Cariprazine

427.41

427.41

1592732-453-0

F6RJL8B278

DTXSID80232867

Off-White to Light Beige

N05AX15|N - Nervous system

log Kow = 4.98 (est)

1.24

>180°C (dec.)

In water, 0.1159 mg/L at 25 °C (est)

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C and 30 °C (59 °F and 86 °F). Protect 3 mg and 4.5 mg capsules from light to prevent potential color fading.

3.13X10-11 mm Hg at 25 °C (est)

Henry's Law constant = 2.29X10-15 atm-cu m/mol at 25 °C (est)

pKa1 = 7.91 (tertiary amine); pKa2 = 15.48 (secondary amine)

Hydroxyl radical reaction rate constant = 1.75X10-10 cu cm/molec-sec at 25 °C (est)

-20°C Freezer, Under inert atmosphere

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including cariprazine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Cariprazine hydrochloride/

Accidental acute overdosage (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation. The patient fully recovered the same day. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Cariprazine is not approved for the treatment of patients with dementia-related psychosis.|IDENTIFICATION AND USE: Cariprazine, as the drug Vraylar, is indicated for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. HUMAN EXPOSURE AND TOXICITY: A patient who accidentally overdosed experienced orthostasis and sedation, and recovered later the same day. Elderly patients with dementia-related psychosis treated with Vraylar are at an increased risk of death. Vraylar is not approved for the treatment of patients with dementia-related psychosis. Cariprazine was not clastogenic in the in vitro human lymphocyte chromosomal aberration assay; its metabolite DDCAR was clastogenic and induced structural chromosomal aberration in the in vitro human lymphocyte chromosomal aberration assay. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. ANIMAL STUDIES: Phospholipidosis was observed in the lungs of rats, dogs, and mice (with or without inflammation) and in the adrenal gland cortex of dogs at clinically relevant exposures (AUC) of total cariprazine. Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following oral daily administration for 13 weeks and/or 1 year and retinal degeneration/atrophy in the rat following oral daily administration for 2 years. Oral administration of cariprazine to pregnant rats during pregnancy and lactation caused a decrease in postnatal survival, birth weight, and post-weaning body weight of first generation pups at the dose that is 0.4 times the Maximum Recommended Human Dose (MRHD) of 6 mg/day based on AUC of total cariprazine in absence of maternal toxicity. First generation pups also had pale, cold bodies and developmental delays. Cariprazine was not mutagenic in the in vitro bacterial reverse mutation assay, nor clastogenic in the in vivo mouse bone marrow micronucleus assay. However, cariprazine increased the mutation frequency in the in vitro mouse lymphoma assay under conditions of metabolic activation. There was no increase in the incidence of tumors following daily oral administration of cariprazine to rats for 2 years and to mice for 6 months at doses which are up to 4 and 19 times respectively, the MRHD.

Serum aminotransferase elevations above 3 times the upper limit of normal occurred in 2% to 4% of patients treated with cariprazine in preregistration studies compared with 0.7% to 2% of placebo recipients. Elevations above 5 times ULN were rare

Table: Drugs Having Clinically Important Interactions with Vraylar [Table#8336]

Usage of Vraylar is not recommended in patients with severe renal impairment (CrCL < 30 mL/minute). Vraylar has not been evaluated in this patient population.|Elderly patients with dementia-related psychosis treated with Vraylar are at an increased risk of death compared to placebo. Vraylaris not approved for the treatment of patients with dementia-related psychosis.|Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There are no available data on Vraylar use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. Based on animal data Vraylar may cause fetal harm.

Cariprazine and its metabolites are highly protein bound (91-97%).

Cariprazine is an atypical antipsychotic indicated for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder.|FDA Label|Reagila is indicated for the treatment of schizophrenia in adult patients.

Cariprazine is an atypical antipsychotic used in the treatment of schizophrenia and manic or mixed episodes of bipolar disorder. Cariprazine has been associated with a low rate of serum aminotransferase elevations during therapy, but it has not been linked to instances of clinically apparent acute liver injury.

