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美国Sankyo Pharma公司宣布Colesevelam（商品名WelChol）作为一种新的降低胆固醇的药物已在全美国上市药品，可供医师和病人选用。
Table 2 Placebo-Controlled Clinical Study of WELCHOL for Primary Hyperlipidemia in heFH Pediatric Patients: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality
Type 2 Diabetes Mellitus: The safety of WELCHOL in patients with type 2 diabetes mellitus was evaluated in 5 add-on combination and 1 monotherapy double-blind, 12-26 week, placebo-controlled clinical trials [see Clinical Studies (14.2)]. In these studies 1022 patients were exposed to WELCHOL. The mean exposure duration was 20 weeks (total exposure 393 patient-years). Patients were to receive 3.8 grams of WELCHOL per day. The mean age of patients exposed to WELCHOL was 55.7 years, 52.8 percent of the population was male and 61.9% were Caucasian, 4.8% were Asian, and 15.9% were Black or African American. At baseline the population had a mean HbA1C of 8.2% and 26% had past medical history suggestive of microvascular complications of diabetes. Baseline characteristics in the placebo group were comparable. In clinical trials of type 2 diabetes, 57% of patients receiving WELCHOL vs. 52% of patients receiving placebo reported an adverse reaction. Table 3 shows common adverse reactions associated with the use of WELCHOL in the 1015 patients with type 2 diabetes. These adverse reactions were not present at baseline, occurred more commonly on WELCHOL than on placebo, and occurred in at least 2% of patients treated with WELCHOL. Table 3 Placebo-Controlled Clinical Studies of WELCHOL for Type 2 Diabetes: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality
One patient in the add-on to sulfonylurea trial discontinued due to body rash and mouth blistering that occurred on the first day of dosing of WELCHOL, which may represent a hypersensitivity reaction to WELCHOL. Hypertriglyceridemia: Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the diabetes trials, 1292 (67.7%) patients had baseline fasting serum TG levels less than 200 mg/dL, 426 (22.3%) had baseline fasting serum TG levels between 200 and less than 300 mg/dL, 175 (9.2%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 16 (0.8%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 160 mg/dL; the median post-treatment fasting TG was 180 mg/dL in the WELCHOL group and 162 mg/dL in the placebo group. WELCHOL therapy resulted in a median placebo-corrected increase in serum TG of 9.7% (p=0.03) in the monotherapy study and of 5% (p=0.22), 11% (p<0.001), 18% (p<0.001), and 22% (p<0.001), when added to metformin, pioglitazone, sulfonylureas, and insulin, respectively [See Warnings and Precautions (5.2) and Clinical Studies (14.2)]. In comparison, WELCHOL resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial [See Clinical Studies (14.1)]. Treatment-emergent fasting TG concentrations ≥500 mg/dL occurred in 0.9% of WELCHOL-treated patients compared to 0.7% of placebo-treated patients in the diabetes trials. Among these patients, the TG concentrations with WELCHOL (median 606 mg/dL; interquartile range 570-794 mg/dL) were similar to that observed with placebo (median 663 mg/dL; interquartile range 542-984 mg/dL). Five (0.6%) patients on WELCHOL and 3 (0.3%) patients on placebo developed TG elevations ≥1000 mg/dL. In all WELCHOL clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia. It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with WELCHOL [See Contraindications (4) and Warnings and Precautions (5.2)]. Cardiovascular adverse events: During the diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 2.2% (22/1015) in the WELCHOL group and 1% (10/1010) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown. 6.2 Post-marketing Experience The following additional adverse reactions have been identified during post-approval use of WELCHOL. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Drug Interactions with concomitant WELCHOL administration include: Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin. Phenytoin should be administered 4 hours prior to WELCHOL. Reduced International Normalized Ratio (INR) in patients receiving warfarin therapy. In warfarin-treated patients, INR should be monitored frequently during WELCHOL initiation then periodically thereafter. Elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy. Thyroid hormone replacement should be administered 4 hours prior to WELCHOL [See Drug Interactions (7)]. Gastrointestinal Adverse Reactions Bowel obstruction (in patients with a history of bowel obstruction or resection), dysphagia (tablet and oral suspension formulations) or esophageal obstruction (occasionally requiring medical intervention), fecal impaction, pancreatitis, abdominal distension, exacerbation of hemorrhoids, and increased transaminases. Laboratory Abnormalities Hypertriglyceridemia 7 DRUG INTERACTIONS Table 4 lists the drugs that have been tested in in vitro binding, in vivo drug interaction studies with colesevelam and/or drugs with postmarketing reports consistent with potential drug-drug interactions. Orally administered drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to WELCHOL. Alternatively, the physician should monitor drug levels of the co-administered drug. Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)] c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL. d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. In an in vivo drug interaction study, WELCHOL and warfarin coadministration had no effect on warfarin drug levels. This study did not assess the effect of WELCHOL and warfarin coadministration on INR. In post-marketing reports, concomitant use of WELCHOL and warfarin has been associated with reduced INR. Therefore, in patients on warfarin therapy, the INR should be monitored before initiating WELCHOL and frequently enough during early WELCHOL therapy to ensure that no significant alteration in INR occurs. Once the INR is stable, continue to monitor the INR at intervals usually recommended for patients on warfarin [See Post-marketing Experience (6.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. There are no adequate and well-controlled studies of colesevelam use in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of fetal harm. Requirements for vitamins and other nutrients are increased in pregnancy. However, the effect of colesevelam on the absorption of fat-soluble vitamins has not been studied in pregnant women. This drug should be used during pregnancy only if clearly needed. In animal reproduction studies, colesevelam revealed no evidence of fetal harm when administered to rats and rabbits at doses 50 and 17 times the maximum human dose, respectively. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. 8.3 Nursing Mothers Colesevelam hydrochloride is not expected to be excreted in human milk because colesevelam hydrochloride is not absorbed systemically from the gastrointestinal tract. 8.4 Pediatric Use The safety and effectiveness of WELCHOL as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age with heFH [See Clinical Studies (14.1)]. The adverse reaction profile was similar to that of patients treated with placebo. In this limited controlled study, there were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo [See Adverse Reactions (6.1)]. Due to tablet size, WELCHOL for Oral Suspension is recommended for use in the pediatric population. Dose adjustments are not required when WELCHOL is administered to children 10 to 17 years of age. WELCHOL has not been studied in children younger than 10 years of age or in pre-menarchal girls. 8.5 Geriatric Use Primary Hyperlipidemia: Of the 1350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were ≥65 years old, and 58 (4%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Type 2 Diabetes Mellitus: Of the 2048 patients enrolled in the six diabetes studies, 397 (19%) were ≥65 years old, and 36 (2%) were ≥75 years old. In these trials, WELCHOL 3.8 g/day or placebo was added onto background anti-diabetic therapy. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No special considerations or dosage adjustments are recommended when WELCHOL is administered to patients with hepatic impairment. 8.7 Renal Impairment Type 2 Diabetes Mellitus: Of the 2048 patients enrolled in the six diabetes studies, 807 (39%) had mild renal insufficiency (creatinine clearance [CrCl] 50-<80 mL/min), 61 (3%) had moderate renal insufficiency (CrCl 30-<50 mL/min), and none had severe renal insufficiency (CrCl <30 mL/min), as estimated from baseline serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. No overall differences in safety or effectiveness were observed between patients with CrCl <50 mL/min (n=53) and those with a CrCl ≥50 mL/min (n=1075) in the add-on to metformin, sulfonylureas, and insulin diabetes studies. In the monotherapy study and add-on to pioglitazone study only 3 and 5 patients respectively had moderate renal insufficiency 10 OVERDOSAGE Doses of WELCHOL in excess of 4.5 g/day have not been tested. Because WELCHOL is not absorbed, the risk of systemic toxicity is low. However, excessive doses of WELCHOL may cause more severe local gastrointestinal effects (e.g., constipation) than recommended doses. 11 DESCRIPTION WELCHOL (colesevelam hydrochloride) is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent intended for oral administration. Colesevelam hydrochloride is a high-capacity bile acid-binding molecule. Colesevelam hydrochloride is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) of colesevelam hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride. The chemical structure of colesevelam hydrochloride is represented by the following formula:
b Should be administered at least 4 hours prior to WELCHOL [See Drug Interactions (7)]. c Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs [See Drug Interactions (7)]. d Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL [See Drug Interactions (7)]. Oral contraceptive containing norethindrone and ethinyl estradiol. N/A – Not Available 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg). Mutagenesis: Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S. typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation.
