Adverse reactions : תופעות לוואי

6           ADVERSE REACTIONS

6.1         Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 84 subjects were treated with at least one dose of ZOKINVY with or without additional therapy, of which 8 were treated at a dosage of at least 115 mg/m2 twice daily for greater than or equal to 10 years.

The safety profile of ZOKINVY is based on 128 patient-years of treatment exposure (62 patients with HGPS and 1 patient with processing-deficient Progeroid Laminopathy with LMNA heterozygous mutation) and pooled results from two Phase 2 open-label, single-arm trials (n=63: 28 patients from Study 1 and 35 treatment naïve patients from Study 2). In Study 1, ZOKINVY treatment was initiated at 115 mg/m2 twice daily and increased to 150 mg/m2 twice daily after approximately 4 months for a total treatment duration of 24 to 30 months. Treatment naïve 


patients in Study 2 received ZOKINVY 150 mg/m2 twice daily for up to 36 months. In both studies, ZOKINVY was administered orally via capsules or the capsule contents were mixed with Ora Blend SF or Ora-Plus and administered orally as a suspension.

In these two studies, a total of 63 patients received ZOKINVY for a median duration of 2.2 years, with approximately 1.9 years at the recommended dose of 150 mg/m2 twice daily. The population was 2 to 17 years old, with a similar proportion of males (33 [52%] patients) and females (30 [48%] patients). Most patients had classic HGPS (60 [95%] patients) compared to non-classic HGPS (2 [3%] patients) and 1 (2%) patient had Progeroid Laminopathy with LMNA heterozygous mutation.

Table 3 summarizes adverse reactions reported in the clinical trials. The most common adverse reactions (≥25%) in the clinical trials were vomiting, diarrhea, infection, nausea, decreased appetite, fatigue, upper respiratory tract infection, abdominal pain, musculoskeletal pain, electrolyte abnormalities, decreased weight, headache, myelosuppression, increased aspartate aminotransferase, decreased blood bicarbonate, cough, hypertension, and increased alanine aminotransferase.

Table 3: Adve rse Reactions in ≥5% of Patie nts in Study 1 and Treatme nt-Naïve Patie nts in Study 2 Receiving ZOKINVY
ZOKINVY n=63
Adverse Reactions                                                               n (%) Gastrointestinal disorders
Vomiting                                                                     57 (90%) Diarrhea                                                                     51 (81%) Nausea                                                                       35 (56%) Abdominal pain1                                                              30 (48%) Constipation                                                                 14 (22%) Flatulence                                                                    4 (6%) General disorders and administration site conditions
Fatigue                                                                      32 (51%) Pyrexia                                                                       9 (14%) Infections and infestations
Infection2                                                                   49 (78%) Upper respiratory tract infection3                                           32 (51%) Rhinitis                                                                     12 (19%) Investigations
Decreased appetite (anorexia)                                                33 (53%) Electrolyte abnormalities4                                                   27 (43%) Weight decreased                                                             23 (37%) Myelosuppression5                                                            22 (35%) Increased aspartate aminotransferase                                         22 (35%) Decreased blood bicarbonate                                                  21 (33%) Hypertension                                                                 18 (29%) Increased alanine aminotransferase                                           17 (27%) Dehydration                                                                   3 (5%) 


ZOKINVY n=63
Adverse Reactions                                                                                                   n (%) Musculoskeletal and connective tissue disorders
Musculoskeletal pain6                                                                                            30 (48%) Nervous system disorders
Headache                                                                                                         23 (37%) Cerebral ischemia7                                                                                                7 (11%) Ophthalmic
Ocular changes8                                                                                                  15 (24%) Psychiatric disorders
Depressed mood                                                                                                     3 (5%) Respiratory, thoracic and mediastinal disorders
Cough                                                                                                            21 (33%) Epistaxis                                                                                                        13 (21%) Skin and subcutaneous tissue disorders
Rash                                                                                                              7 (11%) Pruritus                                                                                                          5 (8%) Mucositis                                                                                                         5 (8%) 1
Abdominal pain includes stomach pain and abdominal pain.
2
Infection includes abdominal infection, candidiasis, chicken pox, Clostridium difficile colitis, colitis, croup, dengue fever, flu syndrome, flu-like symptoms, fungal infection, gastroenteritis, gastrointestinal infection, Helicobacter pylori infection, infection, infection viral, influenza, nail infection, otitis media, parotitis, perirectal abscess, pneumonia, small intestine infection, submandibular lymphadenitis, tonsillitis, viral infection.
3
Upper respiratory infection includes bronchial infection, bronchitis, sinus infection, and upper respiratory infection.
4
Electrolyte abnormalities includes hypermagnesemia, hypokalemia, hyperkalemia, hyponatremia, hypercalcemia, hyperphosphatemia, hypocalcemia, and hypernatremia.
5
Myelosuppression includes absolute neutrophil count decreased, low total white blood cells, lymphopenia, decreased hemoglobin, and hematocrit low.
6
Musculoskeletal pain includes arthritis, back pain, bone pain, foot pain, intercostal pain, joint pain, knee pain, leg pain, musculoskeletal pain, pain in ankle/extremity/fingers/hip/leg/limb/lower limbs/left arm, shoulder pain, unilateral leg pain. Excludes musculoskeletal pain for abdomen.
7
Cerebral ischemia includes cerebral ischemia, central nervous system hemorrhage, and ischemia cerebrovascular.
8
Ocular changes include visual acuity change, corneal clouding, conjunctivitis, watering eyes, keratitis.


