ARIPIPRAZOLE MEVON TABLETS 5 MG [SIN17182P]

Product Info

ARIPIPRAZOLE MEVON TABLETS 5 MG

[SIN17182P]

4.1 Therapeutic indications

Schizophrenia

Aripiprazole is indicated for the treatment of schizophrenia. The efficacy of Aripiprazole in the treatment of schizophrenia was established in four short-term (4- and 6-week) controlled trials in adults and one 6-week trial in paediatrics (13 to 17 years). Maintenance efficacy was demonstrated in one trial in adults and can be extrapolated to paediatrics (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). The physician who elects to use Aripiprazole for extended periods should periodically re-evaluate the long- term usefulness of the drug for the individual patient (see section 4.2).

Bipolar I Disorder

Aripiprazole is indicated for the treatment of acute manic and mixed episodes associated with Bipolar I Disorder and for maintaining stability or preventing recurrence, as monotherapy in adults and in adolescents aged 13 years and older, and as an adjunct to lithium or valproate in adults.
The efficacy of Aripiprazole as monotherapy was established in four 3-week monotherapy trials in adults and one 4-week monotherapy trial in paediatric patients. Efficacy as adjunctive therapy was established in one 6-week adjunctive trial in adults (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).
Maintenance efficacy was demonstrated in one monotherapy maintenance trial and in one adjunctive maintenance trial in adults (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Physicians who elect to use Aripiprazole for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see section 4.2).

Adjunctive Treatment of Major Depressive Disorder

Aripiprazole is indicated for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD).
Efficacy was established in three 6-week trials in adults with MDD who had an inadequate response to antidepressant therapy during the current episode (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Irritability Associated with Autistic Disorder

Aripiprazole is indicated for the treatment of irritability associated with autistic disorder. Efficacy was established in two 8-week trials in paediatric patients (aged 6 to 17 years) with irritability associated with autistic disorder (including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods) (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). The efficacy of Aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established.

Tourette’s Disorder

Aripiprazole is indicated for the treatment of Tourette’s disorder. Efficacy was established in one 8-week (aged 7 to 17 years) and one 10-week (aged 6 to 18 years) placebo-controlled trial in paediatric patients with Tourette’s disorder (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

4.2 Posology and administration

Posology

4.2.1 Schizophrenia

Adults

Usual Dose

The recommended starting and target dose for Aripiprazole is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole has been systematically evaluated and shown to be effective in a dose range of 10 to 30 mg/day; however, doses higher than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady state (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Maintenance Therapy

While there is no body of evidence available to answer the question of how long a patient treated with aripiprazole should remain on it, systematic evaluation of patients with schizophrenia who had been symptomatically stable on other antipsychotic medication, for periods of 3 months or longer, were discontinued from those medications, and were then administered Aripiprazole 15 mg/day and observed for relapse during a period of up to 26 weeks, demonstrated a benefit of such maintenance treatment (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Patients should be periodically reassessed to determine the need for maintenance treatment.

Adolescents

Usual Dose

The recommended target dose of Aripiprazole is 10 mg/day. Aripiprazole was studied in adolescent patients 13 to 17 years of age with Schizophrenia at daily doses of 10 mg and 30mg. The starting daily dose of the tablet formulation in these patients was 2 mg, which was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days. Subsequent dose increases should be administered in 5 mg increments. The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose and was associated with a higher incidence of significant adverse reactions including extrapyramidal disorder, somnolence and tremor (see section 4.8 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Aripiprazole can be administered without regard to meals (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Maintenance Therapy

The efficacy of Aripiprazole for the maintenance treatment of schizophrenia in the adolescent population has not been evaluated. While there is no body of evidence available to answer the question of how long the adolescent patient treated with Aripiprazole should be maintained on the drug, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and paediatric patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

Switching from Other Antipsychotics

There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotics to Aripiprazole or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized.

4.2.2 Bipolar Disorder

Acute Treatment of Manic and Mixed Episodes

Adults

The recommended starting dose in adults is 15 mg given once daily as monotherapy and 10 to 15 mg given once daily as adjunctive therapy with lithium or valproate. Aripiprazole can be given without regard to meals. The recommended target dose of Aripiprazole is 15 mg/day, as monotherapy or as adjunctive therapy with lithium or valproate. The dose may be increased to 30 mg/day based on clinical response. The safety of doses above 30 mg/day has not been evaluated in clinical trials.

Adolescents

The recommended starting dose in adolescent patients as monotherapy is 2 mg/day, with titration to 5 mg/day after 2 days, and a target dose of 10 mg/day after 2 additional days. Subsequent dose increases, if needed, should be administered in 5 mg/day increments. Aripiprazole can be given without regard to meals. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant adverse reactions including extrapyramidal disorder, somnolence, akathisia and salivary hypersecretion. Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring (see section 4.4, section 4.8, and section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, Aripiprazole is not recommended for use in patients below 13 years of age (see section 4.8 and section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Maintenance Therapy

The recommended dose for maintenance treatment is the same dose needed to stabilize patients during acute treatment, both for adult and paediatric patients. Systematic evaluation of adult patients with Bipolar I Disorder experiencing a manic or mixed episode, who had been symptomatically stable on Aripiprazole Tablets (15 mg/day or 30 mg/day with a starting dose of 30 mg/day) for 6 consecutive weeks and then randomized to Aripiprazole Tablets (15 mg/day or 30 mg/day) or placebo for at least 6 months and up to an additional 17 months of observation for relapse, demonstrated a benefit of such maintenance treatment (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Patients should be periodically reassessed to determine the need for maintenance treatment.

