Welchol suspension

Primary Hyperlipidemia

Welchol suspension is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoproteincholesterol (LDL-C) in adults with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with a hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor (statin).

Welchol suspension is indicated as monotherapy or in combination with a statin to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:

1. LDL-C remains ≥ 190 mg/dL or
2. LDL-C remains ≥ 160 mg/dL and
   • there is a positive family history of premature cardiovascular disease or
   • two or more other CVD risk factors are present in the pediatric patient.

Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol whenresponse to diet and non-pharmacological interventions alone has been inadequate.

In patients with coronary heart disease (CHD) or CHD risk equivalents such as diabetes mellitus, LDLC treatment goals are < 100 mg/dL. An LDL-C goal of < 70 mg/dL is a therapeutic option on the basis of recent trial evidence. If LDL-C is at goal but the serum triglyceride (TG) value is > 200 mg/dL, then non-HDL cholesterol (non-HDL-C) (total cholesterol [TC] minus high density lipoprotein cholesterol [HDL-C]) becomes a secondary target of therapy. The goal for non-HDL-C in persons with high serumTG is set at 30 mg/dL higher than that for LDL-C.

Type 2 Diabetes Mellitus

Welchol suspension is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Diabetes mellitus is considered a CHD risk equivalent. In addition to glycemic control, intensive lipid control is warranted.

Important Limitations Of Use

• Welchol suspension should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis.
• Welchol suspension has not been studied in type 2 diabetes in combination with a dipeptidyl peptidase 4 inhibitor.
• Welchol suspension has not been studied in pediatric patients with type 2 diabetes.
• Welchol suspension has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.
• Welchol suspension has not been studied in children younger than 10 years of age or in pre-menarchal girls.

Welchol suspension co-administered with a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) is indicated as adjunctive therapy to diet to provide an additive reduction in low-density lipoprotein cholesterol (LDL-C) levels in adult patients with primary hypercholesterolaemia who are not adequately controlled with a statin alone.

Welchol suspension as monotherapy is indicated as adjunctive therapy to diet for reduction of elevated total-cholesterol and LDL-C in adult patients with primary hypercholesterolaemia, in whom a statin is considered inappropriate or is not well-tolerated.

Welchol suspension can also be used in combination with ezetimibe, with or without a statin, in adult patients with primary hypercholesterolaemia, including patients with familial hypercholesterolaemia.

Primary Hyperlipidemia

The recommended dose of Welchol suspension Tablets in adults, whether used as monotherapy or in combination with a statin, is 6 tablets once daily or 3 tablets twice daily. Welchol suspension Tablets should be taken with a meal and liquid.

The recommended dose of Welchol suspension for Oral Suspension, in adults and children 10 to 17 years of age, is one 3.75 gram packet once daily or one 1.875 gram packet twice daily. To prepare, empty the entire contents of one packet into a glass or cup. Add ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol suspension for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol suspension for Oral Suspension should not be taken in its dry form. Due to tablet size, it is recommended that any patient who has difficulty swallowing tablets use Welchol suspension for Oral Suspension.

Welchol suspension can be dosed at the same time as a statin or the two drugs can be dosed apart.

After initiation of Welchol suspension, lipid levels should be analyzed within 4 to 6 weeks.

Type 2 Diabetes Mellitus

The recommended dose of Welchol suspension Tablets is 6 tablets once daily or 3 tablets twice daily. Welchol suspension should be taken with a meal and liquid.

The recommended dose of Welchol suspension for Oral Suspension is one 3.75 gram packet once daily or one 1.875 gram packet twice daily. To prepare, empty the entire contents of one packet into a glass or cup. Add ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol suspension for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol suspension for Oral Suspension should not be taken in its dry form.

Posology

Combination therapy

The recommended dose of Welchol suspension for combination with a statin with or without ezetimibe is 4 to 6 tablets per day. The maximum recommended dose is 6 tablets per day taken as 3 tablets twice per day with meals or 6 tablets taken once per day with a meal. Clinical trials have shown that Welchol suspension and statins can be co-administered or dosed apart, and that Welchol suspension and ezetimibe can be co-administered or dosed apart.

