CIPRAMIL^®

Citalopram hydrobromide

Presentation

Cipramil 20 mg Tablets: oval, white, film-coated tablet, 8 mm × 5.5 mm, marked "C" and "N" symmetrically around the score-line, containing 24.98 mg citalopram hydrobromide corresponding to 20 mg citalopram base.

Uses

Actions

Biochemical and behavioural studies have shown that citalopram is a potent inhibitor of the serotonin (5-HT)-uptake. Tolerance to the inhibition of 5-HT-uptake is not induced by long-term treatment with citalopram. Citalopram is the most Selective Serotonin Reuptake Inhibitor (SSRI) yet described, with no, or minimal, effect on noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA) uptake. In contrast to many tricyclic antidepressants and some of the newer SSRI's, citalopram has no or very low affinity for a series of receptors including 5-HT1A, 5-HT2, DA D1 and D2 receptors, α1-, α2- β-adrenoceptors, histamine H1, muscarine cholinergic, benzodiazepine, and opioid receptors. A series of functional in vitro tests in isolated organs as well as functional in vivo tests have confirmed the lack of receptor affinity. This absence of effects on receptors could explain why citalopram produces fewer of the traditional side effects of tricyclic antidepressants such as dry mouth, bladder and gut disturbance, blurred vision, sedation, cardiotoxicity and orthostatic hypotension. Suppression of rapid eye movement (REM) sleep is considered a predictor of antidepressant activity. Like tricyclic antidepressants, other SSRIs and MAO inhibitors, citalopram suppresses REM-sleep and increases deep slow-wave sleep. The main metabolites of citalopram are all SSRIs although their potency and selectivity ratios are lower than those of citalopram but higher than those of many of the newer SSRIs. The metabolites do not contribute to the overall antidepressant effect. In humans citalopram does not impair cognitive (intellectual function) and psychomotor performance and has no or minimal sedative properties, either alone or in combination with alcohol. Citalopram did not reduce saliva flow in a single dose study in human volunteers although dry mouth occurred significantly more frequently than with placebo in clinical trials. In none of the studies in healthy volunteers did citalopram have significant influence on cardiovascular parameters. Citalopram has no effect on the serum levels of prolactin and growth hormone. The dose response curve is flat.

Pharmacokinetics

Absorption

Absorption is almost complete and independent of food intake (T_max mean 3 hours). Oral bioavailability is about 80%.

Distribution

The apparent volume of distribution (Vd) _β is about 12-17 L/kg. The plasma protein binding is below 80% for citalopram and its main metabolites.

Biotransformation

Citalopram is metabolized to the active demethylcitalopram, didemethylcitalopram, citalopram-N-oxide and an inactive deaminated propionic acid derivative. All the active metabolites are also SSRIs, although weaker than the parent compound. Unchanged citalopram is the predominant compound in plasma.

Excretion

The elimination half-life (T_½β) is about 1½ days and the systemic citalopram plasma clearance (Cls) is about 0.3-0.4 L/min, and oral plasma clearance (Cloral) is about 0.4 L/min. Citalopram is excreted mainly via the liver (85%) and the remainder (15%) via the kidneys; 12-23% of the daily dose is excreted in urine as unchanged citalopram. Hepatic (residual) clearance is about 0.3 L/min and renal clearance about 0.05-0.08 L/min.

The kinetics is linear. Steady state plasma levels are achieved in 1-2 weeks. Average concentrations of 300 nmol/L (165-405 nmol/L) are achieved at a daily dose of 40 mg. There is no clear relationship between citalopram plasma levels and therapeutic response or side effects.

Elderly patients (> 65 years)

Longer half-lives (1.5-3.75 days) and decreased clearance values (0.08-0.3 L/min) due to a reduced rate of metabolism have been demonstrated in elderly patients. Steady state levels were about twice as high in the elderly than in younger patients treated with the same dose.

