——首个治疗罕见胆汁酸合成障碍新药Cholbam(胆酸胶囊)获FDA批准
2.2 Treatment Monitoring Treatment with CHOLBAM should be initiated and monitored by an experienced hepatologist or pediatric gastroenterologist. Monitor serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum gamma glutamyltransferase (GGT), alkaline phosphatase (ALP), bilirubin and INR every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the subsequent three years and annually thereafter. Monitor more frequently during periods of rapid growth, concomitant disease, and pregnancy. Administer the lowest dose of CHOLBAM that effectively maintains liver function [see Warnings and Precautions (5.1)]. Discontinue treatment with CHOLBAM if liver function does not improve within 3 months of the start of treatment or complete biliary obstruction develops. Discontinue treatment with CHOLBAM at any time if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis [see Warnings and Precautions (5.1)]. Concurrent elevations of serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate CHOLBAM overdose [see Overdosage (10)]. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline. Assessment of serum or urinary bile acid levels using mass spectrometry is used in the diagnosis of bile acid synthesis disorders due to SEDs and PDs including Zellweger spectrum disorders. The utility of bile acid measurements in monitoring the clinical course of patients and in decisions regarding dose adjustment has not been demonstrated. 2.3 Administration Instructions Take CHOLBAM with food. Take CHOLBAM at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin or aluminum-based antacid. Do not crush or chew the capsules. For patients unable to swallow the capsules, the capsules can be opened and the contents mixed with either infant formula or expressed breast milk (for younger children), or soft food such as mashed potatoes or apple puree (for older children and adults) in order to mask any unpleasant taste: Hold the capsule over the prepared liquid/food, gently twist open, and allow the contents to fall into the liquid/food. Mix the entire capsule contents with one or two tablespoons (15 mL to 30 mL) of infant formula, expressed breast milk, or soft food such as mashed potatoes or apple puree. Stir for 30 seconds. The capsule contents will remain as fine granules in the milk or food, and will not dissolve. Administer the mixture immediately 3 DOSAGE FORMS AND STRENGTHS CHOLBAM is available in two capsule strengths. 50 mg capsule: Size number 2 Swedish orange capsule with cap imprinted with "50mg" and body imprinted with "ASK001". The capsules contain a white to off-white powder. 250 mg capsule: Size number 0 white capsule with a cap imprinted with "250mg" and body imprinted with "ASK002". The capsules contain a white to off-white powder. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Exacerbation of Liver Impairment Monitor liver function and discontinue CHOLBAM in patients who develop worsening of liver function while on treatment. Concurrent elevations of serum gamma glutamyltransferase (GGT), alanine aminotransferase (ALT) may indicate CHOLBAM overdose. [see Overdosage (10)]. Discontinue treatment with CHOLBAM at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis. 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. An additional 5 patients (2 SED and 3 PD) who did not have baseline cholestasis experienced an exacerbation of their liver disease while on treatment. Exacerbation of liver impairment by CHOLBAM in these patients cannot be ruled out. Six patients with single enzyme defects underwent liver transplant, including four patients diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency, and one with CYP7A1 deficiency. 6 ADVERSE REACTIONS 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 the 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 their 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. Of the 12 patients with PD in Trial 2, four patients died between the ages of 4 and 8 years (1 new patient and 3 who rolled over from Trial 1). The cause of death in three of these patients was attributed to progression of underlying liver disease or to a worsening of their primary illness. Worsening 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 3: Most Common Adverse Reactions in Trials 1 and 2
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 DRUG INTERACTIONS 7.1. Effects of other drugs on CHOLBAM Drug interactions with CHOLBAM mainly relate to agents capable of interrupting the enterohepatic circulation of bile acids. Inhibitors of Bile Acid Transporters Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitoring of serum transaminases and bilirubin is recommended. Bile Acid Binding Resins Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the efficacy of CHOLBAM. Take CHOLBAM at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin [see Dosage and Administration (2.3)]. Aluminum-Based Antacids Aluminum-based antacids have been shown to adsorb bile acids in vitro and can reduce the bioavailability of CHOLBAM. Take CHOLBAM at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after an aluminum-based antacid [see Dosage and Administration (2.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy surveillance program that monitors pregnancy outcomes in women exposed to CHOLBAM during pregnancy [COCOA Registry (ChOlbam: Child and mOther's heAlth)]. Women who become pregnant during CHOLBAM treatment are encouraged to enroll. Patients or their health care provider should call 1-844-20C-OCOA or 1-844-202-6262 to enroll. Risk Summary No studies in pregnant women or animal reproduction studies have been conducted with CHOLBAM. Limited published case reports discuss pregnancies in women taking cholic acid for 3β-HSD deficiency resulting in healthy infants. These reports may not adequately inform the presence or absence of drug-associated risk with the use of CHOLBAM during pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. 