can be [5.7%):<200 mg/dL) to high ( 240 mg/dL) were reported in 1% of patients; shifts in baseline fasting LDL cholesterol from normal (> <100 mg/dL) to high ( 160 mg/dL) were reported in 1% of patients; and shifts in baseline fasting triglycerides from normal (> <150 mg/dL) to high ( 200 mg/dL) were reported in 8% of patients. In the same study, shifts in baseline fasting total cholesterol from borderline ( 200 mg/dL and> <240 mg/dL) to high ( 240 mg/dL) were reported in 15% of patients; shifts in baseline fasting LDL cholesterol from borderline ( 100 mg/dL and> <160 mg/dL) to high ( 160 mg/dL) were reported in 8% of patients; and shifts in baseline fasting triglycerides from borderline ( 150 mg/dL and> <200 mg/dL) to high ( 200 mg/dL) were reported in 35% of patients. In addition, the proportion of patients with shifts in fasting HDL cholesterol from normal ( 40 mg/dL) to low (> <40 mg/dL) was reported in 15% of patients. Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. The proportion of adult patients with weight gain 7% of body weight is presented in Table 7 . Table 7: Proportion of Adult Patients with Shifts in Weight in the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial Placebo N = 207 (%) Aristada 441 mg N = 207 (%) 882 mg N = 208 (%) Weight Gain 7% increase from baseline 6 10 9 5.6 Pathological Gambling and Other Compulsive Behaviors Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm for the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges. Orthostatic Hypotension Aripiprazole may cause orthostatic hypotension, perhaps due to its α 1 -adrenergic receptor antagonism. Associated adverse reactions related to orthostatic hypotension can include dizziness, lightheadedness and tachycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose, and monitor orthostatic vital signs. Orthostatic hypotension was reported for one patient in the Aristada 882 mg group (0.5%) and no patients in the Aristada 441 mg and placebo groups in the 12-week schizophrenia efficacy study [see Clinical Studies ( 14 )] . In the long-term open-label schizophrenia study, orthostatic hypotension was reported for 1 (0.2%) patient treated with Aristada. Orthostatic hypotension was defined as a decrease in systolic blood pressure 20 mmHg accompanied by an increase in heart rate 25 bpm when comparing standing to supine values. Falls Antipsychotics including Aristada may cause somnolence, postural hypotension, or motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for those patients on long-term antipsychotic therapy. Leukopenia, Neutropenia, and Agranulocytosis In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of Aristada at the first sign of a clinical significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue Aristada in patients with severe neutropenia (absolute neutrophil count> <1000/mm 3 ) and follow their WBC until recovery. Seizures As with other antipsychotic drugs, use Aristada cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older. Potential for Cognitive and Motor Impairment Aristada, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with Aristada does not affect them adversely. Body Temperature Regulation Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Aristada for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration). Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aristada and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Adverse Reactions The following are discussed in more details in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-related Psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 )] Cerebrovascular Adverse Reactions, Including Stroke [see Boxed Warning , Warnings and Precautions ( 5.2 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.3 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.4 )] Metabolic Changes [see Warnings and Precautions ( 5.5 )] Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions ( 5.6 )] Orthostatic Hypotension [see Warnings and Precautions ( 5.7 )] Falls [see Warnings and Precautions ( 5.8 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.9 )] Seizures [see Warnings and Precautions ( 5.10 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.11 )] Body Temperature Regulation [see Warnings and Precautions ( 5.12 )] Dysphagia [see Warnings and Precautions ( 5.13 )] Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Aristada Patient Exposure Aristada has been evaluated for safety in 1019 adult patients in clinical trials in schizophrenia. Commonly Observed Adverse Reactions The most common adverse reaction (incidence 5% and at least twice the rate of placebo in patients treated with Aristada) was akathisia. Adverse Reactions Occurring at an Incidence of 2% or More in Aristada-Treated Patients Adverse reactions associated with the use of Aristada (incidence of 2% or greater, rounded to the nearest percent and Aristada incidence greater than placebo) that occurred are shown in Table 8 . Table 8: Adverse Reaction in 2% or More of Aristada-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial Adverse Reaction System Organ Class Preferred Term Placebo N=207 (%) Aripiprazole Lauroxil 441 mg N=207 (%) 882 mg N=208 (%) General disorders and administration site conditions Injection site pain 2 3 4 Investigations Increased weight 1 2 2 Increased blood creatine phosphokinase 0 2 1 Nervous system disorders Akathisia 4 11 11 Headache 3 3 5 Psychiatric disorders Insomnia 2 3 4 Restlessness 1 3 1 In an open label pharmacokinetic study, the adverse reactions associated with the use of 