Reduced hepatic function

Citalopram is eliminated more slowly in patients with reduced hepatic function. The half-life of citalopram is about twice as long and steady state citalopram concentrations at a given dose will be about twice as high as in patients with normal liver function.

Reduced renal function

Citalopram is eliminated more slowly in patients with mild to moderate reduction of renal function, without any major impact on the pharmacokinetics of citalopram. Patients with a mean serum creatinine value of 278 micromol/L had a mean T_½β of 49.5 hours versus 36.8 hours in healthy volunteers. At present no information is available for treatment of patients with severely reduced renal function (creatinine clearance < 20 mL/min).

Indications

Treatment of depressive illness in the initial phase and as maintenance against potential relapse/recurrence.

Dosage and Administration

The dose may be taken in the morning or evening without regard for food. As the treatment result in general can be evaluated only after 2-3 weeks' treatment, a possible dose increase in increments of 10 mg should take place with intervals of 2-3 weeks.

Adults

Cipramil should be administered as a single oral dose of 20 mg daily. Dependent on individual patient response and severity of depression the dose may be increased to a maximum of 60 mg daily.

Elderly patients

The recommended daily dose is 20 mg, starting with 10 mg daily. Dependent on individual patient response and severity of depression the dose may be increased to a maximum of 40 mg daily.

Children

Cipramil is not recommended in children as safety and efficacy have not been established in this population.

Reduced hepatic function

Patients with reduced hepatic function should receive dosages of no more than 30 mg/day.

Reduced renal function

Dosage adjustment is not necessary in patients with mild or moderate renal impairment. No information is available on treatment of patients with severely reduced renal function (creatinine clearance < 20 mL/min.).

Duration of treatment

The antidepressive effect usually sets in after 2 to 4 weeks. A treatment period of at least six months is usually necessary to provide adequate maintenance against the potential for relapse. Withdrawal phenomena were not reported in clinical trials. However, because other SSRIs have been associated with withdrawal phenomena the dose should be tapered over at least one week if discontinuation is contemplated.

Contra-indications

Hypersensitivity to citalopram and any excipients in Cipramil (see FURTHER INFORMATION).

Warnings and Precautions

As with other SSRIs, Cipramil should not be given to patients receiving Monoamine Oxidase Inhibitors (MAOIs), or for 14 days after their discontinuation. MAOIs should not be introduced for seven days after discontinuation of Cipramil. Rarely, the occurrence of "serotonin syndrome" has been reported in patients receiving SSRIs. A combination of symptoms, possibly including agitation, confusion, tremor, myoclonus and hyperthermia, may indicate the development of this condition (see INTERACTIONS). Sumatriptan's serotonergic effects are suspected to be enhanced by SSRIs. Until further evidence is available it is advised not to use Cipramil simultaneously with 5-HT agonists e.g. sumatriptan (see INTERACTIONS). As with most antidepressants, Cipramil should be discontinued if the patient enters a manic phase. Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported as a rare adverse reaction with the use of SSRIs. Risk factors include old age and concomitant therapy with diuretics; most cases occur during the first 3 weeks of therapy. There is little clinical experience of concurrent use of citalopram and ECT.

Use in patients with cardiac disease

Citalopram has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. However, the electrocardiograms of 1116 patients who received Cipramil in clinical trials were evaluated and the data indicate that Cipramil is not associated with the development of clinically significant ECG abnormalities. Fatal arrhythmias with prolonged QTc interval were observed in preclinical (animal toxicology) studies (see FURTHER INFORMATION). Like other SSRIs, citalopram causes a small decrease in heart rate. Consequently, caution should be observed when citalopram is initiated in patients with pre-existing slow heart rate.

Carcinogenicity/mutagenicity

Citalopram has low acute toxicity. In chronic toxicity studies there were no findings of concern for the therapeutic use of citalopram. Based on data from reproduction toxicity studies (segment I, II and III) there is no reason to have special concern for the use of citalopram in women of child-bearing potential. Citalopram has no mutagenic or carcinogenic potential.

