REAGILA 4.5mg capsules medication leaflet

Each hard capsule contains cariprazine hydrochloride corresponding to 1.5 mg cariprazine.

Each hard capsule contains cariprazine hydrochloride corresponding to 3 mg cariprazine.

Each hard capsule contains 0.0003 mg Allura red AC (E 129).

Each hard capsule contains cariprazine hydrochloride corresponding to 4.5 mg cariprazine.

Each hard capsule contains 0.0008 mg Allura red AC (E 129).

Each hard capsule contains cariprazine hydrochloride corresponding to 6 mg cariprazine.

Each hard capsule contains 0.0096 mg Allura red AC (E 129).

For the full list of excipients, see section 6.1.

Hard capsule

Reagila 1.5 mg hard capsules‘Size 4’ (approximately 14.3 mm in length) hard gelatin capsule with white opaque cap and whiteopaque body imprinted with “GR 1.5” on the capsule body with black ink. The capsules are filled withwhite to yellowish white powder mixture.

Reagila 3 mg hard capsules‘Size 4’ (approximately 14.3 mm in length) hard gelatin capsule with green opaque cap and whiteopaque body imprinted with “GR 3” on the capsule body with black ink. The capsules are filled withwhite to yellowish white powder mixture.

Reagila 4.5 mg hard capsules‘Size 4’ (approximately 14.3 mm in length) hard gelatin capsule with green opaque cap and greenopaque body imprinted with “GR 4.5” on the capsule body with white ink. The capsules are filled withwhite to yellowish white powder mixture.

Reagila 6 mg hard capsules‘Size 3’ (approximately 15.9 mm in length) hard gelatin capsule with purple opaque cap and whiteopaque body imprinted with “GR 6” on the capsule body with black ink. The capsules are filled withwhite to yellowish white powder mixture.

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

The recommended starting dose of cariprazine is 1.5 mg once daily. Thereafter the dose can beincreased slowly in 1.5 mg increments to a maximum dose of 6 mg/day, if needed. The lowesteffective 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 fullyreflected in plasma for several weeks. Patients should be monitored for adverse reactions andtreatment response for several weeks after starting cariprazine and after each dose change (see section5.2).

When switching from another antipsychotic to cariprazine gradual cross-titration should beconsidered, with gradual discontinuation of the previous treatment while cariprazine treatment isinitiated.

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

If the patient misses a dose, the patient should take the missed dose as soon as possible. However, if itis almost time for the next dose, the missed dose should be skipped and the next dose should be takenaccording to the regular schedule. It is not recommended to take a double dose to make up for theforgotten dose.

Special population

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 beenevaluated in patients with severe renal impairment (CrCl < 30 mL/min). Use of cariprazine is notrecommended in patients with severe renal impairment (see section 5.2).

No dose adjustment is required in patients with mild to moderate hepatic impairment (Child-Pughscore between 5-9). Safety and efficacy of cariprazine have not been evaluated in patients with severehepatic impairment (Child-Pugh score between 10 and 15). Use of cariprazine is not recommended inpatients with severe hepatic impairment (see section 5.2).

Available data in elderly patients aged ≥ 65 years treated with cariprazine are not sufficient todetermine whether or not they respond differently from younger patients (see section 5.2). Doseselection for an elderly patient should be more cautious.

The safety and efficacy of cariprazine in children and adolescents aged less than 18 years have notbeen established. No data are available.

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

Reagila orodispersible tablets may be used as an alternative to Reagila hard capsules for patients whohave difficulty swallowing the hard capsules or for whom there is a preference for orodispersibletablets.

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

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).

The possibility of suicidality (suicidal ideation, suicide attempt and completed suicide) is inherent inpsychotic illnesses and, generally, it is reported early after initiation or switch of antipsychotictherapy. Close supervision of high-risk patients should accompany antipsychotic therapy.

Akathisia and restlessness are frequently occurring adverse reactions of antipsychotics. Akathisia is amovement disorder characterized by a feeling of inner restlessness and a compelling need to be inconstant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as ifmarching on the spot, and crossing and uncrossing the legs while sitting. As cariprazine causesakathisia and restlessness, it should be used cautiously in patients who are prone to or already exhibitsymptoms of akathisia. Akathisia develops early in treatment. Therefore, close monitoring in the firstphase of treatment is important. Prevention includes slow up-titration; treatment measures includeslight down-titration of cariprazine or anti-extrapyramidal symptoms (EPS) medicinal product Thedose can be modified based on individual response and tolerability (see section 4.8).