Monotherapy

The recommended starting dose of Welchol suspension is 6 tablets per day taken as 3 tablets twice per day with meals or 6 tablets once per day with a meal. The maximum recommended dose is 7 tablets per day.

During therapy, the cholesterol-lowering diet should be continued, and serum total-C, LDL-C and triglyceride levels should be determined periodically during treatment to confirm favourable initial and adequate long-term responses.

When a drug interaction cannot be excluded with a concomitant medicinal product for which minor variations in the therapeutic level would be clinically important, or where no clinical data are available on co-administration, Welchol suspension should be administered at least four hours before or at least four hours after the concomitant medication in order to minimize the risk of reduced absorption of the concomitant medication.

Elderly population

There is no need for dose adjustment when Welchol suspension is administered to elderly patients.

Paediatric population

The safety and efficacy of Welchol suspension in children aged 0 to 17 years have not yet been established.

Method of administration

Welchol suspension tablets should be taken orally with a meal and liquid.

The tablets should be swallowed whole and not broken, crushed or chewed.

Welchol suspension is contraindicated in patients with

• A history of bowel obstruction
• Serum TG concentrations > 500 mg/dL
• A history of hypertriglyceridemia-induced pancreatitis

-

- Bowel or biliary obstruction

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

General

The effect of Welchol suspension on cardiovascular morbidity and mortality has not been determined.

Serum Triglycerides

Welchol suspension, like other bile acid sequestrants, can increase serum TG concentrations.

Welchol suspension had small effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia.

In clinical trials in patients with type 2 diabetes, greater increases in TG levels occurred when Welchol suspension was used as monotherapy (median increase 9.7% compared to placebo) and when Welchol suspension was used in combination with pioglitazone (median increase 11% compared to placebo in combination with pioglitazone), sulfonylureas (median increase 18% compared to placebo in combination with sulfonylureas), and insulin (median increase 22% compared to placebo in combination with insulin). Hypertriglyceridemia of sufficient severity can cause acute pancreatitis. The long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain. In patients with type 2 diabetes, the effect of Welchol suspension on LDLC levels may be attenuated by Welchol suspension's effects on TG levels and a smaller reduction in non HDL-C compared to the reduction in LDL-C. Caution should be exercised when treating patients with TG levels greater than 300 mg/dL. Because most patients in the Welchol suspension clinical trials had baseline TG < 300 mg/dL, it is unknown whether patients with more uncontrolled baseline hypertriglyceridemia would have greater increases in serum TG levels with Welchol suspension. In addition, the use of Welchol suspension is contraindicated in patients with TG levels > 500 mg/dL. Lipid parameters, including TG levels and non-HDL-C, should be obtained before starting Welchol suspension and periodically thereafter. Welchol suspension should be discontinued if TG levels exceed 500 mg/dL or if the patient develops hypertriglyceridemia-induced pancreatitis.

Vitamin K Or Fat-Soluble Vitamin Deficiencies Precautions

Bile acid sequestrants may decrease the absorption of fat-soluble vitamins A, D, E, and K. No specific clinical studies have been conducted to evaluate the effects of Welchol suspension on the absorption of coadministered dietary or supplemental vitamin therapy. In non-clinical safety studies, rats administered colesevelam hydrochloride at doses greater than 30-fold the projected human clinical dose experienced hemorrhage from vitamin K deficiency. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to Welchol suspension. Caution should be exercised when treating patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins.

Gastrointestinal Disorders

Because of its constipating effects, Welchol suspension 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. Because of the tablet size, Welchol suspension Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. To avoid esophageal distress, Welchol suspension for Oral Suspension should not be taken in its dry form. Always mix Welchol suspension for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting.

Drug Interactions

Welchol suspension reduces gastrointestinal absorption of some drugs. Drugs with a known interaction withcolesevelam should be administered at least 4 hours prior to Welchol suspension. 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 suspension. Alternatively, the physician should monitor drug levels of the co-administered drug.

Phenylketonurics

Welchol suspension for Oral Suspension contains 13.5 mg phenylalanine per 1.875 gram packet and 27 mg phenylalanine per 3.75 gram packet.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular disease risk reduction with Welchol suspension or any other antidiabetic drugs.

Nonclinical Toxicology

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 druginduced 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.

Impairment Of Fertility

Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).

