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COLESEVELAM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Colesevelam, a nonabsorbable hydrogel, is a bile acid sequestrant, binding bile acids in the intestine and preventing their absorption.

Specific Substances

    1) Colesevelam hydrochloride
    2) GT31-104HB
    3) CAS 182815-44-7 (colesevelam hydrochloride)

Available Forms Sources

    A) FORMS
    1) Colesevelam is available as 625 mg tablets, and 1.875 and 3.75 g/packet oral powder for suspension (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    B) USES
    1) Colesevelam is used as adjunctive therapy for the reduction of elevated low-density lipoprotein (LDL) cholesterol in patients with primary hyperlipidemia. It is administered as monotherapy or in combination with a HMG-CoA reductase inhibitor, in addition to diet and exercise (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    2) Colesevelam is also indicated for the management of type 2 diabetes mellitus, as adjunctive therapy to diet and exercise (Prod Info WELCHOL oral tablets, oral suspension, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Colesevelam is used as adjunctive therapy for the reduction of elevated low-density lipoprotein (LDL) cholesterol in patients with primary hyperlipidemia. It is administered as monotherapy or in combination with a HMG-CoA reductase inhibitor, in addition to diet and exercise. Colesevelam is also indicated for the management of type 2 diabetes mellitus, as adjunctive therapy to diet and exercise.
    B) PHARMACOLOGY: Colesevelam hydrochloride is a lipid-lowering polymeric agent that exerts its action by actively binding to bile acids to prevent its reabsorption in the intestines. This action depletes serum bile acids, which activates cholesterol 7-alpha-hydroxylase to convert cholesterol into bile acids. Consequently, a demand for cholesterol in the liver is increased, resulting in increased HMG-CoA reductase transcription and activity, and increased number of low-density lipoprotein (LDL) receptors. This compensatory action increases LDL-cholesterol clearance from the blood, resulting in lowered serum LDL-cholesterol level.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON: Constipation, dyspepsia, and nausea. OTHER EFFECTS (SOME RARE): Hypertriglyceridemia, hypoglycemia (usually when colesevelam was administered with other hypoglycemic agents), hyperglycemia, vomiting, esophageal obstruction, bowel obstruction, diarrhea, pancreatitis, myocardial infarction, aortic stenosis, hypertension, bradycardia, elevated liver enzymes, hypersensitivity reaction, muscle pain, backache, asthenia, headache, fatigue, nasopharyngitis, pharyngitis, AND upper respiratory tract infection.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. It is anticipated that colesevelam overdoses may result in an extension of the gastrointestinal effects observed at therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Colesevelam is classified as FDA pregnancy category B. There were no fetal anomalies in animals following maternal administration at doses up to 50 times the maximum human dose.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and liver enzymes after significant overdose.
    C) Monitor fluid and electrolyte status as indicated in patients with persistent vomiting.
    D) Assess bowel function in all patients following an overdose; monitor for abdominal pain or distention, vomiting, constipation, or evidence of bowel obstruction.
    E) Monitor serum glucose if another hypoglycemic agent was also ingested.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Obstruction of the gastrointestinal tract may occur. Assess bowel function in all patients following an overdose; monitor for abdominal pain or distention, vomiting, constipation, or evidence of bowel obstruction. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) Colesevelam is not absorbed in the gastrointestinal tract; therefore, decontamination measures (ie, activated charcoal, gastric lavage) are not indicated unless another toxic substance is coingested.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Symptomatic patients should be sent to a healthcare facility for evaluation and treatment as necessary.
