Acarbose

Acarbose is an Antidiabetic Agent belonging to pharmacology class of Alpha-Glucosidase Inhibitor.

Acarbose can be used in the treatment of Diabetes mellitus, type 2, treatment.

Acarbose is <2% (as active drug) and approx 35% (as metabolites) are absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 1 hour (active drug) and get Exclusively metabolized in the gastrointestinal tract mainly by intestinal bacteria and digestive enzymes into at least 13 metabolites, including sulfate, methyl, and glucuronide conjugates as the major metabolites and get excreted Via urine (approx 34% as inactive metabolites; <2% as unchanged drug and active metabolites); faeces (approx 51% as unabsorbed drug). Elimination half-life: Approx 2 hours.

Acarbose is available in the form of Tablets.

The molecule is available in India, USA, Japan, Germany.

Acarbose can be used in the treatment of Diabetes mellitus, type 2, treatment. It is also used to treat Postprandial hyperinsulinemic hypoglycemia after gastric bypass surgery.

Acarbose competitively and reversibly inhibits membrane-bound intestinal α-glucosidases and pancreatic α-amylase resulting in the delayed absorption of glucose and degradation of ingested complex carbohydrates and disaccharides in the small intestine. This action leads to a reduced post-prandial rise in blood glucose, therefore decreasing blood glucose fluctuations.

Acarbose is approved for use in the following clinical indications

Diabetes mellitus, type 2, treatment: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Although not approved there have been certain off labelled uses documented for Acarbose which includes:

Postprandial hyperinsulinemic hypoglycemia after gastric bypass surgery.

Diabetes mellitus, type 2, treatment: Note: Dosage must be individualized on the basis of effectiveness and tolerance.

Oral: Initial: 25 mg 3 times daily with the first bite of each main meal (may also initiate at 25 mg once daily with gradual titration to 25 mg 3 times daily as tolerated); increase dose at 4- to 8-week intervals based on 1-hour postprandial glucose or HbA_1c levels and tolerance until maintenance dose of 50 to 100 mg 3 times daily is reached (maximum dose: ≤60 kg: 50 mg 3 times daily; >60 kg: 100 mg 3 times daily).

Postprandial hyperinsulinemic hypoglycemia after gastric bypass surgery (off label): Oral: 25 to 100 mg 3 times daily just prior to the start of each meal, or if more frequent meals may consider 25 to 50 mg up to 6 times daily. Administer in conjunction with dietary modifications aimed at reducing the glycemic index of each meal.

Tablets

25 mg, 50 mg, 100 mg.

Tablets

Dose Adjustment in Kidney impairment patient:

Serum creatinine ≤2 mg/dL or CrCl ≥25 mL/ minute/1.73 m²: There are no dosage adjustments provided in the manufacturer’s labeling.

Serum creatinine >2 mg/dL or CrCl <25 ml/minute/1.73 m²: Use is not recommended; systemic AUC increased 6-fold in patients with CrCl <25 mL/ minute/1.73 m².

Dose Adjustment in Pediatric Patient:

Diabetes mellitus, type 2: Limited data available: Note: Alpha glucosidase inhibitors could be considered an additional therapeutic option in pediatric patients with type 2 diabetes mellitus who are ≥3 months post diagnosis and if target HbA_1c <7% not attained while on metformin therapy (maximized) in addition to a healthy lifestyle (eg, diet and exercise) with or without insulin. However, due to limited data and adverse effects, use of acarbose is limited to those who cannot tolerate other therapies; based on mechanism of action, acarbose will be more effective in those in whom carbohydrates make up a large part of the diet.

Children ≥10 years and Adolescents: Oral: Initial dose: 25 mg 3 times daily with the first bite of each main meal; may also initiate at 25 mg once daily with gradual titration to 25 mg 3 times daily as tolerated; then increase in 25 mg/dose increments in 2- to 4-week intervals as tolerated. Weight-based maximum dose: ≤60 kg: 50 mg/dose, >60 kg: 100 mg/dose. Clinical trials in pediatric patients are lacking; dosing based on expert-reported clinical experience; overall dosing is similar to that used in adult patients

Dumping syndrome (reactive hypoglycemia) after Nissen fundoplication: Limited data available:

Infants ≥4 months and young children who have failed nutritional manipulations: Oral: Initial dose: 12.5 to 25 mg before each bolus feeding of formula containing complex carbohydrates. Increase in 12.5 to 25 mg/dose increments until postprandial serum glucose stable (>60 mg/dL was used in clinical reports). Reported dose range: 12.5 to 100 mg/dose. Dosing based on a few small studies (total n=11). Acarbose was well tolerated in most patients, except for a few patients who experienced flatulence.

Acarbose may be contraindicated in the following conditions:-

Hypersensitivity to acarbose or any component of the formulation; diabetic ketoacidosis; cirrhosis; inflammatory bowel disease, colonic ulceration, partial intestinal obstruction, patients predisposed to intestinal obstruction; chronic intestinal diseases associated with marked disorders of digestion or absorption; conditions that may deteriorate as a result of increased gas formation in the intestine.

Concerns related to adverse effects:

• Elevated serum transaminases: Treatment-emergent elevations of serum transaminases (AST and/or ALT) and hyperbilirubinemia may occur (dose-related). These elevations were asymptomatic, reversible, more common in females, and, in general, were not associated with other evidence of liver dysfunction. Fulminant hepatitis (may be fatal) has been reported. If elevations are observed, a reduction in dosage or withdrawal of therapy may be indicated, particularly if the elevations persist.

