glipiZIDE 2.5 MG 24HR Extended Release Oral Tablet
Generic Name: GLIPIZIDE
Brand Name: Glipizide ER
- Substance Name(s):
- GLIPIZIDE
DRUG INTERACTIONS
7 Certain medications may affect glucose metabolism, requiring glipizide extended-release tablets dose adjustment and close monitoring of blood glucose ( 7.1 ) Miconazole: Monitor patients closely.
Severe hypoglycemia can occur when glipizide and oral miconazole are used concomitantly ( 7.2 , 12.3 ).
Fluconazole: Monitor patients closely.
An increase in glipizide AUC was seen after fluconazole administration ( 7.3 , 12.3 ).
Colesevelam: Glipizide extended-release tablets should be administered at least 4 hours prior to colesevelam ( 7.4 , 12.3 ).
7.1 Drugs Affecting Glucose Metabolism A number of medications affect glucose metabolism and may require glipizide extended release tablets dose adjustment and close monitoring for hypoglycemia or worsening glycemic control.
The following are examples of medication that may increase the glucose lowering effect of glipizide extended release tablets, increase the susceptibility to and/or intensity of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), sulfonamide antibiotics, nonsteroidal anti-inflammatory agents, chloramphenicol, probenecid, coumarins, voriconazole, H2 receptor antagonists, and quinolones.
When these medications are administered to a patient receiving glipizide extended release tablets, monitor the patient closely for hypoglycemia.
When these medications are discontinued from a patient receiving glipizide extended release tablets, monitor the patient closely for worsening glycemic control.
The following are examples of medication that may reduce the glucose-lowering effect of glipizide extended release tablets, leading to worsening glycemic control: atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), thyroid hormones, phenytoin, nicotinic acid, and calcium channel blocking drugs.
When such drugs are administered to patients receiving glipizide extended release tablets, monitor the patients closely for worsening glycemic control.
When these medications are discontinued from patients receiving glipizide extended release tablets, monitor the patient closely for hypoglycemia.
Alcohol, beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of the glucose-lowering effect.
Increased frequency of monitoring may be required when glipizide extended release tablets are co-administered with these drugs.
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.
Increased frequency of monitoring may be required when glipizide extended release tablets are co-administered with these drugs.
7.2 Miconazole Monitor patients closely for hypoglycemia when glipizide extended release tablets are co-administered with miconazole.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported [see Clinical Pharmacology (12.3) ].
7.3 Fluconazole Monitor patients closely for hypoglycemia when glipizide extended release tablets are co-administered with fluconazole.
Concomitant treatment with fluconazole increases plasma concentrations of glipizide, which may lead to hypoglycemia [see Clinical Pharmacology (12.3) ].
7.4 Colesevelam Glipizide extended-release tablets should be administered at least 4 hours prior to the administration of colesevelam.
Colesevelam can reduce the maximum plasma concentration and total exposure of glipizide when the two are co-administered [see Clinical Pharmacology (12.3) ].
OVERDOSAGE
10 Overdosage of sulfonylureas including glipizide extended-release tablets can produce severe hypoglycemia.
Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated with oral glucose.
Severe hypoglycemic reactions with coma, seizure, or other neurological impairment are medical emergencies requiring immediate treatment.
The patient should be treated with glucagon or intravenous glucose.
Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.
Clearance of glipizide from plasma may be prolonged in persons with liver disease.
Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit.
DESCRIPTION
11 Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class.
The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl] phenyl]sulfonyl]urea.
The molecular formula is C 21 H 27 N 5 O 4 S; the molecular weight is 445.55; the structural formula is shown below: Glipizide is a whitish, odorless powder with a pKa of 5.9.
It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide.
Glipizide Extended-Release Tablets are formulated as a polymer matrix based once-a-day controlled release tablet for oral use and is designed to deliver 2.5 mg, 5 mg or 10 mg of glipizide.
Each tablet contains the following inactive ingredients: acetyltributyl citrate, ammonia, butyl alcohol, edible black ink, ferrosoferric oxide, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl alcohol, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type A, polyethylene glycol, propylene glycol and shellac.
