Cariprazine

Cariprazine is an Antimanic Agent / Second Generation Antipsychotic agent belonging to the Dopamine type 2 (D₂) and serotonin type 2 (5-HT₂) receptor antagonist class.

Cariprazine is an atypical antipsychotic used to treat schizophrenia and acute manic or mixed episodes due to bipolar I disorder.

Cariprazine is absorbed well from the gastrointestinal tract. The time taken to reach peak plasma concentration is approximately 3-6 hours. The volume of distribution is Cariprazine, and its major active metabolites are highly bound (91 to 97%) to plasma proteins. Cariprazine is extensively metabolized in the liver by CYP3A4 and, to a lesser extent by CYP2D6 to active metabolites, desmethyl Cariprazine (DCAR) and didesmethyl Cariprazine (DDCAR). DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6 which is then metabolized by CYP3A4 to a hydroxylated metabolite. It is primarily excreted Via urine for about 21 and 1.2% as an unchanged drug.

Cariprazine shows side effects like Extreme tiredness, restlessness, anxiety, agitation, difficulty falling asleep or staying asleep, dizziness, feeling unsteady, etc.

Cariprazine is available in the form of an Oral Capsule.

Cariprazine is available in India, US, Canada, UK, Australia, Germany, France, Singapore, Italy, Poland, Spain, Japan, and China.

Cariprazine belongs to the Dopamine type 2 (D₂) and serotonin type 2 (5-HT₂) receptor antagonist to the class acts as an Antimanic Agent / Second Generation Antipsychotic agent.

Cariprazine is a second-generation antipsychotic with partial agonist activity at dopamine D₂ and serotonin 5-HT_1A receptors and antagonist activity at serotonin 5-HT_2A receptors. It exhibits high affinity for dopamine (D₂ and D₃) and serotonin (5-HT_1A) receptors and has low affinity for serotonin 5-HT_2C and alpha_1A-adrenergic receptors. Cariprazine functions as an antagonist for 5-HT_2B (high affinity) and 5-HT_2A receptors (moderate affinity), binds to histamine H₁ receptors, and has no affinity for muscarinic (cholinergic) receptors.

The Onset and duration of action of Cariprazine is not clinically established.

The Time to peak plasma concentration of Cariprazine is approximately 3-6 hours.

Cariprazine is available in the form of an Oral Capsule.

Cariprazine capsule is taken orally, usually once daily.

Cariprazine is an antipsychotic medication that is used in the treatment of Schizophrenia (a disorder that affects your ability to think, feel and behave clearly) and bipolar disorder (a medical condition in which the person may have extreme mood swings like depression and emotional highs) in adults.

Cariprazine is an Antimanic Agent / Second Generation Antipsychotic agent belonging to the Dopamine type 2 (D₂) and serotonin type 2 (5-HT₂) receptor antagonist class.

Cariprazine, a 2nd generation antipsychotic, exerts its effects through a combination of partial agonist activity at serotonin 5-HT_1A and dopamine D₂ and D₃ receptors and antagonist activity at serotonin 5-HT_2A and 5-HT_2B and histamine H₁ receptors.

Cariprazine is approved for use in the following clinical indications

• Bipolar disorder
• Major depressive disorder
• Schizophrenia

• Bipolar disorder

Acute mania and acute episodes with mixed features (monotherapy)

Oral Dose:

Initial: 1.5 mg once daily; adjust dose based on response and tolerability to 3 mg on day 2 and make further adjustments in 1.5 or 3 mg increments. Recommended dosing range: 3 mg to 6 mg once daily.

Maximum dose: 6 mg/day; doses up to 12 mg/day have been evaluated in clinical trials, however, greater efficacy has not been demonstrated.

Bipolar major depression (monotherapy)

Oral: Initial: 1.5 mg once daily; increase based on response and tolerability to 3 mg on day 15.

Maximum dose: 3 mg/day.

