, 5% of patients receiving Klominal and 1% receiving placebo had weight losses of at least 7% of their initial body weight.

As with closely related tricyclic antidepressants, concurrent administration of Klominal with electroconvulsive therapy may increase the risks; such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience.

Prior to elective surgery with general anesthetics, therapy with Klominal should be discontinued for as long as is clinically feasible, and the anesthetist should be advised.

As with closely related tricyclic antidepressants, Klominal should be used with caution in the following:

1. Hyperthyroid patients or patients receiving thyroid medication, because of the possibility of cardiac toxicity;
2. Patients with increased intraocular pressure, a history of narrow-angle glaucoma, or urinary retention, because of the anticholinergic properties of the drug;
3. Patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma) in whom the drug may provoke hypertensive crises;
4. Patients with significantly impaired renal function.

A variety of withdrawal symptoms have been reported in association with abrupt discontinuation of Klominal, including dizziness, nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia, and irritability. In addition, such patients may experience a worsening of psychiatric status. While the withdrawal effects of Klominal have not been systematically evaluated in controlled trials, they are well known with closely related tricyclic antidepressants, and it is recommended that the dosage be tapered gradually and the patient monitored carefully during discontinuation (see Drug Abuse And Dependence).

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with clomipramine hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for clomipramine hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking clomipramine hydrochloride.

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Physicians are advised to discuss the following issues with patients for whom they prescribe Klominal:

1. The risk of seizure (see WARNINGS);
2. The relatively high incidence of sexual dysfunction among males (see Sexual Dysfunction);
3. Since Klominal may impair the mental and/or physical abilities required for the performance of complex tasks, and since Klominal is associated with a risk of seizures, patients should be cautioned about the performance of complex and hazardous tasks (see WARNINGS);
4. Patients should be cautioned about using alcohol, barbiturates, or other CNS depressants concurrently, since Klominal may exaggerate their response to these drugs;
5. Patients should notify their physician if they become pregnant or intend to become pregnant during therapy;
6. Patients should notify their physician if they are breast-feeding.

Patients should be advised that taking Klominal can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Preexisting glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

(See CONTRAINDICATIONS, WARNINGS and DOSAGE AND ADMINISTRATION.)

(See CONTRAINDICATIONS, WARNINGS and DOSAGE AND ADMINISTRATION.)

No evidence of carcinogenicity was found in two 2-year bioassays in rats at doses up to 100 mg/kg, which is 24 and 4 times the maximum recommended human daily dose (MRHD) on a mg/kg and mg/m2 basis, respectively, or in a 2-year bioassay in mice at doses up to 80 mg/kg, which is 20 and 1.5 times the MRHD on a mg/kg and mg/m2 basis, respectively.

In reproduction studies, no effects on fertility were found in rats given up to 24 mg/kg, which is 6 times, and approximately equal to, the MRHD on a mg/kg and mg/m2 basis, respectively.

No teratogenic effects were observed in studies performed in rats and mice at doses up to 100 mg/kg, which is 24 times the maximum recommended human daily dose (MRHD) on a mg/kg basis and 4 times (rats) and 2 times (mice) the MRHD on a mg/m2 basis. Slight nonspecific embryo/fetotoxic effects were seen in the offspring of treated rats given 50 and 100 mg/kg and of treated mice given 100 mg/kg.

There are no adequate or well-controlled studies in pregnant women. Withdrawal symptoms, including jitteriness, tremor, and seizures, have been reported in neonates whose mothers had taken Klominal until delivery. Klominal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Klominal has been found in human milk. Because of the potential for adverse reactions, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Klominal in a child or adolescent must balance the potential risks with the clinical need.

In a controlled clinical trial in children and adolescents (10 to 17 years of age), 46 outpatients received Klominal for up to 8 weeks. In addition, 150 adolescent patients have received Klominal in open-label protocols for periods of several months to several years. Of the 196 adolescents studied, 50 were 13 years of age or less and 146 were 14 to 17 years of age. The adverse reaction profile in this age group (see ADVERSE REACTIONS) is similar to that observed in adults.

The risks, if any, that may be associated with Klominal’s extended use in children and adolescents with OCD have not been systematically assessed. The evidence supporting the conclusion that Klominal is safe for use in children and adolescents is derived from relatively short term clinical studies and from extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long term Klominal use on the growth, development, and maturation of children and adolescents. Although there is no evidence to suggest that Klominal adversely affects growth, development or maturation, the absence of such findings is not adequate to rule out a potential for such effects in chronic use.