Tardive dyskinesia is a syndrome consisting of potentially irreversible, rhythmical, involuntarymovements, predominantly of the tongue and/or face that can develop in patients treated withantipsychotics. If signs and symptoms of tardive dyskinesia appear in a patient treated withcariprazine, discontinuation should be considered.

If prescribed to patients with Parkinson's disease, antipsychotic medicinal products may exacerbate theunderlying disease and worsen symptoms of Parkinson’s disease. Physicians should, therefore, weighthe risks versus the benefits when prescribing cariprazine to patients with Parkinson's disease.

In the preclinical studies of cariprazine lens opacity/cataract was detected in dogs (see sections 4.8 and5.3). However, a causal relationship between lenticular changes/cataracts observed in human studiesand cariprazine use has not been established. Nevertheless, patients who would develop symptomspotentially related to cataract should be advised to ophthalmologic examination and re-evaluated fortreatment continuation.

A potentially fatal symptom complex referred to as NMS has been reported in association withantipsychotic treatment. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, elevatedserum creatine phosphokinase levels, altered mental status and evidence of autonomic instability(irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signsmay include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs andsymptoms indicative of NMS, or presents with unexplained high fever without additional clinicalmanifestations of NMS, cariprazine must be discontinued immediately.

Cariprazine should be used cautiously in patients with history of seizures or with conditions thatpotentially lower the seizure threshold.

Cariprazine has not been studied in elderly patients with dementia and is not recommended to treatelderly patients with dementia due to increased risk of overall mortality.

An approximately 3-fold increased risk of CVA has been seen in randomised placebo-controlledclinical studies in the dementia population with some atypical antipsychotics. The mechanism for thisincreased risk is not known. An increased risk cannot be excluded for other antipsychotics or otherpatient populations. Cariprazine should be used with caution in patients with risk factors for stroke.

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

QT prolongation can develop in patients treated with antipsychotics.

With cariprazine no QT interval prolongation was detected compared to placebo in a clinical studydesigned 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 beused 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).

Cases of VTE have been reported with antipsychotic medicinal products. Since patients treated withantipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTEshould be identified before and during treatment with cariprazine and preventive measures undertaken.

Patients with an established diagnosis of diabetes mellitus or patients with risk factors for diabetesmellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypicalantipsychotics should be monitored for serum glucose levels. In clinical studies, glucose-relatedadverse reactions have been reported with cariprazine (see section 5.1).

Significant weight gain has been observed with the use of cariprazine. Patients should have theirweight 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 totalcariprazine exposure. Monitoring of the individual response and tolerability is recommended and, ifneeded, the cariprazine dose should be (temporarily) reduced to account for the potential increase inexposure (see section 4.5).

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

Metabolism of cariprazine and its major active metabolites, desmethyl cariprazine (DCAR) anddidesmethyl cariprazine (DDCAR), is mediated mainly by CYP3A4 with a minor contribution of

CYP2D6.

Ketoconazole, a strong CYP3A4 inhibitor, caused two-fold increase in plasma exposure for totalcariprazine (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 oftotal cariprazine can be expected during longer co-administration. Therefore, co-administration ofcariprazine 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 theindividual 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 ofcariprazine and its active metabolites, starting or stopping a treatment with a moderate CYP 3A4inhibitor or changing the dose will not be fully reflected in plasma drug levels until after severalweeks. Patients should be monitored for adverse reactions and treatment response for several weeksafter initiating or stopping an interacting drug or after each cariprazine dose change.

Consumption of grapefruit juice should be avoided.

Co-administration of cariprazine with strong and moderate inducers of CYP3A4 may result in asignificant decrease in total cariprazine exposure, therefore the co-administration of cariprazine andstrong or moderate CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, St.

John’s wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) iscontraindicated (see section 4.3).

CYP2D6 mediated pathway plays a minor role in the metabolism of cariprazine, the major pathway isvia CYP3A4 (see section 5.2). Therefore, CYP2D6 inhibitors are unlikely to have a clinically relevanteffect on cariprazine metabolism.

Cariprazine is a P-gp inhibitor in vitro at its theoretical maximum intestinal concentration. The clinicalconsequences of this effect is not fully understood, however the use of P-gp substrates with narrowtherapeutic index such as dabigatran and digoxin could require extra monitoring and dose adjustment.

In a drug interaction study, 28 days of treatment with cariprazine at 6 mg daily had no clinicallyrelevant effect on the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel).