The 2.5 mg and 5 mg tablets also contain FD&C Yellow #6.
structure
HOW SUPPLIED
16 /STORAGE AND HANDLING Product: 63629-5256 NDC: 63629-5256-1 30 TABLET, FILM COATED, EXTENDED RELEASE in a BOTTLE NDC: 63629-5256-2 60 TABLET, FILM COATED, EXTENDED RELEASE in a BOTTLE
GERIATRIC USE
8.5 Geriatric Use There were no overall differences in effectiveness or safety between younger and older patients, but greater sensitivity of some individuals cannot be ruled out.
Elderly patients are particularly susceptible to the hypoglycemic action of anti-diabetic agents.
Hypoglycemia may be difficult to recognize in these patients.
Therefore, dosing should be conservative to avoid hypoglycemia [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].
DOSAGE FORMS AND STRENGTHS
3 Glipizide extended-release tablets are supplied as 2.5 mg, 5 mg, and 10 mg round, unscored, film-coated tablets and are printed with black ink as follows: 2.5 mg tablets are light orange and printed with “ WPI ” and “ 900 ”.
5 mg tablets are orange and printed with “ WPI ” and “ 844 ”.
10 mg tablets are white to off-white and printed with “ WPI ” and “ 845 ”.
Tablets: 2.5 mg, 5 mg, 10 mg ( 3 ).
MECHANISM OF ACTION
12.1 Mechanism of Action Glipizide primarily lowers blood glucose by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets.
Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.
INDICATIONS AND USAGE
1 Glipizide extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Glipizide extended-release tablets are a sulfonylurea indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus ( 1 ).
Limitations of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis ( 1 ).
1.1 Limitations of Use Glipizide extended-release tablets are not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in children have not been established.
PREGNANCY
8.1 Pregnancy Risk Summary Available data from a small number of published studies and postmarketing experience with glipizide extended-release tablets use in pregnancy over decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal outcomes.
However, sulfonylureas (including glipizide) cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia.
Therefore, glipizide extended-release tablets should be discontinued at least two weeks before expected delivery (see Clinical Considerations) .
Poorly controlled diabetes in pregnancy is also associated with risks to the mother and fetus (see Clinical Considerations) .
In animal studies, there were no effects on embryofetal development following administration of glipizide to pregnant rats and rabbits during organogenesis at doses 833 times and 8 times the human dose based on body surface area, respectively.
However, increased pup mortality was observed in rats administered glipizide from gestation day 15 throughout lactation at doses 2 times the maximum human dose based on body surface area (see Data).
The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20 to 25% in women with HbA1c >10.
The estimated background risk of miscarriage for the indicated population is unknown.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly-controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, miscarriage, preterm delivery, stillbirth, and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Fetal/Neonatal Adverse Reactions Neonates of women with gestational diabetes who are treated with sulfonylureas during pregnancy may be at increased risk for neonatal intensive care admission and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age.
Prolonged severe hypoglycemia, lasting 4 to 10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life.
Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly.
Dose adjustments during pregnancy and the postpartum period Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, glipizide extended-release tablets should be discontinued at least two weeks before expected delivery (see Fetal/Neonatal Adverse Reactions) .
Data Animal Data In teratology studies in rats and rabbits, pregnant animals received daily oral doses of glipizide during the period of organogenesis at doses up to 2000 mg/kg/day and 10 mg/kg/day (approximately 833 and 8 times the human dose based on body surface area), respectively.
There were no adverse effects on embryo-fetal development at any of the doses tested.
In a peri- and postnatal study in pregnant rats, there was a reduced number of pups born alive following administration of glipizide from gestation day 15 throughout lactation through weaning at doses ≥5 mg/kg/day (about 2 times the recommended maximum human dose based on body surface area).
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Hypoglycemia: May be severe.
Ensure proper patient selection, dosing, and instructions, particularly in at-risk populations (e.g., elderly, renally impaired) and when used with other anti-diabetic medications ( 5.1 ).
Hemolytic Anemia: Can occur if glucose 6-phosphate dehydrogenase (G6PD) deficient.
Consider a non-sulfonylurea alternative ( 5.2 ).
Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Inform patient of risks, benefits and treatment alternatives ( 5.3 ).