Use In Specific Populations

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.

Nursing Mothers

Colesevelam hydrochloride is not expected to be excreted in human milk because colesevelam hydrochloride is not absorbed systemically from the gastrointestinal tract.

Pediatric Use

The safety and effectiveness of Welchol suspension as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age with heFH. 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.

Due to tablet size, Welchol suspension for Oral Suspension is recommended for use in the pediatric population. Dose adjustments are not required when Welchol suspension is administered to children 10 to 17 years of age.

Welchol suspension has not been studied in children younger than 10 years of age or in pre-menarchal girls.

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 suspension 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.

Hepatic Impairment

No special considerations or dosage adjustments are recommended when Welchol suspension is administered to patients with hepatic impairment.

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

Secondary causes of hypercholesterolaemia

Prior to initiating therapy with Welchol suspension, if secondary causes of hypercholesterolaemia (i.e., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease) are considered, these should be diagnosed and properly treated.

Interaction with ciclosporin

For patients on ciclosporin starting or stopping Welchol suspension or patients on Welchol suspension with a need to start ciclosporin: ). Patients starting on ciclosporin already taking Welchol suspension should have their ciclosporin blood concentrations monitored as normal and their dose adjusted as normal. Patients starting on Welchol suspension already taking ciclosporin should have their blood concentrations monitored prior to combination therapy and frequently monitored immediately starting co-therapy with the ciclosporin dose adjusted accordingly. It should be noted that stopping Welchol suspension therapy will result in increased ciclosporin blood concentrations. Therefore, patients taking both ciclosporin and Welchol suspension should have their blood concentrations monitored prior to and frequently after when Welchol suspension therapy is stopped with their ciclosporin dose adjusted accordingly.

Effects on triglyceride levels

Caution should be exercised when treating patients with triglyceride levels greater than 3.4 mmol/L due to the triglyceride increasing effect with Welchol suspension. Safety and efficacy are not established for patients with triglyceride levels greater than 3.4 mmol/L, since such patients were excluded from the clinical studies.

The safety and efficacy of Welchol suspension in patients with dysphagia, swallowing disorders, severe gastrointestinal motility disorders, inflammatory bowel disease, liver failure or major gastrointestinal tract surgery have not been established. Consequently, caution should be exercised when Welchol suspension is used in patients with these disorders.

Constipation

Welchol suspension can induce or worsen present constipation. The risk of constipation should especially be considered in patients with coronary heart disease and angina pectoris.

Anticoagulants

).

Oral contraceptives

Welchol suspension can affect the bioavailability of the oral contraceptive pill when administered simultaneously.).

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction ratesobserved 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 Welchol suspension 1.5 g/day to 4.5 g/day from 4 to 24 weeks (total exposure 199 patient-years).

In clinical trials for the reduction of LDL-C, 68% of patients receiving Welchol suspension vs. 64% of patients receiving placebo reported an adverse reaction.

Table 1 : Placebo-Controlled Clinical Studies of Welchol suspension for Primary Hyperlipidemia: Advers e Reactions Reported in ≥ 2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality

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 heterozygous familial hypercholesterolemia (heFH) (n=192), were treated with Welchol suspension tablets (1.9-3.8 g, daily) or placebo tablets.

Table 2 : Placebo-Controlled Clinical Study of Welchol suspension 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

The reported adverse reactions during the additional 18-week open-label treatment period with Welchol suspension 3.8 g per day were similar to those during the double-blind period and included headache (7.6%), nasopharyngitis (5.4%), upper respiratory tract infection (4.9%), influenza (3.8%), and nausea (3.8%).

Type 2 Diabetes Mellitus

The safety of Welchol suspension 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. In these studies 1022 patients were exposed to Welchol suspension. The mean exposure duration was 20 weeks (total exposure 393 patient-years). Patients were to receive 3.8 grams of Welchol suspension per day. The mean age of patients exposed to Welchol suspension 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 suspension vs. 52% of patients receiving placebo reported an adverse reaction.

Table 3 shows common adverse reactions associated with the use of Welchol suspension in the 1015 patients with type 2 diabetes. These adverse reactions were not present at baseline, occurred more commonly on Welchol suspension than on placebo, and occurred in at least 2% of patients treated with Welchol suspension.