    3) ADMISSION CRITERIA: Symptomatic patients (eg, bowel obstruction) should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    G) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    H) PHARMACOKINETICS
    1) Colesevelam is not absorbed; therefore, distribution is limited to the gastrointestinal tract. It is not metabolized and an average of 0.05% of administered radioactivity was excreted in the urine in 16 healthy volunteers after taking a single radiolabeled dose of colesevelam.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Doses up to 4.5 grams/day have been well-tolerated, with gastrointestinal effects (ie, constipation, dyspepsia, nausea) as the most common adverse effects observed.
    B) THERAPEUTIC DOSE: ADULTS: ORAL TABLETS: 6 tablets (625 mg each) daily or 3 tablets twice daily. ORAL SUSPENSION: 3.75 grams daily or 1.875 grams twice daily. CHILDREN: 10 TO 17 YEARS: 3.75 grams daily or 1.875 grams twice daily, in an oral suspension. CHILDREN 9 YEARS AND YOUNGER: Safety and efficacy of colesevelam in children less than 10-years-old and in pre-menarchal girls have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Colesevelam is used as adjunctive therapy for the reduction of elevated low-density lipoprotein (LDL) cholesterol in patients with primary hyperlipidemia. It is administered as monotherapy or in combination with a HMG-CoA reductase inhibitor, in addition to diet and exercise. Colesevelam is also indicated for the management of type 2 diabetes mellitus, as adjunctive therapy to diet and exercise.
    B) PHARMACOLOGY: Colesevelam hydrochloride is a lipid-lowering polymeric agent that exerts its action by actively binding to bile acids to prevent its reabsorption in the intestines. This action depletes serum bile acids, which activates cholesterol 7-alpha-hydroxylase to convert cholesterol into bile acids. Consequently, a demand for cholesterol in the liver is increased, resulting in increased HMG-CoA reductase transcription and activity, and increased number of low-density lipoprotein (LDL) receptors. This compensatory action increases LDL-cholesterol clearance from the blood, resulting in lowered serum LDL-cholesterol level.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON: Constipation, dyspepsia, and nausea. OTHER EFFECTS (SOME RARE): Hypertriglyceridemia, hypoglycemia (usually when colesevelam was administered with other hypoglycemic agents), hyperglycemia, vomiting, esophageal obstruction, bowel obstruction, diarrhea, pancreatitis, myocardial infarction, aortic stenosis, hypertension, bradycardia, elevated liver enzymes, hypersensitivity reaction, muscle pain, backache, asthenia, headache, fatigue, nasopharyngitis, pharyngitis, AND upper respiratory tract infection.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. It is anticipated that colesevelam overdoses may result in an extension of the gastrointestinal effects observed at therapeutic doses.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HEART DISEASE
    1) WITH THERAPEUTIC USE
    a) Serious cardiovascular events developed in 2.2% of patients with type 2 diabetes treated for a mean of 20 weeks with colesevelam alone or in combination (ie, metformin, pioglitazone, sulfonylurea, insulin; n=1015) compared with 1% of placebo-treated patients (n=1010) in double-blind clinical trials. These events showed no particular pattern and included myocardial infarction, aortic stenosis, and bradycardia (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    B) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Hypertension occurred in 2.6% of patients with type 2 diabetes treated for a mean of 20 weeks with colesevelam 3.8 g/day (n=1015) compared with 1.9% of placebo-treated patients (n=1010) in 5 double-blind, add-on combination trials (ie, metformin, pioglitazone, sulfonylureas, insulin) and 1 monotherapy trial (Prod Info WELCHOL oral tablets, oral suspension, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) NASOPHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) Nasopharyngitis occurred in 6.2% of pediatric patients aged 10 to 17 years treated with colesevelam 1.9 to 3.8 g/day for heterozygous familial hypercholesterolemia (n=129) compared with 4.6% of placebo-treated patients (n=65) in an 8-week double-blind trial. Nasopharyngitis incidence was 5.4% with an additional 18 weeks of open-label therapy with colesevelam 3.8 g/day (Prod Info WELCHOL oral tablets, oral suspension, 2013).
    b) Nasopharyngitis occurred in 4.1% of patients with type 2 diabetes treated with colesevelam together with metformin, sulfonylurea, or insulin (n=566) compared with 3.6% of placebo-treated patients (n=562) in 4 double-blind, add-on combination therapy trials of up to 26 weeks' duration (Prod Info WELCHOL oral tablets, oral suspension, 2013).
    B) PHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) Pharyngitis occurred in 3.2% of patients treated with colesevelam 1.5 to 4.5 g/day for primary hyperlipidemia and elevated LDL-C (n=807) compared with 1.9% of placebo-treated patients (n=258) in 7 double-blind trials of up to 24 weeks' duration (Prod Info WELCHOL oral tablets, oral suspension, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In 7 double-blind, placebo-controlled, clinical trials involving 1065 patients with primary hyperlipidemia, 3.6% of patients receiving colesevelam hydrochloride (n=807) reported asthenia compared to 1.9% in the placebo group (n=258) (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache occurred in 4.6% of patients with type 2 diabetes treated with colesevelam monotherapy (n=175) compared with 2.9% of placebo-treated patients (n=171) in a double-blind clinical trial. Patients had received no antidiabetic medication within 3 months of the study (Prod Info WELCHOL oral tablets, oral suspension, 2013).
    b) Headache occurred in 3.9% of pediatric patients aged 10 to 17 years treated with colesevelam 1.9 to 3.8 g/day for heterozygous familial hypercholesterolemia (n=129) compared with 3.1% of placebo-treated patients (n=65) in an 8-week double-blind trial. Headache incidence was 7.6% after an additional 18 weeks of open-label therapy with colesevelam 3.8 g/day (Prod Info WELCHOL oral tablets, oral suspension, 2013).
    C) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue occurred in 3.9% of pediatric patients aged 10 to 17 years treated with colesevelam 1.9 to 3.8 g/day for heterozygous familial hypercholesterolemia (n=129) compared with 1.5% of placebo-treated patients (n=65) in an 8-week double-blind trial (Prod Info WELCHOL oral tablets, oral suspension, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation occurred in 6.5% of patients with type 2 diabetes treated for a mean of 20 weeks with colesevelam 3.8 g/day (n=1015) compared with 2.2% of placebo-treated patients (n=1010) in 5 double-blind, add-on combination trials (ie, metformin, pioglitazone, sulfonylureas, insulin) and 1 monotherapy trial (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    b) Constipation occurred in 11% of patients treated with colesevelam 1.5 to 4.5 g/day for primary hyperlipidemia and elevated LDL-C (n=807) compared with 7% of placebo-treated patients (n=258) in 7 double-blind trials of up to 24 weeks' duration (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    B) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dyspepsia occurred in 2.8% of patients with type 2 diabetes treated for a mean of 20 weeks with colesevelam 3.8 g/day (n=1015) compared with 1% of placebo-treated patients (n=1010) in 5 double-blind, add-on combination trials (ie, metformin, pioglitazone, sulfonylureas, insulin) and 1 monotherapy trial (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    b) Dyspepsia occurred