Adverse reactions : תופעות לוואי

7 ADVERSE REACTIONS

7.1 Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The information below is derived from a clinical trial database for FANAPT tablets consisting of 3229 patients exposed to FANAPT tablets at doses of 10 mg/day or greater, for the treatment of schizophrenia. Of these, 806 received FANAPT tablets for at least 6 months, with 657 exposed to FANAPT tablets for at least 12 months. All of these patients who received FANAPT tablets were participating in multiple-dose clinical trials. The conditions and duration of treatment with FANAPT tablets varied greatly and included (in overlapping categories), open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and flexible-dose studies, and short-term and longer-term exposure.
The information presented in these sections was derived from pooled data from 4 placebo-controlled, 4 or 6-week, fixed- or flexible-dose studies in patients who received FANAPT tablets at daily doses within a range of 10 to 24 mg (n=874).
Adverse Reactions Occurring at an Incidence of 2% or More among FANAPT tablets -Treated Patients and More Frequent than Placebo
Table 7 enumerates the pooled incidences of adverse reactions that were spontaneously reported in four placebo- controlled, 4 or 6-week, fixed- or flexible-dose studies, listing those reactions that occurred in 2% or more of patients treated with FANAPT tablets in any of the dose groups, and for which the incidence in FANAPT tablets -treated patients in any dose group was greater than the incidence in patients treated with placebo.
Table 7: Percentage of Treatment-Emergent Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo-Controlled Trials in Adult Patients* -
Body System or Organ Class                          Placebo            FANAPT 10-16 mg/day               FANAPT 20-24 mg/day %                           %                                %
Dictionary-derived Term                             (N=587)                      (N=483)                         (N=391) Body as a Whole
Arthralgia                                              2                          3                                 3 Fatigue                                            3                          4                                 6 Musculoskeletal Stiffness                          1                          1                                 3 Weight Increased                                   1                          1                                 9 Cardiac Disorders
Tachycardia                                        1                          3                                12 
Eye Disorders
Vision Blurred                                  2                           3                        1 Gastrointestinal Disorders
Nausea                                          8                           7                        10 Dry Mouth                                       1                           8                        10 Diarrhea                                        4                           5                        7 Abdominal Discomfort                            1                           1                        3 Infections
Nasopharyngitis                                 3                           4                        3 Upper Respiratory Tract Infection               1                           2                        3 Nervous System Disorders
Dizziness                                       7                          10                        20 Somnolence                                      5                          9                         15 Extrapyramidal Disorder                         4                          5                         4 Tremor                                          2                          3                         3 Lethargy                                        1                          3                         1 Reproductive System
Ejaculation Failure                             <1                          2                        2 Respiratory
Nasal Congestion                                 2                          5                        8 Dyspnea                                         <1                          2                        2 Skin
Rash                                            2                           3                        2 Vascular Disorders
Orthostatic Hypotension                          1                          3                        5 Hypotension                                     <1                         <1                        3 
* Table includes adverse reactions that were reported in 2% or more of patients in any of the FANAPT tablets dose groups and which occurred at greater incidence than in the placebo group. Figures rounded to the nearest integer.
Dose-Related Adverse Reactions in Clinical Trials
Based on the pooled data from 4 placebo-controlled, 4 or 6-week, fixed- or flexible-dose studies, adverse reactions that occurred with a greater than 2% incidence in the patients treated with FANAPT tablets, and for which the incidence in patients treated with FANAPT tablets 20-24 mg/day were twice than the incidence in patients treated with FANAPT tablets 10-16 mg/day were: abdominal discomfort, dizziness, hypotension, musculoskeletal stiffness, tachycardia, and weight increased.
Common and Drug-Related Adverse Reactions in Clinical Trials
Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, the following adverse reactions occurred in ≥5% incidence in the patients treated with FANAPT tablets and at least twice the placebo rate for at least 1 dose: dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight increased. Dizziness, tachycardia, and weight increased were at least twice as common on 20-24 mg/day as on 10-16 mg/day.
Extrapyramidal Symptoms (EPS) in Clinical Trials
Pooled data from the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies provided information regarding EPS. Adverse event data collected from those trials showed the following rates of EPS-related adverse events as shown in Table 8.
Table 8: Percentage of EPS Compared to Placebo

FANAPT          10-16 mg/day   FANAPT   20-24 mg/day
Placebo (%)
(%)                     (%)
Adverse Event Term                         (N=587)                            (N=483)                 (N=391) All EPS events                               11.6                               13.5                    15.1 Akathisia                                    2.7                                 1.7                     2.3 Bradykinesia                                  0                                  0.6                     0.5 Dyskinesia                                   1.5                                 1.7                     1.0 Dystonia                                     0.7                                 1.0                     0.8 Parkinsonism                                  0                                  0.2                     0.3 
FANAPT           10-16 mg/day   FANAPT   20-24 mg/day
Placebo (%)
(%)                     (%)
Adverse Event Term                   (N=587)                          (N=483)                 (N=391) Tremor                                 1.9                               2.5                     3.1 