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

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

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 usingeffective contraception. After discontinuation of cariprazine treatment contraception should be usedfor at least 10 weeks due to the slow elimination of active moieties.

Neonates exposed to antipsychotics (including cariprazine) during the third trimester of pregnancy areat risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary inseverity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia,tremor, somnolence, respiratory distress or feeding disorder. These complications have varied inseverity; while in some cases symptoms have been self-limited, in other cases, neonates have requiredintensive care unit support and prolonged hospitalization. Consequently, newborns should bemonitored carefully.

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 tothe newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment withcariprazine.

The effect of cariprazine on human fertility has not been evaluated. In rat studies lower female fertilityand conception indices were observed (see section 5.3).

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

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 inseverity.

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

Adverse reactions are ranked by MedDRA system organ class and by frequency, the most frequentfirst, 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 beestimated from the available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.

Table 1 Adverse drug reactions occurring in patients with schizophrenia

MedDRA Very common Common Uncommon Rare Frequency

System (≥1/10) (≥1/100 to (≥1/1 000 to (≥1/10 000 to not known

Organ Class <1/10) <1/100) <1/1 000)

Blood and Anaemia Neutropenialymphatic Eosinophiliasystemdisorders

Immune Hypersensitivisystem tydisorders

Endocrine Blood thyroid Hypothyroidisdisorders stimulating mhormonedecreased

Metabolism Dyslipidaemia Blood sodiumand Weight abnormalnutrition increased Diabetesdisorders Decreased mellitusappetite Blood glucose

Increased increaseda ppetite

Psychiatric Sleep Suicidaldisorders disorders1 behaviour

Anxiety Delirium

Depression

Libidodecreased

Libidoincreased

Erectiledysfunction

Nervous Akathisia2 Sedation Tardive Seizures/ Neurolepticsystem Parkinsonism3 Dizziness dyskinesia Convulsion malignantdisorders Dystonia4 Dyskinesia6 Amnesia syndrome

Other Dysaesthesia Aphasiaextrapyramidal Lethargydiseases andabnormalmovementdisorders5

Eye Vision blurred Intraocular Cataractdisorders pressure Photophobiaincreased

Accommodation disorder

Visual acuityreduced

Eye irritation

Ear and Vertigolabyrinthdisorders

Cardiac Tachyarrhyth Cardiacdisorders mia conductiondisorders

Bradyarrhythmia

Electrocardiogram QTprolonged

Electrocardiogram T waveabnormal

Vascular Hypertension Hypotensiondisorders

Respiratory, Hiccupsthoracic andmediastinaldisorders

Gastrointesti Vomiting Gastrooesopha Dysphagianal Nausea geal refluxdisorders Constipation disease

Hepatobiliar Hepatic Blood Toxic hepatitisy disorders enzymes bilirubinincreased increased

Skin and Pruritussubcutaneou Rashs tissuedisorders

Musculoskel Blood creatine Rhabdomyolyetal and phosphokinase sisconnective increasedtissuedisorders

Renal and Dysuriaurinary Pollakisuriadisorders

Pregnancy, Drugpuerperium withdrawaland syndromeperinatal neonatal (seeconditions section 4.6)

General Fatigue Thirstdisordersandadministration siteconditions1Sleep disorders: Insomnia, Abnormal dreams/nightmare, Circadian rhythm sleep disorder, Dyssomnia,

Hypersomnia, Initial insomnia, Middle insomnia, Nightmare, Sleep disorder, Somnambulism, Terminalinsomnia2Akathisia: Akathisia, Psychomotor hyperactivity, Restlessness3Parkinsonism: Akinesia, Bradykinesia, Bradyphrenia, Cogwheel rigidity, Extrapyramidal disorder, Gaitdisturbance, Hypokinesia, Joint stiffness, Tremor, Masked facies, Muscle rigidity, Musculoskeletal stiffness,

Nuchal rigidity, Parkinsonism4Dystonia: Blepharospasm, Dystonia, Muscle tightness, Oromandibular dystonia, Torticollis, Trismus5Other extrapyramidal diseases and abnormal movement disorders: Balance disorder, Bruxism, Drooling,

Dysarthria, Gait deviation, Glabellar reflex abnormal, Hyporeflexia, Movement disorder, Restless legssyndrome, Salivary hypersecretion, Tongue movement disturbance6Dyskinesia: Choreoathetosis, Dyskinesia, Grimacing, Oculogyric crisis, Protrusion tongue

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 andpatients with existing cataracts were excluded. During the schizophrenia clinical development programof cariprazine, few cataract cases were reported, characterized with minor lens opacities with no visualimpairment (13/3 192; 0.4%). Some of these patients had confounding factors. The most commonlyreported ocular adverse event was blurred vision (placebo: 1/683; 0.1%, cariprazine: 22/2 048; 1.1%).

