- Approval Id
- 2abd885f97e69ab2
- Drug Approval Emc Name
- Reagila 1.5 mg hard capsules
- Drug Name
- Reagila 1.5 mg hard capsules
- Company Name
- Recordati Pharmaceuticals Limited
- Company Address
- Recordati Pharmaceuticals Limited, Breakspear Park, Hemel Hempstead, HP2 4TZ, UK
- Company Website
- http://www.recordati.com
- Company Telephone
- +44 (0)1491 576 336
- Company Medical Info Direct Line
- +44 (0)1491 576 336
- Company Medical Info Email
- medinfo@recordati.co.uk
- Atc Code
- N05AX15
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Gedeon Richter Plc.
Gyömrői út 19-21.
1103 Budapest
Hungary
- Authorisation Number
- \*\*Reagila 1.5 mg hard capsules\*\*
PLGB 04854/0173
\*\*Reagila 3 mg hard capsules\*\*
PLGB 04854/0174
\*\*Reagila 4.5 mg hard capsules\*\*
PLGB 04854/0175
\*\*Reagila 6 mg hard capsules\*\*
PLGB 04854/0176
- Authorisation Date
- 14/03/2025
- Instruction Authorisation Holder
- Gedeon Richter Plc.
Gyömrői út 19-21.
1103 Budapest
Hungary
- Instruction Authorisation Number
- \*\*Reagila 1.5 mg hard capsules\*\*
PLGB 04854/0173
\*\*Reagila 3 mg hard capsules\*\*
PLGB 04854/0174
\*\*Reagila 4.5 mg hard capsules\*\*
PLGB 04854/0175
\*\*Reagila 6 mg hard capsules\*\*
PLGB 04854/0176
- Instruction Authorisation Date
- 14/03/2025
- Instruction Composition
- \*\*Reagila 1.5 mg hard capsules\*\*
Each hard capsule contains cariprazine hydrochloride corresponding to 1.5 mg cariprazine.
\*\*Reagila 3 mg hard capsules\*\*
Each hard capsule contains cariprazine hydrochloride corresponding to 3 mg cariprazine.
\*\*Excipient with known effect\*\*
Each hard capsule contains 0.0003 mg Allura red AC (E 129).
\*\*Reagila 4.5 mg hard capsules\*\*
Each hard capsule contains cariprazine hydrochloride corresponding to 4.5 mg cariprazine.
\*\*Excipient with known effect\*\*
Each hard capsule contains 0.0008 mg Allura red AC (E 129).
\*\*Reagila 6 mg hard capsules\*\*
Each hard capsule contains cariprazine hydrochloride corresponding to 6 mg cariprazine.
\*\*Excipient with known effect\*\*
Each hard capsule contains 0.0096 mg Allura red AC (E 129).
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- Hard capsule
\*\*Reagila 1.5 mg hard capsules\*\*
'Size 4' (approximately 14.3 mm in length) hard gelatin capsule with white opaque cap and white opaque body imprinted with “GR 1.5” on the capsule body with black ink. The capsules are filled with white 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 white opaque body imprinted with “GR 3” on the capsule body with black ink. The capsules are filled with white 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 green opaque body imprinted with “GR 4.5” on the capsule body with white ink. The capsules are filled with white 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 white opaque body imprinted with “GR 6” on the capsule body with black ink. The capsules are filled with white to yellowish white powder mixture.
- Instruction Clinical Particulars
- 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).
\*Elderl\*y
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 highly 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.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX15
\*\*Mechanism of action\*\*
The mechanism of action of cariprazine is not fully known. However the therapeutic effect of cariprazine may be mediated through a combination of partial agonist activity at dopamine D3, D2 (Ki values of 0.085-0.3 nM versus 0.49-0.71 nM respectively) and serotonin 5‑HT1A receptors (Ki values of 1.4-2.6 nM), and antagonist activity at serotonin 5‑HT2B, 5‑HT2A and histamine H1 receptors (Ki values of 0.58-1.1 nM, 18.8 nM and 23.3 nM, respectively). Cariprazine has low affinity for serotonin 5‑HT2C and adrenergic α1 receptors (Ki values of 134 nM and 155 nM, respectively). Cariprazine has no appreciable affinity for cholinergic muscarinic receptors (IC50 > 1000 nM). The two major active metabolites, desmethyl cariprazine and didesmethyl cariprazine have a similar \*in vitro\* receptor binding and functional activity profile as the parent active substance.