The safety and effectiveness in pediatric patients below the age of 10 have not been established. Therefore, specific recommendations cannot be made for the use of Klominal in pediatric patients under the age of 10.

Clinical studies of Klominal did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects; 152 patients at least 60 years of age participating in various U.S. clinical trials received Klominal for periods of several months to several years. No unusual age-related adverse events were identified in this population. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Klominal is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

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.

Paediatric population

Klominal should not be used in the treatment of depressive states, phobias and cataplexy associated with narcolepsy in children and adolescents under the age of 18 years.

Antidepressants increase the risk of suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominately aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long term safety data in children and adolescents concerning growth, maturation and cognitive behavioural development are lacking.

Families and care givers 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 , as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.

Prescriptions for Klominal should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Other psychiatric effects

Many patients with panic disorders experience intensified anxiety symptoms at the start of the treatment with antidepressants. 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 Klominal or to withdraw it and administer an antipsychotic agent. After such episodes have subsided, low dose therapy with Klominal 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.

As improvement in depression may not occur for the first two to four weeks treatment, patients should be closely monitored during this period.

Elderly patients are particularly liable to experience adverse effects, especially agitation, confusion, and postural hypotension.

Cardiac and vascular disorders

Klominal should be administered with particular precaution in patients with cardiovascular disorders, especially those with cardiovascular insufficiency, conduction disorders, (e.g. atrioventricular block grades I to III), 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 Klominal, as occur in the case of co- medication with selective serotonin reuptake inhibitors (SSRIs). Therefore, concomitant administration of drugs that can cause accumulation of Klominal should be avoided. Equally, concomitant administration of drugs that can prolong the QTc interval should be avoided. 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 Klominal.

Before initiating treatment it is advisable to check the patient's blood pressure, because individuals with hypotension or a labile circulation may react to the drug with 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 Klominal is administered with serotonergic co-medications such as SSRIs, SNaRIs, tricyclic antidepressants or lithium. Therefore, concomitant administration of drugs that can cause accumulation of Klominal should be avoided. 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 Klominal 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 Klominal should not be exceeded.

Concomitant treatment of Klominal and electroconvulsive therapy should only be resorted to under careful supervision.

Anticholinergic effects

Because of its anticholinergic properties, Klominal should be used with caution in patients with a history of increased intra-ocular pressure, narrow-angle glaucoma, urinary retention or with symptoms of bladder neck obstruction, e.g. diseases of the prostate, such as prostatic hypertrophy.

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 advised in patients with hyperthyroidism or during concomitant treatment with thyroid preparations since aggravation of unwanted cardiac effects may occur.

It is advisable to monitor cardiac and hepatic function during long-term therapy with Klominal. In patients with hepatic and renal disease, periodic monitoring of hepatic enzyme levels and renal function is recommended.

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.

Caution is called for in patients with chronic constipation. Tricyclic antidepressants may cause paralytic ileus, particularly in the elderly and in bed-ridden 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.

White blood cell count

Although changes in the white blood cell count have been reported with Klominal 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. They are also recommended during prolonged therapy.

Anticoagulants / Non-steroidal anti-inflammatory drugs

Skin and mucous membrane bleeding has been reported with Klominal. The product should be used with caution among patients that simultaneously use medicines that increase the risk of bleeding, for example anticoagulants, salicylic acid derivatives and non-steroidal anti-inflammatory drugs (NSAIDs). Care should be taken in patients with an increased tendency to bleed.

Anaesthesia

Anaesthetics given during tri/tetracyclic antidepressant therapy may increase the risk of arrhythmias and hypotension.

Before general or local anaesthesia, the anaesthetist should be aware that the patient has been receiving Klominal and of the possible interactions.

Treatment discontinuation

Abrupt withdrawal should be avoided because of possible adverse reactions.).

Klominal capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Klominal contains Sunset yellow (E110). May cause allergic reactions.