• Hypoglycemia: Hypoglycemia is unlikely to occur with acarbose monotherapy but may occur with combination therapy (eg, sulfonylureas, insulin, metformin). In patients taking acarbose, oral glucose (dextrose) should be used instead of sucrose (cane sugar) in the treatment of mild-to-moderate hypoglycemia since the hydrolysis of sucrose to glucose and fructose is inhibited by acarbose.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Not recommended in patients with significant impairment (serum creatinine >2 mg/dL or CrCl <25 mL/minute/1.73 m²).

• Stress-related states: It may be necessary to discontinue acarbose and administer insulin if the patient is exposed to stress (ie, fever, trauma, infection, surgery).

There is no sufficient scientific evidence traceable regarding use and safety of Acarbose in concurrent use with alcohol.

It is not known if Acarbose is present in breast milk.

Pregnancy Category (FDA): B The safety of acarbose in pregnant women has not been established. Reproduction studies have been performed in rats at doses up to 480 mg/kg (corresponding to 9 times the exposure in humans, based on drug blood levels) and have revealed no evidence of impaired fertility or harm to the fetus due to acarbose. In rabbits, reduced maternal body weight gain, probably the result of the pharmacodynamic activity of high doses of acarbose in the intestines, may have been responsible for a slight increase in the number of embryonic losses. However, rabbits given 160 mg/kg acarbose (corresponding to 10 times the dose in man, based on body surface area) showed no evidence of embryotoxicity and there was no evidence of teratogenicity at a dose 32 times the dose in man (based on body surface area). There are, however, no adequate and well-controlled studies of acarbose in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

The adverse reactions related to Acarbose can be categorized as

Common Adverse effects:

Increased serum transaminase levels, Thrombocytopenia

Less Common Adverse effects:

Flatulence, diarrhea, abdominal pain, nausea, vomiting, dyspepsia.

Rare Adverse Effects:

The clinically relevant drug interactions of Acarbose is briefly summarized here

May reduce the effect when used with intestinal adsorbents (e.g. charcoal) and digestive enzyme preparations containing carbohydrate splitting enzymes (e.g. pancreatin, amylase). May potentiate the hypoglycemic effects of insulin and sulfonylureas. May cause enhanced reductions of postprandial blood glucose and increased frequency and severity of gastrointestinal side effects with oral neomycin. Colestyramine may enhance the effects of acarbose. May affect the bioavailability of digoxin. May result in loss of blood glucose control when used with certain agents that produce hyperglycemia (e.g. thiazides and other diuretics, phenothiazines, corticosteroids, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, Ca channel blockers, isoniazid).

The most common side effects of Acarbose includes: Increased serum transaminase levels, Thrombocytopenia.

• Pregnancy Category (FDA): B The safety of acarbose in pregnant women has not been established. Reproduction studies have been performed in rats at doses up to 480 mg/kg (corresponding to 9 times the exposure in humans, based on drug blood levels) and have revealed no evidence of impaired fertility or harm to the fetus due to acarbose. In rabbits, reduced maternal body weight gain, probably the result of the pharmacodynamic activity of high doses of acarbose in the intestines, may have been responsible for a slight increase in the number of embryonic losses. However, rabbits given 160 mg/kg acarbose (corresponding to 10 times the dose in man, based on body surface area) showed no evidence of embryotoxicity and there was no evidence of teratogenicity at a dose 32 times the dose in man (based on body surface area). There are, however, no adequate and well-controlled studies of acarbose in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Animal Data

• In animal reproductive studies, pregnant rats and rabbits received Acarbose at doses up to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human oral dose (MRHD) based on body surface area (mg/m2); no teratogenicity was observed. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m2 basis). No functional or behavioral toxicity was observed in rat offspring. When pregnant rats received Acarbose during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately two or more times the MRHD (mg/m2 basis). In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m2 basis).
• There is no FDA guidance on use of Acarbose during labor and delivery.

Nursing Mothers

A small amount of radioactivity has been found in the milk of lactating rats after administration of radiolabeled acarbose. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, acarbose should not be administered to a nursing woman.

Pediatric Use

There is no FDA guidance on the use of Acarbose in pediatric settings.

Geriatric Use

Of the total number of subjects in clinical studies of acarbose in the United States, 27% were 65 and over, while 4% were 75 and over. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. The mean steady-state area under the curve (AUC) and maximum concentrations of acarbose were approximately 1.5 times higher in elderly compared to young volunteers; however, these differences were not statistically significant.

Gender

There is no FDA guidance on the use of Acarbose with respect to specific gender populations.

Race

There is no FDA guidance on the use of Acarbose with respect to specific racial populations.

Renal Impairment

Plasma concentrations of acarbose in renally impaired volunteers were proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine > 2.0 mg/dL) have not been conducted. Therefore, treatment of these patients with acarbose is not recommended.

Hepatic Impairment

There is no FDA guidance on the use of Acarbose in patients with hepatic impairment.

Females of Reproductive Potential and Males

Fertility studies conducted in rats after oral administration produced no untoward effect on fertility or on the overall capability to reproduce.

Immunocompromised Patients

There is no FDA guidance one the use of Acarbose in patients who are immunocompromised.

Signs and Symptoms

During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

Management

In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

Pharmacodynamics:

Acarbose is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

Pharmacokinetics:

Absorption: <2% (as active drug) and approx 35% (as metabolites) are absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 1 hour (active drug).

Metabolism: Exclusively metabolised in the gastrointestinal tract mainly by intestinal bacteria and digestive enzymes into at least 13 metabolites, including sulfate, methyl, and glucuronide conjugates as the major metabolites.

Excretion: Via urine (approx 34% as inactive metabolites; <2% as unchanged drug and active metabolites); faeces (approx 51% as unabsorbed drug). Elimination half-life: Approx 2 hours.

1. https://www.uptodate.com/contents/ Acarbose -drug-information?search= Acarbose &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Acarbose _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Acarbose ?type=full&mtype=generic#mechanism-of-action