\*\*Pharmacodynamic effects\*\*
\*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 brain dopamine D3 and D2 receptors (with preferential occupancy in regions with higher D3 expression) in patients 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 or schizoaffective disorder. Holter monitor-derived electrocardiographic assessments were obtained in 129 patients over a twelve hour period at baseline and steady state. No QT interval prolongation was detected following supratherapeutic doses (9 mg/day or 18 mg/day). No patients treated with cariprazine experienced QTc increases ≥ 60 msec from baseline, nor did any patient experience a QTc of > 500 msec in the study.
\*\*Clinical efficacy and safety\*\*
\*Efficacy with short-term use\*
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 patients with 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 change from baseline to week 6 in the Clinical Global Impressions-Severity (CGI-S) score in all acute schizophrenia studies. In a multinational placebo-controlled study using fixed doses of 1.5 mg, 3.0 mg and 4.5 mg cariprazine and 4.0 mg risperidone for assay sensitivity, all cariprazine doses and the active-control showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo. In another multinational placebo-controlled study using fixed doses of 3.0 mg, and 6.0 mg cariprazine and 10 mg aripiprazole for assay sensitivity, both cariprazine doses and the active-control showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo. In a third multinational placebo-controlled study using fixed/flexible doses of 3.0-6.0 mg and 6.0-9.0 mg cariprazine, both cariprazine doses groups showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo.
Results for the primary outcome parameter are summarized in Table 2 below. Results for the secondary outcome parameter (CGI) and additional endpoints were supportive of the primary endpoint.
\*\*Table 2. Change from baseline to week 6 in the PANSS total score in studies of acute exacerbations of schizophrenia—ITT population\*\*
| | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | \*\*\*Baseline\*\*\* Mean ± SD | | \*\*\*Change\*\*\* LS mean (SE) | | \*\*\*Treatment difference versus placebo (95% CI)\*\*\* | | \*\*\*P-value\*\*\* | |
| \*\*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
\*Efficacy with long-term use\*
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 schizophrenia received cariprazine 3-9 mg/day for 20 weeks, of whom 337 received cariprazine in the dose-range of 3 or 6 mg/day. Stabilized patients were then randomised to receive fixed doses of 3 or 6 mg cariprazine (n=51) or placebo (n=51) in a double-blind manner for up to 72 weeks. The primary outcome of the study was time to relapse. By the end of the study 49.0% of placebo-treated patients versus 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 cariprazine group than in the placebo group (p=0.009).
\*Efficacy in predominantly negative symptoms of schizophrenia\*
The efficacy of cariprazine for the treatment of predominantly negative symptoms of schizophrenia was 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 (dose range 3-6 mg, target dose 4 mg) in patients with persistent, predominant negative symptoms of schizophrenia (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 least 6 months with high level of negative symptoms and low level of positive symptoms [(PANSS factor score for negative symptoms ≥ 24, a score of ≥ 4 on a minimum 2 of the 3 PANSS items (N1: flat affect, 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 symptoms and clinically relevant parkinsonism (EPS) were excluded.