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months were similar across the dose groups. Injection Site Reactions Injection site reactions were reported by 4% of patients treated with 441 mg Aristada and 5% of patients treated with 882 mg Aristada compared to 2% of patients treated with placebo. Most of these were injection site pain (3%, 4% and 2% in the 441 mg Aristada, 882 mg Aristada and placebo groups, respectively) and most were associated with the first injection, and decreased with each subsequent injection to less than or equal to 1% for both doses of Aristada and placebo. Other injection site reactions (induration, swelling and redness) occurred at less than 1%. In an open label pharmacokinetic study evaluating 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months, injection site reactions were similar across the dose groups. Extrapyramidal Symptoms In the 12-week schizophrenia efficacy study [see Clinical Studies ( 14 )] , for Aristada-treated patients, the incidence of other EPS-related events, excluding akathisia and restlessness, was 5% and 7% for patients on 441 mg and 882 mg, respectively, versus 4% for placebo-treated patient ( Table 9 ). Table 9: Incidence of EPS Compared to Placebo Aristada Adverse Reaction Term Placebo N=207 (%) 441 mg N=207 (%) 882 mg N=208 (%) Akathisia 4 11 11 Restlessness 1 3 1 Other EPS 4 5 7 Dystonia 1 2 2 Parkinsonism 3 3 4 Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Other Adverse Reactions Observed in Clinical Studies The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Cardiac angina pectoris, tachycardia, palpitations Gastrointestinal disorders constipation, dry mouth General disorders asthenia Musculoskeletal muscular weakness Nervous system disorders dizziness Psychiatric disorders anxiety, suicide Adverse Reactions Reported in Clinical Trials with Oral Aripiprazole The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for Aristada. Blood and Lymphatic System Disorders: thrombocytopenia Cardiac Disorders: bradycardia, atrial flutter, cardiorespiratory arrest, atrioventricular block, atrial fibrillation, myocardial ischemia, myocardial infarction, cardiopulmonary failure Eye Disorders: photophobia, diplopia Gastrointestinal Disorders: gastroesophageal reflux disease General Disorders and Administration Site Conditions: peripheral edema, chest pain, face edema Hepatobiliary Disorders: hepatitis, jaundice Immune System Disorders: hypersensitivity Injury, Poisoning, and Procedural Complications: fall, heat stroke Investigations: weight decreased, hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased, blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased Metabolism and Nutrition Disorders: anorexia, hypokalemia, hyponatremia, hypoglycemia Musculoskeletal and Connective Tissue Disorders: muscle tightness, rhabdomyolysis, mobility decreased Nervous System Disorders: memory impairment, cogwheel rigidity, hypokinesia, myoclonus, bradykinesia, akinesia, myoclonus, coordination abnormal, speech disorder, choreoathetosis Psychiatric Disorders: aggression, loss of libido, delirium, libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking Renal and Urinary Disorders: urinary retention, nocturia Reproductive System and Breast Disorders: erectile dysfunction, gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism Respiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspnea Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia, urticaria Vascular Disorders: hypotension, hypertension Postmarketing Experience The following adverse reactions have been identified during post-approval use of oral aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or 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. Drug Interactions Drugs Having Clinically Important Interactions with Aristada Table 10: Clinically Important Drug Interactions with Aristada 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 oral aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of oral aripiprazole alone [see Clinical Pharmacology ( 12.3 )]. With concomitant use of Aristada with a strong CYP3A4 inhibitor or CYP2D6 inhibitor for more than 2 weeks reduce the Aristada dose [see Dosage and Administration ( 2.4 )]. Strong CYP3A4 Inducer (e.g., carbamazepine, rifampin) The concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of oral aripiprazole alone [see Clinical Pharmacology ( 12.3 )]. With concomitant use of Aristada with a strong CYP3A4 inducer for more than 2 weeks consider increasing the Aristada dose [see Dosage and Administration ( 2.4 )] . Antihypertensive Drugs Due 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 ( 5.7 )] . 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 ( 5.7 )]. Monitor sedation and blood pressure. Adjust dose accordingly. Drugs Having No Clinically Important Interactions with Aristada Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of Aristada is required when administered concomitantly with famotidine, valproate, lithium [see Clinical Pharmacology ( 12.3 )] . 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, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with Aristada. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, or sertraline when co-administered with Aristada [see Clinical Pharmacology ( 12.3 )] . USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Aristada 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 during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Limited published data on aripiprazole use in pregnant women are not sufficient to inform any drug-associated risks for birth defects or miscarriage. No teratogenicity was observed in animal reproductive studies with intramuscular administration of aripiprazole lauroxil to rats and rabbits during organogenesis at doses up to 5 and 15 times, respectively, the maximum recommended human dose (MRHD) of 1064 mg based on body surface area (mg/m 2 ). However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data ]. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a 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 during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recover within hours or days without specific treatment; others required prolonged hospitalization. Data Animal Data for Aripiprazole Lauroxil Aripiprazole lauroxil did not cause adverse developmental or maternal effects in rats or rabbits when administered intramuscularly during the period of organogenesis at doses of 18, 49, or 144 mg/animal in pregnant rats which are approximately 0.6 to 5 times the maximum recommended human dose (MRHD) of 1064 mg on mg/m 2 basis, and at doses of 241, 723, and 2893 mg/animal in pregnant rabbits which are approximately 1 to 15 times the MRHD on mg/m 2 basis. However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data below] . Animal Data for Aripiprazole Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day which are approximately 1 to 10 times the oral maximum recommended human dose [MRHD] of 30 mg/day on mg/m 2 basis of aripiprazole during the period of organogenesis. Treatment at the highest dose caused a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight, and undescended testes. Delayed skeletal ossification was observed at 3 and 10 times the oral MRHD on mg/m 2 basis. At 3 and 10 times the oral MRHD on mg/m 2 basis, delivered offspring had decreased body weights. Increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed in offspring from the highest dose group (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to the highest dose. Postnatally, delayed vaginal opening was seen at 3 and 10 times the oral MRHD on mg/m 2 basis and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) along with some maternal toxicity were seen at the highest dose; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are 2 to 11 times human exposure at the oral MRHD based on AUC and 6 to 65 times the oral MRHD on mg/m 2 basis of aripiprazole during the period of organogenesis decreased maternal food consumption and increased abortions were seen at the highest dose as well as increased fetal mortality. Decreased fetal weight and increased incidence of fused sternebrae were observed at 3 and 11 times the oral MRHD based on AUC. In rats treated with oral doses of 3, 10, and 30 mg/kg/day which are 1 to 10 times the oral MRHD on mg/m 2 basis of aripiprazole perinatally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at the highest dose. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were also seen at this dose. Lactation Risk Summary Aripiprazole is present in human breast milk; however, there are insufficient data to assess the amount in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Aristada and any potential adverse effects on the breastfed infant from Aristada or from the underlying maternal condition. Pediatric Use Safety and effectiveness of Aristada in patients> <18 years of age have not been evaluated. Geriatric Use Safety and effectiveness of Aristada in patients> 65 years of age have not been evaluated. CYP2D6 Poor Metabolizers Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage and Administration ( 2.4 ), Clinical Pharmacology ( 12.3 )] . Hepatic and Renal Impairment No dosage adjustment for Aristada is required based on 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 )] . Other Specific Populations No dosage adjustment for Aristada is required on the basis of a patient's sex, race, or smoking status [see Clinical Pharmacology ( 12.3 )] . Overdosage Human Experience The largest known case of acute ingestion with a known outcome involved 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) in a patient who fully recovered. 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. Management of Overdosage In case of overdosage, call the Poison control center immediately at 1-800-222-1222. Aristada Description Aristada contains aripiprazole lauroxil, an atypical antipsychotic. The chemical name of aripiprazole lauroxil is 7-4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin-1-yl)methyl dodecanoate. The empirical formula is C 36 H 51 C l2 N 3 O 4 and its molecular weight is 660.7 g/mol. The chemical structure is: Aristada is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in the following strengths of aripiprazole lauroxil (and deliverable volumes from a single-use pre-filled syringe): 441 mg (1.6 mL), 662 mg (2.4 mL), 882 mg (3.2 mL) and 1064 mg (3.9 mL). The inactive ingredients include sorbitan monolaurate (3.8 mg/mL), polysorbate 20 (1.5 mg/mL), sodium chloride (6.1 mg/mL), sodium phosphate dibasic anhydrous, sodium phosphate monobasic and water for injection. Aristada - Clinical Pharmacology Mechanism of Action Aripiprazole lauroxil is a prodrug of aripiprazole. Following intramuscular injection, aripiprazole lauroxil is likely converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. The mechanism of action of aripiprazole in schizophrenia is unknown. However, efficacy could be mediated through a combination of partial agonist activity at dopamine D 2 and serotonin 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors. Pharmacodynamics