• Major depressive disorder

Oral Dose:

Initial: 1.5 mg once daily, which may increase based on response and tolerability to 3 mg daily on day 15.

Maximum dose: 3 mg/day; however, some experts recommend increasing it to 4.5 mg/day based on response and tolerability.

• Schizophrenia

Oral Dose:

Initial: 1.5 mg once daily; adjust dose based on response and tolerability to 3 mg on day 2 and make further adjustments in increments of 1.5 or 3 mg. Recommended dosing range: 1.5 mg to 6 mg once daily.

Maximum dose: 6 mg/day; doses up to 9 mg/day have been evaluated in clinical trials, however, greater efficacy has not been demonstrated.

Cariprazine is available in various strengths as 1.5 mg, 3 mg, 4.5mg and 6mg.

Cariprazine is available in the form of an Oral Capsule.

• Dosage Adjustment in Kidney Patient

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Use not recommended.

• Dosage Adjustment in Hepatic impairment Patient

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): Use not recommended (has not been studied).

Cariprazine is contraindicated in patients with

• History of a hypersensitivity reaction to Cariprazine. Reactions have ranged from rash, pruritus, urticaria, and events suggestive of angioedema (e.g., swollen tongue, lip swelling, face edema, pharyngeal edema, and swelling face).

• Suicidal thoughts and behaviours

Antidepressants increase the risk of suicidal thinking and behaviour in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk before prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behaviour, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with the health care provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Cariprazine is not FDA-approvedFDA-approved for adjunctive treatment of depression in children. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe, abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during the initiation of therapy. Patients should be screened for bipolar disorder before initiation of treatment for major depression.

• Prescriptions should be written for the smallest quantity, consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression or psychosis occur.
• Blood dyscrasias

Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; the presence of risk factors (eg, preexisting low WBC/ANC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm³.

• CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Dyslipidemia

Has been reported with atypical antipsychotics; the risk profile may differ between agents. In clinical trials, lipid changes observed with Cariprazine monotherapy were similar to those observed with a placebo.

• Esophageal dysmotility/aspiration

Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (eg, Alzheimer's disease), particularly in patients >75 years of age.

• Extrapyramidal symptoms

May cause extrapyramidal symptoms (EPS), including pseudo-parkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses use of conventionalconventional antipsychotics males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson's disease, pseudo parkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics. Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

• Falls

May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability.

• Hyperglycemia

Atypical antipsychotics, including Cariprazine, have been associated with the development of hyperglycemia; in some cases, they may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. All patients should be monitored for symptoms of hyperglycemia (eg, polydipsia, polyuria, polyphagia, weakness). Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control.

• Neuroleptic malignant syndrome

Use may be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity, autonomic instability, increased creatine phosphokinase, rhabdomyolysis, and/or acute renal failure. If NMS is suspected, discontinue immediately, provide symptomatic treatment, and monitor the patient. NMS can recur. Following recovery from NMS, reintroduction of drug therapy should be carefully considered; if an antipsychotic agent is resumed, monitor closely for NMS.

• Orthostatic hypotension

May cause orthostatic hypotension; risk is increased at initial dose titration and when increasing the dose. Use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (patients who are antipsychotic-naive or have cerebrovascular disease, cardiovascular disease, hypovolemia, dehydration, or are taking concurrent medication use which may predispose to hypotension/bradycardia). Consider using lower starting dosages and slower titrations in these patients.

• Temperature regulation

Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

• Weight gain

Significant weight gain (>7% of baseline weight) has been observed with antipsychotic therapy, including Cariprazine therapy; incidence varies with product. Monitor waist circumference and BMI.

• Dementia

Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death. Cariprazine is not approved for the treatment of dementia-related psychosis.

• Hepatic impairment

Use with caution in patients with hepatic impairment; use is not recommended in severe impairment.

• Renal impairment

Use with caution in patients with renal impairment; use is not recommended if CrCl <30 mL/minute.