Both cariprazine- and risperidone-treated patient groups have shown statistically significant improvement in the change from baseline for the primary efficacy parameter, PANSS factor score for negative 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 significant improvement 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\*\* \*\*LS mean\*\* | \*\*Risperidone\*\* \*\*LS mean\*\* | \*\*Estimated treatment difference\*\* | \*\*95%CI\*\* | \*\*p-value\*\* |
| PANSS-FSNS at Baseline | 27.8 | 27.5 | - | - | - |
| PANSS-FSNS at Week 26 | 18.5 | 19.6 | - | - | - |
| PANSS-FSNS CfB to Week 26 | -8.9 | -7.4 | -1.5 | -2,4; -0.5 | 0.002 |
| Total PSP at Baseline | 48.8 | 48.2 | - | - | - |
| Total PSP at Week 26 | 64.0 | 59.7 | - | - | - |
| Total PSP CfB to Week 26 | 14.3 | 9.7 | 4.6 | 2.7; 6.6 | <0.001 |
| CfB= change from baseline | | | | | |
\*Paediatric population\*
The European Medicines Agency has deferred the obligation to submit the results of studies with cariprazine in one or more subsets of the paediatric population in the treatment of schizophrenia. See section 4.2 for information on paediatric use.5.2 Pharmacokinetic properties
Cariprazine has two pharmacologically active metabolites with similar activities as cariprazine, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Total cariprazine (sum of cariprazine + DCAR and DDCAR) exposure approaches 50% of steady state exposure in ~1 week of daily dosing while 90% of steady state is achieved in 3 weeks. At steady state, exposure to DDCAR is approximately two to three-fold higher than to cariprazine, and exposure to DCAR is approximately 30% of cariprazine exposure.
\*\*Absorption\*\*
Absolute bioavailability of cariprazine is unknown. Cariprazine is well absorbed after oral administration. Following multiple-dose administration, peak plasma concentrations for cariprazine and 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) did not 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 DCAR and DDCAR was also minimal.
Cariprazine can be administered with or without food.
\*\*Distribution\*\*
Based on a population pharmacokinetic analysis, the apparent volume of distribution (V/F) was 916 L for cariprazine, 475 L for DCAR and 1,568 L for DDCAR, indicating extensive distribution of cariprazine and its major active metabolites. Cariprazine and its major active metabolites are highly bound (96 to 97% for CAR, 94% to 97% for DCAR and 92% to 97% for DDCAR) to plasma proteins.
\*\*Biotransformation\*\*
The metabolism of cariprazine involves demethylation (DCAR and DDCAR), hydroxylation (hydroxy cariprazine, HCAR) and a combination of demethylation and hydroxylation (hydroxy desmethyl cariprazine, HDCAR and hydroxy didesmethyl cariprazine, HDDCAR). The metabolites of HCAR, HDCAR, and HDDCAR are subsequently biotransformed to their corresponding sulfate and glucuronide 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 organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), and the breast cancer resistance protein (BCRP). This suggests that an interaction of cariprazine with inhibitors of P-gp, OATP1B1, OATP1B3 and BCRP is unlikely.
\*\*Elimination\*\*
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 dose was 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) is not predictive of time to reach steady state or plasma concentration decline after treatment discontinuation. For the management of patients treated with cariprazine, the effective half-life is more relevant 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 total cariprazine will gradually decline following dose discontinuation or interruption. The plasma concentration of total cariprazine decreases by 50% in ~1 week and greater than 90% decline in total cariprazine concentration occurs in ~3 weeks.
\*\*Linearity\*\*
After repeated administration plasma exposure of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), increases proportionally over the therapeutic dose range of 1.5 to 6 mg.
\*\*Special populations\*\*
\*Renal impairment\*
Population pharmacokinetic modelling was performed using data from patients enrolled in the schizophrenia cariprazine clinical program with differing levels of renal function, including normal renal function (creatinine clearance (CrCl) ≥ 90 mL/min), as well as mild (CrCl 60 to 89 mL/min) and moderate (CrCl 30 to 59 mL/min) renal impairment. No significant relationship was found between cariprazine plasma clearance and creatinine clearance.
Cariprazine has not been evaluated in patients with severe (CrCl < 30 mL/min) renal impairment (see section 4.2).