a Median % change from baseline. In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), WELCHOL 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another. Combination Therapy: Co-administration of WELCHOL and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156-236 mg/dL), 171 mg/dL in the lovastatin study (range 115-247 mg/dL), and 188 mg/dL in the simvastatin study (range 148-352 mg/dL). As demonstrated in Table 7, WELCHOL doses of 2.3 g to 3.8 g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone. Table 7 Response to WELCHOL in Combination with Atorvastatin, Simvastatin, or Lovastatin Percent Change in Lipid Parameters
aMedian % change from baseline. In all 3 studies, the LDL-C reduction achieved with the combination of WELCHOL and any given dose of statin therapy was statistically superior to that achieved with WELCHOL or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of WELCHOL 3.8 g and atorvastatin 10 mg. The effect of WELCHOL when added to fenofibrate was assessed in 122 patients with mixed hyperlipidemia (Fredrickson Type IIb). Inclusion in the study required LDL-C ≥115 mg/dL and TG 150 mg/dL to 749 mg/dL. Patients were treated with 160 mg of fenofibrate during an 8-week open-label run-in period and then randomly assigned to receive fenofibrate 160 mg plus either WELCHOL 3.8 g or placebo for 6 weeks of double-blind treatment. The overall mean LDL-C at the start of randomized treatment was 144 mg/dL. The results of the study are summarized in Table 8. Table 8 Response to WELCHOL Added to Fenofibrate in Patients with Mixed Hyperlipidemia (Mean % Change from Treated Baselineb at 6 Weeks)
a For triglycerides, median % change from baseline. b Treated Baseline: following 8-week treatment with open-label fenofibrate 160 mg. Pediatric Therapy: The safety and efficacy of WELCHOL in pediatric patients were evaluated in an 8-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study followed by an open-label phase, in 194 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (heFH), taking a stable dose of an FDA-approved statin (with LDL-C >130 mg/dL) or naïve to lipid lowering therapy (with LDL-C >160 mg/dL). This study had 3 periods: a single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo-controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naïve at screening. The mean baseline LDL-C at Day 1 was approximately 199 mg/dL. During the double-blind treatment period, patients were assigned randomly to treatment: WELCHOL 3.8 g/day (n=64), WELCHOL 1.9 g/day (n=65), or placebo (n=65). In total, 186 patients completed the double-blind treatment period. After 8 weeks of treatment, WELCHOL 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non-statistically significant increase in TG was observed versus placebo (Table 9). Table 9 Response to WELCHOL 3.8 g Compared to Placebo in Pediatric Patients 10-17 Years of Age – Mean Percent Change in Lipid Parameters from Baseline to Week 8
Values represent LS mean. Only patients with values at both study baseline and endpoint are included in this table. Study baseline was defined as the last value measured before or on Day 1 prior to the first dose of randomized study medication. a For triglycerides, median % change from baseline. Results were based on the ITT population with LOCF During the open-label treatment period patients were treated with WELCHOL 3.8 g/day. In total, 173 (89%) patients completed 26 weeks of treatment. Results at Week 26 were consistent with those at Week 8. 