Aripiprazole exhibits high affinity for dopamine D 2 and D 3 (K i s 0.34 and 0.8 nM respectively), serotonin 5-HT 1A and 5-HT 2A receptors (K i s 1.7 and 3.4 nM respectively), moderate affinity for dopamine D 4 , serotonin 5-HT 2C and 5-HT 7 , alpha 1 -adrenergic and histamine H 1 receptors (K i s 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (K i 98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 > 1000 nM). Actions at receptors other than D 2 , 5-HT 1A , and 5-HT 2A could explain some of the adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha 1 receptors). Pharmacokinetics Aristada is a prodrug of aripiprazole and its activity is primarily due to aripiprazole, and to a lesser extent dehydro-aripiprazole (major metabolite of aripiprazole), which has been shown to have affinities for D 2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma. Absorption After single intramuscular injection the appearance of aripiprazole in the systemic circulation starts from 5 to 6 days and continues to be released for an additional 36 days. Aripiprazole concentrations increase with consecutive doses of Aristada and reach steady-state four months following treatment initiation. The concentration-time course of dehydro-aripiprazole followed that of aripiprazole. With the addition of oral aripiprazole supplementation for 21 days at the time of the first Aristada dose, aripiprazole concentrations reach therapeutic levels within 4 days. Aripiprazole exposure was similar for deltoid and gluteal intramuscular injections of 441 mg Aristada, thus are interchangeable. Administration of 882 mg every 6 weeks or 1064 mg every 2 months results in plasma aripiprazole concentrations that were similar to exposure with 662 mg monthly and are within the range provided by doses of 441 mg monthly and 882 mg monthly. The doses of 441 mg monthly and 882 monthly showed a similar clinical response to each other. Distribution Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of Aristada was 268 L, indicating extensive extravascular distribution following absorption. At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered 0.5 mg/day to 30 mg/day oral aripiprazole for 14 days, there was dose-dependent D 2 receptor occupancy indicating brain penetration of aripiprazole in humans. Elimination Metabolism The biotransformation of Aristada likely involves enzyme-mediated hydrolysis to form N-hydroxymethyl-aripiprazole, which subsequently undergoes hydrolysis to aripiprazole. Elimination of aripiprazole is mainly through hepatic metabolism involving CYP3A4 and CYP2D6. [see Dosage and Administration ( 2.4 )]. Excretion The mean aripiprazole terminal elimination half-life ranged from 53.9 days to 57.2 days after monthly, every 6-week and every 2 month injections of Aristada. The significantly longer aripiprazole apparent half-life compared to oral aripiprazole (mean 75 hours) is attributed to the dissolution and formation rate-limited elimination of aripiprazole following Aristada administration. Drug Interaction Studies No specific drug interaction studies have been performed with Aristada. The drug interaction data provided below is obtained from studies with oral aripiprazole. Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 1 and Figure 2 , respectively. Based on simulation, a 4.5-fold increase in mean C max and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. After oral administration, a 3-fold increase in mean C max and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors. Figure 1: The Effects of Other Drugs on Aripiprazole Pharmacokinetics Figure 2: The Effects of Other Drugs on Dehydro-aripiprazole Pharmacokinetics The effects of aripiprazole on the exposures of other drugs are summarized in Figure 3 . Figure 3: The Effects of Oral Aripiprazole on Pharmacokinetics of Other Drugs Specific Population Studies A population pharmacokinetic analysis showed no effect of sex, race or smoking on Aristada pharmacokinetics [see Use in Specific Populations ( 8.8 )] . Exposures of aripiprazole and dehydro-aripiprazole using oral aripiprazole in specific populations are summarized in Figure 4 and Figure 5 , respectively. Figure 4: Effects of Intrinsic Factors on Aripiprazole Pharmacokinetics Figure 5: Effects of Intrinsic Factors on Dehydro-aripiprazole Pharmacokinetics Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Lifetime carcinogenicity studies have not been conducted with aripiprazole lauroxil. Lifetime carcinogenicity studies with oral aripiprazole have been conducted in ICR mice and in Sprague-Dawley (SD) and F344 rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to 5 times and 0.3 to 3 times the oral maximum recommended human dose [MRHD] of 30 mg/day based on mg/m 2 , respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day (3 to 19 times the oral MRHD based on mg/m 2 ). Aripiprazole did not induce tumors in male mice or rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses which are 0.1 to 0.9 times human exposure at the oral MRHD based on AUC and 0.5 to 5 times the oral MRHD on mg/m 2 basis. In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose which is 0.1 times human exposure at the oral MRHD based on AUC and 3 times the oral MRHD on mg/m 2 basis; and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose which is 14 times human exposure at oral MRHD based on AUC and 19 times the oral MRHD on mg/m 2 basis. Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. The relevance for human risk of the findings of prolacti could be
look at Aristada from time to time
EmoticonEmoticon