\*Hepatic impairment\*
A 2-part study (a single dose of 1 mg cariprazine [Part A] and a daily dose of 0.5 mg cariprazine for 14 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 hepatic impairment had up to approximately 25% higher exposure (Cmax and AUC) for cariprazine and up to approximately 45% lower exposure for the major active metabolites, desmethyl cariprazine and didesmethyl cariprazine, following the single dose of 1 mg cariprazine or 0.5 mg cariprazine for 14 days.
The total active moiety (CAR+DCAR+DDCAR) exposure (AUC and Cmax) decreased by 21-22% and 13-15% in mild or moderate hepatic impairment (HI), respectively, compared to healthy subjects if unbound + 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).
\*Age, gender and race\*
In the population PK analysis there were no clinically relevant differences in the PK parameters (AUC and 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 50 and 65. Of the 2,844 patients 933 were female (see section 4.2). In elderly patients above 65 years of age data are limited.
\*Smoking status\*
Because cariprazine is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of cariprazine.
\*\*Potential for cariprazine to affect other medicinal products\*\*
Cariprazine and its major active metabolites did not induce CYP1A2, CYP2B6 and CYP3A4 enzymes and 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 of transporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) \*in vitro\*. DCAR and DDCAR were not inhibitors of transporter P-gp although cariprazine was a P-gp inhibitor in the intestine (see section 4.5).5.3 Preclinical safety data
Cariprazine caused bilateral cataract and secondary retinal changes (retinal detachment and cystic degeneration) 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 recommended human dose (MRHD) of 6 mg/day. Increased incidence of retinal degeneration/atrophy was observed in 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) and in the adrenal gland cortex of dogs at clinically relevant exposures. Inflammation was observed in the lungs of dogs dosed for 1 year with a NOAEL at AUC exposures 2.7 (males) and 1.7 (females) times the clinical exposure at the MRHD. No inflammation was observed at the end of 2‑month drug-free period at an exposure 4.2 times the clinical exposure at the MRHD; however, inflammation was still present at higher doses.
Hypertrophy of the adrenal gland cortex was observed at 4.1 times the clinical exposure at the MRHD in rats (females only) and at clinically relevant total cariprazine plasma concentrations in mice. In dogs, reversible hypertrophy/hyperplasia and vacuolation/vesiculation of the adrenal gland cortex were 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 exposures based on mg/m2 body surface area. No effects on male fertility were noted at exposures up to 4.3 times the clinical exposure at the MRHD.
Administration of cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the MRHD of 6 mg/day. In rabbits, cariprazine caused maternal toxicity, but no foetal toxicity at exposures 5.8 times the clinical exposure at the MRHD.
Administration of cariprazine to pregnant rats during the period of organogenesis, throughout pregnancy and lactation at clinically relevant exposures decreased postnatal survival, birth weight, and post-weaning body weight of first-generation pups. In addition, pale, cold bodies and developmental delays (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-generation pups was unaffected; however, second generation pups also had similar clinical signs and lower body weight.
Cariprazine and its metabolites were excreted in milk of rats during lactation.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
\*\*Capsule contents\*\*
Pregelatinized (maize) starch
Magnesium stearate
\*\*Capsule shell (1.5 mg capsule)\*\*
Titanium dioxide (E 171)
Gelatin
\*\*Capsule shell (3 mg capsule)\*\*
Allura red AC (E 129)
Brilliant blue FCF (E 133)
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Gelatin
\*\*Capsule shell (4.5 mg capsule)\*\*
Allura red AC (E 129)
Brilliant blue FCF (E 133)
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Gelatin
\*\*Capsule shell (6 mg capsule)\*\*
Brilliant blue FCF (E 133)
Allura red AC (E 129)
Titanium dioxide (E 171)
Gelatin
\*\*Printing ink (black: 1.5 mg, 3 mg and 6 mg capsules)\*\*
Shellac
Black iron oxide (E 172)
Propylene glycol
Potassium hydroxide
\*\*Printing ink (white: 4.5 mg capsule)\*\*
Shellac
Titanium dioxide (E 171)
Propylene glycol
Simeticone6.2 Incompatibilities
Not applicable.6.3 Shelf life
5 years6.4 Special precautions for storage
Keep the blister in the outer carton in order to protect from light.