Use in pregnancy and lactation

Animal studies have not shown any evidence of teratogenic potential and citalopram does not affect reproduction or perinatal conditions. Due to limited human data, Cipramil should only be used in pregnancy if considered necessary and under the close supervision of a physician. Citalopram appears in breast milk in very low concentrations. In nursing mothers, caution is recommended as it is not known whether citalopram excreted in milk may affect the infant.

Adverse Reactions

Adverse effects observed with Cipramil are in general mild and transient. They are most prominent during the first one or two weeks of treatment and usually attenuate as the depressive state improves. The most commonly observed adverse events associated with the use of Cipramil and not seen at an equal incidence among placebo-treated patients were (p=0.05): nausea, dry mouth, somnolence, increased sweating, tremor, diarrhoea and ejaculation disorder. The incidence of each in excess over placebo is low (< 10%). Adverse events reported in clinical trials include:

Frequent: (≥ 5% - 20%)

Less frequent: (1 - <5%)

Rare: (< 1%)

Interactions

Monoamine Oxidase Inhibitors (MAOIs) should not be used in combination with SSRIs (see WARNINGS AND PRECAUTIONS).

Sumatriptan's serotonergic effects are suspected to be enhanced by SSRIs. Until further evidence is available it is advised not to use Cipramil simultaneously with 5-HT agonists e.g. sumatriptan (see WARNINGS AND PRECAUTIONS).

The metabolism of citalopram is only partly dependent on the hepatic P450 isozyme CYP2D6 and, unlike some other SSRIs, citalopram is only a weak inhibitor of this important enzyme system which is involved in the metabolism of many drugs (including antiarrhythmics, neuroleptics, beta-blockers, tricyclic antidepressants and some SSRIs). Protein binding is relatively low (< 80%). These properties give Cipramil a low potential for clinically significant drug interactions.

There is no pharmacokinetic interaction between lithium and citalopram. However, there have been reports of enhanced serotonergic effects when other SSRIs have been given with lithium and tryptophan and therefore the concomitant use of citalopram with these drugs should be undertaken with caution. Routine monitoring of lithium levels need not be adjusted.

Pharmacokinetic interaction studies have been performed with levomepromazine (prototype of phenothiazines) and imipramine (prototype of tricyclic antidepressants). No pharmacokinetic interactions of clinical importance was found.

Cimetidine, a documented enzyme inhibitor, caused a moderate increase in the average steady state levels of citalopram. It is therefore advised to exercise caution at the upper end of the dose range of citalopram when it is used concomitantly with high doses of cimetidine.

Neither pharmacodynamic nor pharmacokinetic interaction with alcohol has been shown.

No pharmacodynamic interactions have been noted in clinical studies in which citalopram has been given concomitantly with benzodiazepines, neuroleptics, analgesics, lithium, antihistamines, antihypertensive drugs, beta-blockers and other cardiovascular drugs.

Although citalopram does not bind to opioid receptors it potentiates the antinociceptive effect of commonly used opioid analgesics.

Experience with citalopram has not revealed any clinically relevant interactions with neuroleptics. However, as with other SSRIs, the possibility of a pharmacodynamic interaction cannot be excluded.

Overdosage

Citalopram is given to patients at potential risk of suicide and some reports of attempted suicide have been received. Detail is often lacking regarding precise dose or combination with other drugs and/or alcohol.

Symptoms

Experience from cases considered to be due to citalopram alone comprised the following symptoms/signs: drowsiness, somnolence, unconsciousness, convulsions, tachycardia, nausea, vomiting, cyanosis, tremor, sweating and rarely ECG changes. Fatalities have been reported.

Treatment

There is no specific antidote. Treatment is symptomatic and supportive. Gastric lavage should be carried out as soon as possible after oral ingestion. Medical surveillance is advisable.

