Azistar

1 INDICATIONS AND USAGE Colesevelam hydrochloride is a bile acid sequestrant indicated as an adjunct to diet and exercise to: reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia ( 1.1 ). reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH), unable to reach LDL-C target levels despite an adequate trial of diet and lifestyle modification ( 1.1 ). improve glycemic control in adults with type 2 diabetes mellitus ( 1.2 ). Limitations of Use ( 1.3 ): Do not use for treatment of type 1 diabetes or for diabetic ketoacidosis. Not studied in Fredrickson Type I, III, IV, and V dyslipidemias 1.1 Primary Hyperlipidemia Colesevelam hydrochloride is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia. Colesevelam hydrochloride is indicated to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) who are unable to reach LDL-C target levels despite an adequate trial of dietary therapy and lifestyle modification. 1.2 Type 2 Diabetes Mellitus Colesevelam hydrochloride is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus . 1.3 Limitations of Use Colesevelam hydrochloride should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis. Colesevelam hydrochloride has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

2 DOSAGE AND ADMINISTRATION Obtain lipid parameters, including serum triglyceride (TG) levels, before starting colesevelam hydrochloride ( 2.1 ). The recommended dosage for adults and for boys and postmenarchal girls aged 10 to 17 years with primary hyperlipidemia is 3.75 grams daily. The recommended dosage for adults with type 2 diabetes mellitus is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows ( 2.2 , 2.4 ): Tablets Take 6 tablets once daily or 3 tablets twice daily with a meal and liquid. For Oral Suspension Take one packet once daily with a meal. To prepare, empty the entire contents of one packet into a glass or cup. Add 1 cup of water, fruit juice, or diet soft drinks. Stir well and drink. 2.1 Testing Prior to Initiation of Colesevelam Hydrochloride Obtain lipid parameters, including triglyceride (TG) levels, before starting colesevelam hydrochloride. Colesevelam hydrochloride is contraindicated in patients with TG levels >500 mg/dL [see Contraindications (4) and Warnings and Precautions (5.1) ] . 2.2 Recommended Dosage in Primary Hyperlipidemia and Type 2 Diabetes Mellitus The recommended dosage of colesevelam hydrochloride for adults and for boys and postmenarchal girls aged 10 to 17 years with primary hyperlipidemia is 3.75 grams daily. The recommended dosage of colesevelam hydrochloride for adults with type 2 diabetes mellitus is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows: Tablets Take 6 tablets once daily or 3 tablets twice daily. Due to tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population. For Oral Suspension Take one packet once daily. 2.3 Important Dosing Information for Primary Hyperlipidemia Colesevelam hydrochloride can be dosed at the same time as a statin, or colesevelam hydrochloride and the statin can be dosed apart . Monitor lipid levels within 4 to 6 weeks after initiation of colesevelam hydrochloride. 2.4 Administration Instructions…

12.2 Pharmacodynamics A maximum therapeutic response to the lipid-lowering effects of colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to colesevelam hydrochloride, as reflected by a reduction in HbA1c, was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment.

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Hypertriglyceridemia and Pancreatitis [see Warnings and Precautions (5.1) ] Gastrointestinal Obstruction [see Warnings and Precautions (5.2) ] Vitamin K or Fat-Soluble Vitamin Deficiencies [see Warnings and Precautions (5.3) ] In clinical trials, the most common (incidence ≥2% and greater than placebo) adverse reactions with colesevelam hydrochloride included constipation, dyspepsia, and nausea ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice. Primary Hyperlipidemia In 7 double-blind, placebo-controlled clinical trials, 807 patients with primary hyperlipidemia (age range 18-86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with colesevelam hydrochloride 1.5 g/day to 4.5 g/day from 4 to 24 weeks (total exposure 199 patient-years). Table 1 Clinical Studies of Colesevelam Hydrochloride for Primary Hyperlipidemia: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo Colesevelam Hydrochloride N=807 Placebo N=258 Constipation 11.0% 7.0% Dyspepsia 8.3% 3.5% Nausea 4.2% 3.9% Accidental injury 3.7% 2.7% Asthenia 3.6% 1.9% Pharyngitis 3.2% 1.9% Flu syndrome 3.2% 3.1% Rhinitis 3.2% 3.1% Myalgia 2.1% 0.4% Pediatric Patients 10 to 17 Years of Age In an 8-week double-blind, placebo-controlled study, boys and post-menarchal girls, 10 to 17 years of age, with HeFH (n=194), were treated with colesevelam hydrochloride tablets (1.9-3.8 g, daily) or placebo tablets. Table 2 Clinical Study of…