Macrovascular Outcomes: No clinical studies have established conclusive evidence of macrovascular risk reduction with glipizide extended-release tablets or any other anti-diabetic drug ( 5.4 ).
5.1 Hypoglycemia All sulfonylurea drugs, including glipizide extended-release tablets, are capable of producing severe hypoglycemia [see Adverse Reactions ( 6 )] .
Concomitant use of glipizide extended-release tablets with other anti-diabetic medication can increase the risk of hypoglycemia.
A lower dose of glipizide extended-release tablets may be required to minimize the risk of hypoglycemia when combining it with other anti-diabetic medications.
Educate patients to recognize and manage hypoglycemia.
When initiating and increasing glipizide extended-release tablets in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti-diabetic medications) start at 2.5 mg.
Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of anti-diabetic medications.
Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.
The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia.
Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents.
These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.
These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.
Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.
5.2 Hemolytic Anemia Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents, including glipizide extended-release tablets, can lead to hemolytic anemia.
Avoid use of glipizide extended-release tablets in patients with G6PD deficiency.
In post-marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.
5.3 Increased Risk of Cardiovascular Mortality with Sulfonylureas 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 type 2 diabetes mellitus.
The study involved 823 patients who were randomly assigned to one of four treatment groups.
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 advantages 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 oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
5.4 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glipizide extended-release tablets or any other anti-diabetic drug.
5.5 Gastrointestinal Obstruction There have been reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug with this non-dissolvable extended release formulation.
Avoid use of glipizide extended-release tablets in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic).
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform patients of the potential adverse reactions of glipizide extended-release tablets including hypoglycemia.
Explain the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development to patients and responsible family members.
Also inform patients about the importance of adhering to dietary instructions, of a regular exercise program, and of regular testing of glycemic control.
Inform patients that glipizide extended-release tablets should be swallowed whole.
Inform patients that they should not chew, divide or crush tablets and they may occasionally notice in their stool something that looks like a tablet.
In the glipizide extended-release tablet, the medication is contained within a non-dissolvable shell that has been specially designed to slowly release the drug so the body can absorb it.
Pregnancy Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)] .
Lactation Advise breastfeeding women taking glipizide extended-release tablets to monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, hypothermia, excessive sleepiness, poor feeding, seizures) [ see Use in Specific Populations (8.2)] .
This product’s label may have been updated.
For full prescribing information, please visit www.actavis.com.
Brands listed are the trademarks of their respective owners.
Manufactured by: Patheon Pharmaceuticals Inc.
Cincinnati, OH 45237 USA Distributed by: Actavis Pharma, Inc.
Parsippany, NJ 07054 USA Rev.
A 10/2018
DOSAGE AND ADMINISTRATION
2 Recommended starting dose is 5 mg once daily.
Dose adjustment can be made based on the patient’s glycemic control.
Maximum recommended dose is 20 mg once daily ( 2.1 ).
Administer with breakfast or the first meal of the day ( 2.1 ).
For combination therapy with other blood-glucose-lowering agents, initiate the agent at the lowest recommended dose, and observe patients for hypoglycemia ( 2.2 ).
2.1 Recommended Dosing Glipizide extended-release tablets should be administered orally with breakfast or the first main meal of the day.
The recommended starting dose of glipizide extended-release tablets is 5 mg once daily.
Start patients at increased risk for hypoglycemia (e.g.
the elderly or patients with hepatic insufficiency) at 2.5 mg [see Use in Specific Population ( 8.5 , 8.6 )].
Dosage adjustment can be made based on the patient’s glycemic control.
The maximum recommended dose is 20 mg once daily.
Patients receiving immediate release glipizide may be switched to glipizide extended-release tablets once daily at the nearest equivalent total daily dose.
2.2 Use with Other Glucose Lowering Agents When adding glipizide extended-release tablets to other anti-diabetic drugs, initiate glipizide extended-release tablets at 5 mg once daily.
Start patients at increased risk for hypoglycemia at a lower dose.
When colesevelam is co-administered with glipizide ER, maximum plasma concentration and total exposure to glipizide is reduced.
Therefore, glipizide extended-release tablets should be administered at least 4 hours prior to colesevelam.