8.2 Lactation Risk Summary Endogenous cholic acid is present in human milk. Clinical lactation studies have not been conducted to assess the presence of CHOLBAM in human milk, the effects of CHOLBAM on the breastfed infant, or the effects of CHOLBAM on milk production. There are no animal lactation data and no data from case reports available in the published literature. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CHOLBAM and any potential adverse effects on the breastfed infant from CHOLBAM or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of CHOLBAM has been established in pediatric patients 3 weeks of age and older for the treatment of bile acid synthesis disorders due to SEDs, and for adjunctive treatment of patients with PDs including Zellweger spectrum disorders who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption [see Clinical Studies (14)]. 8.5 Geriatric Use Clinical studies of CHOLBAM did not include any patients aged 65 years and over. It is not known if elderly patients respond differently from younger patients. 8.6 Hepatic Impairment Discontinue treatment with CHOLBAM if liver function does not improve within 3 months of the start of treatment. Discontinue treatment with CHOLBAM at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis [see Warnings and Precautions (5.1), Overdosage (10) and Nonclinical Toxicology (13.2)]. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline. 10 OVERDOSAGE Concurrent elevations of serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate CHOLBAM overdose. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline [see Dosage and Administration (2.2)]. In the event of overdose the patient should be monitored and treated symptomatically. 11 DESCRIPTION Cholic acid is a bile acid produced by the liver where it is synthesized from cholesterol. The chemical formula is C24H40O5, the molecular weight is 408.57 and the chemical structure is:
Among SED responsive patients, 45% of the responders met the two clinical criteria plus 1 to 3 laboratory criteria and 55% met the weight criteria. Only six patients had pre- and post-treatment liver biopsies in Trial 1. Where biopsies were available, pre-treatment biopsies showed varying degrees of inflammation, bridging fibrosis, and giant cell formation. Post-treatment biopsies generally showed reduced or absent inflammation and reduced or absent giant cell formation. Fibrosis remained but did not progress. It is difficult to evaluate long term survival in patients with SEDs since there is little natural history survival data for comparison. Overall, 41 of 62, or 67%, of patients with SEDs survived greater than 3 years from trial entry. Thirteen of these 41 patients, or 32%, were "long-term" survivors (range of 10 to 24 years on treatment). Four patients in Trial 1 underwent liver transplant, including two patients diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency, and one with CYP7A1 deficiency and two patients in Trial 2, both with AKR1D1. CHOLBAM's effects on extrahepatic manifestations of SEDs, such as neurologic symptoms are not established. Case Series A published report of a case series described 15 patients with SEDs; thirteen were diagnosed with 3β-HSD deficiency and two with AKR1D1 deficiency by mass spectrometry and gene sequencing. All patients were treated with cholic acid with a median duration of treatment of 12.4 years (range 5.6 to 15 years). Therapy started at a median age of 3.9 years (range 0.3 to 13.1 years). The mean dose at the start of cholic acid treatment was 13 mg/kg and the mean dose at last follow up was 6 mg/kg. Eight patients were initially treated with oral ursodeoxycholic acid prior to receiving a diagnosis of bile acid synthesis defect, after which they were switched to cholic acid. Initial signs and symptoms included jaundice, hepatosplenomegaly, steatorrhea, or symptoms related to deficiency of a fat soluble vitamin (K, D or E). Of the 8 patients who received ursodeoxycholic acid initially, the six with 3β-HSD deficiency demonstrated mild clinical improvement. Following treatment with cholic acid, all patients experienced resolution of their pre-existing jaundice and steatorrhea, and all but one experienced resolution of hepatosplenomegaly. Weight and height improved and sexual maturation progressed normally in all patients. Liver biopsies were performed in 14 patients after at least 5 years of cholic acid treatment and all showed resolution of cholestasis. In one patient with 3β-HSD deficiency, biliary bile acid analysis while on cholic acid therapy showed enrichment of the bile with cholic acid. 14.2 Peroxisomal Disorders including Zellweger Spectrum Disorders The effectiveness of CHOLBAM at a dosage of 10 to 15 mg/kg per day in patients with PDs including Zellweger spectrum disorders was assessed in patients in the same trials described in section 14.1. Trial 1 treated 29 patients with PDs over an 18 year period. Trial 2 treated 2 new patients along with 10 patients who rolled-over from Trial 1 (n=12 total). Efficacy data are available from Trial 2 for 21 months of treatment. Additional efficacy data were obtained from published case reports of 3 patients. Enrollment criteria in Trials 1 and 2 were based on abnormal urinary bile acids analysis by Fast Atom Bombardment ionization - Mass