Antipsychotic Agents

/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Cariprazine is included in the database.|Vraylar is indicated for the treatment of schizophrenia. /Included in US product label/|Vraylar is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder. /Included in US product label/

/BOXED WARNING/ WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Vraylar (cariprazine) is not approved for the treatment of patients with dementia-related psychosis.|Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue Vraylar and provide intensive symptomatic treatment and monitoring.|Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including Vraylar. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment. There is no known treatment for tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. Given these considerations, Vraylar should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on Vraylar, drug discontinuation should be considered. However, some patients may require treatment with Vraylar despite the presence of the syndrome.|Adverse events may first appear several weeks after the initiation of Vraylar treatment, probably because plasma levels of cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer term exposures. Monitor for adverse reactions, including EPS or akathisia, and patient response for several weeks after a patient has begun Vraylar and after each dosage increase. Consider reducing the dose or discontinuing the drug.|For more Drug Warnings (Complete) data for Cariprazine (18 total), please visit the HSDB record page.

Cariprazine acts as a partial agonist at the dopamine D3 and D2 receptors with high binding affinity. Cariprazine acts as an antagonist at 5-HT2B and 5-HT2A receptors with high and moderate binding affinity as well as it binds to the histamine H1 receptors. Cariprazine shows lower binding affinity to the serotonin 5­ HT2C and α1A- adrenergic receptors and has no appreciable affinity for cholinergic muscarinic receptors.

Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. (See all compounds classified as Antipsychotic Agents.)

Urine (21% of dose)|... This was a multicenter, randomized, open-label, parallel-group, fixed-dose (3, 6, or 9 mg/day) study of 28-week duration (< or = 4-week observation, 12-week open-label treatment, and 12-week follow-up). Once-daily cariprazine was administered to 38 adult patients with schizophrenia. The pharmacokinetics of cariprazine, metabolites, and total active moieties (sum of cariprazine and two metabolites) was evaluated; efficacy and safety were also assessed. Steady state was reached within 1-2 weeks for cariprazine and desmethyl-cariprazine, 4 weeks for didesmethyl-cariprazine, and 3 weeks for total active moieties. Cariprazine and desmethyl-cariprazine levels decreased >90% within 1 week after the last dose, didesmethyl-cariprazine decreased approximately 50% at 1 week, and total active moieties decreased approximately 90% within 4 weeks. Terminal half-lives of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine ranged from 31.6 to 68.4, 29.7 to 37.5, and 314 to 446 hours, respectively. Effective half-life (calculated from time to steady state) of total active moieties was approximately 1 week. Incidence of treatment-emergent adverse events was 97.4%; 15.8% of patients discontinued due to adverse events. No abnormal laboratory values or major differences from baseline in extrapyramidal symptoms were observed. Cariprazine and its active metabolites reached steady state within 4 weeks, and exposure was dose proportional over the range of 3-9 mg/day. Once-daily cariprazine was generally well tolerated in adult patients with schizophrenia.|Cariprazine and its major active metabolites are highly bound (91 to 97%) to plasma proteins.|Following administration of 12.5 mg/day cariprazine to patients with schizophrenia for 27 days, about 21% of the daily dose was found in urine, with approximately 1.2% of the daily dose was excreted in urine as unchanged cariprazine.|After single dose administration of Vraylar, the peak plasma cariprazine concentration occurred in approximately 3-6 hours. Administration of a single dose of 1.5 mg Vraylar capsule with a high-fat meal did not significantly affect the Cmax and AUC of cariprazine or desmethyl cariprazine (DCAR).|/MILK/ Lactation studies have not been conducted to assess the presence of cariprazine in human milk, the effects on the breastfed infant, or the effects on milk production. Cariprazine is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Vraylar and any potential adverse effects on the breastfed infant from Vraylar or from the underlying maternal condition.

Cariprazine is extensively metabolized by hydroxylation and demethylation. It is primarily metabolized by CYP3A4, and CYP2D6 to a lesser extent to active metabolites desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). DCAR is then further metabolized to DDCAR by CYP3A4 and CYP2D6, and DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite. Both DCAR and DDCAR display similar functions and are as pharmacologically potent as the parent drug.|Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6. DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite.|... Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug.|... This was a multicenter, randomized, open-label, parallel-group, fixed-dose (3, 6, or 9 mg/day) study of 28-week duration (< or = 4-week observation, 12-week open-label treatment, and 12-week follow-up). Once-daily cariprazine was administered to 38 adult patients with schizophrenia. The pharmacokinetics of cariprazine, metabolites, and total active moieties (sum of cariprazine and two metabolites) was evaluated; efficacy and safety were also assessed. Steady state was reached within 1-2 weeks for cariprazine and desmethyl-cariprazine, 4 weeks for didesmethyl-cariprazine, and 3 weeks for total active moieties. Cariprazine and desmethyl-cariprazine levels decreased >90% within 1 week after the last dose, didesmethyl-cariprazine decreased approximately 50% at 1 week, and total active moieties decreased approximately 90% within 4 weeks. Terminal half-lives of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine ranged from 31.6 to 68.4, 29.7 to 37.5, and 314 to 446 hours, respectively. Effective half-life (calculated from time to steady state) of total active moieties was approximately 1 week. ...