4.2.3 Adjunctive Treatment of Major Depressive Disorder

The recommended starting dose for Aripiprazole as adjunctive treatment for patients already taking an antidepressant is 2 to 5 mg/day. The recommended dosage range is 2 to 15 mg/day. Dosage adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Patients should be periodically reassessed to determine the continued need for maintenance treatment.

4.2.4 Irritability Associated with Autistic Disorder

Paediatric Patients (6 to 17 years)

The recommended dosage range for the treatment of paediatric patients with irritability associated with autistic disorder is 5 to 15 mg/day.
Dosing should be initiated at 2 mg/day. The dose should be increased to 5 mg/day, with subsequent increases to 10 or 15 mg/day if needed. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Patients should be periodically reassessed to determine the continued need for maintenance treatment.

4.2.5 Tourette’s Disorder

Paediatric Patients (6 to 18 years)

The recommended dosage range for Tourette’s Disorder is 5 to 20 mg/day.
For patients weighing less than 50 kg, dosing should be initiated at 2 mg/day with a target dose of 5 mg/day after 2 days. The dose can be increased to 10 mg/day in patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually at intervals of no less than 1 week.
For patients weighing 50 kg or more, dosing should be initiated at 2 mg/day for 2 days, and then increased to 5 mg/day for 5 days, with a target dose of 10 mg/day on day 8. The dose can be increased up to 20 mg/day for patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of no less than 1 week (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Patients should be periodically reassessed to determine the continued need for maintenance treatment.

4.2.6 Dosage Adjustments for Cytochrome P450 Considerations

Dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 1). When the co-administered drug is withdrawn from the combination therapy, Aripiprazole dosage should then be adjusted to its original level. When the co-administered CYP3A4 inducer is withdrawn, Aripiprazole dosage should be reduced to the original level over 1 to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favourable clinical response.

When adjunctive Aripiprazole is administered to patients with major depressive disorder, Aripiprazole should be administered without dosage adjustment as specified in section 4.2.3.

4.6.7 Special Populations

Paediatric population

Safety and effectiveness in paediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established.
The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight (see section 5.2 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Schizophrenia

Safety and effectiveness in paediatric patients with schizophrenia were established in a 6-week, placebo-controlled clinical trial in 202 paediatric patients aged 13 to 17 years (see section 4.2, section 4.8, and section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Although maintenance efficacy in paediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and paediatric patients.

Bipolar I Disorder

Safety and effectiveness in paediatric patients with bipolar mania were evaluated in a 4-week, placebo-controlled clinical trial in 197 paediatric patients aged 10 to 17 years. Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, Aripiprazole is not recommended for use in patients below 13 years of age (see section 4.2, section 4.8, and section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Although maintenance efficacy in paediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and paediatric patients.
The efficacy of adjunctive Aripiprazole with concomitant lithium or valproate in the treatment of manic or mixed episodes in paediatric patients has not been systematically evaluated.

Irritability Associated with Autistic Disorder

Safety and effectiveness in paediatric patients demonstrating irritability associated with autistic disorder were established in two 8-week, placebo-controlled clinical trials in 212 paediatric patients aged 6 to 17 years (see section 4.1, section 4.2, section 4.8, and section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). A maintenance trial was conducted in paediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the ABC-I subscale, and a CGI-I rating of “much improved” or “very much improved”) on Aripiprazole for 12 consecutive weeks. Overall, 85 patients were stabilized and entered the second, 16-week, double-blind phase where they were randomized to either continue Aripiprazole treatment or switch to placebo. In this trial, the efficacy of Aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established.

Tourette’s Disorder

Safety and effectiveness of aripiprazole in paediatric patients with Tourette’s Disorder were established in one 8-week (aged 7 to 17) and one 10-week trial (aged 6 to 18) in 194 paediatric patients (see section 4.2, section 4.8, and section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Maintenance efficacy in paediatric patients has not been systematically evaluated.

CYP2D6 Poor Metabolizers

Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3 to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM). The rest are extensive metabolizers (EM). PMs have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total active moieties from a given dose of aripiprazole compared to EMs. Co-administration of Aripiprazole with known inhibitors of CYP2D6, such as quinidine or fluoxetine in EMs, approximately doubles aripiprazole plasma exposure, and dose adjustment is needed (see section 4.5 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Similarly, PMs have higher exposure to aripiprazole compared to EMs; hence, PMs should have their initial dose reduced by one-half. Laboratory tests are available to identify CYP2D6 PMs. Aripiprazole does not inhibit or induce the CYP2D6 pathway (see section 4.2 and section 5.2 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Hepatic impairment

No dosage adjustment for Aripiprazole is required on the basis of a patient’s hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15) (see section 5.2 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Renal impairment

No dosage adjustment for Aripiprazole is required on the basis of a patient’s renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) (see section 5.2 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Elderly

No dosage adjustment is recommended for elderly patients.

Of the 13,543 patients treated with oral Aripiprazole in clinical trials, 1,073 (8%) were ≥ 65 years old and 799 (6%) were ≥ 75 years old. Placebo-controlled studies of oral Aripiprazole in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.
Aripiprazole is not approved for treatment of patients with psychosis associated with Alzheimer's disease (see section 4.4 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Other Specific Populations

No dose adjustment for Aripiprazole is required on the basis of a patient’s sex, race or smoking status (see section 5.2 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Method of administration

Aripiprazole is for oral use.

4.3 Contraindications

Aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis.