Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Gedeon Richter Plc., Gyömrői út 19-21., 1103, Budapest, Hungary
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concomitant administration of strong or moderate CYP3A4 inhibitors (see section 4.5).
Concomitant administration of strong or moderate CYP3A4 inducers (see section 4.5).
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 and restlessness is a frequently occurring adverse reaction of antipsychotics. Akathisia is a movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. As cariprazine causes akathisia and restlessness, it should be used cautiously in patients who are prone to or already exhibit symptoms of akathisia. Akathisia develops early in treatment. Therefore close monitoring in the first phase of treatment is important. Prevention includes slow up-titration; treatment measures include slight down-titration of cariprazine or anti-EPS medication. The dose can be modified based on individual response and tolerability (see section 4.8).
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.
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.
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.
A potentially fatal symptom complex referred to as neuroleptic malignant syndrome (NMS) has been reported in association with antipsychotic treatment. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, elevated serum creatine phosphokinase levels, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, cariprazine must be discontinued immediately.
Cariprazine should be used cautiously in patients with history of seizures or with conditions that potentially lower the seizure threshold.
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.
An approximately 3-fold increased risk of cerebrovascular adverse reactions has been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Cariprazine should be used with caution in patients with risk factors for stroke.
Cariprazine can cause orthostatic hypotension as well as hypertension (see section 4.8). Cariprazine should be used with caution in patients with known cardiovascular disease predisposing to blood pressure changes. Blood pressure should be monitored.
QT prolongation can develop in patients treated with antipsychotics. With cariprazine no QT interval prolongation was detected compared to placebo in a clinical trial designed to assess QT prolongation (see section 5.1). In clinical trials, only a few, non-serious, QTprolongations 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).
Cases of venous thromboembolism 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.
Patients with an established diagnosis of diabetes mellitus or patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should be monitored for serum glucose levels. In clinical trials, glucose-related adverse reactions have been reported with cariprazine (see section 5.1).
Women of childbearing potential must use highly effective contraception while taking cariprazine and at least for 10 weeks after stopping treatment (see sections 4.5 and 4.6). Women using systemically acting hormonal contraceptives should add a second barrier method.
Significant weight gain has been observed with the use of cariprazine. Patients should have their weight monitored regularly (see section 4.8).
Reagila 3 mg, 4.5 mg and 6 mg hard capsules contain Allura red AC (E129), which may cause allergic reactions.
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.
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 or moderate inhibitors of CYP3A4 (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, diltiazem, erythromycin, fluconazole verapamil) is contraindicated (see section 4.3). Consumption of grapefruit juice should be avoided.
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 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.
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.
It is currently unknown whether cariprazine may reduce the effectiveness of systemically acting hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives should add a second barrier method.
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.
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. It is currently unknown if cariprazine may reduce the effectiveness of systemically acting hormonal contraceptives and therefore women using systemically acting hormonal contraceptives should add a barrier method (see section 4.5).
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.
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.
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).
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.
The most frequently reported 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.
Adverse drug reactions (ADRs) based upon pooled data from cariprazine schizophrenia studies are shown by system organ class and by preferred term.
Adverse reactions are ranked by frequency, the most frequent first, using the following convention: very common (≥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.
Adverse drug reactions occurring in patients with schizophrenia:
Anaemia, Eosinophilia
Rare: Neutropenia
Rare: Hypersensitivity
Uncommon: Blood thyroid stimulating hormone decreased
Rare: Hypothyroidism
Common: Weight increased, Decreased appetite, Increased appetite, Dyslipidaemia
Uncommon: Blood sodium abnormal, Blood glucose increased, Diabetes mellitus
Common: Sleep disorders1 Anxiety
Uncommon: Suicidal behaviour, Delirium, Depression, Libido decreased, Libido increased, Erectile dysfunction
Very common: Akathisia2, Parkinsonism3
Common: Sedation, Dizziness, Dystonia4, Other extrapyramidal diseases and abnormal movement disorders5
Uncommon: Lethargy, Dysaesthesia, Dyskinesia6, Tardive dyskinesia
Rare: Seizures/Convulsion, Amnesia, Aphasia
Frequency not known: Neuroleptic malignant syndrome
Common: Vision blurred
Uncommon: Eye irritation, Intraocular pressure increased, Accommodation disorder, Visual acuity reduced
Rare: Photophobia, Cataract
Uncommon: Vertigo
Common: Tachyarrhytmia
Uncommon: Cardiac conduction disorders, Bradyarrhytmia, Electrocardiogram QT prolonged, Electrocardiogram T wave abnormal
Common: Hypertension
Uncommon: Hypotension
Uncommon: Hiccups
Common: Nausea, Constipation, Vomiting
Uncommon: Gastrooesophageal reflux disease
Rare: Dysphagia
Common: Hepatic enzymes increased
Uncommon: Blood bilirubin increased
Frequency not known: Toxic hepatitis
Uncommon: Pruritus, Rash
Common: Blood creatine phosphokinase increased
Rare: Rhabdomyolysis
Uncommon: Dysuria, Pollakisuria
Frequency not known: Drug withdrawal syndrome neonatal (see section 4.6)
Common: Fatigue
Uncommon: Thirst
1 Sleep disorders: Insomnia, Abnormal dreams/nightmare, Circadian rhythm sleep disorder, Dyssomnia, Hypersomnia, Initial insomnia, Middle insomnia, Nightmare, Sleep disorder, Somnambulism, Terminal insomnia
2 Akathisia: Akathisia, Psychomotor hyperactivity, Restlessness
3 Parkinsonism: Akinesia, Bradykinesia, Bradyphrenia, Cogwheel rigidity, Extrapyramidal disorder, Gait disturbance, Hypokinesia, Joint stiffness, Tremor, Masked facies, Muscle rigidity, Musculoskeletal stiffness, Nuchal rigidity, Parkinsonism
4 Dystonia: Blepharospasm, Dystonia, Muscle tightness, Oromandibular dystonia, Torticollis, Trismus
5 Other extrapyramidal diseases and abnormal movement disorders: Balance disorder, Bruxism, Drooling, Dysarthria, Gait deviation, Glabellar reflex abnormal, Hyporeflexia, Movement disorder, Restless legs syndrome, Salivary hypersecretion, Tongue movement disturbance
6 Dyskinesia: Choreoathetosis, Dyskinesia, Grimacing, Oculogyric crisis, Protrusion tongue
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%).
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.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotics – Frequency unknown.
Elevated liver transaminases (ALT, AST) are frequently observed with antipsychotic treatment. In the cariprazine clinical studies the incidence of ALT, AST elevation ADRs occurred in 2.2% of cariprazine-, 1.6% of risperidone- and 0.4% of placebo-treated patients. None of the cariprazine-treated patients had any liver damage.
In the short term studies, there were slightly greater mean increases in body weight in the 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.
With cariprazine no QT interval prolongation was detected compared to placebo in a clinical trial designed to assess QT prolongation (see section 5.1). In other clinical trials, only a few, non-serious, QT-prolongations have been reported with cariprazine. During the long-term, open-label treatment period in, 3 patients (0.4%) had QTcB >500 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 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 the national reporting system listed in Appendix V.
Not applicable.
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