Vraylar is an antipsychotic drug that contains Cariprazine. It can improve your mood, thinking and behavior. It is a prescription medication that has been FDA-approved for certain mental health conditions in adults, such as schizophrenia, mania, and mixed manic episodes.
Bipolar I disorder can cause manic episodes or mixed episodes. Bipolar I disorder can cause episodes of manic or mixed moods that last for at least seven days. If they are severe enough, it may require hospitalization. These episodes are known as manic episodes. Mixed episodes are when you experience both mania (high mood) and depression (lower mood). Vraylar can be used to treat manic episodes or mixed episodes.
Bipolar I disorder can cause depressive episodes. Vraylar is also an option to treat depression episodes in bipolar I disorder. These episodes are sometimes referred to as bipolar depression.
Schizophrenia. You may experience psychotic symptoms like hallucinations, which are seeing or hearing things that you don’t know exist. Delusions are false beliefs.
Vraylar Uses (Indications):
It is indicated for the treatment of:
- Schizophrenia in adults
- adult bipolar I disorder symptoms in the acute phase.
- Treatment of depression episodes in adults with bipolar I disorder (bipolar depression).
Vraylar Dose and how to administer?
VRAYLAR can be taken orally once daily, with or without food.
Changes in dosage will not reflect fully in plasma due to the long half-life and active metabolites of cariprazine. For several weeks and after adjustment in the dose, monitor patients for any adverse reactions or treatment responses.
Vraylar dose in patients with Schizophrenia:
It is recommended to take 1.5 mg to 6 mg daily. VRAYLAR should be taken at a starting dose of 1.5 mg daily.
On Day 2, the dosage can be increased up to 3 mg. You can adjust the dose in increments of 1.5 mg or 3.0 mg depending on your clinical response.
The maximum recommended daily dosage is 6 mg. Doses above 6 mg per day are not recommended in short-term controlled studies.
Vraylar dose in the treatment of Bipolar I Disorder: Manic Episodes or Mixed Episodes
Daily intake is recommended to be between 3 and 6 mg. VRAYLAR should be taken as a starting dose at 1.5 mg. This dose should then be increased to 3 mg by Day 2. You can adjust the dose in increments of 1.5 mg or three mg depending on your clinical response. Maximum recommended daily dosage is 6 mg
Short-term controlled trials have shown that dosages exceeding 6 mg per day do not increase effectiveness enough to overcome dose-related adverse effects.
Vraylar dose in the treatment of depressive episodes in patients with Bipolar I Disorder (Bipolar Depression):
VRAYLAR starts at 1.5 mg daily. The daily dose can be increased or decreased depending on clinical response and tolerance. Maximum recommended daily dosage is 3 mg
Vraylar Dosage adjustments for CYP3A4 inhibitors and inducers
Heptic CYP3A4 controls the formation and elimination major active metabolites in cariprazine.
Dosage recommendation for patients who are starting strong CYP3A4 inhibitors while on a stable dose of Vraylar:
- Reduce the dosage of VRAYLAR by half if you are taking a strong CYP3A4 antagonist.
- Patients who are taking 4.5 mg daily should reduce their dosage to 1.5 mg or three mg daily.
- Patients taking 1.5 mg daily should adjust their dosing schedule to once a day. VRAYLAR may be required to be taken at a higher dose after the CYP3A4 inhibitor has been discontinued.
Dosage recommendations for patients who are starting Vraylar therapy while already taking a strong CYP3A4 inhibitor:
On Day 1, patients should receive 1.5 mg of VRAYLAR, and Day 3, respectively. No dose should be given on Day 2. The dose should be increased from Day 4 to 1.5 mg daily. VRAYLAR may be required to be taken at a higher dose after the CYP3A4 inhibition is removed.
Dosage recommendation for patients who are taking Vraylar and CYP3A4 Inducers simultaneously.
- The concomitant use VRAYLAR with a CYP3A4 inducer has not been evaluated. It is not recommended.
Vraylar dose in patients with liver disease:
No dosage adjustment for cariprazine is required in patients with mild to moderate liver disease (Child-Pugh score between 5 and 9). Usage of VRAYLAR is not recommended in patients with severe liver disease (Child-Pugh score between 10 and 15).
Vraylar dose adjustment in patients with renal impairment:
No dosage adjustment is required for Cariprazine in patients with mild to moderate (CrCL ≥ 30 mL/minute) kidney disease.
It is not recommended to be used in patients with severe renal impairment (CrCL < 30 mL/minute). VRAYLAR has not been evaluated in this patient population.
How to discontinue the treatment?
Patients’ clinical symptoms may not reflect the decrease in plasma levels of active drug or metabolites following discontinuation of VRAYLAR. The plasma concentrations will drop by 50% within a week. We don’t have any data that can be used to identify patients who switch from VRAYLAR to antipsychotics, or those who are taking antipsychotics concurrently with VRAYLAR.
