Reagila 1.5, 3, 4.5, 6

/ Dexcel

Schizophrenia
The recommended starting dose of cariprazine is 1.5 mg once daily. Thereafter the dose can be increased slowly in 1.5 mg increments to a maximum dose of 6 mg/day, if needed. The lowest effective dose should be maintained according to the clinical judgement of the treating physician. Because of the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks. Patients should be monitored for adverse reactions and treatment response for several weeks after starting cariprazine and after each dose change.
Manic or Mixed Episodes Associated with Bipolar I Disorder
The recommended dosage range is 3 mg to 6 mg once daily. The starting dose of cariprazine is 1.5 mg and should be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. The maximum recommended dosage is 6 mg daily.
Depressive Episodes Associated with Bipolar I Disorder (Bipolar Depression)
The starting dose is 1.5 mg once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg once daily on Day 15. Maximum recommended dosage is 3 mg once daily. Clinical trials have not demonstrated statistical efficacy in treatment of the higher dose of 3 mg once daily, hence the option of treatment with the maximum daily dose of 3 mg should be reserved only for patients resistant to the low dose of 1.5 mg once daily.
Adjunctive Therapy to Antidepressants in Treatment of Major Depressive Disorder (MDD)
The starting dosage of cariprazine is 1.5 mg once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg once daily on Day 15. In clinical trials, dosage titration at intervals of less than 14 days resulted in a higher incidence of adverse reactions. Maximum recommended dosage is 3 mg once daily.
Switching from other antipsychotics to cariprazine
When switching from another antipsychotic to cariprazine gradual cross-titration should be considered, with gradual discontinuation of the previous treatment while cariprazine treatment is initiated.
Switching to another antipsychotic from cariprazine
When switching to another antipsychotic from cariprazine, no gradual cross-titration is needed, the new antipsychotic should be initiated in its lowest dose while cariprazine is discontinued. It should be considered that plasma concentration of cariprazine and its active metabolites will decline by 50% in ~1 week.
Missed dose
If the patient misses a dose, the patient should take the missed dose as soon as possible. However, if it is almost time for the next dose, the missed dose should be skipped and the next dose should be taken according to the regular schedule. It is not recommended to take a double dose to make up for the forgotten dose.
Renal impairment
No dose adjustment is required in patients with mild to moderate renal impairment (Creatinine Clearance (CrCl) ≥ 30 mL/min and < 89 mL/min). Safety and efficacy of cariprazine have not been evaluated in patients with severe renal impairment (CrCl < 30 mL/min). Use of cariprazine is not recommended in patients with severe renal impairment.
Hepatic impairment
No dose adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5-9). Safety and efficacy of cariprazine have not been evaluated in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). Use of cariprazine is not recommended in patients with severe hepatic impairment.
Elderly
Available data in elderly patients aged ≥65 years treated with cariprazine are not sufficient to determine whether or not they respond differently from younger patients. Dose selection for an elderly patient should be more cautious.
Paediatric population
The safety and efficacy of cariprazine in children and adolescents aged less than 18 years have not been established. No data are available.
This medicinal product can be administered with or without food.
See prescribing information for full details.

* Treatment of schizophrenia in adult patients.
* Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.
* Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults.
* Adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults

* Hypersensitivity to the active substance or to any of the excipients
* Concomitant administration of strong CYP3A4 inhibitors and of strong or moderate inducers