Spectrometry (FAB-MS) and a neurologic exam. Most patients received concomitant DHA (docosahexaenoic acid) and Vitamins A, D, E and K. Documentation of adherence to treatment, concomitant medications and response to treatment were incomplete during Trial 1. Trials 1 and 2 The majority of patients (80%, 25/31) were less than 2 years of age at the start of CHOLBAM treatment (range 3 weeks to 10 years). The majority of patients were treated for an average of 254 weeks (4.8 years). Sufficient data were available to assess baseline liver function and effects of CHOLBAM treatment in 23 patients in Trial 1 and in one new patient in Trial 2. A responder analysis was performed in the patients who had received at least one dose of CHOLBAM and had sufficient data available to assess baseline liver impairment. Response to CHOLBAM treatment was assessed by the following laboratory criteria: (1) ALT or AST values reduced to less than 50 U/L, or baseline levels reduced by 80%; (2) total bilirubin values reduced to less than or equal to 1 mg/dL; and (3) no evidence of cholestasis on liver biopsy; and the following clinical criteria: (1) body weight increased by 10% or stable at greater than the 50th percentile; and (2) survival for greater than 3 years on treatment or alive at the end of Trial 2 CHOLBAM responders were defined as patients who either: (1) met at least two laboratory criteria and were alive at the last follow-up; or (2) met at least one laboratory criterion, had increased body weight and were alive at the last follow-up. Overall, 11 of 24 patients (46%) were responders. The breakdown by disorder is as follows: Table 5: Response to CHOLBAM Treatment by Type of Peroxisomal Disorders including Zellweger Spectrum Disorders
No evidence of improvement in survival over that seen in historical controls could be demonstrated from the data presented. Overall, 13 of 31, or 42%, of patients survived greater than 3 years from the time of trial entry. Eight of these 13 patients, or 62% were "long-term" survivors (range of 10 to 17 years on treatment). Nine patients had both pre- and post-treatment liver biopsies. One patient showed improvement in histology, while the majority of patients remained unchanged. Two patients demonstrated worsening histology, which was consistent with a worsening of other liver laboratory parameters (bilirubin, serum transaminase values). CHOLBAM's effects on extrahepatic manifestations of PDs including Zellweger spectrum disorders, such as neurologic symptoms are not established. One patient, who did not have cholestasis on pre-treatment liver biopsy, developed cholestasis on treatment with CHOLBAM and subsequently died. Case Reports In case reports from the literature, a 6 month old patient with Zellweger syndrome treated with a combination of cholic and chenodeoxycholic acids experienced normalization of serum transaminases and bilirubin, improvement in liver histology, reduced serum and urinary atypical bile acid intermediates, and improvement in steatorrhea and growth. Two patients with Zellweger syndrome treated with oral bile acids showed decreased serum transaminases. 16 HOW SUPPLIED/STORAGE AND HANDLING 50 mg Capsules CHOLBAM capsules are available as two-piece gelatin capsules with a Swedish orange cap imprinted with "50mg" and Swedish orange body with imprinted with "ASK001". The capsules contain a white or off-white powder and are supplied in bottles of: 90 capsules (NDC 45043-001-02) 250 mg Capsules CHOLBAM capsules are available as two-piece gelatin capsules with a white cap imprinted with "250mg" and white body with imprinted with "ASK002". The capsules contain a white or off-white powder and are supplied in bottles of: 90 capsules (NDC 45043-002-02) Storage and Handling Store at 20–25°C (69-77°F), excursions permitted between 15-30°C (59-86°F). [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Exacerbation of Liver Impairment Advise patients that they will need to undergo laboratory testing periodically while on treatment to assess liver function. Advise patients that CHOLBAM may worsen liver impairment and that they should immediately report to their health care provider any symptoms associated with liver impairment (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown [tea colored], pain on the right side of stomach, bleeding or bruising occurs more easily than normal, or increased lethargy) Administration Advise patients: to take CHOLBAM with food. to take CHOLBAM at least one hour before or 4 to 6 hours after taking a bile acid binding resin or an aluminum-based antacid. not to crush or chew the capsules. for infants and children who cannot swallow capsules, the capsules can be opened and the contents mixed with either infant formula or expressed breast milk (for younger children), or soft food such as mashed potatoes or apple puree (for older children and adults) in order to mask any unpleasant taste: Hold the capsule over the prepared liquid/food, gently twist open, and allow the contents to fall into the liquid/food. Mix the entire capsule contents with one or two tablespoonfuls (15 mL to 30 mL) of infant formula, expressed breast milk, or soft food such as mashed potatoes or apple puree. Stir for 30 seconds. The capsule contents will remain as fine granules in the milk or food, and will not dissolve. Administer the mixture immediately. Pregnancy Registry: Advise patients there is a pregnancy surveillance program that monitors pregnancy outcomes in women exposed to CHOLBAM during pregnancy [see Use in Specific Populations (8.1)]. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e5b67402-8550-4604-97a0-c7b149fbf753 |