Drug Interaction Report

MONITOR: Limited data suggest that clarithromycin may potentiate the hypoglycemic effect of sulfonylureas in susceptible individuals such as the elderly and patients with renal impairment. The exact mechanism is unknown but may involve clarithromycin displacement of sulfonylureas from plasma protein binding sites. The interaction was suspected in two elderly patients (72 and 82 years old) who developed severe hypoglycemia and profound mental status changes within 48 hours after initiating clarithromycin 1000 mg/day for bronchitis. Both patients had type II diabetes that was previously well controlled on diet and sulfonylurea therapy (glipizide 15 mg/day and glyburide 5 mg/day), and both had mild to moderately impaired renal function. The patients were given intravenous glucose with no further incident after discontinuing the sulfonylurea.

MANAGEMENT: Clarithromycin should be prescribed cautiously to diabetic patients with renal impairment who are receiving sulfonylurea therapy, particularly if they are also elderly. Patients should be advised to regularly monitor their blood sugar and counseled on how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, and palpitations. The physician should be notified if an interaction is suspected.

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MONITOR: Concomitant use of insulin and other antidiabetic agents with clarithromycin may cause significant hypoglycemia. There have been rare reports of hypoglycemia in patients treated with clarithromycin, some of whom were taking oral hypoglycemic agents or insulin. The exact mechanism of interaction has not been established. With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of the CYP450 3A4 isoenzyme by clarithromycin may be involved.

MANAGEMENT: Caution is advised if clarithromycin is prescribed to patients receiving antidiabetic agents. Patients should be advised to regularly monitor their blood sugar and counseled on how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia.

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MONITOR: Coadministration of metformin with an insulin secretagogue (e.g., sulfonylurea, meglitinide) or insulin may potentiate the risk of hypoglycemia. Although metformin alone generally does not cause hypoglycemia under normal circumstances of use, the added therapeutic effect when combined with other antidiabetic agents may result in hypoglycemia. The risk is further increased when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplementation.

MANAGEMENT: A lower dosage of the insulin secretagogue or insulin may be required when used with metformin. Blood glucose should be closely monitored, and patients should be educated on the potential signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, tachycardia) and appropriate remedial actions to take if it occurs. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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MONITOR: Concomitant use of insulin and other antidiabetic agents with clarithromycin may cause significant hypoglycemia. There have been rare reports of hypoglycemia in patients treated with clarithromycin, some of whom were taking oral hypoglycemic agents or insulin. The exact mechanism of interaction has not been established. With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of the CYP450 3A4 isoenzyme by clarithromycin may be involved.

MANAGEMENT: Caution is advised if clarithromycin is prescribed to patients receiving antidiabetic agents. Patients should be advised to regularly monitor their blood sugar and counseled on how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia.

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ADJUST DOSE: Coadministration of a sulfonylurea with insulin may potentiate the risk of hypoglycemia. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.

MANAGEMENT: Caution and close blood glucose monitoring are advised during coadministration of these agents. A lower dosage of sulfonylurea or insulin may be required. Patients should be counseled to recognize the symptoms of hypoglycemia such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients should initiate appropriate remedial therapy immediately and contact their physician. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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MONITOR: Coadministration of metformin with an insulin secretagogue (e.g., sulfonylurea, meglitinide) or insulin may potentiate the risk of hypoglycemia. Although metformin alone generally does not cause hypoglycemia under normal circumstances of use, the added therapeutic effect when combined with other antidiabetic agents may result in hypoglycemia. The risk is further increased when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplementation.

MANAGEMENT: A lower dosage of the insulin secretagogue or insulin may be required when used with metformin. Blood glucose should be closely monitored, and patients should be educated on the potential signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, tachycardia) and appropriate remedial actions to take if it occurs. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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MONITOR: Concomitant use of insulin and other antidiabetic agents with clarithromycin may cause significant hypoglycemia. There have been rare reports of hypoglycemia in patients treated with clarithromycin, some of whom were taking oral hypoglycemic agents or insulin. The exact mechanism of interaction has not been established. With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of the CYP450 3A4 isoenzyme by clarithromycin may be involved.

MANAGEMENT: Caution is advised if clarithromycin is prescribed to patients receiving antidiabetic agents. Patients should be advised to regularly monitor their blood sugar and counseled on how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia.

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ADJUST DOSE: Coadministration of a sulfonylurea with insulin may potentiate the risk of hypoglycemia. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.

MANAGEMENT: Caution and close blood glucose monitoring are advised during coadministration of these agents. A lower dosage of sulfonylurea or insulin may be required. Patients should be counseled to recognize the symptoms of hypoglycemia such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients should initiate appropriate remedial therapy immediately and contact their physician. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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MONITOR: Coadministration of metformin with an insulin secretagogue (e.g., sulfonylurea, meglitinide) or insulin may potentiate the risk of hypoglycemia. Although metformin alone generally does not cause hypoglycemia under normal circumstances of use, the added therapeutic effect when combined with other antidiabetic agents may result in hypoglycemia. The risk is further increased when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplementation.

MANAGEMENT: A lower dosage of the insulin secretagogue or insulin may be required when used with metformin. Blood glucose should be closely monitored, and patients should be educated on the potential signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, tachycardia) and appropriate remedial actions to take if it occurs. Patients should also be advised to take precautions to avoid hypoglycemia while driving or operating hazardous machinery.

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GENERALLY AVOID: Alcohol can potentiate the effect of metformin on lactate metabolism and increase the risk of lactic acidosis. In addition, alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Although hypoglycemia rarely occurs during treatment with metformin alone, the risk may increase with acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes.

Food may have varying effects on the absorption of metformin from immediate-release versus extended-release formulations. When a single 850 mg dose of immediate-release metformin was administered with food, mean peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 40% and 25%, respectively, and time to peak plasma concentration (Tmax) increased by 35 minutes compared to administration under fasting conditions. By contrast, administration of extended-release metformin with food increased AUC by 50% without affecting Cmax or Tmax, and both high- and low-fat meals had the same effect. These data may not be applicable to formulations that contain metformin with other oral antidiabetic agents.

MANAGEMENT: Metformin should be taken with meals, and excessive alcohol intake should be avoided during treatment. Diabetes patients in general should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Alcohol should not be consumed on an empty stomach or following exercise, as it may increase the risk of hypoglycemia. Patients should contact their physician immediately if they experience potential signs and symptoms of lactic acidosis such as malaise, myalgia, respiratory distress, increasing somnolence, and nonspecific abdominal distress (especially after stabilization of metformin therapy, when gastrointestinal symptoms are uncommon). With more marked acidosis, there may also be associated hypothermia, hypotension, and resistant bradyarrhythmias. Metformin should be withdrawn promptly if lactic acidosis is suspected. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful in establishing a diagnosis. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

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GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

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GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

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GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

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Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.

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The recommended maximum number of medicines in the 'antidiabetic drugs' category to be taken concurrently is usually three. Your list includes four medicines belonging to the 'antidiabetic drugs' category:

• glipizide
• metformin
• Humulin N (insulin isophane)
• Levemir (insulin detemir)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'intermediate- and long-acting insulins' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'intermediate- and long-acting insulins' category:

• Humulin N (insulin isophane)
• Levemir (insulin detemir)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.