Adverse reactions : תופעות לוואי

4.8      Undesirable effects

Patients with Schizophrenia
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 MedDRA system organ class and 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             Very             Common                Uncommon (≥1/1,000          Rare (≥1/10,000 Frequency System Organ       common           (≥1/100 to <1/10)     to <1/100)                  to <1/1,000)    not known Class              (≥1/10)
Blood and                                                 Anaemia                     Neutropenia lymphatic system                                          Eosinophilia disorders
Immune system                                                                         Hypersensitivity disorders
Endocrine                                                 Blood thyroid               Hypothyroidism disorders                                                 stimulating hormone decreased

Metabolism and                          Dyslipidaemia          Blood sodium nutrition                               Weight increased       abnormal disorders                               Decreased appetite     Diabetes mellitus Increased appetite     Blood glucose increased
Psychiatric                             Sleep disorders1       Suicidal behaviour disorders                               Anxiety                Delirium Depression
Libido decreased
Libido increased
Erectile dysfunction
Nervous                Akathisia2       Sedation               Tardive dyskinesia     Seizures/          Neuroleptic system disorders       Parkinsonism3    Dizziness              Dyskinesia6            Convulsion         malignant Dystonia4              Dysaesthesia           Amnesia            syndrome Other                  Lethargy               Aphasia extrapyramidal diseases and abnormal movement disorders5


Eye disorders                              Vision blurred          Intraocular pressure       Cataract increased                  Photophobia
Accommodation disorder
Visual acuity reduced
Eye irritation
Ear and labyrinth                                                  Vertigo disorders
Cardiac disorders                          Tachyarrhytmia          Cardiac conduction disorders
Bradyarrhytmia
Electrocardiogram
QT prolonged
Electrocardiogram
T wave abnormal
Vascular                                   Hypertension            Hypotension disorders
Respiratory,                                                       Hiccups thoracic and mediastinal disorders
Gastrointestinal                           Vomiting                Gastrooesophageal          Dysphagia disorders                                  Nausea                  reflux disease Constipation

Hepatobiliary                              Hepatic enzymes         Blood bilirubin                                 Toxic disorders                                  increased               increased                                       hepatitis 
Skin and                                                           Pruritus subcutaneous                                                       Rash tissue disorders
Musculoskeletal                            Blood creatine                                     Rhabdomyolysis and connective                             phosphokinase tissue disorders                           increased

Renal and urinary                                                  Dysuria disorders                                                          Pollakisuria Pregnancy,                                                                                                         Drug puerperium and                                                                                                     withdrawal perinatal                                                                                                          syndrome conditions                                                                                                         neonatal (see section 4.6)
General disorders                          Fatigue                 Thirst and administration site conditions
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 


Patients with Bipolar Mania

The following findings are based on three placebo-controlled, 3-week bipolar mania trials with cariprazine doses ranging from 3 to 12 mg once daily. The maximum recommended dosage is 6 mg daily.
Adverse Reactions Associated with Discontinuation of Treatment: The adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in cariprazine -treated patients and at least twice the rate of placebo was akathisia (2%). Overall, 12% of the patients who received cariprazine discontinued treatment due to an adverse reaction, compared with 7% of placebo-treated patients in these trials.
Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness.
Adverse Reactions with an incidence of ≥ 2% and greater than placebo at any dose are shown in Table 2 below:
Table 2: Adverse Reactions Occurring in ≥ 2% of cariprazine-treated Patients and > Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials
System Organ Class /               Placebo                        cariprazine* Preferred Term                  (N= 442)              3-6 mg/day           9-12 mg/day⸰ (%)                 (N=263)               (N=360)
(%)                   (%)
Cardiac Disorders
Tachycardiaa                           1                      2                      1 Eye Disorders
Vision blurred                         1                      4                      4 Gastrointestinal Disorders
Nausea                                 7                     13                     11 Constipation                           5                      6                     11 Vomiting                               4                     10                      8 Dry mouth                              2                      3                      2 Dyspepsia                              4                      7                      9 Abdominal painb                        5                      6                      8 Diarrheac                              5                      5                      6 Toothache                              2                      4                      3 General Disorders/Administration Site Conditions
Fatigued                               2                      4                      5 Pyrexiae                               2                      1                      4 Investigations
Blood creatine                         2                      2                      3 phosphokinase increased
Hepatic enzymes increasedf            <1                      1                      3 Weight increased                       2                      2                      3 Metabolism and Nutrition Disorders
Decreased appetite                     3                      3                      4 Musculoskeletal and Connective Tissue Disorders
Pain in extremity                      2                      4                      2 Back pain                              1                      1                      3 Nervous System Disorders
Akathisia                              5                     20                     21 Extrapyramidal Symptomsg              12                     26                     29 Headacheh                             13                     14                     13 Dizziness                              4                      7                      6 Somnolencei                            4                      7                      8 Psychiatric Disorders
Insomniaj                              7                      9                      8 Restlessness                           2                      7                      7 Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain                     2                      1                      3 Vascular Disorders
Hypertensionk                          1                      5                      4 
Note: Figures rounded to the nearest integer
*Data shown by modal daily dose, defined as most frequently administered dose per patient a
Tachycardia terms: heart rate increased, sinus tachycardia, tachycardia b
Abdominal pain terms: abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, c
Diarrhea: diarrhea, frequent bowel movements d
Fatigue terms: asthenia, fatigue e
Pyrexia terms: body temperature increased, pyrexia f
Hepatic enzymes increased terms: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, transaminases increased g
Extrapyramidal Symptoms terms: bradykinesia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, oromandibular dystonia, parkinsonism, salivary hypersecretion, tremor h
Headache terms: headache, tension headache i
Somnolence terms: hypersomnia, sedation, somnolence j
Insomnia terms: initial insomnia, insomnia, middle insomnia k
Hypertension terms: blood pressure diastolic increased, blood pressure increased, hypertension o The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.

Patients with Bipolar Depression

The following findings are based on three placebo-controlled, two 6-week and one 8-week bipolar depression trials with cariprazine doses of 1.5 mg and 3 mg once daily.

Adverse Reactions Associated with Discontinuation of Treatment: There were no adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in cariprazine -treated patients and at least twice the rate of placebo. Overall, 6% of the patients who received cariprazine discontinued treatment due to an adverse reaction, compared with 5% of placebo-treated patients in these trials.
Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): nausea, akathisia, restlessness, and extrapyramidal symptoms.

Adverse Reactions with an incidence of ≥ 2% and greater than placebo at 1.5 mg or 3 mg doses are shown in Table 3 below:

Table 3: Adverse Reactions Occurring in ≥ 2% of cariprazine-treated Patients and > Placebo- treated Adult Patients in two 6-week and one 8-week Bipolar Depression trials Placebo                 cariprazine
(N=468)          1.5 mg/day       3 mg/day
(%)              (N=470)        (N=469)
(%)             (%)
Restlessness                               3                 2                7 Akathisia                                  2                 6               10 Extrapyramidal symptomsa                   2                 4                6 Dizziness                                  2                 4                3 Somnolence   b
4                 7                6
Nausea                                     3                 7                7 Increased appetite                         1                 3                3 Weight increase                           1<                 2                2 Fatigue c
2                 4                3
Insomniad                                  7                 7               10 a
Extrapyramidal symptoms terms: akinesia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, muscle tightness, musculoskeletal stiffness, myoclonus, oculogyric crisis, salivary hypersecretion, tardive dyskinesia, tremor b
Somnolence terms: hypersomnia, sedation, somnolence c
Fatigue terms: asthenia, fatigue, malaise d
Insomnia terms: initial insomnia, insomnia, insomnia related to another mental condition, middle insomnia, sleep disorder terminal insomnia


Adjunctive Therapy in Major Depressive Disorder (MDD)

The following findings are based on two placebo-controlled, fixed-dose 6-week trials with cariprazine doses of 1.5 and 3 mg once daily plus an antidepressant and one placebo-controlled, flexible-dose 8-week trial with cariprazine doses of (1 to 2 mg) and (2 to 4.5 mg) once daily plus an antidepressant for adjunctive therapy in MDD.

Adverse Reactions Associated with Discontinuation of Treatment: The adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in cariprazine-treated patients and at least twice the rate of placebo was akathisia (2%). Overall, 6% of the patients who received cariprazine discontinued treatment due to an adverse reaction, compared with 3% of placebo-treated patients in these trials.

Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): Akathisia, nausea, and insomnia occurred in two 6-week, fixed-dose trials. Akathisia, restlessness, fatigue, constipation, nausea, increased appetite, dizziness, insomnia, and extrapyramidal symptoms occurred in one 8- week flexible-dose trial.

Adverse Reactions with an incidence of ≥ 2% and greater than placebo at 1.5 mg or 3 mg doses are shown in Table 4 below:

Table 4: Adverse Reactions Occurring in ≥ 2% of cariprazine-Treated Patients and > Placebo-Treated Adult Patients in Two Fixed-Dose 6-Week Placebo-Controlled Trials of Adjunctive Treatment of Major Depressive Disorder

System Organ Class /                  Placebo+ADT                         cariprazine Preferred Term                         (N=503)               1.5 mg/day+ADT      3 mg/day +ADT (%)                      (N=502)           (N=503)
(%)                (%)
Eye Disorders
Vision Blurred                                    <1                        <1                2 Gastrointestinal Disorders
Nausea                                             3                         7                6 Dry mouth                                          2                         3                3 Constipation                                       1                         2                2 Vomiting                                           1                         1                2 General Disorders
Fatigue                                            2                         3                3 Investigation
Weight increased                                   1                         2                2 Nervous System Disorders
Akathisiaa                                         2                         7                10 Somnolenceb                                        4                         5                 7 Extrapyramidal                                     4                         5                 6 symptoms c
Psychiatric disorders
Insomniad                                          5                         9                10 Restlessness                                       2                         4                 4 Anxitey                                            1                         2                 1 Skin and subcutaneous Tissue Disorder
Hyperhidrosis                                      1                         1                2 Note: Figures rounded to the nearest integer a
Akathisia terms: akathisia, psychomotor hyperactivity, feeling jittery, nervousness, tension b
Somnolence terms: hypersomnia, sedation, lethargy, somnolence


c
Extrapyramidal symptoms terms: drooling, dyskinesia, extrapyramidal disorder, hypotonia, muscle contractions involuntary, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, musculoskeletal stiffness, myoclonus, oromandibular dystonia, parkinsonism, resting tremor, restless legs syndrome, stiff leg syndrome, salivary hypersecretion, stiff tongue, tardive dyskinesia, tremor, trismus d
Insomnia terms: initial insomnia, insomnia, middle insomnia, poor sleep quality, sleep disorder, terminal insomnia

Adverse Reactions with an incidence of ≥ 2% and greater than placebo at 1 mg to 2 mg per day or 2 mg to 4.5 mg per day doses are shown in Table 5 below:

Table 5: Adverse Reactions Occurring in ≥ 2% of cariprazine-Treated Patients and > Placebo-Treated Adult Patients in a Flexible-dose 8-Week Placebo-Controlled Trial of Adjunctive Treatment of Major Depressive Disorder