This medicinal product does not require any special temperature storage conditions.6.5 Nature and contents of container
Transparent hard PVC/PE/PVDC blister heat-sealed with hard aluminium foil backing packed in folded carton box.
\*\*Reagila 1.5 mg and Reagila 3 mg hard capsules\*\*
Cartons contain 7, 14, 21, 28, 30, 49, 56, 60, 84, 90 or 98 hard capsules.
\*\*Reagila 4.5 mg and Reagila 6 mg hard capsules\*\*
Cartons contain 7, 21, 28, 30, 49, 56, 60, 84, 90 or 98 hard capsules.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
\*\*Reagila 1.5 mg hard capsules\*\*
Each hard capsule contains cariprazine hydrochloride corresponding to 1.5 mg cariprazine.
\*\*Reagila 3 mg hard capsules\*\*
Each hard capsule contains cariprazine hydrochloride corresponding to 3 mg cariprazine.
\*\*Excipient with known effect\*\*
Each hard capsule contains 0.0003 mg Allura red AC (E 129).
\*\*Reagila 4.5 mg hard capsules\*\*
Each hard capsule contains cariprazine hydrochloride corresponding to 4.5 mg cariprazine.
\*\*Excipient with known effect\*\*
Each hard capsule contains 0.0008 mg Allura red AC (E 129).
\*\*Reagila 6 mg hard capsules\*\*
Each hard capsule contains cariprazine hydrochloride corresponding to 6 mg cariprazine.
\*\*Excipient with known effect\*\*
Each hard capsule contains 0.0096 mg Allura red AC (E 129).
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
Hard capsule
\*\*Reagila 1.5 mg hard capsules\*\*
'Size 4' (approximately 14.3 mm in length) hard gelatin capsule with white opaque cap and white opaque body imprinted with “GR 1.5” on the capsule body with black ink. The capsules are filled with white 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 white opaque body imprinted with “GR 3” on the capsule body with black ink. The capsules are filled with white 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 green opaque body imprinted with “GR 4.5” on the capsule body with white ink. The capsules are filled with white 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 white opaque body imprinted with “GR 6” on the capsule body with black ink. The capsules are filled with white to yellowish white powder mixture.
## Clinical Particulars
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).
\*Elderl\*y
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 highly 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.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX15
\*\*Mechanism of action\*\*
The mechanism of action of cariprazine is not fully known. However the therapeutic effect of cariprazine may be mediated through a combination of partial agonist activity at dopamine D3, D2 (Ki values of 0.085-0.3 nM versus 0.49-0.71 nM respectively) and serotonin 5‑HT1A receptors (Ki values of 1.4-2.6 nM), and antagonist activity at serotonin 5‑HT2B, 5‑HT2A and histamine H1 receptors (Ki values of 0.58-1.1 nM, 18.8 nM and 23.3 nM, respectively). Cariprazine has low affinity for serotonin 5‑HT2C and adrenergic α1 receptors (Ki values of 134 nM and 155 nM, respectively). Cariprazine has no appreciable affinity for cholinergic muscarinic receptors (IC50 > 1000 nM). The two major active metabolites, desmethyl cariprazine and didesmethyl cariprazine have a similar \*in vitro\* receptor binding and functional activity profile as the parent active substance.
\*\*Pharmacodynamic effects\*\*
\*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 brain dopamine D3 and D2 receptors (with preferential occupancy in regions with higher D3 expression) in patients 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 or schizoaffective disorder. Holter monitor-derived electrocardiographic assessments were obtained in 129 patients over a twelve hour period at baseline and steady state. No QT interval prolongation was detected following supratherapeutic doses (9 mg/day or 18 mg/day). No patients treated with cariprazine experienced QTc increases ≥ 60 msec from baseline, nor did any patient experience a QTc of > 500 msec in the study.
