Acarbose

... A possible interaction between digoxin and acarbose was reported. In these reports, absorption of digoxin was decreased dramatically by coadministration of acarbose. The hypoglycemic action of acarbose stems from the reversible and competitive inhibition of alpha-glucosidase that hydrolyzes oligosaccharides absorbed later as glucose molecules. Acarbose functions exclusively in intestine, and most of it appears unchanged in feces. Digoxin is a well-known medication used in the treatment of heart failure and/or chronic atrial fibrillation. Acarbose delays the digestion of sucrose and starch in humans; as a result, a disturbance of gastrointestinal transit, causing loose stools, follows. Therefore, it is possible that gastrointestinal motility is increased, and absorption of digoxin decreased, by coadministration with acarbose. It is also possible that acarbose interferes with the hydrolysis of digoxin before its absorption, resulting in alteration in the release of the corresponding genine and thus affecting the reliability of the digoxin laboratory test. These case reports indicate that the absorption of digoxin is decreased by the administration of acarbose. ...

In a single-centre, placebo-controlled, clinical study, the influence of an antacid containing magnesium hydroxide and aluminium hydroxide (Maalox 70; 10 mL) on the pharmacodynamics of the oral antidiabetic drug acarbose (Glucobay 100, Bay g 5421, CAS 56180; 100 mg) was tested in 24 healthy male volunteers. The drugs were given alone or in combination and were compared with placebo. Volunteers were randomized into four different treatment groups. The daily medication over 4 days was 1 x 1 placebo tablet, or 1 x 1 tablet containing 100 mg acarbose, or 1 x 1 tablet containing 100 mg acarbose plus 10 mL antacid suspension, or 1 x 1 placebo tablet plus 10 ml antacid suspension, interrupted by wash-out phases of 6-10 days between successive treatments. Efficacy was assessed on the basis of postprandial blood glucose and serum insulin levels after administration of 75 g sucrose, and was measured as maximal concentrations and 'area under the curve' (0-4 hr). No influence of the antacid on the blood glucose and insulin-lowering effect of acarbose could be detected. Hence, there does not appear to be a significant interaction between acarbose and the antacid tested. Antacids similar to that tested do not need to be classified as a contraindication when used in combination with acarbose.

To investigate whether treatment with acarbose alters the pharmacokinetics (PK) of coadministered rosiglitazone. Sixteen healthy volunteers (24-59-years old) received a single 8-mg dose of rosiglitazone on day 1, followed by 7 days of repeat dosing with acarbose [100 mg three times daily (t.i.d.) with meals]. On the last day of acarbose t.i.d. dosing (day 8), a single dose of rosiglitazone was given with the morning dose of acarbose. PK profiles following rosiglitazone dosing on days 1 and 8 were compared, and point estimates (PE) and associated 95% confidence intervals (CI) were calculated. Rosiglitazone absorption [as measured with peak plasma concentration (Cmax) and time to peak concentration (Tmax)] was unaffected by acarbose. The area under the concentration-time curve from time zero to infinity [AUC(0-infinity)] was on average 12% lower (95% CI-21%, -2%) during rosiglitazone + acarbose coadministration and was accompanied by an approximate 1-hr (23%) reduction in terminal elimination half-life (4.9 hr versus 3.8 hr). This small decrease in AUC(0-infinity) appears to be due to an alteration in systemic clearance of rosiglitazone and not changes in absorption. These observed changes in AUC(0-infinity) and half-life are not likely to be clinically relevant. Coadministration of rosiglitazone and acarbose was well tolerated. Acarbose administered at therapeutic doses has a small, but clinically insignificant, effect on rosiglitazone pharmacokinetics.

In several large clinical trials, serum enzyme elevations above 3 times the upper limit of normal were more common with acarbose therapy (2% to 5%) than with placebo, but all elevations were asymptomatic and resolved rapidly with stopping therapy. These studies reported no instances of clinically apparent liver injury. Subsequent to approval and with wide clinical use, however, at least a dozen instances of clinically apparent liver injury have been linked to acarbose use. The liver injury typically arises 2 to 8 months after starting therapy and is associated with a hepatocellular pattern of serum enzyme elevations with marked increases in serum ALT levels, suggestive of acute viral hepatitis. Immunoallergic features and autoantibody formation are not typical. While most cases are mild, some are associated with marked jaundice and cases with a fatal outcome have been reported to the sponsor. No cases of chronic liver injury or vanishing bile duct syndrome have been linked to acarbose use, and most large series of cases of drug induced liver injury and acute liver failure have not identified cases due to acarbose. Rechallenge has been carried out in several instances and resulted in recurrence with a shortening of the time to onset.

The most common adverse effects are GI symptoms, including flatulence, diarrhea, and abdominal pain. A high carbohydrate diet may worsen the adverse effects on the GI tract. GI symptoms tend to become reduced throughout treatment. Adherence to acarbose pharmacotherapy can be a problem because of side effects.

/HUMAN EXPOSURE STUDIES/ Fifty-gram carbohydrate tolerance tests were performed on healthy volunteers to test the activity and specificity of an alpha-glucoside hydrolase inhibitor, acarbose (BAY g 5421). Two hundred milligrams acarbose reduced the area under the blood glucose response curve by 89% (P less than 0.001) after sucrose by 80% (P less than 0.002) after starch, by 19% (N.S.) after maltose, with no effect on glucose. Breath hydrogen measurements indicated an almost complete malabsorption of the sucrose. At 50 mg acarbose, some reduction in blood glucose and insulin response to sucrose was still seen, but no significant hydrogen production.