4 CONTRAINDICATIONS Colesevelam hydrochloride is contraindicated in patients with: Serum TG concentrations >500 mg/dL [see Warnings and Precautions (5.1) ] History of hypertriglyceridemia-induced pancreatitis [see Warnings and Precautions (5.1) ] A history of bowel obstruction [see Warnings and Precautions (5.2) ] Patients with serum triglyceride levels >500 mg/dL ( 4 ) Patients with a history of hypertriglyceridemia-induced pancreatitis ( 4 ) Patients with a history of bowel obstruction ( 4 )

5 WARNINGS AND PRECAUTIONS Hypertriglyceridemia and Pancreatitis: Colesevelam hydrochloride can increase TG. Hypertriglyceridemia can cause acute pancreatitis. Monitor lipids, including TG. Instruct patients to discontinue colesevelam hydrochloride and seek prompt medical attention if the symptoms of acute pancreatitis occur ( 5.1 ). Gastrointestinal Obstruction: Cases of bowel obstruction have occurred. Colesevelam hydrochloride is not recommended in patients with gastroparesis, other gastrointestinal motility disorders, and in those who have had major gastrointestinal tract surgery and who may be at risk for bowel obstruction ( 5.2 ). Vitamin K or Fat-Soluble Vitamin Deficiencies: Colesevelam hydrochloride may decrease absorption of fat-soluble vitamins. Patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins may be at increased risk. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to colesevelam hydrochloride ( 5.3 ). Drug Interactions: Due to the potential for decreased absorption of other drugs that have not been tested for interaction, consider administering at least 4 hours prior to colesevelam hydrochloride ( 5.4 , 7 , 12.3 ). Risks in Patients with Phenylketonuria (PKU): Phenylalanine can be harmful to patients with phenylketonuria. Colesevelam hydrochloride for oral suspension contains 27 mg phenylalanine per 3.75 gram packet ( 5.5 , 11 ). 5.1 Hypertriglyceridemia and Pancreatitis Colesevelam hydrochloride, like other bile acid sequestrants, can increase serum TG concentrations. Hypertriglyceridemia can cause acute pancreatitis. Colesevelam hydrochloride had effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia. In trials in patients with type 2 diabetes, greater increases in TG levels occurred when colesevelam hydrochloride was used as monotherapy (median…

7 DRUG INTERACTIONS Concomitant use with colesevelam hydrochloride may decrease the exposure of the following drugs: Drugs with a narrow therapeutic index (e.g., cyclosporine), phenytoin, thyroid hormone replacement therapy, warfarin, oral contraceptives containing ethinyl estradiol and norethindrone, olmesartan medoxomil, and sulfonylureas (glimepiride, glipizide, glyburide). Administer these drugs 4 hours prior to colesevelam hydrochloride. For patients on warfarin, monitor International Normalized Ratio (INR) frequently during initiation then periodically ( 7.1 ). Concomitant use with colesevelam hydrochloride may increase the exposure of the following drugs: Metformin extended release. Monitor patients' glycemic control ( 7.2 ). 7.1 Colesevelam Hydrochloride Drug Interactions that Decrease the Exposure of the Concomitant Medication Table 4 includes a list of drugs that decrease exposure of the concomitant medication when administered concomitantly with colesevelam hydrochloride and instructions for preventing or managing them. Table 4 Colesevelam Hydrochloride Drug Interactions that Decrease the Exposure of the Concomitant Medication Drugs with a Narrow Therapeutic Index Clinical Impact: Concomitant use with colesevelam hydrochloride may decrease the exposure of the narrow therapeutic index drug. In vivo drug interactions studies showed a decrease in exposure of cyclosporine when coadministered with colesevelam hydrochloride [see Clinical Pharmacology (12.3) ]. Intervention: Administer the narrow therapeutic index drug at least 4 hours prior to colesevelam hydrochloride. Monitor drug levels when appropriate. Examples: Cyclosporine Phenytoin Clinical Impact: There have been postmarketing reports of increased seizure activity or decreased phenytoin levels in patients receiving phenytoin [see Adverse Reactions (6.2) ]. Intervention: Administer phenytoin 4 hours prior to colesevelam hydrochloride. Thyroid Hormone Replacement Therapy Clinical Impact: In vivo drug…