In the short-term studies the incidence of EPS was observed in 27%; 11.5%; 30.7% and 15.1% inpatients treated with cariprazine, placebo, risperidone and aripiprazole respectively. Akathisia wasreported in 13.6%; 5.1%; 9.3% and 9.9% in patients treated with cariprazine, placebo, risperidone andaripiprazole respectively. Parkinsonism was experienced in 13.6%; 5.7%; 22.1% and 5.3% in patientstreated with cariprazine, placebo, risperidone and aripiprazole respectively. Dystonia was observed in1.8%; 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 thecariprazine group compared to 3.0% in the placebo treated patients. Akathisia was reported in 3.9% inpatients treated with cariprazine, versus 2.0% in the placebo group. Parkinsonism was experienced in7.8% 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 therisperidone treated patients. Akathisia was reported in 10.0% in patients treated with cariprazine and5.2% in the risperidone group. Parkinsonism was experienced in 5.2% and 7.4% in cariprazine andrisperidone treated patients respectively. Most EPS cases were mild to moderate in intensity and couldbe handled with common anti-EPS medicinal products. The rate of discontinuation due to EPS related

ADRs was low.

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

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

In the short-term studies, there were slightly greater mean increases in body weight in the cariprazinegroup compared to the placebo group; 1 kg and 0.3 kg, respectively. In the long-term maintenance ofeffect study, there was no clinically relevant difference in change of body weight from baseline to endof treatment (1.1 kg for cariprazine and 0.9 kg for placebo). In the open-label phase of the studyduring 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 thepatients who continued with cariprazine treatment had PCS weight gain versus 7.1% of the patientswho were randomized to placebo after the 20 week open-label cariprazine treatment. In the negativesymptom study, the mean change of body weight was -0.3 kg for cariprazine and +0.6 kg forrisperidone and PCS weight gain was observed in 6% of the cariprazine group while 7.4% of therisperidone group.

With cariprazine no QT interval prolongation was detected compared to placebo in a clinical studydesigned 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 treatmentperiod in, 3 patients (0.4%) had QTcB > 500 msec, one of whom also had QTcF > 500 msec. A > 60msec 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 increaseof 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 observedin 3 cariprazine-treated patients (3.1%) and 2 placebo-treated patients (2%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Accidental acute overdose (48 mg/day) was reported in one patient. This patient experiencedorthostasis and sedation. The patient fully recovered the same day.

Management of overdose should concentrate on supportive therapy including maintenance of anadequate airway, oxygenation and ventilation and management of symptoms. Cardiovascularmonitoring should commence immediately, including continuous electrocardiographic monitoring forpossible arrhythmias. In case of severe extrapyramidal symptoms, anticholinergic medicinal productsshould be administered. Since cariprazine is highly bound to plasma proteins, haemodialysis isunlikely to be useful in the management of overdose. Close medical supervision and monitoringshould continue until the patient recovers.

There is no specific antidote to cariprazine.

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX15

The mechanism of action of cariprazine is not fully known. However the therapeutic effect ofcariprazine may be mediated through a combination of partial agonist activity at dopamine D3, D2 (Kivalues of 0.085-0.3 nM versus 0.49-0.71 nM respectively) and serotonin 5-HT1A receptors (Ki valuesof 1.4-2.6 nM), and antagonist activity at serotonin 5-HT2B, 5-HT2A and histamine H1 receptors (Kivalues of 0.58-1.1 nM, 18.8 nM and 23.3 nM, respectively). Cariprazine has low affinity for serotonin5-HT2C and adrenergic α1 receptors (Ki values of 134 nM and 155 nM, respectively). Cariprazine hasno appreciable affinity for cholinergic muscarinic receptors (IC50 > 1 000 nM). The two major activemetabolites, desmethyl cariprazine and didesmethyl cariprazine have a similar in vitro receptorbinding and functional activity profile as the parent active substance.

In vivo non-clinical studies demonstrated that cariprazine occupies D3 receptors to a similar extent as

D2 receptors at pharmacologically effective doses. There was a dose-dependent occupancy of braindopamine D3 and D2 receptors (with preferential occupancy in regions with higher D3 expression) inpatients with schizophrenia within the therapeutic dose range of cariprazine for 15 days.

