Reagila CapsuleS

Reagila is indicated for the treatment of acute relapses of schizophrenia and maintenance therapy in adult patients.

Posology
The recommended starting dose of Reagila 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 healthcare professional. 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 Reagila and after each dosage change (see section 5.2).

Switching from other antipsychotics to cariprazine
When switching from another antipsychotic to Reagila gradual cross-titration should be considered, with gradual discontinuation of the previous treatment while Reagila treatment is initiated.

Switching to another antipsychotic from cariprazine
When switching to another antipsychotic from Reagila , no gradual cross-titration is needed, the new antipsychotic should be initiated in its lowest dose while Reagila is discontinued. It should be considered that plasma concentration of cariprazine and its active metabolites will decline by 50 % in approximately 1 week (see section 5.2).

Special populations
Renal impairment
No dose adjustment is required in patients with mild to moderate renal impairment (Creatinine Clearance (CrCl) u2265 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 Reagila 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 Reagila have not been evaluated in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). Use of Reagila is not recommended in patients with severe hepatic impairment (see section 5.2).

Elderly
Available data in elderly patients aged u2265 65 years treated with Reagila 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 Reagila 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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concomitant administration of strong or moderate CYP3A4 inhibitors (see section 4.5).
Concomitant administration of strong or moderate CYP3A4 inducers (see section 4.5).
Pregnancy and lactation (see 4.6).

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 frequently occurring adverse reactions of antipsychotics. Akathisia is a movement disorder characterised 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 Reagila 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 Reagila , or medicines used for treatment of extrapyramidal symptoms. 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 Reagila , discontinuation should be considered.

Parkinson's disease
If prescribed to patients with Parkinson's disease, antipsychotic medicines such as Reagila may exacerbate the underlying disease and worsen symptoms of Parkinsonu2019s disease.

Ocular symptoms/cataract
In the preclinical studies of Reagila , 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 Reagila 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 neuroleptic malignant syndrome (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, Reagila must be discontinued immediately.

Seizures and convulsions
Reagila should be used cautiously in patients with history of seizures or with conditions that potentially lower the seizure threshold.

Elderly patients with dementia
Reagila 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 cerebrovascular adverse reactions has been seen in randomised placebo controlled clinical trials 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. Reagila should be used with caution in patients with risk factors for stroke.

Cardiovascular disorders
Blood pressure changes
Reagila can cause orthostatic hypotension as well as hypertension (see section 4.8). Reagila should be used with caution in patients with known cardiovascular disease predisposing to blood pressure changes. Blood pressure should be monitored.

ECG changes
QT prolongation can develop in patients treated with antipsychotics. With Reagila no QT interval prolongation was detected compared to placebo in a clinical trial designed to assess QT prolongation (see section 5.1). In clinical trials, only a few, non-serious, QT-prolongations have been reported with cariprazine (see section 4.8). Therefore, Reagila 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 medicines that might cause QT prolongation (see section 5.1).

Venous thromboembolism (VTE)
Cases of venous thromboembolism have been reported with antipsychotic medicines. 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 Reagila 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 trials, glucose-related adverse reactions have been reported with Reagila (see section 5.1).

Women of childbearing potential
Women of childbearing potential must use highly effective contraception while taking Reagila and at least for 10 weeks after stopping treatment (see sections 4.5 and 4.6). Women using systemically acting hormonal contraceptives should add a second barrier method.

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

Excipients
Reagila 3 mg, 4,5 mg and 6 mg hard capsules contain Allura red AC (E129), which may cause allergic reactions.

Potential for other medicines 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 plus 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 or moderate inhibitors of CYP3A4 (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, diltiazem, erythromycin, fluconazole, verapamil) is contraindicated (see section 4.3). 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, phenobarbitone, phenytoin, rifampicin, St. Johnu2019s 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 medicines
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 are 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
It is currently unknown whether cariprazine may reduce the effectiveness of systemically acting hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives should add a second barrier method.

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

Women of childbearing potential/contraception
Women of childbearing potential must be advised to not become pregnant while on Reagila (see 4.3). 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 Reagila . It is currently unknown if cariprazine may reduce the effectiveness of systemically acting hormonal contraceptives and therefore women using systemically acting hormonal contraceptives should add a barrier method (see section 4.5).

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 for use 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. Administration of cariprazine to rats during the period of organogenesis caused malformations and lower pup survival. Cariprazine caused foetal developmental toxicity at all dose levels (0,5 to 7,5 mg/kg/day) and included reduced foetal body weight, decreased male anogenital distance and skeletal malformations of bent limb bones, scapula and humerus. 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.

Breastfeeding
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. Breastfeeding should be discontinued during treatment with cariprazine (see 4.3).

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).