in 8.3% of patients treated with colesevelam 1.5 to 4.5 g/day for primary hyperlipidemia and elevated LDL-C (n=807) compared with 3.5% of placebo-treated patients (n=258) in 7 double-blind trials of up to 24 weeks' duration (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    C) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea occurred in 2.6% of patients with type 2 diabetes treated for a mean of 20 weeks with colesevelam 3.8 g/day (n=1015) compared with 1.6% of placebo-treated patients (n=1010) in 5 double-blind, add-on combination trials (ie, metformin, pioglitazone, sulfonylureas, insulin) and 1 monotherapy trial (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    b) Nausea occurred in 4.2% of patients treated with colesevelam 1.5 to 4.5 g/day for primary hyperlipidemia and elevated LDL-C (n=807) compared with 3.9% of placebo-treated patients (n=258) in 7 double-blind trials of up to 24 weeks' duration (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    D) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting occurred in 2.3% of pediatric patients aged 10 to 17 years treated with colesevelam 1.9 to 3.8 g/day for heterozygous familial hypercholesterolemia (n=129) compared with 1.5% of placebo-treated patients (n=65) in an 8-week double-blind trial (Prod Info WELCHOL oral tablets, oral suspension, 2013).
    E) OBSTRUCTION OF ESOPHAGUS
    1) WITH THERAPEUTIC USE
    a) Esophageal obstruction that has required medical intervention has been reported in postmarketing surveillance with colesevelam use (Prod Info WELCHOL oral tablets, oral suspension, 2013).
    F) INTESTINAL OBSTRUCTION
    1) WITH THERAPEUTIC USE
    a) Bowel obstruction has been reported in postmarketing surveillance with colesevelam use in patients with a history of bowel resection or obstruction (Prod Info WELCHOL oral tablets, oral suspension, 2013).
    G) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea occurred in 4% of patients with type 2 diabetes treated with colesevelam monotherapy (n=175) compared with 1.8% of placebo-treated patients (n=171) in a double-blind clinical trial. Patients had received no antidiabetic medication within 3 months of the study (Prod Info WELCHOL oral tablets, oral suspension, 2013).
    H) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) There were no reports of acute pancreatitis associated with hypertriglyceridemia during studies of patients with type 2 diabetes and patients with primary hyperlipidemia. However, pancreatitis has been reported in postmarketing surveillance. Marked increases in triglyceride (TG) levels may lead to acute pancreatitis (Prod Info WELCHOL oral tablets, oral suspension, 2013).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) Increased transaminase levels have been reported with colesevelam use in postmarketing surveillance (Prod Info WELCHOL oral tablets, oral suspension, 2013).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia occurred in 2.1%% of patients treated with colesevelam 1.5 to 4.5 g/day for primary hyperlipidemia and elevated LDL-C (n=807) compared with 0.4% of placebo-treated patients (n=258) in 7 double-blind trials of up to 24 weeks' duration (Prod Info WELCHOL oral tablets, oral suspension, 2013).
    B) BACKACHE
    1) WITH THERAPEUTIC USE
    a) Back pain occurred in 2.3% of patients with type 2 diabetes treated for a mean of 20 weeks with colesevelam 3.8 g/day (n=1015) compared with 1.3% of placebo-treated patients (n=1010) in 5 double-blind, add-on combination trials (ie, metformin, pioglitazone, sulfonylureas, insulin) and 1 monotherapy trial (Prod Info WELCHOL oral tablets, oral suspension, 2014).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERTRIGLYCERIDEMIA
    1) WITH THERAPEUTIC USE
