Adverse reactions : תופעות לוואי

7. ADVERSE REACTIONS
The following clinically significant adverse reaction is described elsewhere in the labeling: 
•      Exacerbation of Liver Impairment


7.1 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.

Clinical safety experience with CHOLBAM consists of:

•   Trial 1: a non-randomized, open-label, single-arm trial of 50 patients with bile acid synthesis disorders due to SEDs and 29 patients with PDs including Zellweger spectrum disorders.
Safety data are available over the 18 years of the trial.

•   Trial 2: an extension trial of 12 new patients (10 SED and 2 PD) along with 31 (21 SED and 10 PD) patients who rolled over from Trial 1. Safety data are available for 3 years and 11 months of treatment.

Adverse events were not collected systematically in either of these trials. Most patients received an oral dose of 10 to 15 mg/kg/day of CHOLBAM.
Deaths

In Trial 1, among the 50 patients with SEDs, 5 patients aged 1 year or less died, which included three patients originally diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency and one with CYP7A1 deficiency. The cause of death was attributed to progression of underlying liver disease in every patient.


Two additional patients in Trial 1 (1 SED and 1 PD) died who had been off study medication for more than one year with the cause of death most likely being a progression of underlying liver disease. Of the patients who died with disease progression, laboratory testing showed abnormal serum transaminases, bilirubin, or cholestasis on liver biopsy suggesting worsening of their underlying cholestasis.

In Trial 2, among the 31 patients with SED, two patients (1 new patient and 1 who rolled over from Trial 1) died. The cause of death in both cases was unrelated to their primary treatment or progression of their underlying liver disease.

Worsening of Liver Impairment

Seven patients in Trial 1 (4 SED and 3 PD) and 3 patients in Trial 2 (1 SED and 2 PD) experienced worsening serum transaminases, elevated bilirubin values, or worsening cholestasis on liver biopsy during treatment.

Common Adverse Reactions

There were 12 adverse reactions reported across 9 patients in the trials, with diarrhea being the most common reaction in approximately 2% of the patient population. All other adverse reactions represented 1% of the patient population. The breakdown by trial follows:

Table 1:            Most Common Adverse Reactions in Trials 1 and 2
Overall
Adverse Reactions                 Trial 1                    Trial 2*                     n (%) Diarrhea                             1                          2*                        3 (2) Reflux Esophagitis                   1                          0                         1 (1) Malaise                              1                          0                         1 (1) Jaundice                             1                          0                         1 (1) Skin lesion                          1                          0                         1 (1) Nausea                               0                          1*                        1 (1) Abdominal Pain                       0                          1*                        1 (1) Intestinal Polyp                     0                          1*                        1 (1) Urinary Tract Infection              0                          1*                        1 (1) Peripheral Neuropathy                0                          1                         1 (1) *Adverse reactions that occurred in new patients

Only one of the reactions (peripheral neuropathy) resulted in discontinuation of medication for a patient in Trial 2. An additional five SED patients (3 from Trial 1 and 2 from Trial 2) and 1 PD patient (Trial 1) discontinued medication and withdrew from the study due to a worsening of their primary disease.

The development of symptomatic cholelithiasis requiring cholecystectomy has been reported in a single patient with 3β-HSD deficiency.


7.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of CHOLBAM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their relative frequency or to establish a causal relationship to CHOLBAM exposure: 
•   Gastrointestinal disorders: discomfort and distention, emesis, constipation •    General disorders and administrative site conditions: pyrexia/fever 
•    Skin and subcutaneous tissue disorders: rash

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