Cariprazine - Uses, Dosage, Side Effects, and Drug Warnings.

Overview

Cariprazine is an antipsychotic drug used to treat schizophrenia and manic or mixed episodes in adults with bipolar disorder type 1. The drug was approved by the Food and Drug Administration (FDA) for the treatment of mood disorders in 2015.

The active ingredient in Cariprazine is Cariprazine hydrochloride, formed by the combination of Cariprazine with one molar equivalent of hydrochloric acid. Cariprazine mainly acts as a D3 receptor and D2 receptor partial agonist with a higher affinity toward the D3 receptor. In 2012 the Phase III results were positive for schizophrenia and mania. In 2015 the Phase II trial was also positive for bipolar disorder I depression. Cariprazine is also potentially useful as adjuvant therapy for major depressive disorder.

How Does Cariprazine Work?

Cariprazine acts as a partial agonist, and these agonist properties depend on endogenous dopamine levels. Cariprazine acts as an antagonist by blocking dopamine receptors when dopamine levels are high. However, cariprazine works more as an agonist when dopamine levels are low and increases dopamine receptor activity.

Uses of Cariprazine:

Cariprazine is indicated for the following:

• Treatment of schizophrenia.

• Acute treatment of mixed or manic episodes associated with bipolar 1 disorder.

• Improving depressive symptoms across a wide range of patients with bipolar 1 depression. It acts as an effective and well-tolerated treatment for the condition.

Dosage Restrictions:

1. Route of Administration- Oral.

2. Maximum recommended dose- 6 mg daily.

Warnings:

1. Older Adults With Dementia - Older adults who take antipsychotic drugs like Cariprazine for dementia (a disorder that affects memory, thinking, communication, and the inability of an individual to perform daily activities) may develop an increased risk of death during the treatment. Furthermore, these older individuals are at a higher risk of transient ischemic attack or stroke during the treatment. The Food and Drug Administration (FDA) does not recommend Cariprazine to treat dementia in elderly patients.

2. People With Episodes of Depression - Clinical studies of this drug have revealed that some young adults up to the age of 24 who were treated with Cariprazine showed suicidal symptoms like causing self-harm. Even in adults above 24 years of age, unexpected changes in mental health have been documented if Cariprazine or any other antipsychotic drug is administered.

The physician should be contacted immediately if the symptoms of depression worsen like

• Thinking about self-harm.

• Extreme worry.

• Agitation.

• Panic attacks.

• Difficulty falling asleep or staying asleep.

• Aggressive behavior; irritability.

• Acting without thinking.

• Severe restlessness.

• Abnormal excitement.

Administration of Cariprazine:

Instructions:

The drug is taken orally with or without food.

Discontinuation of the drug may lead to

• Plasma concentration reduction by 50 % in around one week.

• A decline in plasma concentrations of active drugs and metabolites may not be seen immediately in the patient's clinical symptoms.

• There is no authentic data to address switching patients from Cariprazine to other antipsychotic drugs.

For Patients

What Is Schizophrenia and Bipolar Disorder Type 1?

Schizophrenia is a severe mental disorder resulting from a combination of symptoms such as delusions, hallucinations, and unusual thinking and behavior that affects the daily activities of individuals. Bipolar 1 disorder is another mental disorder in which an individual experiences manic episodes (a period of abnormal or irritable mood and high energy) and abnormal behavior that affects daily functioning. Bipolar 1 disorder is usually associated with episodes of depression. It leads to a cycling pattern between mania (high energy) and depression.

Why Is Cariprazine Prescribed?

Cariprazine belongs to the class of atypical antipsychotic drugs. It is responsible for altering the activity of some natural substances in the brain. Cariprazine is used to treat Schizophrenia and episodes of depression in patients with bipolar 1 disorder to control the symptoms. It does not cure the condition. Cariprazine can take several weeks or months to feel better, but the medication should not be discontinued even if the patient feels better.

How to Take Cariprazine?

• Cariprazine is available in the form of a capsule that is taken orally.

• It is usually administered once daily with or without food.

• The medicine should be taken at the same time daily. Initially, a small dose is prescribed that is increased gradually depending on how well the medication is tolerated by the patient and the side effects experienced.

• The medicine should be taken as told by the doctor.

• In case of side effects, the physician should be informed immediately.

Is Cariprazine Safe?

The patient or the caregiver must consult the doctor about the risks and benefits of Cariprazine before taking the medication. The patient should know that depression or other mental disorders show a high risk of self-destruction. This risk is increased if a patient's family member has ever had bipolar disorder. The patient should inform the doctor about the condition, symptoms, and personal and family medical history.