Table 3 : Placebo-Controlled Clinical Studies of Welchol suspension 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

A total of 5.3% of Welchol suspension-treated patients and 3.6% of placebo-treated patients were discontinued from the diabetes trials due to adverse reactions. This difference was driven mostly by gastrointestinal adverse reactions such as abdominal pain and constipation.

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 suspension, which may represent a hypersensitivity reaction to Welchol suspension.

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 suspension group and 162 mg/dL in the placebo group. Welchol suspension 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. In comparison, Welchol suspension resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial.

Treatment-emergent fasting TG concentrations ≥ 500 mg/dL occurred in 0.9% of Welchol suspension-treated patients compared to 0.7% of placebo-treated patients in the diabetes trials. Among these patients, the TG concentrations with Welchol suspension (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 suspension and 3 (0.3%) patients on placebo developed TG elevations ≥ 1000 mg/dL. In all Welchol suspension 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 suspension.

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 suspension 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.

Post-marketing Experience

The following additional adverse reactions have been identified during post-approval use of Welchol suspension. 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 suspension Administration include:

• Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin. Phenytoin should be administered 4 hours prior to Welchol suspension.
• Reduced International Normalized Ratio (INR) in patients receiving warfarin therapy. In warfarin-treated patients, INR should be monitored frequently during Welchol suspension 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 suspension.

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

Summary of the safety profile

The most frequently occurring adverse reactions are flatulence and constipation, found within the gastrointestinal disorders system organ class.

Tabulated list of adverse reactions

In controlled clinical studies involving approximately 1400 patients and during post-approval use, the following adverse reactions were reported in patients given Welchol suspension.

The reporting rate is classified as very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

* see section below for further information

** adverse reactions from post-marketing experience

Description of selected adverse events

The background incidence of flatulence and diarrhoea were higher in patients receiving placebo in the same controlled clinical studies. Only constipation and dyspepsia were reported by a higher percentage among those receiving Welchol suspension, compared with placebo.

The incidence of intestinal obstruction is likely to be increased among patients with a history of bowel obstruction or removal.

Welchol suspension in combination with statins and in combination with ezetimibe was well tolerated and the adverse reactions observed were consistent with the known safety profile of statins or ezetimibe alone.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed below:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Doses of Welchol suspension in excess of 4.5 g/day have not been tested. Because Welchol suspension is not absorbed, the risk of systemic toxicity is low. However, excessive doses of Welchol suspension may cause more severe local gastrointestinal effects (e.g., constipation) than recommended doses.

Since Welchol suspension is not absorbed, the risk of systemic toxicity is low. Gastrointestinal symptoms could occur. Doses in excess of the maximum recommended dose (4.5 g per day (7 tablets)) have not been tested.

Should overdosage occur, however, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction and the presence or absence of normal gut motility would determine treatment.

A maximum therapeutic response to the lipid-lowering effects of Welchol suspension was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to Welchol suspension, as reflected by a reduction in hemoglobin A1C (A1C), was initially noted following 4-6 weeks of treatment and reached maximal or near maximal effect after 12-18 weeks of treatment.

Pharmacotherapeutic group: Lipid modifying agent, bile acid sequestrants, ATC code: C10A C 04

Mechanism of action

The mechanism of action for the activity of colesevelam, the active substance in Welchol suspension, has been evaluated in several in vitro and in vivo studies. These studies have demonstrated that colesevelam binds bile acids, including glycocholic acid, the major bile acid in humans. Cholesterol is the sole precursor of bile acids. During normal digestion, bile acids are secreted into the intestine. A major portion of bile acids is then absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation.

Colesevelam is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. The LDL-C lowering mechanism of bile acid sequestrants has been previously established as follows: As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effects of increasing transcription and activity of the cholesterol biosynthetic enzyme, hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase, and increasing the number of hepatic low-density lipoprotein receptors. A concomitant increase in very low density lipoprotein synthesis can occur. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels.