• Seizures

Use with caution in patients at risk of seizures or with conditions that potentially lower the seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.

Consumption of alcohol is not recommended during treatment with Cariprazine due to the increased risk of severe side effects such as dizziness, difficulty in concentration, impaired judgment.

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 Cariprazine and any potential adverse effects on the breast-fed infant from Cariprazine or from the underlying maternal condition.

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 Cariprazine use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. Based on animal data Cariprazine may cause fetal harm. Administration of Cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the maximum recommended human dose (MRHD) of 6 mg/day. However, Cariprazine was not teratogenic in rabbits at doses up to 4.6 times the MRHD of 6 mg/day. The estimated background risk of major birth defects and miscarriage for the indicated populations is 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.

• Common

Nausea, Akathisia, extrapyramidal reaction, headache, insomnia, Hypertension, tachycardia, Weight gain, Abdominal pain, constipation, decreased appetite, diarrhea, dyspepsia, increased appetite, toothache, vomiting, xerostomia Increased serum transaminases, Agitation, anxiety, dizziness, drowsiness, fatigue, restlessness, Arthralgia, back pain, increased creatine phosphokinase in blood specimen, limb pain, Blurred vision.

• Rare

Double vision, Difficulty in speaking, Stomach upset, Skin rash, hives, or itching, Bladder pain.

• Acetylcholinesterase Inhibitors (Central)

May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients.

• Agents With Seizure Threshold Lowering Potential

May enhance the adverse/toxic effect of Cariprazine. Specifically, the risk of seizures may be increased.

• Alcohol (Ethyl)

CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).

• Alizapride

May enhance the CNS depressant effect of CNS Depressants.

• Amifampridine

Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine.

• Amisulpride (Oral)

May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome or increased QTc interval may be increased.

• Amisulpride (Oral)

Agents With Seizure Threshold Lowering Potential may enhance Amisulpride'sAmisulpride's adverse/toxic effect (Oral). Specifically, the risk of seizures may be increased.

• Antidiabetic Agents

Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.

• Anti-Parkinson Agents (Dopamine Agonist)

Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonists). Management: Consider avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin).

• Aripiprazole

Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Aripiprazole. Specifically, the risk of seizures may be increased.

• Asenapine

Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Asenapine. Specifically, the risk of seizures may be increased.

• Azelastine (Nasal)

May enhance the CNS depressant effect of CNS Depressants.

• Benperidol

Agents With Seizure Threshold Lowering Potential may enhance Benperidol's adverse/toxic effect. Specifically, the risk of seizures may be increased.

• Blonanserin

CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin.

• Buprenorphine

CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants.

• Bupropion

May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential.

• Cabergoline

May diminish the therapeutic effect of Antipsychotic Agents.

• Cannabinoid-Containing Products

CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.

• Chlormethiazole

May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used.

• CYP3A4 Inhibitors (Moderate)

May increase serum concentrations of the active metabolite(s) of Cariprazine. Specifically, concentrations of didesmethylCariprazine (DDCAR), the primary active metabolite of Cariprazine, may increase. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cariprazine.

• CYP3A4 Inhibitors (Strong)

May increase serum concentrations of the active metabolite(s) of Cariprazine. Specifically, concentrations of didesmethylCariprazine (DDCAR), the primary active metabolite of Cariprazine, may increase. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Decrease Cariprazine dose 50% (4.5 mg to 1.5 mg or 3 mg; 1.5 mg to 1.5 mg every other day) if starting a strong CYP3A4 inhibitor. If on a strong CYP3A4 inhibitor, start Cariprazine at 1.5 mg day 1, 0 mg day 2, then 1.5 mg daily. May increase to 3 mg daily.

• Daridorexant

May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended.

• Deutetrabenazine

May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased.