Suicidal ideation and behavior
The possibility of suicidality (suicidal ideation, suicide attempt and completed suicide) is inherent in psychotic illnesses and, generally, it is reported early after initiation or switch of antipsychotic therapy. Close supervision of high-risk patients should accompany antipsychotic therapy.
Akathisia, restlessness
Akathisia and restlessness are frequently occurring adverse reaction of antipsychotics. Akathisia is a movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. As cariprazine causes akathisia and restlessness, it should be used cautiously in patients who are prone to or already exhibit symptoms of akathisia. Akathisia develops early in treatment. Therefore close monitoring in the first phase of treatment is important. Prevention includes slow up-titration; treatment measures include slight down-titration of cariprazine or anti-EPS medicinal product. The dose can be modified based on individual response and tolerability (see section side effects).
Tardive dyskinesia
Tardive dyskinesia is a syndrome consisting of potentially irreversible, rhythmical, involuntary movements, predominantly of the tongue and/or face that can develop in patients treated with antipsychotics. If signs and symptoms of tardive dyskinesia appear in a patient treated with cariprazine, discontinuation should be considered.
Parkinson’s disease
If prescribed to patients with Parkinson’s disease, antipsychotic medicinal products may exacerbate the underlying disease and worsen symptoms of Parkinson’s disease. Physicians should, therefore, weigh the risks versus the benefits when prescribing cariprazine to patients with Parkinson’s disease.
Ocular symptoms/cataract
In the preclinical studies of cariprazine lens opacity/cataract was detected in dogs. However, a causal relationship between lenticular changes / cataracts observed in human studies and cariprazine use has not been established. Nevertheless, patients who would develop symptoms potentially related to cataract should be advised to ophthalmologic examination and re-evaluated for treatment continuation.
Neuroleptic malignant syndrome (NMS)
A potentially fatal symptom complex referred to as NMS has been reported in association with antipsychotic treatment. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, elevated serum creatine phosphokinase levels, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure.
If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, cariprazine must be discontinued immediately.
Seizures and convulsions
Cariprazine should be used cautiously in patients with history of seizures or with conditions that potentially lower the seizure threshold.
Elderly patients with dementia
Cariprazine has not been studied in elderly patients with dementia and is not recommended to treat elderly patients with dementia due to increased risk of overall mortality.
Risk of cerebrovascular accidents (CVA)
An approximately 3-fold increased risk of CVA has been seen in randomised placebo controlled clinical studies in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Cariprazine should be used with caution in patients with risk factors for stroke.
Cardiovascular disorders
Blood pressure changes:
Cariprazine can cause orthostatic hypotension as well as hypertension (see section side effects). Cariprazine should be used with caution in patients with known cardiovascular disease predisposing to blood pressure changes. Blood pressure should be monitored.
Electrocardiogram (ECG) changes:
QT prolongation can develop in patients treated with antipsychotics.
With cariprazine no QT interval prolongation was detected compared to placebo in a clinical study designed to assess QT prolongation. In clinical studies, only a few, non-serious, QT-prolongations have been reported with cariprazine (see section side effects). Therefore, cariprazine should be used cautiously in patients with known cardiovascular disease or in patients with a family history of QT prolongation and in patients treated with medicinal products that might cause QT prolongation.
Venous thromboembolism (VTE):
Cases of  VTE have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with cariprazine and preventive measures undertaken.
Hyperglycaemia and diabetes mellitus
Patients with an established diagnosis of diabetes mellitus or patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should be monitored for serum glucose levels.
In clinical studies, glucose-related adverse reactions have been reported with cariprazine.
Weight change
Significant weight gain has been observed with the use of cariprazine. Patients should have their weight monitored regularly (see section side effects).
Concomitant treatment with moderate CYP3A4 inhibitors
Co-administration of cariprazine with moderate inhibitors of CYP3A4 may lead to increased total cariprazine exposure. Monitoring of the individual response and tolerability is recommended and, if needed, the cariprazine dose should be (temporarily) reduced to account for the potential increase in exposure
See prescribing information for full details.

Schizophrenia:
Very common: Akathisia, parkinsonism. 
Common: Dyslipidaemia, weight increased, decreased appetite, increased appetite, sleep disorders, anxiety, sedation, dizziness, dystonia, other extrapyramidal diseases and abnormal movement disorders, vision blurred, tachyarrhytmia, hypertension, vomiting, nausea, constipation, hepatic enzymes increased, blood creatine phosphokinase increased, fatigue.
Bipolar Mania:
Common: Extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, restlessness.
Bipolar Depression:
Common: Nausea, akathisia, restlessness, extrapyramidal symptoms.
Adjunctive Therapy in Major Depressive Disorder (MDD)
Common: Akathisia, nausea, insomnia, restlessness, fatigue, constipation, increased appetite, dizziness and extrapyramidal symptoms
See prescribing information for full details.