Effects on ability to drive and use machines

Patients receiving Klominal 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 have been observed. In the presence of such effects, patients should not drive, operate machinery or do anything else which may require alertness or quick actions. Patients should also be warned that alcohol or other drugs may potentiate these effects.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive

- Do not drive until you know how the medicine affects you

- It is an offence to drive while under the influence of this medicine

- However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

Dosage (Posology) and method of administration

The treatment regimens described below are based on those used in controlled clinical trials of Klominal in 520 adults, and 91 children and adolescents with OCD. During initial titration, Klominal should be given in divided doses with meals to reduce gastrointestinal side effects. The goal of this initial titration phase is to minimize side effects by permitting tolerance to side effects to develop or allowing the patient time to adapt if tolerance does not develop.

Because both CMI and its active metabolite, DMI, have long elimination half-lives, the prescriber should take into consideration the fact that steady-state plasma levels may not be achieved until 2 to 3 weeks after dosage change (see CLINICAL PHARMACOLOGY). Therefore, after initial titration, it may be appropriate to wait 2 to 3 weeks between further dosage adjustments.

Treatment with Klominal should be initiated at a dosage of 25 mg daily and gradually increased, as tolerated, to approximately 100 mg during the first 2 weeks. During initial titration, Klominal should be given in divided doses with meals to reduce gastrointestinal side effects. Thereafter, the dosage may be increased gradually over the next several weeks, up to a maximum of 250 mg daily. After titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.

As with adults, the starting dose is 25 mg daily and should be gradually increased (also given in divided doses with meals to reduce gastrointestinal side effects) 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 (see PRECAUTIONS, Pediatric Use). As with adults, after titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.

While there are no systematic studies that answer the question of how long to continue Klominal, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of Klominal after 10 weeks has not been documented in controlled trials, patients have been continued in therapy under double-blind conditions for up to 1 year without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. During maintenance, the total daily dose may be given once daily at bedtime.

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Klominal. Conversely, at least 14 days should be allowed after stopping Klominal before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).

Do not start Klominal in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).

In some cases, a patient already receiving Klominal therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Klominal should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Klominal may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Klominal is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).

Posology

Before initiating treatment with Klominal, hypokalaemia should be treated.

After a response has been obtained, maintenance therapy should be continued at the optimum dose to avoid relapse. Patients with a history of recurrence 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 Klominal 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.

Abrupt discontinuation of Klominal 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 Klominal therapy is discontinued.

Adults

Oral - 10 mg/day initially, increasing gradually to 30-150 mg/day, if required, in divided doses throughout the day or as a single dose at bedtime. Many patients will be adequately maintained on 30-50 mg/day. Higher doses may be needed in some patients, particularly those suffering from obsessional or phobic disorders. In severe cases this dosage can be increased up to a maximum of 250 mg per day. Once a distinct improvement has set in, the daily dosage may be adjusted to a maintenance level of about 50-100 mg.

Elderly

Elderly patients generally show a stronger response to Klominal than patients of intermediate age groups, Klominal should be used with caution in elderly patients and doses should be increased cautiously. The initial dose should be 10 mg/day, which may be increased with caution under close supervision to an optimum level of 30-75 mg daily which should be reached after about 10 days and then maintained until the end of treatment.

Paediatric population

Not recommended.

Obsessional/phobic states

The maintenance dosage of Klominal is generally higher than that used in depression. It is recommended that the dose be built up to 100-150 mg Klominal daily, according to the severity of the condition. This should be attained gradually over a period of 2 weeks starting with 1 x 25 mg Klominal daily. In elderly patients and those sensitive to tricyclic antidepressants a starting dose of 1 x 10 mg Klominal daily is recommended. Again where a higher dosage is required the sustained-release 75 mg formulation may be preferable.

Adjunctive treatment of cataplexy associated with narcolepsy

(Oral treatment): 10-75 mg daily. It is suggested that treatment is commenced with 10 mg Klominal daily and gradually increased until a satisfactory response occurs. Control of cataplexy should be achieved within 24 hours of reaching the optimal dose. Where necessary, therapy may be combined with capsules up to the maximum dose of 75 mg per day.

Treatment discontinuation

Abrupt withdrawal should be avoided because of possible adverse reactions.8 for a description of the risks of discontinuation of Klominal).

Renal impairment

Klominal should be given with caution in patients with renal impairment.

Hepatic impairment

Klominal should be given with caution in patients with hepatic impairment.

Method of administration

For oral use

Special precautions for disposal and other handling

Not applicable.