The common side effects of Cariprazine include the following

• Common side effects

Extreme tiredness, restlessness, anxiety, agitation, difficulty falling asleep or staying asleep, dizziness, feeling unsteady, or having trouble keeping your balance, increased appetite, weight gain, constipation, indigestion, nausea, increased saliva or drooling, blurred vision,

• Rare side effects

Seizures, unusual movements of your body or face that you cannot control, slow movements or shuffling walk, loss of ability to move, falling, fever, sweating, confusion, fast breathing, fast or irregular heartbeat, and severe muscle stiffness, muscle weakness or aching, blank facial expression, difficulty swallowing or breathing, tightness in the throat, tongue that sticks out of the mouth, rash, itching, hives, swelling of the face, throat, tongue, lips, or eyes, dark or cola-colored urine, swelling in legs and feet, decreased urination.

• Pregnancy

Pregnancy Category

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 Cariprazine use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. Based on animal data Cariprazine may cause fetal harm. Administration of Cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the maximum recommended human dose (MRHD) of 6 mg/day. However, Cariprazine was not teratogenic in rabbits at doses up to 4.6 times the MRHD of 6 mg/day. The estimated background risk of major birth defects and miscarriage for the indicated populations is 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.

• Nursing Mothers

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 Cariprazine and any potential adverse effects on the breast-fed infant from Cariprazine or from the underlying maternal condition.

• Pediatric Use

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 Cariprazine and any potential adverse effects on the breast-fed infant from Cariprazine or from the underlying maternal condition.

• Geriatric Use

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 Cariprazine and any potential adverse effects on the breast-fed infant from Cariprazine or from the underlying maternal condition.

Symptoms: Orthostasis and sedation.

Management: Supportive and symptomatic treatment (e.g. maintenance of adequate airway, ventilation, oxygenation). May perform ECG for possible arrythmia. May give anticholinergic in cases of severe extrapyramidal symptoms.

• Pharmacodynamic

Cariprazine is an antipsychotic agent. In clinical trials, it reduced positive and negative symptoms in patients with schizophrenia and acute mania in patients with bipolar I disorder. In animal models, Cariprazine showed therapeutic benefits against cognitive deficits, mania, and catalepsy. In a meta-analysis study, Cariprazine was shown to improve anxiety and depressed mood in patients with psychosis. As Cariprazine is a partial agonist at dopamine D2 and D3 receptors, it produces an apparent lower blockade level than other antipsychotic agents that block dopamine receptors. This receptor binding profile is advantageous as dopamine receptor blockade is associated with extrapyramidal symptoms as side effects. Partial agonism would stimulate the dopamine receptor even at maximal receptor occupancy by the drug. Antagonism at 5-HT_1A and 5-HT_2A receptors by Cariprazine can increase dopaminergic neurotransmission in the nigrostriatal pathway, thereby further reducing the risk of extrapyramidal symptoms.

• Pharmacokinetics

Absorption

Cariprazine is absorbed well from the gastrointestinal tract. The time taken to reach peak plasma concentration is approximately 3-6 hours.

Distribution

The volume of distribution is Cariprazine, and its major active metabolites are highly bound (91 to 97%) to plasma proteins.

Metabolism and Excretion

Cariprazine is extensively metabolized in the liver by CYP3A4 and, to a lesser extent by CYP2D6 to active metabolites, desmethyl Cariprazine (DCAR) and didesmethyl Cariprazine (DDCAR). DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6 which CYP3A4 then metabolizes to a hydroxylated metabolite.

It is primarily excreted Via urine for about 21 and 1.2% as unchanged drug.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204370lbl.pdf
• https://www.drugs.com/mtm/Cariprazine.html
• https://go.drugbank.com/drugs/DB06016
• https://medlineplus.gov/druginfo/meds/a615050.html
• https://www.uptodate.com/contents/Cariprazine-drug-information?search=Cariprazine&source=panel_search_result&selectedTitle=1~9&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://www.rxlist.com/schizophrenia_slideshow/article.html