Gastrointestinal Adverse Reactions
As noted in Table 3, gastrointestinal adverse reactions were the most frequently reported adverse reactions. Of the 57 patients who experienced vomiting, 30 (53%) patients had mild vomiting (defined as no intervention required), 26 (46%) patients had moderate vomiting (defined as outpatient intravenous hydration; medical intervention required), and 1 (2%) patient had severe vomiting (defined as tube feeding, total parental nutrition, or hospitalization indicated). Of the 35 patients who experienced nausea, 34 (97%) patients had mild nausea (defined as loss of appetite without alteration in eating habits) and 1 (3%) patient had moderate nausea (defined as oral intake decreased without significant weight loss, dehydration, or malnutrition). During the first four months of treatment in Study 1, 19 (68%) patients had vomiting and 10 (36%) patients had nausea. By the end of therapy, 4 (14%) patients who were still on ZOKINVY required antiemetics or anti-nauseants. A total of 4 patients discontinued ZOKINVY, mostly due to nausea or vomiting.

Of the 51 patients who experienced diarrhea, the majority of patients (approximately 92%) experienced mild or moderate diarrhea; 38 (75%) patients reported mild diarrhea (defined as an increase of less than 4 stools per day over baseline) and 9 (18%) patients reported moderate diarrhea (defined as an increase of 4 to 6 stools per day over baseline; limiting instrumental 


activities of daily living). Four (8%) patients reported severe diarrhea (defined as an increase of seven or more stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care activities of daily living). During the first four months of treatment in Study 1, 23 (82%) patients had diarrhea; by the end of therapy, 3 (11%) patients had diarrhea. Twelve (43%) patients were treated with loperamide.

Alanine Aminotransferase and Aspartate Aminotransferase Elevations
Increased alanine aminotransferase was commonly reported (17 [27%] patients). Of the 17 patients with increased alanine aminotransferase, 14 (82%) patients had mild increases (defined as greater than upper limit of normal (ULN) to 3.0 times ULN if baseline was normal; 1.5 to 3.0 times ULN if baseline was abnormal), 1 (6%) patient had moderate increases (defined as greater than 3.0 to 5.0 times ULN if baseline was normal or abnormal), and 2 (12%) patients had severe increases (defined as greater than 5.0 to 20.0 times ULN if baseline was normal or abnormal). Increased aspartate aminotransferase was also commonly reported (22 [35%] patients). Of the 22 patients with increased aspartate aminotransferase, 21 (95%) patients had mild increases (defined as greater than ULN to 3.0 times ULN if baseline was normal; 1.5 to 3.0 times ULN if baseline was abnormal) and 1 (5%) patient had a severe increase (defined as greater than 5.0 to 20.0 times ULN if baseline was normal or abnormal). One patient with alanine and aspartate aminotransferase elevations also experienced hypertriglyceridemia and hyperglycemia resulting in discontinuation of ZOKINVY.

Hypertension
Increases in blood pressure have been documented in patients treated with ZOKINVY. At baseline 22 (35%) patients had either a systolic blood pressure or a diastolic blood pressure or both above the 95th percentile. Over the course of the trials, 18 (29%) patients had hypertension based on systolic blood pressure or diastolic blood pressure measurements above the 95th percentile on 3 or more occasions. Five (8%) patients who were normotensive at baseline had either systolic blood pressure or diastolic blood pressure above the 95th percentile at the end of treatment.

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 and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com