~1 week for the combined drug.|... This was a multicenter, randomized, open-label, parallel-group, fixed-dose (3, 6, or 9 mg/day) study of 28-week duration (< or = 4-week observation, 12-week open-label treatment, and 12-week follow-up). Once-daily cariprazine was administered to 38 adult patients with schizophrenia. The pharmacokinetics of cariprazine, metabolites, and total active moieties (sum of cariprazine and two metabolites) was evaluated; efficacy and safety were also assessed. ... Terminal half-lives of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine ranged from 31.6 to 68.4, 29.7 to 37.5, and 314 to 446 hours, respectively. Effective half-life (calculated from time to steady state) of total active moieties was approximately 1 week. ...

The mechanism of action of cariprazine in schizophrenia and bipolar I disorder is unknown. However, the efficacy of cariprazine could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug.|All clinically effective antipsychotics are known to act on the dopaminergic system, and previous studies have demonstrated that repeated treatment with antipsychotics produced region-specific changes in dopamine receptor levels. Cariprazine is a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. We examined the effects of chronic cariprazine administration on dopamine receptor levels. Rats were administered either vehicle or cariprazine (0.06, 0.2, or 0.6 mg/kg) for 28 days. Dopamine receptor levels were quantitated using autoradiographic assays on brain tissue sections from the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), caudate putamen (CPu), hippocampus (HIPP), olfactory tubercle (OT), and islands of Calleja (ICj). Chronic treatment with cariprazine did not alter D1 receptor levels in any brain region tested. Cariprazine increased D2 receptor levels in mPFC (27%-43%), NAc (40%-45%), medial (41%-53%) and lateral (52%-63%) CPu, and HIPP (38%). Cariprazine dose-dependently upregulated D3 receptor levels in ICj (32%-57%), OT (27%-67%), and NAc shell (31%-48%). Repeated cariprazine treatment increased D4 receptor in NAc (53%-82%), medial (54%-98%) and lateral (58%-74%) CPu, and HIPP (38%-98%). Similar to other antipsychotics, cariprazine upregulated D2 and D4 receptor levels in various brain regions. Cariprazine was unique among antipsychotics in increasing D3 receptor levels, which may support its unique psychopharmacologic properties.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue Vraylar and provide intensive symptomatic treatment and monitoring.|/CASE REPORTS/ In pre-marketing clinical trials involving Vraylar in approximately 5000 patients or healthy subjects, accidental acute overdosage (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation. The patient fully recovered the same day.|/GENOTOXICITY/ Cariprazine was not ... clastogenic in the in vitro human lymphocyte chromosomal aberration assay ... The major human metabolite DDCAR ... was clastogenic and induced structural chromosomal aberration in the in vitro human lymphocyte chromosomal aberration assay.|/OTHER TOXICITY INFORMATION/ Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including Vraylar. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment. There is no known treatment for tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. Given these considerations, Vraylar should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on Vraylar, drug discontinuation should be considered. However, some patients may require treatment with Vraylar despite the presence of the syndrome.|For more Human Toxicity Excerpts (Complete) data for Cariprazine (7 total), please visit the HSDB record page.

3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

Vraylar (cariprazine) capsules are available in four strengths: 1.5 mg capsules: White cap and body imprinted with "FL 1.5"; 3 mg capsules: Green to blue-green cap and white body imprinted with "FL 3"; 4.5 mg capsules: Green to blue-green cap and body imprinted with "FL 4.5"; 6 mg capsules: Purple cap and white body imprinted with "FL 6"

Human drugs -> Reagila -> EMA Drug Category|Psycholeptics -> Human pharmacotherapeutic group