    a) In double-blind add-on and monotherapy clinical trials, the median fasting triglyceride (TG) concentration in patients with type 2 diabetes rose from 160 mg/dL to 180 mg/dL in patients treated with colesevelam (n=1015) compared with 162 m/dL in placebo-treated patients (n=1010) with a mean 20 weeks of treatment. In 0.9% of colesevelam-treated patients, a treatment-emergent fasting TG concentration of 500 mg/dL or more occurred (median TG, 606 mg/dL) compared with 0.7% of placebo-treated patients (median TG, 663 mg/dL). TG elevation of 1000 mg/dL or greater occurred in 0.6% and 0.3% of colesevelam- and placebo-treated patients, respectively. Colesevelam monotherapy was associated with a 9.7% increase in median placebo-corrected serum TG levels. Patients coadministered pioglitazone, sulfonylureas, or insulin had median placebo-corrected TG level increases of 11%, 18%, and 22%, respectively. Combination therapy with metformin resulted in a nonsignificant 5% increase in median placebo-corrected serum TG levels (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    b) In a 24-week monotherapy lipid-lowering trial (n=277), treatment with colesevelam increased serum triglycerides (TG) 5% compared with placebo (p=0.42) (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    B) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hypoglycemia occurred in 3.4% of patients with type 2 diabetes treated for a mean of 20 weeks with colesevelam 3.8 g/day (n=1015) compared with 3.1% of placebo-treated patients (n=1010) in 5 double-blind, add-on combination trials (ie, metformin, pioglitazone, sulfonylureas, insulin) and 1 monotherapy trial (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    C) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia occurred in 2.9% of patients with type 2 diabetes treated with colesevelam monotherapy (n=175) compared with 1.8% of placebo-treated patients (n=171) in a double-blind clinical trial. Patients had received no antidiabetic medication within 3 months of the study (Prod Info WELCHOL oral tablets, oral suspension, 2013).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) In a double-blind clinical trial (n=2025), hypersensitivity reaction (ie, body rash, mouth blistering) occurred in 1 patient with type 2 diabetes with an initial dose of colesevelam 3.8 g/day in combination with sulfonylurea (Prod Info WELCHOL oral tablets, oral suspension, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Colesevelam is classified as FDA pregnancy category B. There were no fetal anomalies in animals following maternal administration at doses up to 50 times the maximum human dose.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Offspring of animals given colesevelam at doses up to 50 times the maximum human dose did not show any anomalies (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified colesevelam as FDA pregnancy category B (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF EFFECT
    1) Since the drug is not absorbed systemically, colesevelam should not be present in breast milk (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Colesevelam did not impair fertility in animals at doses approximately 50 times the maximum human dose, based on body weight (Prod Info WELCHOL oral tablets, oral suspension, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS182815-44-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) ADENOMA
    1) In a 2–year study involving Harlan Sprague-Dawley rats, a statistically significant increase in pancreatic acinar cell adenoma was observed in male rats treated with a dose greater than 1.2 g/kg/day (approximately 20 times the maximum human dose based on body weight) (trend test only) (Prod Info WELCHOL oral tablets, 2008). A statistically significant increase in thyroid C-cell adenoma was observed in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight) (Prod Info WELCHOL oral tablets, 2008).
    B) LACK OF EFFECT
    1) A 2–year carcinogenicity study was conducted in CD-1 mice at an oral dose up to 3 g/kg/day (approximately 50 times the maximum recommended human dose of 4.5 g/day) (Prod Info WELCHOL oral tablets, 2008). In this study, no significant drug-induced tumors were found in male or female mice.

