4.1. Therapeutic indications

Reagila is indicated for the treatment of schizophrenia in adult patients.

4.2. Posology and method of administration

Posology

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 (see section 5.2).

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 (see section 5.2).

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.

Special population

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 (see section 5.2).

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 (see section 5.2).

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 (see section 5.2). 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.

Method of administration

Reagila is for oral use, to be taken once daily at the same time of the day with or without food.

Alcohol should be avoided when taking cariprazine (see section 4.5).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant administration of strong CYP3A4 inhibitors (see section 4.5).

Concomitant administration of strong or moderate CYP3A4 inducers (see section 4.5).

4.4. Special warnings and precautions for use

Suicidal ideation and behaviour

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 a frequently occurring adverse reactions 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 4.8).

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 (see sections 4.8 and 5.3). 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 4.8). 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 (see section 5.1). In clinical studies, only a few, non-serious, QT-prolongations have been reported with cariprazine (see section 4.8). 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 (see section 5.1).

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 (see section 5.1).

Weight change

Significant weight gain has been observed with the use of cariprazine. Patients should have their weight monitored regularly (see section 4.8).

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 section 4.5).

Excipients

Reagila 3 mg, 4.5 mg and 6 mg hard capsules contain Allura red AC (E 129), which may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

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 (see section 4.3).

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 CYP 3A4 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 (see section 4.3).

CYP2D6 inhibitors

CYP2D6 mediated pathway plays a minor role in the metabolism of cariprazine, the major pathway is via CYP3A4 (see section 5.2). 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 on the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel).

Pharmacodynamic interactions

Given the primary central nervous system effects of cariprazine, Reagila should be used with caution in combination with other centrally acting medicinal products and alcohol.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

Women of childbearing potential must be advised to avoid pregnancy while on Reagila. Female patients of child-bearing potential must use effective contraceptive methods during treatment and for at least 10 weeks following the last dose of Reagila.

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 (see section 5.3).

Reagila 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 (see section 5.3). 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 section 5.3).

4.7. Effects on ability to drive and use machines

Cariprazine has minor or moderate influence on the ability to drive and use machines. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with Reagila does not affect them adversely.

4.8. Undesirable effects

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) with cariprazine in the dose range (1.5‑6 mg) were akathisia (19%) and parkinsonism (17.5%). Most events were mild to moderate in severity.

Tabulated list of adverse reactions

ADRs based upon pooled data from cariprazine schizophrenia studies are shown by system organ class and by preferred term in Table 1.

Adverse reactions are ranked by frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse drug reactions occurring in patients with schizophrenia

MedDRA

System Organ Class

Very common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Frequency not known

Blood and lymphatic system disorders

Anaemia

Eosinophilia

Neutropenia

Immune system disorders

Hypersensitivity

Endocrine disorders

Blood thyroid stimulating hormone decreased

Hypothyroidism

Metabolism and nutrition disorders

Dyslipidaemia

Weight increased

Decreased appetite

Increased appetite

Blood sodium abnormal

Diabetes mellitus

Blood glucose increased

Psychiatric disorders

Sleep disorders1

Anxiety

Suicidal behaviour

Delirium

Depression

Libido decreased

Libido increased

Erectile dysfunction

Nervous system disorders

Akathisia2

Parkinsonism3

Sedation

Dizziness

Dystonia4

Other extrapyramidal diseases and abnormal movement disorders5

Tardive dyskinesia

Dyskinesia6

Dysaesthesia

Lethargy

Seizures/ Convulsion

Amnesia

Aphasia

Neuroleptic malignant syndrome

Eye disorders

Vision blurred

Intraocular pressure increased

Accommodation disorder

Visual acuity reduced

Eye irritation

Cataract

Photophobia

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Tachyarrhythmia

Cardiac conduction disorders

Bradyarrhythmia

Electrocardiogram QT prolonged

Electrocardiogram T wave abnormal

Vascular disorders

Hypertension

Hypotension

Respiratory, thoracic and mediastinal disorders

Hiccups

Gastrointestinal disorders

Vomiting

Nausea

Constipation

Gastrooesophageal reflux disease

Dysphagia

Hepatobiliary disorders

Hepatic enzymes increased

Blood bilirubin increased

Toxic hepatitis

Skin and subcutaneous tissue disorders

Pruritus

Rash

Musculoskeletal and connective tissue disorders

Blood creatine phosphokinase increased

Rhabdomyolysis

Renal and urinary disorders

Dysuria

Pollakisuria

Pregnancy, puerperium and perinatal conditions

Drug withdrawal syndrome neonatal (see section 4.6)

General disorders and administration site conditions

Fatigue

Thirst

1Sleep disorders: Insomnia, Abnormal dreams/nightmare, Circadian rhythm sleep disorder, Dyssomnia, Hypersomnia, Initial insomnia, Middle insomnia, Nightmare, Sleep disorder, Somnambulism, Terminal insomnia