/HUMAN EXPOSURE STUDIES/ To explore the long-term metabolic effects of acarbose in man, 6 healthy men (25 +/- 2 years; BMI: 21.6 +/- 2.7) were fed a controlled diet in a metabolic ward for 7 consecutive weeks. After an initial 3-week period to ensure a metabolic steady-state, they received 300 mg/d of acarbose (100 mg before each meal) for the remaining 4 weeks. Stool and urine collections were made over 7 d on weeks 3 and 7. Fecal excretion of water, nitrogen, carbohydrate, fat, zinc, magnesium, copper, chromium, iron, calcium and phosphorus and urinary excretion of nitrogen, urea and calcium were measured. In addition, fasting and postprandial blood glucose and insulin levels, as well as fasting triglycerides, total cholesterol, apolipoproteins (Apo) A-I, A-II, and B, zinc and copper, vitamins A, B1, B2, B6, C, and E concentrations were measured before and at the end of the acarbose period. Weight, food consumption, and water balance were not modified by acarbose. Fecal nitrogen excretion increased significantly but the nitrogen balance remained positive. Fecal excretion of carbohydrate, fat, iron and chromium were significantly increased by acarbose. Apos A-I and A-II decreased significantly. Plasma levels of vitamin B6 increased and vitamin A concentrations decreased with acarbose. This study provides new insights into the metabolic effects of acarbose with respect to nitrogen, mineral and vitamin metabolism.

/HUMAN EXPOSURE STUDIES/ The effect of acarbose on hydrolysis of a pure starch meal was investigated in normal subjects and ileostomy patients by means of (13)CO2 breath tests and blood glucose levels as parameters of absorption, and of H2 breath tests, serum acetate levels, and ileal loss of carbohydrate as parameters of malabsorption. Additional information on the effect of acarbose on alpha-amylase activity was obtained by in vitro experiments. Acarbose (200 and 400 mg) significantly delayed starch absorption. Serum acetate was found to be a less sensitive marker of malabsorption than breath H2 excretion. After intake of 50 g starch plus 400 mg acarbose, 23-71% of the starch load was lost in the ileostomy effluent, for a large part as starch. This suggests that acarbose considerably inhibits alpha-amylase, and not only brush-border enzymes. In vitro experiments confirm that an inhibition of two thirds of alpha-amylase activity can be expected from pharmacologically used doses of acarbose.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Acarbose

vMost-DILI-concern

8

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The present study investigated the effects of acarbose treatment on the site and extent of starch digestion, large-bowel fermentation and intestinal mucosal cell proliferation. Eighteen young male Wistar rats were fed "Westernised" diets containing 0, 250 and 500 mg acarbose/kg (six rats/diet) for 21 days. For most variables measured, both acarbose doses had similar effects. Acarbose treatment suppressed starch digestion in the small bowel but there was compensatory salvage by bacterial fermentation in the large bowel. This was accompanied by a substantial hypertrophy of small- and large-bowel tissue and a consistent increase in crypt width along the intestine. Cecal total SCFA pool size was increased more than 4-fold, with even bigger increases for butyrate. These changes in butyrate were reflected in increased molar proportions of butyrate in blood from both the portal vein and heart. There was little effect of acarbose administration on crypt-cell proliferation (significant increase for mid-small intestine only). This is strong evidence against the hypothesis that increased fermentation and increased supply of butyrate enhances intestinal mucosal cell proliferation. In conclusion, apart from the increased fecal loss of starch, there was no evidence of adverse effects of acarbose on the aspects of large-bowel function investigated.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a rat study, Sprague-Dawley rats received acarbose in feed at high doses (up to approximately 500 mg/kg body weight) for 104 weeks. Acarbose treatment resulted in a significant increase in the incidence of renal tumors (adenomas and adenocarcinomas) and benign Leydig cell tumors. This study was repeated with a similar outcome.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ ... Studies to separate direct carcinogenic effects of acarbose from indirect effects resulting from the carbohydrate malnutrition induced by the large doses of acarbose employed in the studies /were performed/. In one study using Sprague-Dawley rats, acarbose was mixed with feed but carbohydrate deprivation was prevented by the addition of glucose to the diet. In a 26-month study of Sprague-Dawley rats, acarbose was administered by daily postprandial gavage so as to avoid the pharmacologic effects of the drug. In both of these studies, the increased incidence of renal tumors found in the original studies did not occur. Acarbose was also given in food and by postprandial gavage in two separate studies in Wistar rats. No increased incidence of renal tumors was found in either of these Wistar rat studies. In two feeding studies of hamsters, with and without glucose supplementation, there was also no evidence of carcinogenicity.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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).

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.

Patients with severe renal impairment (Clcr < 25 mL/min/1.73 sq m) attained about 5 times higher peak plasma concentrations of acarbose and 6 times larger AUCs than volunteers with normal renal function.

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.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Emergency and support measures: Maintain an open airway and assist ventilation if necessary. Treat coma and seizures if they occur. Obtain finger stick blood glucose levels every 1-2 hours until stabilized. /Antidiabetic agents/

For more Antidote and Emergency Treatment (Complete) data for Acarbose (6 total), please visit the HSDB record page.

Acarbose

1.7

7.4

The recommended starting dosage of acarbose tablets is 25 mg given orally three times daily at the start (with the first bite) of each main meal.

Data used to generate the benchmarks include the following: Lowest Daily Dose (LDD): 75 mg/day, Lowest Therapeutic Dose (LTD): 0.9 mg/kg-day, and Screening Dose: 0.0003 mg/kg-day.

16-Sep-20

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including acarbose, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Use (kg; approx.) in Germany (2009): >2500