How to take Vraylar (Cariprazine)?
Vraylar is available as a capsule and is usually taken once daily. Vraylar comes in four strengths: 1.5 mg, 3 mg, 4.5 mg, and 6 mg. The treatment is usually initiated at a starting dose of 1.5 mg and gradually titrated until an optimal response is achieved.
Vraylar can interact with CYP3A4 inhibitors and inducers. Vraylar is not a controlled substance as it does not have the potential to be misused or the person becomes addicted to it.
What are the Side Effects of Vraylar?
Vraylar can cause the following side effects:
- extrapyramidal symptoms (muscle spasms, muscle rigidity, tremor, jerking movements),
- Agitation, restlessness, insomnia or somnolence, and anxiety
- indigestion, nausea, vomiting, constipation, abdominal pain, diarrhea, loss of appetite, dry mouth, and dizziness
- Weight gain
- Headache, Toothache, Pain in the extremities, and Back pain
- Cough and rhinitis.
Seek emergency medical attention immediately if you have symptoms like:
- urticaria, breathing difficulty, or swelling of the face and lips.
- Sudden numbness or weakness of the limbs (especially on one side)
- Problems with vision and speech
- A lightheaded feeling that you feel like you are going to pass out.
- severe agitation or aggression
- Uncontrolled muscle movements in your face (chewing and lip smacking), frowning, tongue movement or blinking;
- Trouble swallowing or accidental inhalation of food or drink
- Low white blood cell count – It may manifest as fever, colds, sore throats, mouth sores and skin sores or may be identified on routine work up.
- High blood sugar can cause increased thirst, increased urination and dry mouth.
- Nervous system reactions severe: Extreme stiffness (rigid), confusion, sweating, fast or uneven heartbeats. You feel like you are going to faint.
Long-lasting effects can be caused by Cariprazine. You may experience side effects that last several weeks after stopping taking this medication. If your dose is adjusted, you may experience new side effects.
Side effects that are common include:
- Involuntary muscle movements
- upset stomach, vomiting;
- Feeling restless.
Vraylar during Pregnancy and Breastfeeding
Vraylar can cause withdrawal symptoms and extrapyramidal effects in neonates who have been exposed to it during the third trimester. Vraylar may pass into breast milk, but data in this regard is limited. It is best to consult your doctor before you start breastfeeding.
Neonates may develop extrapyramidal symptoms if they are exposed to antipsychotic drugs especially during the third trimester of pregnancy. Neonates who are exposed to antipsychotics are at risk of developing withdrawal symptoms after delivery.
DDCAR is the most active metabolite of cariprazine that has been found in adult patients up to three months after the drug has been discontinued. Animal data suggests, Cariprazine could harm the fetus.
Cariprazine administration to rats during organogenesis led to malformations, lower survival rates, and developmental delays when drug exposures were less than the recommended human dose (MRHD), of 6 mg/day.
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. Major birth defects and miscarriages in U.S. pregnancies is estimated to be around 2 – 4% and 15 – 20% respectively.
What happens if the mother was exposed to antipsychotic drugs during the 3rd timester?
Neonatals whose mothers had been exposed to antipsychotic drugs in the third trimester have experienced extrapyramidal or withdrawal symptoms. These include agitation, hypotonia and tremor as well as respiratory distress and feeding disorders. These signs and symptoms can vary in severity and may be missed when subtle.
When the withdrawal symptoms are mild, recovery is rapid and may take hours. In severely symptomatic neonates, hospitalization may be needed. All neonates with a maternal exposure to the drug need to be observed for extrapyramidal symptoms and/or withdrawal symptoms.
Pregnant patients should notify their obstetricians if they are exposed to the drug especially during their third trimesters. Neonatologists should be prepared to manage extrapyramidal symptoms and withdrawal symptoms in the neonate.
Lactation Risk Summary
To assess the presence of cariprazine, its effects on breastfed infants, and the effects on milk production, lactation studies have not been done. Cariprazine can also be found in human milk. Consider the health and development benefits of breastfeeding, as well as the mother’s clinical need to VRAYLAR and potential adverse effects on the infant breastfed from VRAYLAR or the underlying maternal condition.
How to store the medicine? Storage and Handling
Keep at 20 deg C to 25 C, (68 deg F – 77 deg F), and allow for excursions between 15 deg C (30 deg C) (59 deg F – 86 deg F). To prevent color fading, protect capsules 3 mg and 4 mg from the light.
Warnings and Precautions!
Higher Mortality in Elderly Patients with Dementia-Related Psychosis:
The all-cause death rate in dementia-related psychosis patients aged over 65 increases when they take antipsychotic drugs. The majority of deaths occur due to cardiovascular causes such as heart failure, pneumonia, and death.