An adult patient has survived intoxication with 5,200 mg citalopram.

Pharmaceutical Precautions

Cipramil 20 mg Tablets are stable for 5 years when stored in the original pack at less than 25°C.

Package Quantities

Cipramil 20 mg Tablets: 28 Tablets.

Further Information

Citalopram hydrobromide is a fine white to off-white, crystalline material. Citalopram hydrobromide is sparingly soluble in water, soluble in ethanol (96%), freely soluble in chloroform and very slightly soluble in diethylether. No polymorphic forms have been detected.

Excipients

Excipients in Cipramil include maize starch, lactose, cellulose-microcrystalline, PVP/VA copolymer, glycerol, croscarmellose sodium, magnesium stearate, hypromellose, macrogol and titanium dioxide.

Animal toxicity

For comparison the recommended daily therapeutic dose is 0.3-0.9 mg/kg. Fatty infiltration of the liver was seen in male rats but not in females and was greater when citalopram was given by gavage (8 mg/kg/day for 3 months) than in a more sustained manner via the diet (32 mg/kg/day for 12 months). Citalopram (25 mg/kg/day for 28 days) given as infusion over 30 minutes did not induce signs of fatty infiltration. The fatty infiltrations, which are completely reversible, are therefore connected with excessive first-pass metabolic transformation in the male rat. This has no clinical parallel, since first-pass metabolism is modest in man. Induction of completely reversible phospholipidosis was seen in both male and female rodents receiving 60 and 120 mg/kg/day (rats, 52 weeks) and 100 and 240 mg/kg/day (mice, 26 weeks). There was no evidence of phospholipidosis in dogs. Citalopram has not shown any signs of phospholipidosis in humans. The ratio between the doses which caused phospholipidosis in rats and mice and the therapeutic dose is high (ratio rats/human 53 and ratio mice/humans 167). The phenomenon is also seen with many other marketed cationic amphiphilic drugs including most tricyclic antidepressants, several neuroleptics, some cardiovascular agents and no clinical problems related to phospholipidosis have been observed with these drugs. After life-long treatment (2 years) retinal changes was observed in the top dose group of albino rats given 80 mg/kg/day. No changes was observed after 1 year. Albino rats having no pigmentation are light sensitive and the changes are most likely related to drug-induced mydriasis (pupillary dilatation). No changes have been observed in pigmented mice or in dogs. In dogs convulsions and death occurred when plasma citalopram levels exceeded 6,000 nmol/L (more than 20 times the average patient level). By preventing convulsive episodes with diazepam intravenous infusion could be continued up to 70 mg/kg resulting in plasma concentrations of up to 21,000 nmol/L without indications of serious toxicity. Repeated dose toxicity studies demonstrated that fatal arrhythmias may occur at combined high levels of the didemethyl metabolite (which affects the heart) and citalopram (central nervous effects). Neither citalopram alone nor the metabolite alone produce dangerous arrhythmias. The didemethyl metabolite, however, prolongs the QT interval - an action which can develop into fatal arrhythmia when coupled with centrally mediated effects induced by convulsive or near convulsive doses of citalopram. Fatal arrhythmias may occur in dogs simultaneously exposed to citalopram levels exceeding about 2,600 nmol/L and didemethyl metabolite levels exceeding about 1,000 nmol/L. However, the kinetics differ greatly between dogs and man and the didemethyl metabolite is much less prominent in man.

Pharmacokinetic data indicate that high levels of citalopram following an overdose will not be combined with immediate high levels of the metabolite, which require a two step demethylation, i.e. maximum levels of the didemethyl metabolite are obtained 2-3 days after a single dose. The highest didemethyl level of 140 nmol/L was found 2-3 days after an overdose of 1200 mg citalopram and the citalopram level at that time was 1950 nmol/L. The metabolite related cardiovascular findings in dogs are therefore of no concern for the clinical use of citalopram.

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