Aripiprazole: Package Insert and Label Information (Page 4 of 7)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups and blood glucose fluctuation.

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with Aripiprazole

Table 25: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see D OSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]. Monitor sedation and blood pressure. Adjust dose accordingly.

7.2 Drugs Having No Clinically Important Interactions with Aripiprazole

Based on pharmacokinetic studies, no dosage adjustment of aripiprazole is required when administered concomitantly with famotidine, valproate, lorazepam.

In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin), or CYP3A4 (e.g., dextromethorphan) when co-administered with aripiprazole. Additionally, no dosage adjustment is necessary for valproate, lamotrigine, lorazepam, or sertraline when co-administered with aripiprazole. [see CLINICAL PHARMACOLOGY (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to aripiprazole during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs (including aripiprazole) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. Adequate and well controlled studies with aripiprazole have not been conducted in pregnant women. Animal reproduction studies were conducted with aripiprazole in rats and rabbits during organogenesis, and in rats during the pre-and post-natal period. Oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses higher than the maximum recommended human dose (MRHD) produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses higher than the maximum recommended human dose (MRHD) produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. Administer aripiprazole during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including aripiprazole) during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms.

Data

Animal Data

In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits.

Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the maximum recommended human dose [MRHD] on a mg/m 2 basis) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg/day. Treatment at the high dose of 30 mg/kg/day caused a slight delay in fetal development (decreased fetal weight), undescended testes, and delayed skeletal ossification (also seen at 10 mg/kg/day). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 and 30 mg/kg/day), and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 10 and 30 mg/kg/day and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg/day. Some maternal toxicity was seen at 30 mg/kg/day however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

Pregnant rabbits were treated with oral doses of 10, 30 , and 100 mg/kg/day (2 , 3, and 11 times human exposure at MRHD based on AUC and 6, 19 , and 65 times the MRHD based on mg/m 2) of aripiprazole during the period of organogenesis. At the high dose of 100 mg/kg/day decreased maternal food consumption, and increased abortions were seen as well as increased fetal mortality, decreased fetal weight (also seen at 30 mg/kg/day), increased incidence of a skeletal abnormality (fused sternebrae) (also seen at 30 mg/kg/day).

In a study in which rats were treated peri- and post-natally with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the MRHD on a mg/m 2 basis) of aripiprazole from gestation day 17 through day 21 postpartum, slight maternal toxicity, slightly prolonged gestation an increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were seen at 30 mg/kg/day.

8.2 Labor and Delivery

The effect of aripiprazole on labor and delivery in humans is unknown.

8.3 Nursing Mothers

Aripiprazole is present in human breast milk. Because of the potential for serious adverse reactions in nursing infants from aripiprazole, 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.

8.4 Pediatric Use

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see CLINICAL PHARMACOLOGY (12.3)].

Schizophrenia

Safety and effectiveness in pediatric patients with schizophrenia were established in a 6-week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years [see DOSAGE AND ADMINISTRATION (2.1), ADVERSE REACTIONS (6.1), and CLINICAL STUDIES (14.1)]. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.

Information describing a clinical study in which efficacy was not demonstrated in patients ages 6 to 17 years is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY ® (aripiprazole). Additional pediatric use information in patients ages 6 to 18 years is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY ® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Juvenile Animal Studies

Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies.

Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period.

8.5 Geriatric Use

No dosage adjustment is recommended for elderly patients [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.1), and CLINICAL PHARMACOLOGY (12.3)].

Of the 13,543 patients treated with oral aripiprazole in clinical trials, 1073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of oral aripiprazole in schizophrenia, or other indications did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Aripiprazole is not approved for the treatment of patients with psychosis associated with Alzheimer’s disease [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)].

8.6 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) [see DOSAGE AND ADMINISTRATION (2.7) and CLINICAL PHARMACOLOGY (12.3)].

8.7 Hepatic and Renal 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), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see CLINICAL PHARMACOLOGY (12.3)].

8.8 Other Specific Populations


No dosage adjustment for aripiprazole is required on the basis of a patient’s sex, race, or smoking status [see CLINICAL PHARMACOLOGY (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance


Aripiprazole is not a controlled substance.

9.2 Abuse

Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of aripiprazole misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

9.3 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.

10 OVERDOSAGE

MedDRA terminology has been used to classify the adverse reactions.

10.1 Human Experience

In clinical trials and in postmarketing experience, adverse reactions 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 with aripiprazole alone. The largest known dose with a known outcome involved acute ingestion of 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 and younger) involving oral aripiprazole ingestions up to 195 mg with no fatalities.

Common adverse reactions (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.

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