The doctor can then decide which treatment is most suitable. Patients with schizophrenia are more prone to develop diabetes than people who do not have Schizophrenia. In addition, the administration of Cariprazine or similar medications can increase this risk. It is imperative to inform the doctor immediately, as high blood sugar can cause a severe condition known as ketoacidosis, which may become life-threatening if it is not treated promptly.

Symptoms of ketoacidosis include

• Dry mouth.

• Nausea and vomiting.

• Shortness of breath.

• The breath smells fruity.

• Decreased consciousness.

Precautions to Be Discussed With the Doctor Before Taking Cariprazine:

• Allergies: The patient should inform the doctor about allergies to Cariprazine, any other medications, or any ingredient in Cariprazine capsules. The patient should ask about the ingredients present in the medication.

• Medical History: The patient should tell the doctor about any other illness in the past or any comorbidities present.

• Drug History: The doctor should be provided with a list of prescribed or non-prescribed drugs that the patient is taking, including vitamins and natural or herbal supplements.

Patients should inform the doctor if they are taking the following drugs:

• Anticholinergics such as atropine.

• Benztropine.

• Dicyclomine.

• Glycopyrrolate.

• Hyoscyamine.

• Propantheline.

• Scopolamine.

• Carbamazepine.

• Itraconazole.

• Ketoconazole.

• Rifampin.

• Medications for blood pressure.

Doctors must be informed about these medications as they may interact with Cariprazine and cause side effects.

• Pregnancy: The patient should tell the doctor about their pregnancy or if they are planning to conceive or are breastfeeding. Cariprazine can lead to problems in infants after delivery if administered during the last trimester of pregnancy.

• Vigorous Exercise: Cariprazine causes delayed body cooling after it gets very hot. Therefore the patients should inform their doctor they are involved in vigorous exercise or are exposed to heat. In addition, the patient is advised to consume adequate water and contact the doctor if they experience heavy sweating, thirst, dry mouth, and reduced urination.

Is There a Special Diet That Must Be Followed?

A normal diet should be followed unless the doctor suggests some changes.

What Should Be Done if a Dose Is Missed?

The patient should take the missed dose as soon as they remember. However, if it is time for the next dose, the missed dose should not be taken, and the regular schedule should be continued. A double dose should not be taken to compensate for the missed dose.

How Should Cariprazine Be Stored?

• The container of Cariprazine should be tightly closed and kept out of reach of children.

• Cariprazine should be stored at room temperature and not exposed to excessive moisture and heat.

• If Cariprazine is no longer required, it should be disposed of properly so that pets and children do not consume the medications by mistake.

What Side Effects of Cariprazine?

The common side effects caused by Cariprazine are as follows:

• Extreme exhaustion.

• Restlessness.

• Anxiety.

• Agitation.

• Dizziness, inability to maintain balance.

• Nausea.

• Increased appetite.

• Difficulty falling asleep.

• Weight gain.

• Constipation.

• Indigestion.

• Increased saliva or drooling.

• Blurred vision.

Sometimes serious side effects may occur. In such cases, the patient should contact the doctor immediately for emergency treatment:

• Seizures.

• Abnormal involuntary movements in the body or face.

• Inability to move.

• Difficulty swallowing or breathing.

• Slow movements.

• Throat tightness.

• Tongue sticking out of the mouth.

• Rash.

• Itching.

• Urticaria or hives.

• Fever, sweating, confusion, fast breathing, or irregular heartbeat.

• Severe muscle stiffness.

• Muscle weakness.

• Swelling of the face, lips, throat, or eyes.

• Dark urine.

• Swelling in legs and feet.

• Decreased urination.

Cariprazine may also cause other side effects. The doctor should be informed if any unusual behavior is noticed.

What to Do in Case of Overdose?

• In the case of Cariprazine, the doctor should be contacted immediately.

• Suppose severe side effects like seizures or breathing difficulty are experienced. In that case, a bystander or family member should take the patient to an emergency room, or local poison control services should be contacted.

Symptoms of overdose may include the following:

• Sedation.

• Lightheadedness or dizziness while standing up from a sitting or lying down position.

Additional Information:

Maintaining a written list of all the prescribed and non-prescribed (over-the-counter) drugs that are being taken by the patient, including other supplements like vitamins or minerals. The patient should carry this list for every visit to a doctor or a hospital. It is extremely important in case of emergencies. The doctor may suggest certain lab tests before the administration of Cariprazine to check the body's response to this medication.