The effects of cariprazine on the QT interval were evaluated in patients with schizophrenia orschizoaffective disorder. Holter monitor-derived electrocardiographic assessments were obtained in129 patients over a twelve hour period at baseline and steady state. No QT interval prolongation wasdetected following supratherapeutic doses (9 mg/day or 18 mg/day). No patients treated withcariprazine experienced QTc increases ≥ 60 msec from baseline, nor did any patient experience a QTcof > 500 msec in the study.

The efficacy of cariprazine for the treatment of acute schizophrenia was studied in three multi-center,multinational, randomized, double-blind, placebo-controlled 6-week studies including 1 754 patientswith the age of 18 to 60 years. The primary endpoint was change from baseline to week 6 in the

Positive and Negative Syndrome Scale (PANSS) total score and the secondary endpoint was changefrom baseline to week 6 in the Clinical Global Impressions-Severity (CGI-S) score in all acuteschizophrenia studies. In a multinational placebo-controlled study using fixed doses of 1.5 mg, 3.0 mgand 4.5 mg cariprazine and 4.0 mg risperidone for assay sensitivity, all cariprazine doses and theactive-control showed statistically significant improvement in both primary as well as secondaryendpoint compared to placebo. In another multinational placebo-controlled study using fixed doses of3.0 mg, and 6.0 mg cariprazine and 10 mg aripiprazole for assay sensitivity, both cariprazine dosesand the active-control showed statistically significant improvement in both primary as well assecondary endpoint compared to placebo. In a third multinational placebo-controlled study usingfixed/flexible doses of 3.0-6.0 mg and 6.0-9.0 mg cariprazine, both cariprazine doses groups showedstatistically significant improvement in both primary as well as secondary endpoint compared toplacebo.

Results for the primary outcome parameter are summarized in Table 2 below. Results for thesecondary outcome parameter (CGI) and additional endpoints were supportive of the primaryendpoint.

Table 2. Change from baseline to week 6 in the PANSS total score in studies of acuteexacerbations of schizophrenia—ITT population

Baseline Change Treatment difference P-value

Mean ± SD LS mean (SE) versus placebo (95%

CI)

PANSS total (MMRM)

RGH-MD-16 (n=711)

Placebo 97.3 ± 9.22 -13.29 (1.82) — —

Cariprazine 1.5 mg/day 97.1 ± 9.13 -21.27 (1.77) -7.97 (-12.94, -3.01) 0.0017

Cariprazine 3 mg/day 97.2 ± 8.66 -21.45 (1.74) -8.16 (-13.09, -3.22) 0.0013

Cariprazine 4.5 mg/day 96.7 ± 9.01 -23.77 (1.74) -10.48 (-15.41, -5.55) < 0.0001

Risperidone 4 mg/day 98.1 ± 9.50 -29.27 (1.74) -15.98 (-20.91, -11.04) < 0.0001*

RGH-MD-04 (n=604)

Placebo 96.5 ± 9.1 -14.3 (1.5) — —

Cariprazine 3 mg/day 96.1 ± 8.7 -20.2 (1.5) -6.0 (-10.1, -1.9) 0.0044

Cariprazine 6 mg/day 95.7 ± 9.4 -23.0 (1.5) -8.8 (-12.9, -4.7) < 0.0001

Aripiprazole 10 mg/day 95.6 ± 9.0 -21.2 (1.4) -7.0 (-11.0, -2.9) 0.0008*

RGH-MD-05 (n=439)

Placebo 96.6 ± 9.3 -16.0 (1.6) — —

Cariprazine 3 to 6 mg/day 96.3 ± 9.3 -22.8 (1.6) -6.8 (-11.3, -2.4) 0.0029

Cariprazine 6 to 9 mg/day 96.3 ± 9.0 -25.9 (1.7) -9.9 (-14.5, -5.3) < 0.0001

CI = confidence interval; ITT = intent to treat; LS mean = least squares mean; PANSS = Positive and Negative

Syndrome Scale.