Suicidal tendency in children, adolescents and young adults:
- Most clinical trials have attributed suicidal tendencies with the use of SSRIs and antidepressants.
- All patients treated with antidepressants or antipsychotics should be monitored for suicidal risk as manifested by a change in behavior or clinical worsening of the underlying condition, and emergence of suicidal thoughts and behaviors. The risk is highest especially during the first few months of the treatment, and at times of dosage changes.
- Family members and caregivers should be able to monitor patients’ behavior and alert their healthcare provider if they notice any changes. Patients with persistent depression or suicidal thoughts and behaviors, who have been recently initiated on VRAYLAR treatment, should be considered changing their treatment regimen.
- Encourage caregivers and patients to be aware of the possibility of suicidal thoughts or behaviors. This is especially important during the first stages of treatment. Also, inform them to notify their healthcare provider if they notice such symptoms.
CNS Side effects, including stroke and dementia:
- Patients randomized to risperidone or aripiprazole in placebo-controlled trials with elderly patients with dementia had a higher rate of stroke and transient Ischemia, including fatal stroke. VRAYLAR is not approved to treat patients with dementia-related schizophrenia.
Neuroleptic Malignant Syndrome (NMS):
- Neuroleptic Malignant syndrome (NMS), which can lead to fatal symptoms, has been linked to antipsychotic drug administration. Hyperpyrexia, muscle rigidity and delirium are some of the symptoms of NMS. Other signs include hyperpyrexia, muscle rigidity, and myoglobinuria (rhabdomyolysis), as well as elevated creatine phosphokinase.
- NMS should be suspected immediately and treatment initiated on urgent basis. Talk to patients about the possible fatal side effect, Neuroleptic Malignant syndrome (NMS), which has been linked to antipsychotic drug administration. If patients or their family members or caregivers experience symptoms or signs of Neuroleptic Malignant Syndrome (NMS), they should contact their healthcare provider immediately.
- Patients who have been prescribed antipsychotic drugs such as VRAYLAR may be at risk for developing tardive dyskinesia. This is a condition that causes involuntary and potentially irreversible dyskinetic movements. While the risk is highest in the elderly, particularly elderly women, it is difficult to predict who will develop the syndrome. It is not known if antipsychotic drugs have different potential to cause tardive dyskinesia.
- The cumulative dose and duration of treatment will affect the risk of tardive dyskinesia. Even at low doses, the syndrome can occur after a short treatment period. It can also develop after treatment is stopped.
- Antipsychotic treatment may be stopped and tardive dyskinesia can be remitted partially or fully. The signs and symptoms of tardive dyskinesia may be suppressed (or partially suppressed) by antipsychotic medication. This could mask the true cause. It is not known what effect symptomatic suppression may have on the long-term course tardive dyskinesia.
- A patient who is on VRAYLAR should be evaluated if they exhibit tardive dyskinesia symptoms. Some patients may still need treatment for VRAYLAR, despite having the syndrome. Talk to patients about the symptoms and how to notify their doctor if they experience tardive dyskinesia.
Late-Occurring side effects of Vraylar:
Because plasma levels of cariprazine (and its major metabolites) accumulate over time, adverse events can appear as soon as weeks after VRAYLAR treatment is initiated. The incidence of adverse reactions may be lower in short-term trials than it is for longer-term exposures.
Monitoring for adverse reactions such as extrapyramidal or akathisia for several weeks after VRAYLAR has been started and after each dose increase is recommended. Reduce the dosage or stop using the drug.
Patients should be aware that adverse reactions can occur up to several weeks after the VRAYLAR treatment has been initiated. Metabolic changes may occur (Hyperglycemia and Diabetes Mellitus, Dyslipidemia and Weight Gain). Educate patients on the dangers of metabolic changes and how to recognize the symptoms of diabetes mellitus and hyperglycemia.
- VRAYLAR, an antipsychotic drug that is not commonly prescribed, has caused metabolic changes including weight gain, diabetes mellitus and hyperglycemia. Although all drugs in this class have shown some metabolic effects, each drug is unique.
Diabetes Mellitus and Impaired Glucose control:
- Patients who have been treated with antipsychotics atypically have experienced hyperglycemia. This can be severe and even fatal. Monitor long-term antipsychotic treatment and assess fasting plasma glucose levels.
- Negative lipid changes can be caused by atypical antipsychotics. Get a baseline fasting lipid profile and monitor it periodically throughout treatment.
- Use of atypical antipsychotics such as VRAYLAR has been associated with weight gain. Keep track of your weight at baseline and every few weeks thereafter.
- During treatment with antipsychotic drugs, such as VRAYLAR, leukopenia or neutropenia were reported. Other agents in this class have been associated with agranulocytosis, including fatal cases.