For Doctors

Indications:

Cariprazine is indicated for the following:

• Treatment of schizophrenia.

• Acute treatment of mixed or manic episodes associated with bipolar I disorder.

• Improving depressive symptoms across a wide range of patients with bipolar I depression. It acts as an effective and well-tolerated treatment for the condition.

Pharmacology:

The exact mechanism of Cariprazine for treating schizophrenia or bipolar disorder is not completely understood.

Storage:

• Store (controlled room temperature) of 20 to 25 degrees Celsius or 68 to 77 degrees Fahrenheit.

• A temperature range between 15 to 30 degrees Celsius or 59 to 86 degrees Fahrenheit is permitted.

• 3 mg and 4.5 mg capsules should be protected from light to prevent color fading.

Efficacy:

The efficacy is mediated by combining the partial agonist activity of central dopamine (D2) and serotonin 5-HT1A receptors.

Cariprazine forms two main metabolites that have in vitro receptor binding profiles that resemble the parent drug:

• Desmethyl cariprazine (DCAR).

• Didesmethyl cariprazine (DDCAR).

Distribution:

Protein-bound (Parent Drug and Metabolites): 91 to 97 %.

Absorption:

Peak plasma time of Cariprazine: Three to six hours.

Mean concentrations of Cariprazine concentrations by the end of 12-week treatment:

• Desmethyl cariprazine (DCAR): ~30 %.

• Didesmethyl cariprazine (DDCAR): 400 %.

Metabolism of Cariprazine:

Active Metabolites:

• Desmethyl cariprazine (DCAR).

• Didesmethyl cariprazine (DDCAR).

CYP3A4: Causes extensive metabolization (metabolizes DDCAR to a hydroxylated metabolite).

CYP2D6: Metabolizes to a lesser extent.

Elimination of Cariprazine

• Half-life: 2 to 4 days (1 to 3 weeks for DDCAR).

• Excretion: 12.5 mg/day.

Available Dosage of the Drug:

The capsule is available in the following doses:

• 1.5 mg.

• 3 mg.

• 4.5 mg.

• 6 mg.

Dosage for Schizophrenia:

• Day 1: 1.5 mg/day.

• Day 2: 3 mg/day.

• Day 3: Dose can be adjusted between 1.5 to 3 mg depending upon clinical response and tolerability. Further doses can be increased up to 6 mg/day.

Dosages >6 mg/day are not recommended as it does not confer increased effectiveness and may cause dose-related adverse effects.

Dosage for Bipolar Disorder

• Day 1: 1.5 mg/day.

• Day 2: Increased to 3 mg/day.

• Day 3 Onwards: According to the clinical response and tolerability, further dose adjustments in dosage can be made between the range of 3 to 6 mg/day but should not exceed 6 mg/day.

Dosage for Depressive Episodes:

• Initially: 1.5 mg/day.

• Dosage can be increased to 3 mg/day on day 15, depending upon tolerability and clinical response, but the dose should not exceed 3 mg/day.

What Modifications Are Made in the Dosage of Cariprazine?

Renal Impairment:

• For mild-to-moderate renal impairment, no dosage modification is required.

• Cariprazine is not recommended for severe renal impairment because safety and efficacy have not been established.

Hepatic Impairment:

• For mild to moderate cases, no dosage adjustment is required.

• For severe cases, Cariprazine is not recommended.

To Start a Strong cyp3a4 Inhibitor While on a Stable Dose of Cariprazine:

• The current dose of Cariprazine should be reduced by 50 %.

• The dose should be reduced to 1.5 mg or 3 mg/day for patients taking cariprazine at 4.5 mg/day.

• For patients taking 1.5 mg daily, the dose should be adjusted frequently.

• Cariprazine dose can be increased when the CYP3A4 inhibitor is discontinued.

To Begin Cariprazine While Already on a Strong cyp3a4 Inhibitor:

• 1.5 mg of Cariprazine should be administered on days 1 and 3 with no dose on day 2.

• From day four onwards, administer 1.5 mg/day, which can be increased to a maximum of 3 mg/day.

• On discontinuation of a CYP3A4 inhibitor, cariprazine dosage should be increased.

Coadministration of Cariprazine With cyp3a4 Inducers:

• Coadministration has not been studied. Therefore, it is not recommended. Its effect on active drugs and metabolites is still unclear.