Genotoxicity

    A) Colesevelam and four degradants present in the drug have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test (Prod Info WELCHOL oral tablets, 2008). The four degradants and an extract of colesevelam 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 (Prod Info WELCHOL oral tablets, 2008). An extract of colesevelam 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 (Prod Info WELCHOL oral tablets, 2008). The results of the CHO cell chromosomal aberration assay with two of the four degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation ; however, the other two degradants, didecylamine HCl and 6–decylamino-hexyltrimethyl ammonium chloride HCl, were both negative in the presence and absence of metabolic activation (Prod Info WELCHOL oral tablets, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and liver enzymes after significant overdose.
    C) Monitor fluid and electrolyte status as indicated in patients with persistent vomiting.
    D) Assess bowel function in all patients following an overdose; monitor for abdominal pain or distention, vomiting, constipation, or evidence of bowel obstruction.
    E) Monitor serum glucose if another hypoglycemic agent was also ingested.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Symptomatic patients (eg, bowel obstruction) should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients should be sent to a healthcare facility for evaluation and treatment as necessary.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and liver enzymes after significant overdose.
    C) Monitor fluid and electrolyte status as indicated in patients with persistent vomiting.
    D) Assess bowel function in all patients following an overdose; monitor for abdominal pain or distention, vomiting, constipation, or evidence of bowel obstruction.
    E) Monitor serum glucose if another hypoglycemic agent was also ingested.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Colesevelam is not absorbed in the gastrointestinal tract; therefore, decontamination measures (ie, activated charcoal, gastric lavage) are not indicated unless another toxic substance is coingested.
    6.5.2) PREVENTION OF ABSORPTION
    A) Colesevelam is not absorbed in the gastrointestinal tract; therefore, decontamination measures (ie, activated charcoal, gastric lavage) are not indicated unless another toxic substance was coingested.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Obstruction of the gastrointestinal tract may occur. Assess bowel function in all patients following an overdose; monitor for abdominal pain or distention, vomiting, constipation, or evidence of bowel obstruction. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and liver enzymes after significant overdose.
    3) Monitor fluid and electrolyte status as indicated in patients with persistent vomiting.
    4) Assess bowel function in all patients following an overdose; monitor for abdominal pain or distention, vomiting, constipation, or evidence of bowel obstruction.
    5) Monitor serum glucose if another hypoglycemic agent was also ingested.
    C) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Doses up to 4.5 grams/day have been well-tolerated, with gastrointestinal effects (ie, constipation, dyspepsia, nausea) as the most common adverse effects observed.
    B) THERAPEUTIC DOSE: ADULTS: ORAL TABLETS: 6 tablets (625 mg each) daily or 3 tablets twice daily. ORAL SUSPENSION: 3.75 grams daily or 1.875 grams twice daily. CHILDREN: 10 TO 17 YEARS: 3.75 grams daily or 1.875 grams twice daily, in an oral suspension. CHILDREN 9 YEARS AND YOUNGER: Safety and efficacy of colesevelam in children less than 10-years-old and in pre-menarchal girls have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) PRIMARY HYPERLIPIDEMIA
    1) ORAL TABLETS: 6 tablets daily or 3 tablets twice daily (Prod Info WELCHOL oral tablets, oral suspension, 2014)
    2) ORAL SUSPENSION: 3.75 grams daily or 1.875 grams twice daily (Prod Info WELCHOL oral tablets, oral suspension, 2014)
    B) TYPE 2 DIABETES MELLITUS
    1) ORAL TABLETS: 6 tablets daily or 3 tablets twice daily (Prod Info WELCHOL oral tablets, oral suspension, 2014)
    2) ORAL SUSPENSION: 3.75 grams daily or 1.875 grams twice daily (Prod Info WELCHOL oral tablets, oral suspension, 2014)
    7.2.2) PEDIATRIC
    A) PRIMARY HYPERLIPIDEMIA
    1) CHILDREN 10 TO 17 YEARS: 3.75 grams daily or 1.875 grams twice daily, in an oral suspension (Prod Info WELCHOL oral tablets, oral suspension, 2014)
    2) CHILDREN 9 YEARS AND YOUNGER: Safety and efficacy of colesevelam in children less than 10-years-old and in pre-menarchal girls have not been established (Prod Info WELCHOL oral tablets, oral suspension, 2014).
    B) TYPE 2 DIABETES MELLITUS
    1) Safety and efficacy of colesevelam in the pediatric and adolescent population have not been established (Prod Info WELCHOL oral tablets, oral suspension, 2014).

Maximum Tolerated Exposure

    A) A specific toxic dose has not been established. Doses up to 4.5 grams/day have been well-tolerated, with gastrointestinal effects (ie, constipation, dyspepsia, nausea) as the most common adverse effects observed (Prod Info WELCHOL oral tablets, oral suspension, 2014).

Workplace Standards

    A) ACGIH TLV Values for CAS182815-44-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS182815-44-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS182815-44-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS182815-44-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Colesevelam is a bile acid sequestrant (cross-linked hydrogel polymer) used for the treatment of hypercholesterolemia and type 2 diabetes mellitus (Prod Info WELCHOL oral tablets, oral suspension, 2014; Mesner et al, 1998; Rosenbaum et al, 1997). Following oral administration, colesevelam binds bile acids in the intestine, preventing their absorption; this deficiency results in hepatic conversion of cholesterol to bile acids. The depletion of hepatic cholesterol elicits an upregulation of the LDL receptor and clearance of LDL from the plasma (Mandeville & Arbeeny, 1999; Rosenbaum et al, 1997; Anon, 1999b).
    B) Animal studies suggest minimal-to-no systemic absorption of colesevelam after oral doses (Rosenbaum et al, 1997).
    C) The method by which colesevelam improves glycemic control in patients with type 2 diabetes mellitus is unknown (Prod Info WELCHOL oral tablets, oral suspension, 2014).

References

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