Adverse reactions : תופעות לוואי

8       ADVERSE REACTIONS

8.1     Clinical Trials 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.
In the Alagille syndrome clinical development program, which includes five clinical studies comprising 86 patients, patients received doses of LIVMARLI up to 760 mcg/kg per day with a median duration of exposure of 32.3 months (range: 0.03 - 60.9 months). In Trial 1, the 4-week placebo control period occurred after 18 weeks of LIVMARLI treatment. In two supportive studies that included long-term open-label extensions, only 13 weeks of placebo-controlled treatment occurred which evaluated doses lower than 380 mcg/kg/day. The majority of LIVMARLI exposure in the development program occurred without a placebo control in open-label trial extensions.
The most common adverse reactions (≥5%) for ALGS patients treated with LIVMARLI are presented in Table 2 below. Treatment interruptions or dose reductions occurred in 5 (6%) patients due to diarrhea, abdominal pain, or vomiting.

Table 2: Adverse Reactions Occurring in ≥ 5% of Patients Treated with LIVMARLI in the ALGS Clinical Development Program

LIVMARLI (n=86)

Adverse Reaction                Any Grade            Number of events n (%)               per 100 person- years1
Diarrhea                          48 (55.8%)                   41.6
Abdominal pain*                   46 (53.5%)                   38.6
Vomiting                          35 (40.7%)                   19.8
Nausea                             7 (8.1%)                     2.9
Fat-Soluble Vitamin               22 (25.6%)                   11.1 deficiency*
Transaminases                     16 (18.6%)                    6.9 increased
(ALT, AST)*

Bone Fractures*                    8 (9.3%)                     3.3

*Terms were defined as:
Fat-Soluble Vitamin deficiency includes: A, D, E, or K deficiency, or INR increase Abdominal Pain includes: abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper
Transaminases increased includes: ALT abnormal, ALT increased, AST abnormal, AST increased Bone Fracture includes: tibia fracture, rib fracture, hand fracture, humerus fracture, pathological fracture, forearm fracture, clavicle fracture
1 Exposure adjusted incidence rate for each adverse reaction type was calculated using the first occurrence of this  adverse reaction per patient
Liver Test Abnormalities
Increase in Transaminases
In a pooled analysis of patients with ALGS (N=86) administered LIVMARLI, increases in hepatic transaminases (ALT) were observed. Seven (8.1%) patients discontinued LIVMARLI due to ALT increases. Three (3.5%) patients had a decrease in dose or interruption of LIVMARLI in response to ALT increases. In the majority of cases, the elevations resolved or improved after discontinuation or dose modification of LIVMARLI. In some cases, the elevations resolved or improved without change in LIVMARLI dosing. Increases to more than three times baseline in ALT occurred in 26% of patients treated with LIVMARLI and increases to more than five times baseline occurred in 3%. AST increases to more than three times baseline occurred in 16% of patients treated with LIVMARLI, and an increase to more than five times baseline occurred in one patient. Elevations in transaminases were asymptomatic and not associated with bilirubin elevations or other laboratory abnormalities.


Increases in Bilirubin
Four (4.6%) patients in the pooled analysis experienced bilirubin increases above baseline, and LIVMARLI was subsequently withdrawn in two of these patients, who had elevated bilirubin at baseline.


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