2Akathisia: Akathisia, Psychomotor hyperactivity, Restlessness

3Parkinsonism: Akinesia, Bradykinesia, Bradyphrenia, Cogwheel rigidity, Extrapyramidal disorder, Gait disturbance, Hypokinesia, Joint stiffness, Tremor, Masked facies, Muscle rigidity, Musculoskeletal stiffness, Nuchal rigidity, Parkinsonism

4Dystonia: Blepharospasm, Dystonia, Muscle tightness, Oromandibular dystonia, Torticollis, Trismus

5Other extrapyramidal diseases and abnormal movement disorders: Balance disorder, Bruxism, Drooling, Dysarthria, Gait deviation, Glabellar reflex abnormal, Hyporeflexia, Movement disorder, Restless legs syndrome, Salivary hypersecretion, Tongue movement disturbance

6Dyskinesia: Choreoathetosis, Dyskinesia, Grimacing, Oculogyric crisis, Protrusion tongue

Description of selected adverse reactions

Lens opacity/Cataract

Development of cataracts was observed in cariprazine non‑clinical studies (see section 5.3). Therefore, cataract formation was closely monitored with slit lamp examinations in the clinical studies and patients with existing cataracts were excluded. During the schizophrenia clinical development program of cariprazine, few cataract cases were reported, characterized with minor lens opacities with no visual impairment (13/3192; 0.4%). Some of these patients had confounding factors. The most commonly reported ocular adverse event was blurred vision (placebo: 1/683; 0.1%, cariprazine: 22/2048; 1.1%).

Extrapyramidal symptoms (EPS)

In the short-term studies the incidence of EPS was observed in 27%; 11.5%; 30.7% and 15.1% in patients treated with cariprazine, placebo, risperidone and aripiprazole respectively. Akathisia was reported in 13.6%; 5.1%; 9.3% and 9.9% in patients treated with cariprazine, placebo, risperidone and aripiprazole respectively. Parkinsonism was experienced in 13.6%; 5.7%; 22.1% and 5.3% in patients treated with cariprazine, placebo, risperidone and aripiprazole respectively. Dystonia was observed in 1.8%; 0.2%; 3.6% and 0.7% in patients on cariprazine, placebo, risperidone and aripiprazole, respectively.

In the placebo-controlled part of the long-term maintenance of effect study EPS was 13.7% in the cariprazine group compared to 3.0% in the placebo treated patients. Akathisia was reported in 3.9% in patients treated with cariprazine, versus 2.0% in the placebo group. Parkinsonism was experienced in 7.8% and 1.0% in cariprazine and placebo group respectively.

In the negative symptom study EPS was reported in 14.3% in the cariprazine group and 11.7% in the risperidone treated patients. Akathisia was reported in 10.0% in patients treated with cariprazine and 5.2% in the risperidone group. Parkinsonism was experienced in 5.2% and 7.4% in cariprazine and risperidone treated patients respectively. Most EPS cases were mild to moderate in intensity and could be handled with common anti-EPS medicinal products. The rate of discontinuation due to EPS related ADRs was low.

Venous thromboembolism (VTE)

Cases of VTE, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotics - Frequency unknown.

Elevated liver transaminases

Elevated liver transaminases (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST]) are frequently observed with antipsychotic treatment. In the cariprazine clinical studies the incidence of ALT, AST elevation ADRs occurred in 2.2% of cariprazine-, 1.6% of risperidone- and 0.4% of placebo-treated patients. None of the cariprazine-treated patients had any liver damage.

Weight changes

In the short-term studies, there were slightly greater mean increases in body weight in the cariprazine group compared to the placebo group; 1 kg and 0.3 kg, respectively. In the long-term maintenance of effect study, there was no clinically relevant difference in change of body weight from baseline to end of treatment (1.1 kg for cariprazine and 0.9 kg for placebo). In the open-label phase of the study during 20 weeks cariprazine treatment 9.0% of patients developed potentially clinically significant (PCS) weight gain (defined as increase ≥ 7%) while during the double-blind phase, 9.8 % of the patients who continued with cariprazine treatment had PCS weight gain versus 7.1% of the patients who were randomized to placebo after the 20 week open-label cariprazine treatment. In the negative symptom study, the mean change of body weight was -0.3 kg for cariprazine and +0.6 kg for risperidone and PCS weight gain was observed in 6% of the cariprazine group while 7.4% of the risperidone group.

QT- prolongation

With cariprazine no QT interval prolongation was detected compared to placebo in a clinical study designed to assess QT prolongation (see section 5.1). In other clinical studies, only a few, non-serious, QT-prolongations have been reported with cariprazine. During the long-term, open-label treatment period in, 3 patients (0.4%) had QTcB > 500 msec, one of whom also had QTcF > 500 msec. A > 60 msec increase from baseline was observed in 7 patients (1%) for QTcB and in 2 patients (0.3%) for QTcF. In the long-term, maintenance of effect study, during the open-label phase, > 60 msec increase of from baseline was observed in 12 patients (1.6%) for QTcB and in 4 patients (0.5%) for QTcF. During the double-blind treatment period, > 60 msec increases from baseline in QTcB were observed in 3 cariprazine-treated patients (3.1%) and 2 placebo-treated patients (2%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.