Glipizide XL

GLIPIZIDE XL- glipizide tablet, extended release
Greenstone LLC

1 INDICATIONS AND USAGE

GLIPIZIDE XL is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

1.1 Limitations of Use

GLIPIZIDE XL is not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

GLIPIZIDE XL should be administered orally with breakfast or the first main meal of the day.

The recommended starting dose of GLIPIZIDE XL 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 XL once daily at the nearest equivalent total daily dose.

2.2 Use with Other Glucose Lowering Agents

When adding GLIPIZIDE XL to other anti-diabetic drugs, initiate GLIPIZIDE XL at 5 mg once daily. Start patients at increased risk for hypoglycemia at a lower dose.

When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total exposure to glipizide is reduced. Therefore, GLIPIZIDE XL should be administered at least 4 hours prior to colesevelam.

3 DOSAGE FORMS AND STRENGTHS

GLIPIZIDE XL (glipizide) Extended Release tablets:

2.5 mg, blue and imprinted with “GLIPIZIDE XL 2.5” or “GXL 2.5” on one side

5 mg, white and imprinted with “GLIPIZIDE XL 5” or “GXL 5” on one side

10 mg, white and imprinted with “GLIPIZIDE XL 10” or “GXL 10” on one side

4 CONTRAINDICATIONS

Glipizide is contraindicated in patients with:

Known hypersensitivity to glipizide or any of the product’s ingredients.
Hypersensitivity to sulfonamide derivatives.

5 WARNINGS AND PRECAUTIONS

5.1 Hypoglycemia

All sulfonylurea drugs, including GLIPIZIDE XL, are capable of producing severe hypoglycemia [see Adverse Reactions (6)]. Concomitant use of GLIPIZIDE XL with other anti-diabetic medication can increase the risk of hypoglycemia. A lower dose of GLIPIZIDE XL 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 XL 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 XL, can lead to hemolytic anemia. Avoid use of GLIPIZIDE XL 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 XL 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 XL in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic).

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling:

Hypoglycemia [see Warnings and Precautions (5.1)]
Hemolytic anemia [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, 580 patients from 31 to 87 years of age received GLIPIZIDE XL in doses from 5 mg to 60 mg in both controlled and open trials. The dosages above 20 mg are not recommended dosages. In these trials, approximately 180 patients were treated with GLIPIZIDE XL for at least 6 months.

Table 1 summarizes the incidence of adverse reactions, other than hypoglycemia, that were reported in pooled double-blind, placebo-controlled trials in ≥3% of GLIPIZIDE XL-treated patients and more commonly than in patients who received placebo.

Table 1: Incidence (%) of Adverse Reactions Reported in ≥3% of Patients Treated in Placebo-Controlled Clinical Trials and More Commonly in Patients Treated with GLIPIZIDE XL (Excluding Hypoglycemia)
GLIPIZIDE XL (%) (N=278) Placebo (%) (N=69)
Adverse Effect

Dizziness

6.8

5.8

Diarrhea

5.4

0.0

Nervousness

3.6

2.9

Tremor

3.6

0.0

Flatulence

3.2

1.4

Hypoglycemia

Of the 580 patients that received GLIPIZIDE XL in clinical trials, 3.4% had hypoglycemia documented by a blood-glucose measurement <60 mg/dL and/or symptoms believed to be associated with hypoglycemia and 2.6% of patients discontinued for this reason. Hypoglycemia was not reported for any placebo patients.

Gastrointestinal Reactions

In clinical trials, the incidence of gastrointestinal (GI) side effects (nausea, vomiting, constipation, dyspepsia), occurred in less than 3% of GLIPIZIDE XL-treated patients and were more common in GLIPIZIDE XL-treated patients than those receiving placebo.

Dermatologic Reactions

In clinical trials, allergic skin reactions, i.e., urticaria occurred in less than 1.5% of treated patients and were more common in GLIPIZIDE XL treated patients than those receiving placebo. These may be transient and may disappear despite continued use of glipizide XL; if skin reactions persist, the drug should be discontinued.

Laboratory Tests

Mild to moderate elevations of ALT, LDH, alkaline phosphatase, BUN and creatinine have been noted. The relationship of these abnormalities to glipizide is uncertain.

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