Adverse Reactions Associated with Discontinuation of Treatment in Clinical Trials Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, there was no difference in the incidence of discontinuation due to adverse events between FANAPT tablets -treated (5%) and placebo-treated (5%) patients. The types of adverse events that led to discontinuation were similar for the FANAPT tablets - and placebo- treated patients.
Demographic Differences in Adverse Reactions in Clinical Trials
An examination of population subgroups in the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies did not reveal any evidence of differences in safety on the basis of age, gender or race Laboratory Test Abnormalities in Clinical Trials
There were no differences between FANAPT tablets and placebo in the incidence of discontinuation due to changes in hematology, urinalysis, or serum chemistry.
In short-term placebo-controlled trials (4- to 6-weeks), there were 1.0% (13/1342) iloperidone-treated patients with hematocrit at least one time below the extended normal range during post-randomization treatment, compared to 0.3% (2/585) on placebo. The extended normal range for lowered hematocrit was defined in each of these trials as the value 15% below the normal range for the centralized laboratory that was used in the trial.
Other Reactions During the Pre-marketing Evaluation of FANAPT tablets The following is a list of MedDRA terms that reflect adverse reactions in patients treated with FANAPT tablets at multiple doses ≥ 4 mg/day during any phase of a trial with the database of 3210 FANAPT tablets -treated patients. All reported reactions are included except those already listed in Table 7, or other parts of the Adverse Reactions (7) section, those considered in the Warnings and Precautions (6), those reaction terms which were so general as to be uninformative, reactions reported in fewer than 3 patients and which were neither serious nor life-threatening, reactions that are otherwise common as background reactions, and reactions considered unlikely to be drug related.
Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not listed in Table 7 appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Blood and Lymphatic Disorders: Infrequent – anemia, iron deficiency anemia; Rare – leukopenia Cardiac Disorders: Frequent – palpitations; Rare – arrhythmia, atrioventricular block first degree, cardiac failure (including congestive and acute)
Ear and Labyrinth Disorders: Infrequent – vertigo, tinnitus
Endocrine Disorders: Infrequent – hypothyroidism
Eye Disorders: Frequent - conjunctivitis (including allergic); Infrequent – dry eye, blepharitis, eyelid edema, eye swelling, lenticular opacities, cataract, hyperemia (including conjunctival) Gastrointestinal Disorders: Infrequent – gastritis, salivary hypersecretion, fecal incontinence, mouth ulceration; Rare - aphthous stomatitis, duodenal ulcer, hiatus hernia, hyperchlorhydria, lip ulceration, reflux esophagitis, stomatitis General Disorders and Administrative Site Conditions: Infrequent – edema (general, pitting, due to cardiac disease), difficulty in walking, thirst; Rare - hyperthermia
Hepatobiliary Disorders: Infrequent – cholelithiasis
Investigations: Frequent: weight decreased; Infrequent – hemoglobin decreased, neutrophil count increased, hematocrit decreased
Metabolism and Nutrition Disorders: Infrequent – increased appetite, dehydration, hypokalemia, fluid retention 

Musculoskeletal and Connective Tissue Disorders: Frequent – myalgia, muscle spasms; Rare – torticollis Nervous System Disorders: Infrequent – paresthesia, psychomotor hyperactivity, restlessness, amnesia, nystagmus; Rare – restless legs syndrome
Psychiatric Disorders: Frequent – restlessness, aggression, delusion; Infrequent – hostility, libido decreased, paranoia, anorgasmia, confusional state, mania, catatonia, mood swings, panic attack, obsessive-compulsive disorder, bulimia nervosa, delirium, polydipsia psychogenic, impulse-control disorder, major depression Renal and Urinary Disorders: Frequent – urinary incontinence; Infrequent – dysuria, pollakiuria, enuresis, nephrolithiasis; Rare – urinary retention, renal failure acute
Reproductive System and Breast Disorders: Frequent – erectile dysfunction; Infrequent – testicular pain, amenorrhea, breast pain; Rare – menstruation irregular, gynecomastia, menorrhagia, metrorrhagia, postmenopausal hemorrhage, prostatitis.
Respiratory, Thoracic and Mediastinal Disorders: Infrequent – epistaxis, asthma, rhinorrhea, sinus congestion, nasal dryness; Rare – dry throat, sleep apnea syndrome, dyspnea exertional 

Reporting of suspected adverse reactions
Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorization 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
7.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of FANAPT tablets: retrograde ejaculation and hypersensitivity reactions (including anaphylaxis; angioedema; throat tightness; oropharyngeal swelling; swelling of the face, lips, mouth, and tongue; urticaria; rash; and pruritus). Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.