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Abilify (Aripiprazole) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

Potential for Other Drugs to Affect ABILIFY

Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely.

Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism. Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in aripiprazole clearance and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, quinidine, fluoxetine, or paroxetine) can inhibit aripiprazole elimination and cause increased blood levels.

Valproate: When valproate (500-1500 mg/day) and aripiprazole (30 mg/day) were coadministered at steady state, the Cmax and AUC of aripiprazole were decreased by 25%. No dosage adjustment of aripiprazole is required when administered concomitantly with valproate.

Lithium: A pharmacokinetic interaction of aripiprazole with lithium is unlikely because lithium is not bound to plasma proteins, is not metabolized, and is almost entirely excreted unchanged in urine. Coadministration of therapeutic doses of lithium (1200-1800 mg/day) for 21 days with aripiprazole (30 mg/day) did not result in clinically significant changes in the pharmacokinetics of aripiprazole or its active metabolite, dehydro-aripiprazole (Cmax and AUC increased by less than 20%). No dosage adjustment of aripiprazole is required when administered concomitantly with lithium.

Potential for ABILIFY to Affect Other Drugs

Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo studies, 10- to 30-mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates. Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro (see PRECAUTIONS: Drug-Drug Interactions).

Aripiprazole had no clinically important interactions with the following drugs:

Famotidine: Coadministration of aripiprazole (given in a single dose of 15 mg) with a 40-mg single dose of the H2 antagonist famotidine, a potent gastric acid blocker, decreased the solubility of aripiprazole and, hence, its rate of absorption, reducing by 37% and 21% the Cmax of aripiprazole and dehydro-aripiprazole, respectively, and by 13% and 15%, respectively, the extent of absorption (AUC). No dosage adjustment of aripiprazole is required when administered concomitantly with famotidine.

Valproate: When aripiprazole (30 mg/day) and valproate (1000 mg/day) were coadministered at steady state, there were no clinically significant changes in the Cmax or AUC of valproate. No dosage adjustment of valproate is required when administered concomitantly with aripiprazole.

Lithium: Coadministration of aripiprazole (30 mg/day) with lithium (900 mg/day) did not result in clinically significant changes in the pharmacokinetics of lithium. No dosage adjustment of lithium is required when administered concomitantly with aripiprazole.

Dextromethorphan: Aripiprazole at doses of 10 to 30 mg per day for 14 days had no effect on dextromethorphan’s O-dealkylation to its major metabolite, dextrorphan, a pathway known to be dependent on CYP2D6 activity. Aripiprazole also had no effect on dextromethorphan’s N-demethylation to its metabolite 3-methyoxymorphan, a pathway known to be dependent on CYP3A4 activity. No dosage adjustment of dextromethorphan is required when administered concomitantly with aripiprazole.

Warfarin: Aripiprazole 10 mg per day for 14 days had no effect on the pharmacokinetics of R- and S-warfarin or on the pharmacodynamic end point of International Normalized Ratio, indicating the lack of a clinically relevant effect of aripiprazole on CYP2C9 and CYP2C19 metabolism or the binding of highly protein-bound warfarin. No dosage adjustment of warfarin is required when administered concomitantly with aripiprazole.

Omeprazole: Aripiprazole 10 mg per day for 15 days had no effect on the pharmacokinetics of a single 20-mg dose of omeprazole, a CYP2C19 substrate, in healthy subjects. No dosage adjustment of omeprazole is required when administered concomitantly with aripiprazole.

Lorazepam: Coadministration of lorazepam injection (2 mg) and aripiprazole injection (15 mg) to healthy subjects (n=40: 35 males and 5 females; ages 19-45 years old) did not result in clinically important changes in the pharmacokinetics of either drug. No dosage adjustment of aripiprazole is required when administered concomitantly with lorazepam. However, the intensity of sedation was greater with the combination as compared to that observed with aripiprazole alone and the orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone (see PRECAUTIONS: General).

OVERDOSAGE

MedDRA terminology has been used to classify the adverse events.

Human Experience

A total of 76 cases of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide. These include overdoses with oral aripiprazole alone and in combination with other substances. No fatality was reported from these cases. Of the 44 cases with known outcome, 33 recovered without sequelae and one recovered with sequelae (mydriasis and feeling abnormal). The largest known acute ingestion with a known outcome involved 1080 mg of oral aripiprazole (36 times the maximum recommended daily dose) in a patient who fully recovered. Included in the 76 cases are 10 cases of deliberate or accidental overdosage in children (age 12 and younger) involving oral aripiprazole ingestions up to 195 mg with no fatalities.

Common adverse events (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

Management of Overdosage

No specific information is available on the treatment of overdose with aripiprazole. An electrocardiogram should be obtained in case of overdosage and, if QTc interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.

Charcoal: In the event of an overdose of ABILIFY, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15-mg oral dose of aripiprazole, decreased the mean AUC and Cmax of aripiprazole by 50%.

Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with aripiprazole, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

CONTRAINDICATIONS

ABILIFY is contraindicated in patients with a known hypersensitivity to the product.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

ABILIFY (aripiprazole) is not a controlled substance.

Abuse and Dependence

Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (eg, development of tolerance, increases in dose, drug-seeking behavior).

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