- There are several risk factors that could lead to leukopenia. These include a low WBC or absolute neutrophil count (ANC), and a history of drug-induced neutropenia. Perform a complete blood count (CBC), especially in patients who have a low WBC or ANC, or a history drug-induced neutropenia or leukopenia. If there is a clinically significant decrease in WBC, discontinue VRAYLAR.
- Patients with clinically significant neutropenia should be monitored for fever and other signs or symptoms of infection. If symptoms or signs develop, treat immediately. Patients with an absolute neutrophil count below 1000/mm3 should be stopped from VRAYLAR and continue to follow their WBC until they are fully recovered.
- Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia or neutropenia that they should have their CBC monitored while taking VRAYLAR.
Postural Hypotension and Syncopal attacks:
- Syncope and orthostatic hypotension can be caused by antipsychotics that are not standard. The risk of developing syncope is usually greatest when the dose is increased or titrated at the beginning.
- Patients with hypotension should have their orthostatic vital signs monitored. This includes elderly patients, patients with hypovolemia and concomitant antihypertensive medication treatment, patients with congenital heart disease (history or conduction abnormalities), patients with cerebrovascular diseases, patients with ischemic heart disease, heart attack, myocardial disease, heart failure, and those with a history of myocardial damage.
- Patients with a history of myocardial injury or unstable cardiovascular disease have not been evaluated for VRAYLAR because they were not eligible to be included in the clinical trials.
- Counsel patients as they may develop hypotension and frequent postural dizziness. The risks are highest while on treatment and when a change in the dose is recommended.
- Antipsychotics including VRAYLAR can cause excessive sleepiness and postural hypotension. They also may cause motor and sensory instability. This could lead to falls, and consequently, fractures and other injuries. Patients with conditions or medications that may exacerbate these effects should be assessed for fall risk before initiating antipsychotic treatment. This is also true for long-term antipsychotic patients.
- VRAYLAR, like other antipsychotic drugs can cause seizures. Patients with a history or condition that lowers the seizure threshold are at greater risk. Patients with lower seizure thresholds may have more severe conditions.
Potential for Motor and Cognitive Impairment:
- Like other antipsychotics VRAYLAR can impair judgement, thinking or motor skills.
- Six-week schizophrenia trials revealed that somnolence (hypersomnia and sedation) was more common in VRAYLAR-treated patients than it was in placebo-treated patients. 3 week bipolar mania trials revealed that somnolence was experienced by 8% of VRAYLAR treated patients, compared to 4% in placebo-treated patients.
- Patients are advised to avoid operating dangerous machinery, such as motor vehicles, until they can be certain that VRAYLAR therapy will not cause them harm.
- Caution patients if they are performing activities that require mental alertness, such as operating hazardous machinery or driving a motor vehicle, until they are reasonably certain that VRAYLAR therapy does not affect them adversely.
Body Temperature Dysregulation:
- The body’s ability reduce core body temperature may be affected by antipsychotics that are not typical. The body may be affected by strenuous exercise, extreme heat, dehydration and anticholinergic medication.
- VRAYLAR should be used with caution for patients who might experience these conditions. Patients need to be made aware of the drug’s effect on their body thermoregulation so as to avoid dehydration and high temperatures.
- Antipsychotic drug abuse has been linked to aspiration and esophageal dysmotility. VRAYLAR has been linked to dysphagia. Patients at high risk of aspiration should not take VRAYLAR or other antipsychotic medications.
Mechanism Of Action of Vraylar (MOA of Cariprazine):
The mode of action of Vraylar (Cariprazine) in patients with schizophrenia and bipolar I disorder is not well known. However, cariprazine is thought to act via a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and inhibits the activity of serotonin 5-HT2A receptors.
Cariprazine is metabolized into two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have similar receptor binding profiles as the parent drug.
Pharmacokinetics of Vraylar (Cariprazine):
VRAYLAR activity is thought to be mediated by cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), which are pharmacologically equipotent to cariprazine.
- The steady-state concentration of Cariprazine and DCAR is achieved within one to two weeks and that of DDCAR is achieved at around 8 to 12 weeks when administered regularly at scheduled time.
- Cariprazine: 2 – 4 days
- DCAR: 1 – 2 days
- DDCAR: 1 – 3 weeks
- The peak plasma concentration is achieved in 3 – 6 hours after one dose. High-fat meals do not affect the AUC and the maximum plasma concentration.
- 91 to 97% of the drug is strongly bound to plasma proteins.
- Cariprazine is extensively metabolized with CYP3A4 as well as, to a lesser degree, by CYP2D6 and DDCAR. CYP3A4 then CYP2D6 further metabolize DCAR to DDCAR. DDCAR is then metabolized to a hydroxylated metabolite by CYP3A4.
- 21% is excreted via the kidneys.