System Organ Class /       Placebo+ADT                   Cariprazine                      Cariprazine Preferred Term              (N= 266)              1 to 2 mg/day +ADT               2 to 4.5 mg/day+ADT (%)                        (N=273)                           (N=273)
(%)                               (%)
Cardiac disorders
Palpitations                        1                            2                                <1 Eye Disorders
Vision Blurred                      1                            1                                 4 Gastrointestinal Disorders
Nausea                              5                            7                                13 Constipation                        2                            2                                5 Dry mouth                           3                            5                                4 Vomiting                           <1                            1                                3 General Disorders
Fatigue                    4                                  7                                10 Edema                       <1                                  2                                1 Infections
Nasopharyngitis              2                                  4                                 1 Investigations
Increased appetite           2                                  2                                 5 Weight increased             1                                  2                                 3 Musculoskeletal and Connective Tissue disorders
Back pain                    1                                  2                                 3 Myalgia                      0                                  1                                 2 Nervous System Disorders
Akathisiaa                   3                                  8                                23 Extrapyramidal
5                                  12                               18 Symptomsb
Somnolencec                  6                                  10                               11 Dizziness                    2                                  4                                5 Psychiatric disorders
Insomniad                    8                                 14                                16 Restlessness                 3                                 8                                 8 Agitation                   <1                                 <1                                3 Anxiety                     <1                                 1                                 3 a
Akathisia terms: akathisia, feeling jittery, nervousness, tension b
Extrapyramidal symptoms terms: cogwheel rigidity, drooling, dyskinesia, extrapyramidal disorder, hypertonia, jaw stiffness, muscle contractions involuntary, muscle disorder, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, musculoskeletal stiffness, nuchal rigidity, parkinsonism, psychomotor retardation, reduced facial expression, resting tremor, restless legs syndrome, sensation of heaviness, salivary hypersecretion, tremor c
Somnolence terms: hypersomnia, sedation, lethargy, somnolence d
Insomnia terms: initial insomnia, insomnia, middle insomnia, terminal insomnia, sleep disorder, poor sleep quality 


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 schizophrenia 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 in schizophrenia 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 schizophrenia 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.

In 3-week bipolar mania trials, the incidence of reported adverse reactions related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 28% for cariprazine-treated patients versus 12% for placebo-treated patients. These reactions led to a discontinuation in 1% of cariprazine-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 20% for cariprazine- treated patients versus 5% for placebo-treated patients. These reactions led to discontinuation in 2% of cariprazine-treated patients versus 0% of placebo-treated patients.

In the two 6-week and one 8-week bipolar depression trials, the incidence of reported adverse reactions related to EPS, excluding akathisia and restlessness was 4% for cariprazine-treated patients versus 2% for placebo-treated patients. These reactions led to discontinuation in 0.4% of cariprazine-treated patients versus 0% of placebo-treated patients. The incidence of akathisia was 8% for cariprazine-treated patients versus 2% for placebo-treated patients. These reactions led to discontinuation in 1.5% of cariprazine-treated patients versus 0% of placebo-treated patients.

In the two 6-week adjunctive treatment of major depressive disorder trials, the incidence of reported adverse reactions related to EPS, excluding akathisia and restlessness, was 6% for cariprazine-treated patients versus 4% for placebo-treated patients. These reactions led to discontinuation in 0.3% of cariprazine-treated patients versus 0.6% of placebo-treated patients. The combined incidence of akathisia and restlessness was 12% for cariprazine-treated patients versus 4% for placebo-treated patients. These reactions led to discontinuation in 2% of cariprazine-treated patients versus 0.4% of placebo-treated patients.

In one 8-week adjunctive treatment of major depressive disorder trial, the incidence of reported adverse 

reactions related to EPS, excluding akathisia and restlessness, was 12% for cariprazine-treated patients versus 5% for placebo-treated patients. These reactions led to discontinuation in 1% of cariprazine- treated patients versus 0.4% of placebo-treated patients. The incidence of akathisia and restlessness was 22% for cariprazine-treated patients versus 6% for placebo-treated patients. These reactions led to discontinuation in 3% of cariprazine-treated patients versus 0.0% of placebo-treated patients.

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 in schizophrenia 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.
The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 3-week bipolar mania trials ranged between 2% and 4% for cariprazine-treated patients depending on dose group administered and 2% for placebo-treated patients.
The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 6-week and 8-week bipolar depression trials ranged between 0% and 0.5% for cariprazine-treated patients depending on dose group administered and 0.4% for placebo-treated patients.
The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in two 6-week adjunctive treatment of major depressive disorder trials ranged between 0% and 1% for cariprazine-treated patients depending on dose group administered and 0% for placebo- treated patients.

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 in schizophrenia, 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 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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il