In a 6-month dose-response study in patients with primary hypercholesterolaemia receiving 3.8 or 4.5 g Welchol suspension daily, a 15 to 18% decrease in LDL-C levels was observed, which was evident within 2 weeks of administration. In addition, Total-C decreased 7 to 10%, HDL-C increased 3% and triglycerides increased 9 to 10%. Apo B decreased by 12%. In comparison, in patients given placebo, LDL-C, Total-C, HDL-C and Apo-B were unchanged, while triglycerides increased 5%. Studies examining administration of Welchol suspension as a single dose with breakfast, a single dose with dinner, or as divided doses with breakfast and dinner did not show significant differences in LDL-C reduction for different dosing schedules. However, in one study triglycerides tended to increase more when Welchol suspension was given as a single dose with breakfast.

In a 6 week study 129 patients with mixed hyperlipidaemia were randomised to fenofibrate 160 mg plus 3.8 g Welchol suspension or fenofibrate alone. The fenofibrate plus Welchol suspension group (64 patients) demonstrated a 10% reduction on LDL-C levels versus 2% increase for the fenofibrate group (65 patients). Reductions were also seen for non-HDL-C, Total-C and Apo B. A small 5%, non-significant increase in triglycerides was noted. The effects of combination of fenofibrate and Welchol suspension on the risks of myopathy or hepatotoxicity are not known.

Multi-centre, randomised, double-blind, placebo-controlled studies in 487 patients demonstrated an additive reduction of 8 to 16% in LDL-C when 2.3 to 3.8 g Welchol suspension and a statin (atorvastatin, lovastatin or simvastatin) were administered at the same time.

The effect of 3.8 g Welchol suspension plus 10 mg ezetimibe versus 10 mg ezetimibe alone on LDL-C levels was assessed in a multicentre, randomised, double-blind, placebo-controlled, parallel-group study in 86 patients with primary hypercholesterolaemia over a 6-week treatment period. The combination of ezetimibe 10 mg and Welchol suspension 3.8 g daily therapy in the absence of a statin resulted in a significant combined effect for LDL-C lowering by 32% demonstrating an additional effect of 11% LDL-C lowering with Welchol suspension and ezetimibe compared to ezetimibe alone.

The addition of Welchol suspension 3.8 g daily to maximally-tolerated statin and ezetimibe therapy was assessed in a multi-centre, randomised, double-blind, placebo-controlled study in 86 patients with familial hypercholesterolaemia. A total of 85% of the patients were on either atorvastatin (50% of whom received 80 mg dose) or rosuvastatin (72% of whom received 40 mg dose). Welchol suspension resulted in a statistically significant LDL-C reduction of 11% and 11% at 6 and 12 weeks vs an increase of 7% and 1% in the placebo group; mean baseline levels were 3.75 mmol/L and 3.86 mmol/L, respectively. Triglycerides in the Welchol suspension group increased by 19% and 13% at 6 and 12 weeks vs an increase of 6% and 13% in the placebo group, but the increases were not significantly different. HDL-C and hsCRP levels were also not significantly different compared to placebo at 12 weeks.

Paediatric population

In the paediatric population, the safety and efficacy of 1.9 or 3.8 g/day Welchol suspension was assessed in an 8 week multi-centre, randomised, double-blind, placebo-controlled study in 194 boys and postmenarchal girls, aged 10-17 years, with heterozygous FH on a stable dose of statins (47 patients, 24%) or treatment-naïve to lipid-lowering therapy (147 patients, 76%). For all patients, Welchol suspension resulted in a statistically significant LDL-C reduction of 11% at 3.8 g/day and 4% at 1.9 g/day, versus a 3% increase in the placebo group. For statin-naïve patients on monotherapy, Welchol suspension resulted in a statistically significant LDL-C reduction of 12% at 3.8 g/day and 7% at 1.9 g/day, versus a 1% reduction in the placebo group. There were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors, and the adverse reaction profile for Welchol suspension was comparable to that seen with placebo.

Welchol suspension has not been compared directly to other bile acid sequestrants in clinical trials.

So far, no studies have been conducted that directly demonstrate whether treatment with Welchol suspension as monotherapy or combination therapy has any effect on cardiovascular morbidity or mortality.

Absorption

Colesevelam hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed.

Distribution

Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract.

Metabolism

Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450.

Excretion

In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single ¹⁴C-labeled colesevelam hydrochloride dose was excreted in the urine.

Welchol suspension is not absorbed from the gastrointestinal tract.