\*\*Clinical efficacy and safety\*\*
\*Efficacy with short-term use\*
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 patients with 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 change from baseline to week 6 in the Clinical Global Impressions-Severity (CGI-S) score in all acute schizophrenia studies. In a multinational placebo-controlled study using fixed doses of 1.5 mg, 3.0 mg and 4.5 mg cariprazine and 4.0 mg risperidone for assay sensitivity, all cariprazine doses and the active-control showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo. In another multinational placebo-controlled study using fixed doses of 3.0 mg, and 6.0 mg cariprazine and 10 mg aripiprazole for assay sensitivity, both cariprazine doses and the active-control showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo. In a third multinational placebo-controlled study using fixed/flexible doses of 3.0-6.0 mg and 6.0-9.0 mg cariprazine, both cariprazine doses groups showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo.
Results for the primary outcome parameter are summarized in Table 2 below. Results for the secondary outcome parameter (CGI) and additional endpoints were supportive of the primary endpoint.
\*\*Table 2. Change from baseline to week 6 in the PANSS total score in studies of acute exacerbations of schizophrenia—ITT population\*\*
| | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | \*\*\*Baseline\*\*\* Mean ± SD | | \*\*\*Change\*\*\* LS mean (SE) | | \*\*\*Treatment difference versus placebo (95% CI)\*\*\* | | \*\*\*P-value\*\*\* | |
| \*\*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
\*Efficacy with long-term use\*
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 schizophrenia received cariprazine 3-9 mg/day for 20 weeks, of whom 337 received cariprazine in the dose-range of 3 or 6 mg/day. Stabilized patients were then randomised to receive fixed doses of 3 or 6 mg cariprazine (n=51) or placebo (n=51) in a double-blind manner for up to 72 weeks. The primary outcome of the study was time to relapse. By the end of the study 49.0% of placebo-treated patients versus 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 cariprazine group than in the placebo group (p=0.009).
\*Efficacy in predominantly negative symptoms of schizophrenia\*
The efficacy of cariprazine for the treatment of predominantly negative symptoms of schizophrenia was 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 (dose range 3-6 mg, target dose 4 mg) in patients with persistent, predominant negative symptoms of schizophrenia (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 least 6 months with high level of negative symptoms and low level of positive symptoms [(PANSS factor score for negative symptoms ≥ 24, a score of ≥ 4 on a minimum 2 of the 3 PANSS items (N1: flat affect, 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 symptoms and clinically relevant parkinsonism (EPS) were excluded.
Both cariprazine- and risperidone-treated patient groups have shown statistically significant improvement in the change from baseline for the primary efficacy parameter, PANSS factor score for negative 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 significant improvement 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\*\* \*\*LS mean\*\* | \*\*Risperidone\*\* \*\*LS mean\*\* | \*\*Estimated treatment difference\*\* | \*\*95%CI\*\* | \*\*p-value\*\* |
| PANSS-FSNS at Baseline | 27.8 | 27.5 | - | - | - |
| PANSS-FSNS at Week 26 | 18.5 | 19.6 | - | - | - |
| PANSS-FSNS CfB to Week 26 | -8.9 | -7.4 | -1.5 | -2,4; -0.5 | 0.002 |
| Total PSP at Baseline | 48.8 | 48.2 | - | - | - |
| Total PSP at Week 26 | 64.0 | 59.7 | - | - | - |
| Total PSP CfB to Week 26 | 14.3 | 9.7 | 4.6 | 2.7; 6.6 | <0.001 |
| CfB= change from baseline | | | | | |
\*Paediatric population\*
The European Medicines Agency has deferred the obligation to submit the results of studies with cariprazine in one or more subsets of the paediatric population in the treatment of schizophrenia. See section 4.2 for information on paediatric use.5.2 Pharmacokinetic properties
Cariprazine has two pharmacologically active metabolites with similar activities as cariprazine, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Total cariprazine (sum of cariprazine + DCAR and DDCAR) exposure approaches 50% of steady state exposure in ~1 week of daily dosing while 90% of steady state is achieved in 3 weeks. At steady state, exposure to DDCAR is approximately two to three-fold higher than to cariprazine, and exposure to DCAR is approximately 30% of cariprazine exposure.
