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warnings and cautions
5 WARNINGS AND PRECAUTIONS Exacerbation of Liver Impairment: Monitor liver function. Discontinue CHOLBAM if liver function worsens while on treatment. ( 5.1 ) 5.1 Exacerbation of Liver Impairment In clinical trials, evidence of liver impairment was present before treatment with CHOLBAM in approximately 86% (44/51) of patients with bile acid synthesis disorders due to SEDs and in approximately 50% (14/28) of patients with PDs including Zellweger spectrum disorders. Five of the patients (3 SED and 2 PD) with liver impairment at baseline experienced worsening serum transaminases, elevated bilirubin values, or worsening cholestasis on liver biopsy following treatment. Five additional patients (2 SED and 3 PD) who did not have baseline cholestasis experienced exacerbation of their liver disease while on treatment. In patients with cirrhosis, cases of severe hepatotoxicity have also been observed following postmarket use of CHOLBAM. Exacerbation of liver impairment by CHOLBAM in these patients cannot be ruled out. Six patients with SEDs underwent liver transplant, including four patients diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency, and one with CYP7A1 deficiency. Concurrent elevations of serum GGT and ALT may indicate CHOLBAM overdose [see Dosage and Administration ( 2.2 ) and Overdosage ( 10 )] . Monitor liver function and discontinue CHOLBAM in patients who develop worsening of liver function while on treatment. Discontinue treatment with CHOLBAM at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis [see Dosage and Administration ( 2.2 )].
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adverse reactions
6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling: • Exacerbation of Liver Impairment [see Warnings and Precautions ( 5.1 )] Most common adverse reactions (≥1%) are diarrhea, reflux esophagitis, malaise, jaundice, skin lesion, nausea, abdominal pain, intestinal polyp, urinary tract infection, and peripheral neuropathy. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mirum Pharmaceuticals at 1-855-MRM-4YOU or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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. Of 29 patients in Trial 1 with PDs including Zellweger spectrum disorders, 12 patients between the ages of 7 months and 2.5 years died. In the majority of these patients (8/12), the cause of death was attributed to progression of underlying liver disease or to a worsening of their primary illness. 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, bi...
adverse reactions table
Table 3: Most Common Adverse Reactions in Trials 1 and 2*Adverse reactions that occurred in new patientsAdverse ReactionsTrial 1Trial 2*Overall n (%)Diarrhea12*3 (2)Reflux Esophagitis101 (1)Malaise101 (1)Jaundice101 (1)Skin lesion101 (1)Nausea01*1 (1)Abdominal Pain01*1 (1)Intestinal Polyp01*1 (1)Urinary Tract Infection01*1 (1)Peripheral Neuropathy011 (1)