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Pramixa Plus

Brand Name: Pramixa Plus

Composition: Escitalopram Oxalate 10 mg + Clonazepam 0.5mg

Dosage Form : Tablet

Packing: 10×10 Tablets

Composition

Pramixa Plus

Each tablet contains

Escitalopram oxalate equivalent to Escitalopram… 10 mg

Clonazepam …………………………………………. 0.5 mg

Dosage Form

Film coated tablet

Pharmacology

Pharmacodynamics

Escitalopram

The mechanism of the antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to the potentiation of serotonergic activity in the central nervous system (CNS), resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).

In vitro and in vivo studies suggests that escitalopram is a highly selective serotonin (5-HT) reuptake inhibitor (SSRI) with a high affinity for the primary binding site, and has minimal effects on norepinephrine and dopamine neuronal reuptake. It also binds to an allosteric site on the serotonin transporter, with a 1,000-fold lower affinity. Escitalopram is at least 100-fold more potent than the R-enantiomer with respect to the inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Tolerance to a model of antidepressant effect in rats was not induced by long-term (up to 5 weeks) treatment with escitalopram. Escitalopram has no or very low affinity for serotonergic (5-HT1–7)or other receptors including alpha- and beta-adrenergic, dopamine (D1–5), histamine (H1–3), muscarinic (M1–5), benzodiazepine and opiod receptors. Escitalopram also does not bind to or has low affinity for various ion channels, including Sodium (Na+), Potassium (K+), Chloride (Cl–) and Calcium (Ca++) channels. Antagonism of the muscarinic, histaminergic and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular side effects of other psychotropic drugs.

Clonazepam

The precise mechanism by which clonazepam exerts its anxiolytic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.

Pharmacokinetics

Escitalopram

Absorption

The single- and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day.

Absorption is almost complete and independent of food intake (mean time to maximum concentration is 4 hours after multiple dosing). As with racemic citalopram, the absolute bio-availability of escitalopram is expected to be about 80%. Following a single oral dose (20 mg tablet or solution) of escitalopram, peak blood levels occur at about 5 hours.

Distribution

The binding of escitalopram to human plasma proteins is approximately 56%. The apparent volume of distribution (Vd,β/F) after oral administration is about 12–26 L/kg. At the steady state, the extent of accumulation of escitalopram in plasma in young healthy subjects was 2.2–2.5 times the plasma concentrations observed after a single dose.

Metabolism

Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27–32 hours. Escitalopram is metabolized to S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT). Both of these are pharmacologically active. Alternatively, the nitrogen may be oxidized to form the N-oxide metabolite. Both parent substance and metabolites are partly excreted as glucuronides. After multiple dosing, the mean concentrations of the demethyl and didemethyl metabolites are usually 28–31% and <5%, respectively, of the escitalopram concentration. In humans, unchanged escitalopram is the predominant compound in plasma. At the steady state, the concentration of the escitalopram metabolite, S-DCT, in plasma is approximately one-third that of escitalopram.

In vitro studies show that escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT1–7) or other receptors, including alpha- and beta-adrenergic, dopamine (D1–5), histamine (H1–3), muscarinic (M1–5) and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels, including Na+, K+, Cl– and Ca++ channels. In vitro studies using human liver microsomes indicated that cytochrome (CY) P3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram. Some contribution by the enzymes, CYP3A4 and CYP2D6, is also possible.

Elimination

The elimination half-life (t½β) after multiple dosing is about 30 hours and the oral plasma clearance (Cloral) is about 0.6 L/min. Following oral administration of escitalopram, the fraction of drug recovered in the urine as escitalopram and S-DCT is about 8% and 10%, respectively. The major metabolites have a significantly longer half-life. Escitalopram and its major metabolites are assumed to be eliminated by both the hepatic (metabolic) and the renal routes, with the major part of the dose excreted as metabolites in the urine. The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance.

With once-daily dosing, steady-state plasma concentrations are achieved within approximately 1 week. Average steady-state concentrations of 50 nmol/L (range: 20 to 125 nmol/L) are achieved at a daily dose of 10 mg.

