Glipizide and Metformin

Glipizide/metformin is a prescription medication used in the management of type 2 diabetes mellitus.

It is a single tablet containing 2 medications: glipizide and metformin.

Glipizide belongs to a group of drugs called sulfonylureas. These work by stimulating the release of insulin from the pancreas. Metformin belongs to a group of drugs called biguanides. These work by decreasing the amount of glucose absorbed from food and decreasing the amount of glucose that is produced by the liver.

This medication comes in tablet form and is taken once or twice daily with meals.

Common side effects of glipizide/metformin include stomach pain, nausea or vomiting, diarrhea, and dizziness.

Glipizide/metformin can also cause dizziness. Do not drive or operate heavy machinery until you know how glipizide/metformin affects you.

Glipizide/metformin is a prescription medication used in the management of type 2 diabetes mellitus. It helps to lower the amount of glucose (sugar) in the blood.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Glipizide and Metformin may be found in some form under the following brand names:

• Metaglip

Serious side effects have been reported with glipizide/metformin. See the “Glipizide/metformin Precautions” section.

Common side effects of glipizide/metformin include the following:

• stomach pain
• nausea or vomiting
• diarrhea
• dizziness

This is not a complete list of glipizide/metformin side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• acetazolamide (Diamox)
• amiloride (Midamor, in Moduretic)
• angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik)
• anticoagulants ('blood thinners') such as warfarin (Coumadin)
• aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) or naproxen (Aleve, Naprosyn)
• beta-blockers such as atenolol (Tenormin), labetalol (Normodyne), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), and propranolol (Inderal)
• calcium channel blockers such as amlodipine (Norvasc), diltiazem (Cardizem, Dilacor, Tiazac, others), felodipine (Plendil), isradipine (DynaCirc), nicardipine (Cardene), nifedipine (Adalat, Procardia), or verapamil (Calan, Isoptin, Verelan)
• chloramphenicol
• cimetidine (Tagamet)
• clarithromycin (Biaxin)
• cyclosporine (Neoral, Sandimmune)
• digoxin (Lanoxin)
• disopyramide (Norpace)
• diuretics ('water pills')
• fluconazole (Diflucan)
• fluoxetine (Prozac, Sarafem)
• furosemide (Lasix)
• hormone replacement therapy
• insulin or other medications for diabetes
• isoniazid
• MAO inhibitors such as isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelaplar), and tranylcypromine (Parnate)
• medications for allergies, asthma, and colds
• medications for mental illness and nausea
• miconazole (Lotrimin, Monistat, others)
• morphine (MS Contin, others)
• niacin
• oral contraceptives (birth control pills)
• oral steroids such as dexamethasone (Decadron, Dexone), methylprednisolone (Medrol), and prednisone (Deltasone)
• phenytoin (Dilantin Phenytek)
• probenecid (Benemid, in Colbenemid)
• procainamide (Procanbid)
• quinidine
• quinine
• quinolone and fluoroquinolone antibiotics such as cinoxacin (Cinobac), ciprofloxacin (Cipro), enoxacin (Penetrex), gatifloxacin (Tequin), levofloxacin (Levaquin), lomefloxacin (Maxaquin), moxifloxacin (Avelox), nalidixic acid (NegGram), norfloxacin (Noroxin), and ofloxacin (Floxin)
• ranitidine (Zantac)
• rifampin
• salicylate pain relievers such as choline magnesium trisalicylate, choline salicylate (Arthropan), diflunisal (Dolobid), magnesium salicylate (Doan's, others), or salsalate (Argesic, Disalcid, Salgesic)
• sulfa antibiotics such as Bactrim and Septra
• sulfasalazine (Azulfidine)
• thyroid medications
• topiramate (Topamax)
• triamterene (in Dyazide, Maxzide, others)
• trimethoprim (Primsol)
• vancomycin (Vancocin, others)
• zonisamide (Zonegran)

This is not a complete list of glipizide/metformin drug interactions. Ask your doctor or pharmacist for more information.

Serious side effects have been reported with glipizide/metformin including the following:

• Lactic acidosis. Tell your healthcare provider right away if you have some or all of the following symptoms of lactic acidosis.
  • Extreme tiredness
  • Weakness or discomfort
  • Unusual or unexpected stomach pain
  • Decreased appetite
  • Deep and rapid breathing or shortness of breath
  • Dizziness
  • Lightheadedness
  • Fast or slow heart beat
  • Flushing of the skin
  • Muscle pain
  • Feeling cold
• Hypoglycemia (low blood sugar). Tell your healthcare provider right away if you have some or all of the following symptoms of hypoglycemia.
  • Lightheadedness
  • Dizziness
  • Shakiness
  • Hunger
• Chest pain
• Rash
• Yellowing of the skin or eyes
• Light-colored stools
• Dark urine
• Pain in the upper right part of the abdomen
• Unusual bleeding or bruising
• Fever
• Sore throat
• Swelling of the eyes, face, tongue, or throat

Glipizide/metformin can cause dizziness. Do not drive or operate heavy machinery until you know how Metaglip affects you.

Do not take glipizide/metformin if you:

• are allergic to glipizide/metformin or to any of its ingredients
• have liver or kidney disease
• have acute or chronic metabolic acidosis
• have congestive heart failure that is treated with digoxin (Lanoxin) or furosemide (Lasix)
• drink alcohol excessively
• are dehydrated
• are going to have procedures (such as an X-ray) with injectable contrast agents
• are going to have surgery
• have a heart attack, stroke, or severe infection
• are older than 80 years and have not had your kidney function tested

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of glipizide/metformin, there are no specific foods that you must exclude from your diet when receiving this medication.

Before taking glipizide/metformin, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to glipizide/metformin or to any of its ingredients
• have kidney problems, other than diabetes
• have liver problems
• have heart problems
• have a G6PD deficiency
• have acute or chronic metabolic acidosis
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Glipizide/metformin falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if glipizide/metformin crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using glipizide/metformin.

Take glipizide/metformin exactly as prescribed.

Glipizide/metformin comes in tablet form and is taken once or twice daily with meals.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of glipizide/metformin at the same time.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

• The dose your doctor recommends may be based on the following:
• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication

The recommended starting dose of glipizide/metformin for the management of type 2 diabetes is 2.5 mg glipizide/250 mg metformin once daily with meals. The dose should be adjusted based on patient response, blood glucose levels, and other medications the patient is taking.

If you take too much glipizide/metformin, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If glipizide/metformin is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

• Store glipizide/metformin at room temperature away from excess heat, light, and moisture.
• Keep this and all medicines out of the reach of children.
• Avoid unnecessary or prolonged exposure to sunlight and wear protective clothing, sunglasses, and sunscreen. Glipizide/metformin may make your skin sensitive to sunlight.

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 19 (Suppl. 2):747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glipizide and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

WARNING

Metformin Hydrochloride

Lactic acidosis:

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Glipizide and Metformin HCl Tablets; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving Metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal

hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.

Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Glipizide and Metformin HCl Tablets treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Glipizide and Metformin HCl Tablets should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Glipizide and Metformin HCl Tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking Glipizide and Metformin HCl Tablets, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, Glipizide and Metformin HCl Tablets should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Glipizide and Metformin HCl Tablets should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of Glipizide and Metformin HCl Tablets, gastrointestinal symptoms, which are common during initiation of therapy with metformin, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking Glipizide and Metformin HCl Tablets do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking Glipizide and Metformin HCl Tablets, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.