\*\*Absorption\*\*
Absolute bioavailability of cariprazine is unknown. Cariprazine is well absorbed after oral administration. Following multiple-dose administration, peak plasma concentrations for cariprazine and 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) did not 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 DCAR and DDCAR was also minimal.
Cariprazine can be administered with or without food.
\*\*Distribution\*\*
Based on a population pharmacokinetic analysis, the apparent volume of distribution (V/F) was 916 L for cariprazine, 475 L for DCAR and 1,568 L for DDCAR, indicating extensive distribution of cariprazine and its major active metabolites. Cariprazine and its major active metabolites are highly bound (96 to 97% for CAR, 94% to 97% for DCAR and 92% to 97% for DDCAR) to plasma proteins.
\*\*Biotransformation\*\*
The metabolism of cariprazine involves demethylation (DCAR and DDCAR), hydroxylation (hydroxy cariprazine, HCAR) and a combination of demethylation and hydroxylation (hydroxy desmethyl cariprazine, HDCAR and hydroxy didesmethyl cariprazine, HDDCAR). The metabolites of HCAR, HDCAR, and HDDCAR are subsequently biotransformed to their corresponding sulfate and glucuronide 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 organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), and the breast cancer resistance protein (BCRP). This suggests that an interaction of cariprazine with inhibitors of P-gp, OATP1B1, OATP1B3 and BCRP is unlikely.
\*\*Elimination\*\*
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 dose was 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) is not predictive of time to reach steady state or plasma concentration decline after treatment discontinuation. For the management of patients treated with cariprazine, the effective half-life is more relevant 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 total cariprazine will gradually decline following dose discontinuation or interruption. The plasma concentration of total cariprazine decreases by 50% in ~1 week and greater than 90% decline in total cariprazine concentration occurs in ~3 weeks.
\*\*Linearity\*\*
After repeated administration plasma exposure of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), increases proportionally over the therapeutic dose range of 1.5 to 6 mg.
\*\*Special populations\*\*
\*Renal impairment\*
Population pharmacokinetic modelling was performed using data from patients enrolled in the schizophrenia cariprazine clinical program with differing levels of renal function, including normal renal function (creatinine clearance (CrCl) ≥ 90 mL/min), as well as mild (CrCl 60 to 89 mL/min) and moderate (CrCl 30 to 59 mL/min) renal impairment. No significant relationship was found between cariprazine plasma clearance and creatinine clearance.
Cariprazine has not been evaluated in patients with severe (CrCl < 30 mL/min) renal impairment (see section 4.2).
\*Hepatic impairment\*
A 2-part study (a single dose of 1 mg cariprazine [Part A] and a daily dose of 0.5 mg cariprazine for 14 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 hepatic impairment had up to approximately 25% higher exposure (Cmax and AUC) for cariprazine and up to approximately 45% lower exposure for the major active metabolites, desmethyl cariprazine and didesmethyl cariprazine, following the single dose of 1 mg cariprazine or 0.5 mg cariprazine for 14 days.
The total active moiety (CAR+DCAR+DDCAR) exposure (AUC and Cmax) decreased by 21-22% and 13-15% in mild or moderate hepatic impairment (HI), respectively, compared to healthy subjects if unbound + 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).
\*Age, gender and race\*
In the population PK analysis there were no clinically relevant differences in the PK parameters (AUC and 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 50 and 65. Of the 2,844 patients 933 were female (see section 4.2). In elderly patients above 65 years of age data are limited.
\*Smoking status\*
Because cariprazine is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of cariprazine.