14.2 Type 2 Diabetes Mellitus WELCHOL has been studied as monotherapy and in combination with metformin, pioglitazone, sulfonylureas, and insulin. In these studies, WELCHOL and placebo were administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone. Monotherapy: The efficacy of WELCHOL 3.8 g/day as anti-diabetes monotherapy was evaluated in a randomized double-blind, placebo-controlled trial involving 357 patients (176 WELCHOL and 181 placebo) with T2DM who were treatment-naïve or had not received antihyperglycemic medication within 3 months prior to the start of the study. Statin use at baseline was reported in 13% of the WELCHOL-treated patients and 16% of the placebo-treated patients. WELCHOL resulted in a statistically significant reduction in A1C of 0.27% compared to placebo (Table 10). The mean baseline LDL-C was 121 mg/dL in the monotherapy trial. WELCHOL treatment resulted in a placebo-corrected 11% reduction in LDL-C. WELCHOL treatment also reduced serum TC, ApoB, and non-HDL-C (Table 11). The mean change in body weight was -0.6 kg for WELCHOL and -0.7 kg for placebo treatment groups. Table 10 Glycemic Parameters in a 24-Week Placebo-Controlled Study of WELCHOL Monotherapy in Patients with Type 2 Diabetes
bNominal p=value, not controlled for multiplicity testing. A1C = hemoglobin A1C, FPG = fasting plasma glucose Table 11 Percent Change in Lipid Parameters in a 24-Week Placebo-Controlled Study of WELCHOL Monotherapy in Patients with Type 2 Diabetes
a Median % change from baseline. †The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter. Add-on combination Therapy: The efficacy of WELCHOL 3.8 g/day in patients with type 2 diabetes mellitus was evaluated in 5 double-blind, placebo-controlled add-on therapy trials involving a total of 1691 patients with baseline A1C 7.5-9.5%. Patients were enrolled and maintained on their pre-existing, stable, background anti-diabetic regimen. Statin use at baseline was reported in 41% of the WELCHOL-treated patients and 48% of the placebo-treated patients. In 3 add-on combination therapy trials (metformin, sulfonylurea and insulin), treatment with WELCHOL resulted in a statistically significant reduction in A1C of 0.5% compared to placebo. Similar placebo-corrected reductions in A1C occurred in patients who received WELCHOL in combination with metformin, sulfonylurea, or insulin monotherapy or combinations of these therapies with other anti-diabetic agents. In the pioglitazone trial, treatment with WELCHOL resulted in a statistically significant reduction in A1C of 0.32% compared to placebo. In the metformin, pioglitazone, and sulfonylurea trials, treatment with WELCHOL also resulted in statistically significant reductions in fasting plasma glucose (FPG) of at least 14 mg/dL compared to placebo. WELCHOL had consistent effects on A1C across subgroups of age, gender, race, body mass index, and baseline A1C. WELCHOL’s effects on A1C were also similar for the two dosing regimens (3 tablets with lunch and with dinner or 6 tablets with dinner alone). The mean baseline LDL-C was 104 mg/dL in the metformin study (range 32-214 mg/dL), 107 mg/dL in the pioglitazone study (range 48-263 mg/dL), 106 mg/dL in the sulfonylurea study (range 41-264 mg/dL), 102 mg/dL in the insulin study (range 35-204 mg/dL). In these trials, WELCHOL treatment was associated with a 12% to 16% reduction in LDL-C levels. The percentage decreases in LDL-C were of similar magnitude to those observed in patients with primary hyperlipidemia. WELCHOL treatment was associated with statistically significant increases in TG levels in the studies of patients on insulin, patients on a sulfonylurea, and patients on pioglitazone but not in the study of patients on metformin. The clinical significance of these increases is unknown. WELCHOL is contraindicated in patients with TG levels > 500 mg/dL [See Contraindications (4)] and periodic monitoring of lipid parameters including TG and non-HDL-C levels is recommended [See Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Body weight did not significantly increase from baseline with WELCHOL therapy, compared with placebo, in any of the add-on combination diabetes studies. Add-on Combination Therapy with Metformin: WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 316 patients already receiving treatment with metformin alone (N=159) or metformin in combination with other oral agents (N=157). A total of 60% of these patients were receiving ≥1,500 mg/day of metformin. In combination with metformin, WELCHOL resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 12). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C (Table 13). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -16% among statin users and statin non-users; the median percent change in serum TG levels with WELCHOL compared to placebo was -2% among statin users and 10% among statin non-users. The mean change in body weight was -0.5 kg for WELCHOL and -0.3 kg for placebo. Table 12 Glycemic Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Metformin in Patients with Type 2 Diabetes
A1C = hemoglobin A1C, FPG = fasting plasma glucose Table 13 Percent Change in Lipid Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Metformin in Patients with Type 2 Diabetes
a Median % change from baseline. The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter. Add-on Combination Therapy with pioglitazone: WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 24-week trial of 562 patients already receiving treatment with pioglitazone alone (N=51) or pioglitazone in combination with other oral agents (N=511). Of these, most were on dual therapy with metformin (N=298) or triple therapy with metformin and a sulfonylurea (N=139). In combination with pioglitazone-based therapy, WELCHOL resulted in statistically significant reductions in A1C and FPG compared to placebo (Table 14). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C but increased serum TG (Table 15). The mean change in body weight was 0.8 kg for WELCHOL and 0.4 kg for placebo. Table 14 Glycemic Parameters in a 24-Week Placebo-Controlled Study of WELCHOL in Combination with Pioglitazone Based Therapy in Patients with Type 2 Diabetes
A1C = hemoglobin A1C, FPG = fasting plasma glucose Table 15 Percent Change in Lipid Parameters in a 24-Week Placebo-Controlled Study of WELCHOL in Combination with Pioglitazone Based Therapy in Patients with Type 2 Diabetes
a Median % change from baseline The N given represents the smallest number of patients included in the analysis for any parameter. Add-on Combination Therapy with Sulfonylurea: WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 460 patients already treated with sulfonylurea alone (N=156) or sulfonylurea in combination with other oral agents (N=304). A total of 72% of these patients were receiving at least half-maximal doses of sulfonylurea therapy. In combination with a sulfonylurea, WELCHOL resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 16). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C, but increased serum TG (Table 17). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -18% among statin users and -15% among statin non-users; the median percent increase in serum TG with WELCHOL compared to placebo was 29% among statin users and 9% among statin non-users. The mean change in body weight was 0.0 kg for WELCHOL and -0.4 kg for placebo. Table 16 Glycemic Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Sulfonylurea in Patients with Type 2 Diabete
A1C = hemoglobin A1C, FPG = fasting plasma glucose Table 17 Percent Change in Lipid Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination With Sulfonylurea in Patients with Type 2 Diabetes