*compared to placebo

The efficacy of cariprazine for maintaining antipsychotic effect was investigated in a randomized-withdrawal, long-term clinical study. Totally, 751 patients with acute symptoms of schizophreniareceived cariprazine 3-9 mg/day for 20 weeks, of whom 337 received cariprazine in the dose-range of3 or 6 mg/day. Stabilized patients were then randomised to receive fixed doses of 3 or 6 mgcariprazine (n=51) or placebo (n=51) in a double-blind manner for up to 72 weeks. The primaryoutcome of the study was time to relapse. By the end of the study 49.0% of placebo-treated patientsversus 21.6% of cariprazine-treated patients had a relapse of schizophrenic symptoms. Time to relapse(92 vs. 326 days-based on the 25th percentile) was therefore significantly longer in the cariprazinegroup than in the placebo group (p=0.009).

The efficacy of cariprazine for the treatment of predominantly negative symptoms of schizophreniawas investigated in a 26-week, multi-centre, double-blind, and active-controlled clinical study.

Cariprazine (dose range 3-6 mg, target dose 4.5 mg) was investigated compared to risperidone (doserange 3-6 mg, target dose 4 mg) in patients with persistent, predominant negative symptoms ofschizophrenia (n=461). 86% of patients were less than 55 years old, 54% of them were male.

Persistent predominant negative symptoms were defined as symptoms lasting for a period of at least6 months with high level of negative symptoms and low level of positive symptoms [(PANSS factorscore for negative symptoms ≥ 24, a score of ≥ 4 on a minimum 2 of the 3 PANSS items (N1: flataffect, N4: avolition, and N6: poverty of speech) and PANSS factor score for positive symptoms≤ 19]. Patients with secondary negative symptoms, such as moderate to severe depressive symptomsand clinically relevant parkinsonism (EPS) were excluded.

Both cariprazine- and risperidone-treated patient groups have shown statistically significantimprovement in the change from baseline for the primary efficacy parameter, PANSS factor score fornegative symptoms (PANSS-FSNS) (p < 0.001). However, a statistically significant difference(p=0.002) in favour of cariprazine over risperidone was observed from Week 14 onward (Table 3).

Both cariprazine- and risperidone-treated patient groups have shown statistically significantimprovement in the change from baseline for the secondary efficacy parameter, Personal and Social

Performance (PSP) total score (p < 0.001). However, a statistically significant difference (p < 0.001)in favour of cariprazine over risperidone was observed from Week 10 onward (Table 3).

Differences on the Clinical Global Impression Severity (p=0.005) and Improvement (p < 0.001)scales, as well as PANSS-FSNS response rates (PANSS FSNS ≥ 30% improvement at Week 26;p=0.003) were supportive of findings on the primary and secondary efficacy parameters.

Table 3 Summary of results in study RGH-188-005

Efficacy parameter Cariprazine Risperidone Estimated 95% p-value

LS mean LS mean treatment CIdifference

PANSS-FSNS at 27.8 27.5 - - -

Baseline

PANSS-FSNS at Week 18.5 19.6 - - -

PANSS-FSNS CfB to -8.9 -7.4 -1.5 -2,4; - 0.002

Week 26 0.5

Total PSP at Baseline 48.8 48.2 - - -

Total PSP at Week 26 64.0 59.7 - - -

Total PSP CfB to Week 14.3 9.7 4.6 2.7; 6.6 <0.001

CfB= change from baseline

The European Medicines Agency has deferred the obligation to submit the results of studies withcariprazine in one or more subsets of the paediatric population in the treatment ofschizophrenia. See section 4.2 for information on paediatric use.

Cariprazine has two pharmacologically active metabolites with similar activities as cariprazine,desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Total cariprazine (sum ofcariprazine + DCAR and DDCAR) exposure approaches 50% of steady state exposure in ~1 week ofdaily dosing while 90% of steady state is achieved in 3 weeks. At steady state, exposure to DDCAR isapproximately two to three-fold higher than to cariprazine, and exposure to DCAR is approximately30% of cariprazine exposure.

Absolute bioavailability of cariprazine is unknown. Cariprazine is well absorbed after oraladministration. Following multiple-dose administration, peak plasma concentrations for cariprazineand the major active metabolites generally occur at approximately 3-8 hours post dose.

Administration of a single dose of 1.5 mg cariprazine with a high-fat meal (900 to 1 000 calories) didnot significantly affect the Cmax or AUC of cariprazine (AUC0-∞ increased by 12%, Cmax decreased by< 5% under fed condition versus fasting). The effect of food on the exposure of the metabolites DCARand DDCAR was also minimal.

Cariprazine can be administered with or without food.