Reagila has an influence on the ability to drive and use machines, e.g. somnolence, fatigue, vertigo, dyskinesia. 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.

Summary of the safety profile
The most frequently reported ADRs with Reagila in the dose range (1,5 u2013 6 mg) were akathisia (19 %) and parkinsonism (17,5 %). Most events were mild to moderate in severity.

Tabulated list of adverse reactions
Adverse drug reactions (ADRs) based upon pooled data from Reagila schizophrenia studies are shown by system organ class and by preferred term.

Adverse reactions are ranked by frequency, the most frequent first, using the following convention: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 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.

Adverse drug reactions occurring in patients with schizophrenia

MedDRA System Organ Class Very common ( u2265 1/10) Common ( u2265 1/100 to <1/10) Uncommon ( u2265 1/1 000 to < 1/100) Rare ( u2265 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 Weight increased Decreased appetite Increased appetite Dyslipidaemia Blood sodium abnormal Blood glucose increased Diabetes mellitus Psychiatric disorders Sleep disorders 1 Anxiety Suicidal behaviour Delirium Depression Libido decreased Libido increased Erectile dysfunction Nervous system disorders Akathisia 2 Parkinsonism 3 Sedation Dizziness Dystonia 4 Other extrapyramidal diseases and abnormal movement disorders 5 Lethargy Dysaesthesia Dyskinesia 6 Tardive dyskinesia Seizures/ Convulsion Amnesia Aphasia Neuroleptic malignant syndrome Eye disorders Vision blurred Eye irritation Intraocular pressure increased Accommodation disorder Visual acuity reduced Photophobia Cataract Ear and labyrinth disorders Vertigo Cardiac disorders Tachy - dysrhythmia Cardiac conduction disorders Brady- dysrhythmia Electrocardiogram QT prolonged Electrocardiogram T wave abnormal Vascular disorders Hypertension Hypotension Respiratory, thoracic and mediastinal disorders Hiccups Gastrointestinal disorders Nausea Constipation Vomiting Gastroesophageal 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 Fatigue Thirst

1 Sleep disorders: insomnia, abnormal dreams/nightmare, circadian rhythm sleep disorder, dyssomnia, hypersomnia, initial insomnia, middle insomnia, nightmare, sleep disorder, somnambulism, terminal insomnia.
2 Akathisia: akathisia, psychomotor hyperactivity, restlessness.
3 Parkinsonism: akinesia, bradykinesia, bradyphrenia, cogwheel rigidity, extrapyramidal disorder, gait disturbance, hypokinesia, joint stiffness, tremor, masked facies, muscle rigidity, musculoskeletal stiffness, nuchal rigidity, parkinsonism.
4 Dystonia: blepharospasm, dystonia, muscle tightness, oromandibular dystonia, torticollis, trismus.
5 Other 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.
6 Dyskinesia: choreoathetosis, dyskinesia, grimacing, oculogyric crisis, protrusion tongue.

Description of selected adverse reactions
Lens opacity/Cataract
Development of cataracts was observed in Reagila 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 Reagila , few cataract cases were reported, characterised 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 and two comparator molecules respectively. Akathisia was reported in 13,6 %; 5,1 %; 9,3 % and 9,9 % in patients treated with cariprazine, placebo and two comparator molecules respectively. Parkinsonism was experienced in 13,6 %; 5,7 %; 22,1 % and 5,3 % in patients treated with cariprazine, placebo and two comparator molecules respectively. Dystonia was observed in 1,8 %; 0,2 %; 3,6 % and 0,7 % in patients on cariprazine, placebo and two comparator molecules 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 comparator treated patients. Akathisia was reported in 10,0 % in patients treated with cariprazine and 5,2 % in the comparator group. Parkinsonism was experienced in 5,2 % and 7,4 % in cariprazine and comparator treated patients respectively. Most EPS cases were mild to moderate in intensity and could be handled with common anti-EPS medicines. The rate of discontinuation due to EPS related ADRs was low.

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

Elevated liver transaminases
Elevated liver transaminases (ALT, 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 comparator 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 u2265 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 randomised 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 the comparator and PCS weight gain was observed in 6 % of the cariprazine group while 7,4 % of the comparator group.

QT- prolongation
With cariprazine no QT interval prolongation was detected compared to placebo in a clinical trial designed to assess QT prolongation (see section 5.1). In other clinical trials, 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 ms, one of whom also had QTcF > 500 ms. A > 60 ms 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 ms 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 ms increases from baseline in QTcB were observed in 3 cariprazine-treated patients (3,1 %) and 2 placebo-treated patients (2 %).

Symptoms
Accidental acute overdose (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation.

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 dysrhythmias. In case of severe extrapyramidal symptoms, anticholinergic medicines 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.