a Median % change from baseline. The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter. Add-on Combination Therapy with Insulin: WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 16-week trial of 287 patients already treated with insulin alone (N=116) or insulin in combination with oral agents (N=171). At baseline, the median daily insulin dose was 70 units in the WELCHOL group and 65 units in the placebo group. In combination with insulin, WELCHOL resulted in a statistically significant placebo-corrected reduction in A1C (Table 18). WELCHOL also reduced LDL-C and Apo B, but increased serum TG (Table 19). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -13% among statin users and statin non-users; the median percent increase in serum TG levels with WELCHOL compared to placebo was 24% among statin users and 17% among statin non-users. The mean change in body weight was 0.6 kg for WELCHOL and 0.2 kg for placebo. Table 18 Glycemic Parameters in a 16-Week Placebo-Controlled Study of WELCHOL in Combination with Insulin in Patients with Type 2 Diabetes
A1C = hemoglobin A1C, FPG = fasting plasma glucose Table 19 Percent Change in Lipid Parameters in a 16-Week Placebo-Controlled Study of WELCHOL in Combination with Insulin in Patients with Type 2 Diabetes
a Median % change from baseline. The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter. 16 HOW SUPPLIED/STORAGE AND HANDLING WELCHOL (colesevelam hydrochloride) Tablets, 625 mg, are supplied as an off-white, solid tablet imprinted with the word “Sankyo” and “C01” on one side. WELCHOL tablets are available as follows: Bottles of 180 - NDC 65597-701-18 Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Brief exposure to 40°C (104°F) does not adversely affect the product. Protect from moisture. WELCHOL (colesevelam hydrochloride) for Oral Suspension is a white to pale yellow powder containing yellow granules. WELCHOL for Oral Suspension is available as follows: 1.875 gram single-dose packet Cartons of 60 packets – NDC 65597-903-60 3.75 gram single-dose packet Cartons of 30 packets – NDC 65597-902-30 Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4a06d3b2-7229-4398-baba-5d0a72f63821 Welchol (Colesevelam Tablets/Oral suspension)考来维仑 盐酸考来维仑是三共公司开发的一个非吸收性聚合物类降脂药物，它可与肠道中的胆酸结合并显著减少后者的再吸收。由于胆酸的耗竭会提高胆固醇转化为胆酸的平衡，故能用来降低胆固醇浓度。盐酸考来维仑的这种作用机制与考来烯胺（cholestyramine／Questran等）和考来替泊（ colestipol/Colestid）等已有药物相似，但因其对胆酸的结合亲和力更强，所以可以更低剂量使用，胃肠道副反应减少，药物相互作用潜力亦更低。 盐酸考来维仑被批准用作饮食和运动疗法的辅助疗法，单用或再并用一种他汀类药物降低原发性高血胆固醇症患者的高水平低密度脂蛋白胆固醇（LDL－C）。在临床研究中，盐酸考来维仑显现可以降低LDL－C浓度15％～18％，提高高密度脂蛋白胆固醇（HDL－C）浓度3％。受试患者的甘油三酯浓度稍有上升，然与安慰剂治疗者相比没有统计学显著差异性。盐酸考来维仑尚未与考来烯胺和考来替泊进行对照研究，但其对脂质构成作用的类型和程度似仍和此两药相似。 胆酸螫合剂、包括盐酸考来维仑对脂质浓度的作用强度均不如他汀类药物，故单用此类药物治疗高血胆固醇症患者大多会逐渐转向单用他汀类药物或再并用一种他汀类药物。在并用阿伐他汀、洛伐他汀或辛伐他汀的临床研究中，盐酸考来维仑显现可使患者的LDL－C浓度较单用他汀类药物再额外最高降低16％。这些研究发现,阿伐他汀80mg／天剂量与阿伐他汀10mg／天加盐酸考来维仑3.8g／天两方案所致患者LDL－C浓度降低值在统计学显著范围内没有差异。研究还发现，阿伐他汀和辛伐他汀即使在它们剂量低至10mg／天时亦能显著降低甘油三酯。但若并用盐酸考来维仑，则阿伐他汀的这一作用几乎完全抵消，然辛伐他汀降低甘油三酯的效应却仅受到很小影响。盐酸考来维仑并用辛找他汀似更有益。 盐酸考来维仑的最常见副反应包括肠胃气胀（12％）、便秘（11％）、消化不良（8％）、感染（l％）和头痛（6％）等，其中胃肠道副应、尤是便秘发生率明显小于考来烯胺和考来替泊、上述三个胆酸鳌合剂的胃肠道副反应都大于他汀类药物，然因它们不被吸收，故系统副反应发生率却小于他汀类药物。盐酸考来维仑禁忌用于肠梗阻患者并应谨慎给药于吞咽困难、吞烟机能障碍、严重胃肠道功能障碍或已施行主要胃肠道手术者。 考来烯胺和考来替泊会减少脂溶性维生素A、D．E、K的吸收，但盐酸考来维仑却无此不良作用。考来烯胺和考来替泊因也能与其它药物结合，故它们通常宜于使用其它药物前1小时或4小时后给药。然盐酸考来维仑却在药物相互作用研究中显现，其并不明显影响地高辛、洛伐他汀、美托洛尔（meto-prolol／LOpressor）、奎尼T、丙戌酸（valproicacid／DePakene等）或华法林的生物利用度。盐酸考来维仑似亦不会降低缓释维拉帕米（veraPamil／Calan SR）的血药峰值和生物利用度，尽管后者的个体生物利用度变化很大。 盐酸考来维仑为片剂，每片含药625mg。盐酸考来维仑的推荐初始剂量每天2次、每次3片或每天1次6片。盐酸考来维仑的最大治疗效应约出现于开始给药的2周时，其最大治疗剂量推荐为每天7片。盐酸考来维仑与他汀类药物合用时可以同服，且其推荐剂量方案不变。 圣路易斯(MD Consult)——2009年10月7日，日本第一制药三共公司宣布，美国食品药物管理局(FDA)已批准增加降胆固醇药考来维仑(Welchol)的一个新适应证。这项新批准令使得考来维仑可作为10~17岁、患杂合子家族性高胆固醇血症(heFH)男孩及月经初潮后女孩饮食和运动疗法外的辅助治疗药，以降低其升高的低密度脂蛋白胆固醇(LDL-C)水平。可在这类患者对充分的饮食疗法试验无效后单独应用考来维仑，亦可联用一种他汀类药物。 FDA同时还批准了考来维仑口服混悬液，这使得现有片剂有了替代剂型。口服混悬液可作为成人2型糖尿病患者饮食和运动疗法外的辅助治疗药以改善血糖控制，还可作为成人原发性高脂血症患者饮食和运动疗法外的辅助治疗药以降低其升高的LDL-C水平，以上两种情况均可单独应用考来维仑口服混悬液或联用羟甲基戊二酰辅酶A还原酶抑制剂(他汀类药物)。口服混悬液亦适用于10~17岁、患heFH男孩及月经初潮后女孩饮食控制和运动疗法外的辅助治疗，以降低其升高的LDL-C水平，在认为其对饮食疗法无效后应用，既可单独用药，亦可与他汀类药物联合应用。考来维仑口服混悬液的推荐剂量为1日1包(规格：3.75 g/包)。 批准考来维仑用于治疗儿科heFH患者是基于一项历时8周、多中心、随机、安慰剂对照临床研究的数据。该研究旨在评价考来维仑单药(1.875 g/d 或3.75 g/d，片剂)或与他汀类药物联用的疗效。研究所纳入的男孩及月经初潮后女孩的年龄介于10~17岁，他们先前未接受过治疗或一直接受稳定剂量的他汀类药物治疗。 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