Based on a population pharmacokinetic analysis, the apparent volume of distribution (V/F) was 916 Lfor cariprazine, 475 L for DCAR and 1 568 L for DDCAR, indicating extensive distribution ofcariprazine and its major active metabolites. Cariprazine and its major active metabolites are highlybound (96 to 97% for CAR, 94% to 97% for DCAR and 92% to 97% for DDCAR) to plasma proteins.

The metabolism of cariprazine involves demethylation (DCAR and DDCAR), hydroxylation (hydroxycariprazine, HCAR) and a combination of demethylation and hydroxylation (hydroxy desmethylcariprazine, HDCAR and hydroxy didesmethyl cariprazine, HDDCAR). The metabolites of HCAR,

HDCAR, and HDDCAR are subsequently biotransformed to their corresponding sulfate andglucuronide conjugates. An additional metabolite, desdichlorophenyl piperazine cariprazine(DDCPPCAR) acid, is produced by dealkylation and subsequent oxidation of cariprazine.

Cariprazine is metabolized by CYP3A4 and, to a lesser extent, by CYP2D6, to DCAR and HCAR.

DCAR is further metabolized by CYP3A4 and to a lesser extent by CYP2D6 into DDCAR and

HDCAR. DDCAR is further metabolised to HDDCAR by CYP3A4.

Cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), the organicanion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), and the breast cancerresistance protein (BCRP). This suggests that an interaction of cariprazine with inhibitors of P-gp,

OATP1B1, OATP1B3 and BCRP is unlikely.

Elimination of cariprazine and its major active metabolites is mainly through hepatic metabolism.

Following administration of 12.5 mg/day cariprazine to patients with schizophrenia, 20.8% of the dosewas excreted in urine as cariprazine and its metabolites.

Unchanged cariprazine is excreted by 1.2% of the dose in urine and 3.7% of the dose in faeces.

The mean terminal half-life (1 to 3 days for cariprazine and DCAR and 13 to 19 days for DDCAR) isnot predictive of time to reach steady state or plasma concentration decline after treatmentdiscontinuation. For the management of patients treated with cariprazine, the effective half-life is morerelevant than the terminal half-life. The effective (functional) half-life is ~ 2 days for cariprazine and

DCAR, 8 days for DDCAR and is ~1 week for total cariprazine. The plasma concentration of totalcariprazine will gradually decline following dose discontinuation or interruption. The plasmaconcentration of total cariprazine decreases by 50% in ~1 week and greater than 90% decline in totalcariprazine concentration occurs in ~3 weeks.

After repeated administration plasma exposure of cariprazine and its two major active metabolites,desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), increases proportionally overthe therapeutic dose range of 1.5 to 6 mg.

Population pharmacokinetic modelling was performed using data from patients enrolled in theschizophrenia cariprazine clinical program with differing levels of renal function, including normalrenal function (creatinine clearance (CrCl) ≥ 90 mL/min), as well as mild (CrCl 60 to 89 mL/min) andmoderate (CrCl 30 to 59 mL/min) renal impairment. No significant relationship was found betweencariprazine plasma clearance and creatinine clearance.

Cariprazine has not been evaluated in patients with severe (CrCl < 30 mL/min) renal impairment (seesection 4.2).

A 2-part study (a single dose of 1 mg cariprazine [Part A] and a daily dose of 0.5 mg cariprazine for14 days [Part B] was conducted in patients with varying degrees of impaired hepatic function (Child-

Pugh Classes A and B). Compared to healthy subjects, patients with either mild or moderate hepaticimpairment had up to approximately 25% higher exposure (Cmax and AUC) for cariprazine and up toapproximately 45% lower exposure for the major active metabolites, desmethyl cariprazine anddidesmethyl cariprazine, following the single dose of 1 mg cariprazine or 0.5 mg cariprazine for14 days.

The total active moiety (CAR+DCAR+DDCAR) exposure (AUC and Cmax) decreased by 21-22% and13-15% in mild or moderate hepatic impairment (HI), respectively, compared to healthy subjects ifunbound + bound concentrations were considered, while for unbound total moiety a decrease of 12-13% and an increase of 20-25% were calculated in mild HI patients and in moderate HI patients,respectively, after multiple dosing of cariprazine.

Cariprazine has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C)(see section 4.2).

In the population PK analysis there were no clinically relevant differences in the PK parameters (AUCand Cmax of the sum of cariprazine and its major active metabolites) based on age, gender and race.

This analysis included 2 844 patients of different races, involving 536 patients between the ages of 50and 65. Of the 2 844 patients 933 were female (see section 4.2). In elderly patients above 65 years ofage data are limited.