Dosage Considerations:

After Cariprazine is discontinued, the plasma concentrations of active drugs and metabolites may not decline immediately. The plasma concentration of Cariprazine and its active metabolites eventually declines in around one week 50%.

Treatment response and adverse effects should be monitored for several weeks after starting the drug.

Interactions of the Drug:

Coadministration of Cariprazine with a strong CYP3A4 inhibitor increases the exposure of Cariprazine and its major active metabolite (di-desmethyl cariprazine) as compared to the use of Cariprazine alone. The effect of CYP3A4 inducers on the exposure of Cariprazine has not been studied, and the net effect is not completely understood.

Metabolic Changes:

• Hyperglycemia has been reported in some cases when Cariprazine was administered. It has been associated with ketoacidosis, hyperosmolar coma, or death. Plasma glucose levels should be assessed before or after the antipsychotic medication is started and monitored periodically.

• Lipid changes have also been reported. Hence, a fasting lipid profile should be performed before or after the initiation of the drug. In addition, it should be monitored periodically.

Warnings and Precautions:

• Increased mortality is associated with elderly patients with dementia.

• The drug has not been approved for patients with dementia-related psychosis.

• Antipsychotics increase the risk of destructive thoughts and behaviors in pediatric and young adult patients.

• All antidepressant-treated patients should be monitored closely for worsening conditions and developing destructive thoughts and behaviors.

• The effectiveness and safety of Cariprazine have not been studied in pediatric patients.

Special Considerations:

Hypersensitivity to Cariprazine:

Hypersensitivity reactions include the following symptoms:

• Rash.

• Pruritus.

• Urticaria.

• Angioedema (swollen tongue or lip swelling, pharyngeal edema, facial edema).

Neuroleptic Malignant Syndrome:

The following symptoms should be monitored:

• Hyperpyrexia (fever of 106 degrees Fahrenheit or higher).

• Muscle rigidity.

• Delirium.

• Autonomic instability.

• Myoglobinuria (rhabdomyolysis).

• Acute renal failure.

The treatment should be discontinued immediately if the neuroleptic malignant syndrome is suspected.

Tardive Dyskinesia:

A potentially involuntary, irreversible, dyskinetic movement syndrome can occur in patients undergoing treatment with antipsychotics. Adverse effects may appear weeks after initiating the treatment. Therefore, the patient should be monitored for extrapyramidal symptoms as metabolite levels accumulate.

Leukopenia and Neutropenia:

Agranulocytosis (including fatal cases) was associated with other atypical antipsychotics. Cariprazine should be discontinued in patients with an absolute neutrophil count of less than 1000/mm³.

Hypotension:

Caution should be taken in patients with hypotension.

Body Temperature Dysregulation:

Cariprazine can disturb the ability to reduce core body temperature. Caution should be taken in the following cases:

• Strenuous exercise.

• Exposure to extreme heat.

• Dehydration.

• Coadministration with anticholinergic medications.

Esophageal Dysmotility and Aspiration:

It can be reported in the case of antipsychotic drug use and leads to the following symptoms:

• Somnolence.

• Postural hypotension.

• Motor and sensory instability.

• This condition can lead to injuries and fractures in patients. Fall risk assessments should be done completely before starting antipsychotic medications, and they should be repeated periodically for patients on long-term antipsychotic drug therapy.

Pregnancy:

Exposure to antipsychotic drugs during the third trimester of pregnancy may cause:

• Extrapyramidal symptoms.

• Withdrawal symptoms after delivery.

The severity of these complications may vary, ranging from being self-limiting to cases requiring intensive care unit (ICU) support and long-term hospitalization.

Lactation:

• The distribution of Cariprazine in breast milk is still unknown.

• Animal studies have reported that it is present in rat milk.

• The health benefits of breastfeeding and the mother's requirement for the drug should be carefully evaluated.

What Have Trials Shown Concerning Cariprazine?

Administration of Cariprazine dose 0.2 to 3.5 times the maximum recommended human dose in pregnant rats during organogenesis led to fetal developmental toxicity at all doses. It reduced body weight, skeletal malformations of limbs, scapula, and humerus, and decreased male anogenital distance.

Other abnormalities that were observed included:

• Decreased postnatal survival.

• Birth weight.

• Post-weaning body weight.

Pooled studies of placebo-controlled trials of antipsychotic drugs proved an increased risk of suicidal thoughts or behavior in patients less than 24 years after taking these medications. Symptoms of worsening depression, suicidal thoughts, and unusual changes in mood or behavior Should be monitored. The caregivers or family members of the patients should be informed about the symptoms.