Potential for other medicinal products to affect cariprazine
Metabolism of cariprazine and its major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), is mediated mainly by CYP3A4 with a minor contribution of CYP2D6.
CYP3A4 inhibitors:
Ketoconazole, a strong CYP3A4 inhibitor, caused two fold increase in plasma exposure for total cariprazine (sum of cariprazine and its active metabolites) during short-term (4 days) co-administration, either if unbound or unbound+bound moieties considered.
Due to the long half-life of the active moieties of cariprazine a further increase in plasma exposure of total cariprazine can be expected during longer co-administration. Therefore, co-administration of cariprazine with strong CYP3A4 inhibitors (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) is contraindicated.
Erythromycin (500 mg twice daily), a moderate CYP3A4 inhibitor, caused on average a 1.4-fold (range 1.03-2.32-fold) increase in plasma exposure of total cariprazine after 3 weeks of co-administration. Therefore, during a period of co-administration of cariprazine with a moderate CYP3A4 inhibitor (e.g., erythromycin, fluconazole, diltiazem, verapamil), monitoring of the individual response and tolerability is recommended and, if needed, the cariprazine dose should be (temporarily) reduced to account for the potential increase in exposure. Because of the long half-life of cariprazine and its active metabolites, starting or stopping a treatment with a moderate CYP3A4 inhibitor or changing the dose will not be fully reflected in plasma drug levels until after several weeks. Patients should be monitored for adverse reactions and treatment response for several weeks after initiating or stopping an interacting drug or after each cariprazine dose change.
Consumption of grapefruit juice should be avoided.
CYP3A4 inducers:
Co-administration of cariprazine with strong and moderate inducers of CYP3A4 may result in a significant decrease in total cariprazine exposure, therefore the co-administration of cariprazine and strong or moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) is contraindicated.
CYP2D6 inhibitors:
CYP2D6 mediated pathway plays a minor role in the metabolism of cariprazine, the major pathway is via CYP3A4. Therefore CYP2D6 inhibitors are unlikely to have a clinically relevant effect on cariprazine metabolism.
Potential for cariprazine to affect other medicinal products
P-glycoprotein (P-gp) substrates:
Cariprazine is a P-gp inhibitor in vitro at its theoretical maximum intestinal concentration. The clinical consequences of this effect is not fully understood, however the use of P-gp substrates with narrow therapeutic index such as dabigatran and digoxin could require extra monitoring and dose adjustment.
Hormonal contraceptives:
In a drug interaction study, 28 days of treatment with cariprazine at 6 mg daily had no clinically relevant effect of the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel).
Pharmacodynamic interactions
Given the primary central nervous system effects of cariprazine, this medicinal product should be used with caution in combination with other centrally acting medicinal products and alcohol.
See prescribing information for full details.

Women of childbearing potential/contraception
Women of childbearing potential must be advised to avoid pregnancy while on cariprazine. Female patients of child-bearing potential must use highly effective contraceptive methods during treatment and for at least 10 weeks following the last dose of this medicinal product.
Pregnancy
There are no or limited amount of data from the use of cariprazine in pregnant women.
Studies in animals have shown reproductive toxicity including developmental malformations in rats.
this medicinal product is not recommended during pregnancy and in women of childbearing potential not using effective contraception. After discontinuation of cariprazine treatment contraception should be used for at least 10 weeks due to the slow elimination of active moieties.
Neonates exposed to antipsychotics (including cariprazine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress or feeding disorder. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases, neonates have required intensive care unit support and prolonged hospitalization. Consequently, newborns should be monitored carefully.
Breast-feeding
It is unknown whether cariprazine or its major active metabolites are excreted in human milk. Cariprazine and its metabolites are excreted in milk of rats during lactation. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with cariprazine.
Fertility
The effect of cariprazine on human fertility has not been evaluated. In rat studies lower female fertility and conception indices were observed.
See prescribing information for full details.

Symptoms
Accidental acute overdose (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation. The patient fully recovered the same day.
Management of overdose
Management of overdose should concentrate on supportive therapy including maintenance of an adequate airway, oxygenation and ventilation and management of symptoms. Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. In case of severe extrapyramidal symptoms, anticholinergic medicinal products should be administered. Since cariprazine is highly bound to plasma proteins, haemodialysis is unlikely to be useful in the management of overdose. Close medical supervision and monitoring should continue until the patient recovers.
There is no specific antidote to cariprazine.