Because cariprazine is not a substrate for CYP1A2, smoking is not expected to have an effect on thepharmacokinetics of cariprazine.

Cariprazine and its major active metabolites did not induce CYP1A2, CYP2B6 and CYP3A4 enzymesand were not inhibitors of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP219, CYP2D6,

CYP2E1 and CYP3A4 in vitro. Cariprazine and its major active metabolites are not inhibitors oftransporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic aniontransporters 1 and 3 (OAT1 and OAT3) in vitro. DCAR and DDCAR were not inhibitors oftransporter P-gp although cariprazine was a P-gp inhibitor in the intestine (see section 4.5).

Cariprazine caused bilateral cataract and secondary retinal changes (retinal detachment and cysticdegeneration) in the dog. The exposure (AUC of total cariprazine) at the no-observed-adverse-effect-level (NOAEL) for ocular toxicity is 4.2-fold the clinical AUC exposure at the maximal recommendedhuman dose (MRHD) of 6 mg/day. Increased incidence of retinal degeneration/atrophy was observedin albino rats in the 2-year study at clinically relevant exposures.

Phospholipidosis was observed in the lungs of rats, dogs, and mice (with or without inflammation) andin the adrenal gland cortex of dogs at clinically relevant exposures. Inflammation was observed in thelungs of dogs dosed for 1 year with a NOAEL at AUC exposures 2.7 (males) and 1.7 (females) timesthe clinical exposure at the MRHD. No inflammation was observed at the end of 2-month drug-freeperiod at an exposure 4.2 times the clinical exposure at the MRHD; however, inflammation was stillpresent at higher doses.

Hypertrophy of the adrenal gland cortex was observed at 4.1 times the clinical exposure at the MRHDin rats (females only) and at clinically relevant total cariprazine plasma concentrations in mice. Indogs, reversible hypertrophy/hyperplasia and vacuolation/vesiculation of the adrenal gland cortexwere observed with a NOAEL 4.2 times the clinical exposure at the MRHD.

In female rats, lower fertility and conception indices were observed at clinically relevant exposuresbased on mg/m2 body surface area. No effects on male fertility were noted at exposures up to 4.3 timesthe clinical exposure at the MRHD.

Administration of cariprazine to rats during the period of organogenesis caused malformations, lowerpup survival, and developmental delays at drug exposures less than the human exposure at the MRHDof 6 mg/day. In rabbits, cariprazine caused maternal toxicity, but no foetal toxicity at exposures5.8 times the clinical exposure at the MRHD.

Administration of cariprazine to pregnant rats during the period of organogenesis, throughoutpregnancy and lactation at clinically relevant exposures decreased postnatal survival, birth weight, andpost-weaning body weight of first-generation pups. In addition, pale, cold bodies and developmentaldelays (renal papillae not developed/underdeveloped and decreased auditory startle response in males)were observed in the absence of maternal toxicity. Reproductive performance of the first-generationpups was unaffected; however, second generation pups also had similar clinical signs and lower bodyweight.

Cariprazine and its metabolites were excreted in milk of rats during lactation.

Pregelatinized (maize) starch

Magnesium stearate

Titanium dioxide (E 171)

Gelatin

Allura red AC (E 129)

Brilliant blue FCF (E 133)

Titanium dioxide (E 171)

Yellow iron oxide (E 172)

Gelatin

Allura red AC (E 129)

Brilliant blue FCF (E 133)

Titanium dioxide (E 171)

Yellow iron oxide (E 172)

Gelatin

Brilliant blue FCF (E 133)

Allura red AC (E 129)

Titanium dioxide (E 171)

Gelatin

Shellac

Black iron oxide (E 172)

Potassium hydroxide

Shellac

Titanium dioxide (E 171)

Simeticone

Not applicable.

5 years

Keep the blister in the outer carton in order to protect from light.

This medicinal product does not require any special temperature storage conditions.

Transparent hard PVC/PE/PVDC blister heat-sealed with hard aluminium foil backing packed infolded carton box.

Cartons contain 7, 14, 21, 28, 30, 49, 56, 60, 84, 90 or 98 hard capsules.

Cartons contain 7, 21, 28, 30, 49, 56, 60, 84, 90 or 98 hard capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Gedeon Richter Plc.

Gyömrői út 19-21.1103 Budapest

Hungary

EU/1/17/1209/001-042

Date of first authorisation: 13 July 2017

Date of latest renewal: 04 April 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.