\*\*Potential for cariprazine to affect other medicinal products\*\*
Cariprazine and its major active metabolites did not induce CYP1A2, CYP2B6 and CYP3A4 enzymes and 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 of transporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) \*in vitro\*. DCAR and DDCAR were not inhibitors of transporter P-gp although cariprazine was a P-gp inhibitor in the intestine (see section 4.5).5.3 Preclinical safety data
Cariprazine caused bilateral cataract and secondary retinal changes (retinal detachment and cystic degeneration) 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 recommended human dose (MRHD) of 6 mg/day. Increased incidence of retinal degeneration/atrophy was observed in 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) and in the adrenal gland cortex of dogs at clinically relevant exposures. Inflammation was observed in the lungs of dogs dosed for 1 year with a NOAEL at AUC exposures 2.7 (males) and 1.7 (females) times the clinical exposure at the MRHD. No inflammation was observed at the end of 2‑month drug-free period at an exposure 4.2 times the clinical exposure at the MRHD; however, inflammation was still present at higher doses.
Hypertrophy of the adrenal gland cortex was observed at 4.1 times the clinical exposure at the MRHD in rats (females only) and at clinically relevant total cariprazine plasma concentrations in mice. In dogs, reversible hypertrophy/hyperplasia and vacuolation/vesiculation of the adrenal gland cortex were 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 exposures based on mg/m2 body surface area. No effects on male fertility were noted at exposures up to 4.3 times the clinical exposure at the MRHD.
Administration of cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the MRHD of 6 mg/day. In rabbits, cariprazine caused maternal toxicity, but no foetal toxicity at exposures 5.8 times the clinical exposure at the MRHD.
Administration of cariprazine to pregnant rats during the period of organogenesis, throughout pregnancy and lactation at clinically relevant exposures decreased postnatal survival, birth weight, and post-weaning body weight of first-generation pups. In addition, pale, cold bodies and developmental delays (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-generation pups was unaffected; however, second generation pups also had similar clinical signs and lower body weight.
Cariprazine and its metabolites were excreted in milk of rats during lactation.
## Pharmaceutical Particulars
6.1 List of excipients
\*\*Capsule contents\*\*
Pregelatinized (maize) starch
Magnesium stearate
\*\*Capsule shell (1.5 mg capsule)\*\*
Titanium dioxide (E 171)
Gelatin
\*\*Capsule shell (3 mg capsule)\*\*
Allura red AC (E 129)
Brilliant blue FCF (E 133)
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Gelatin
\*\*Capsule shell (4.5 mg capsule)\*\*
Allura red AC (E 129)
Brilliant blue FCF (E 133)
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Gelatin
\*\*Capsule shell (6 mg capsule)\*\*
Brilliant blue FCF (E 133)
Allura red AC (E 129)
Titanium dioxide (E 171)
Gelatin
\*\*Printing ink (black: 1.5 mg, 3 mg and 6 mg capsules)\*\*
Shellac
Black iron oxide (E 172)
Propylene glycol
Potassium hydroxide
\*\*Printing ink (white: 4.5 mg capsule)\*\*
Shellac
Titanium dioxide (E 171)
Propylene glycol
Simeticone6.2 Incompatibilities
Not applicable.6.3 Shelf life
5 years6.4 Special precautions for storage
Keep the blister in the outer carton in order to protect from light.
This medicinal product does not require any special temperature storage conditions.6.5 Nature and contents of container
Transparent hard PVC/PE/PVDC blister heat-sealed with hard aluminium foil backing packed in folded carton box.
\*\*Reagila 1.5 mg and Reagila 3 mg hard capsules\*\*
Cartons contain 7, 14, 21, 28, 30, 49, 56, 60, 84, 90 or 98 hard capsules.
\*\*Reagila 4.5 mg and Reagila 6 mg hard capsules\*\*
Cartons contain 7, 21, 28, 30, 49, 56, 60, 84, 90 or 98 hard capsules.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