Special Populations

Adolescents

In a single-dose study of 10 mg escitalopram, the area under the concentration curve (AUC) of escitalopram decreased by 19% and the Cmax increased by 26% in healthy adolescent subjects (12 to 17 years of age), compared to adults. Following multiple dosing of 40 mg/day escitalopram, the citalopram elimination half-life, steady-state Cmax and the AUC were similar in patients with major depressive disorder (12 to 17 years of age), compared to adult patients. No adjustment of dosage is needed in adolescent patients.

Geriatric

Escitalopram pharmacokinetics in subjects who were ≥65 years of age were compared to younger subjects in a single-dose and a multiple-dose study. Escitalopram AUC and half-life were increased by approximately 50% in elderly subjects and the Cmax was unchanged. for elderly patients, 10 mg is the recommended dose. Escitalopram appears to be eliminated more slowly in elderly patients compared to younger patients.

Gender

Based on data from single- and multiple-dose studies measuring escitalopram in the elderly, young adults and adolescents, no dosage adjustment on the basis of gender is needed.

Reduced Hepatic Function

Escitalopram oral clearance was reduced by 37%, the exposure was increased by 60% and the half-life was doubled in patients with mild or moderate hepatic impairment (Child-Pugh criteria A and B). the recommended dose of escitalopram for most hepatically impaired patients is10 mg.

Reduced Renal Function

In patients with mild-to-moderate renal function impairment, oral clearance of escitalopram was reduced by 17%. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of escitalopram in patients with severely reduced renal function (creatinine clearance <20 mL/min). With racemic citalopram, a longer half-life and a minor increase in exposure have been observed in patients with reduced kidney function (creatinine clearance 10–53 ml/min). Plasma concentrations of the metabolites have not been studied, but they may be elevated.

Polymorphism

It has been observed that poor metabolisers with respect to CYP2C19 have twice as high a plasma concentration of escitalopram as extensive metabolizers. No significant change in exposure was observed in poor metabolizers with respect to CYP2D6.

Clonazepam

Absorption

Clonazepam is rapidly and completely absorbed after oral administration. Peak plasma concentrations are reached in most cases within 1 – 4 hours after an oral dose. Bioavailability is 90% after oral administration. Routine monitoring of plasma concentrations of clonazepam is of unproven value since this does not appear to correlate well with either therapeutic response or side-effects.

Distribution

The mean volume of distribution of clonazepam is estimated at about 3 L/kg. Clonazepam must be assumed to cross the placental barrier and has been detected in maternal milk.

Metabolism

The biotransformation of clonazepam involves oxidative hydroxylation and reduction of the 7-nitro group by the liver with formation of 7-amino or 7-acetylamino compounds, with trace amounts of 3-hydroxy derivatives of all three compounds, and their glucuronide and sulphate conjugates. The nitro compounds are pharmacologically active, whereas the amino compounds are not.

Within 4 – 10 days 50 – 70% of the total radioactivity of a radiolabelled oral dose of clonazepam is excreted in the urine and 10 – 30% in the faeces, almost exclusively in the form of free or conjugated metabolites. Less than 0.5% appears as unchanged clonazepam in the urine.

Elimination

The elimination half-life is between 20 and 60 hours (mean 30 hours).

Special populations

Age and Gender

Controlled studies examining the influence of gender and age on clonazepam pharmacokinetics have not been conducted.

Renal impairment

Controlled studies examining the influence of renal impairment on clonazepam pharmacokinetics have not been conducted.

Hepatic impairment

Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Thus, caution should be exercised when administering clonazepamto these patients.

Indications

PRAMIXA PLUS PLUS/FORTE Tablets are indicated for the treatment of patients with comorbid depression and anxiety disorder

Dosage and Administration

The administration of PRAMIXA PLUS PLUS/FORTE Tablets is once daily for the specified indication in adults.

The recommended dose of escitalopram is 10 mg/day in adults. The dose should not be increased considering the presence of clonazepam.

Initial dose of clonazepam is 0.5 mg/day in the initial stages of treatment. Dosage of clonazepam should not exceed 1 mg/day.

Contraindications

Hypersensitivity to PRAMIXA PLUS PLUS/FORTE Tablets and any of its component

Acute angle glaucoma

Concomitant use of monoamine oxidase inhibitors (MAOIs)

Concomitant use in patients taking pimozide.

In patients with clinical or biochemical evidence of significant liver disease.