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PrandiMet(repaglinide and metformin HCl Tablets)

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use PrandiMet safely and effectively.
See full prescribing information for PrandiMet.
PrandiMet ® (repaglinide and metformin HCl) Tablets
Initial U.S. Approval: 2008
wARNING: LACTIC ACIDOSIS
See full prescribing information for complete boxed warning

Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. (5.1)
Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. (5.1)
If acidosis is suspected, discontinue PrandiMet and hospitalize the patient immediately.

RECENT MAJOR CHANGES

Warnings and Precautions, Drug Interactions (5.7) 3/2012

INDICATIONS AND USAGE

PrandiMet is a meglitinide and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a meglitinide and metformin HCl or who have inadequate glycemic control on a meglitinide alone or metformin HCl alone. (1)
Important Limitations of Use:

Do not use to treat type 1 diabetes or diabetic ketoacidosis. (1)

DOSAGE AND ADMINISTRATION

The dosage of PrandiMet should be individualized. (2)
Start with 1 mg/500 mg twice daily unless the patient is already taking higher co-administered doses of repaglinide and metformin HCl. (2)
Do not exceed 10 mg repaglinide/2500 mg metformin HCl daily or 4 mg repaglinide/1000 mg metformin HCl per meal. (2)
Give in divided doses within 15 minutes prior to meals. (2)
Patients who skip a meal should skip the PrandiMet dose for that meal. (2)

DOSAGE FORMS AND STRENGTHS

Tablets:

1 mg repaglinide/500 mg metformin HCl (3)
2 mg repaglinide/500 mg metformin HCl (3)

CONTRAINDICATIONS

Do not use in patients:

with renal impairment. (4, 5.2)
with metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
receiving gemfibrozil. (4, 5.7, 7.2, 12.3)

WARNINGS AND PRECAUTIONS

Metformin HCl is contraindicated in renal impairment. Assess renal function before initiating PrandiMet and at least annually thereafter, and verify as normal. (4, 5.2)
Temporarily discontinue PrandiMet in patients receiving iodinated contrast for radiological studies. (5.3)
Hepatic impairment is associated with lactic acidosis. Recommend not using in patients with hepatic impairment. (5.4)
Alcohol potentiates the effect of metformin on lactate metabolism. Warn patients against excess alcohol intake. (5.5)
PrandiMet should not be used in combination with NPH insulin. (5.6)
Gemfibrozil substantially increases repaglinide exposure. Coadministration of gemfibrozil and PrandiMet is not recommended. (4, 5.7, 7.2, 12.3)
The repaglinide component can cause hypoglycemia. Initiate PrandiMet at the lowest available dose in patients naive to meglitinide therapy. (5.8)
Metformin can cause vitamin B12 deficiency. Measure hematological parameters annually. (5.9)
May need to discontinue PrandiMet and temporarily use insulin if glycemic control deteriorates during periods of stress or if there is decreased intake of fluids and food (e.g., infection, surgery). (5.10)
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with PrandiMet or any other oral anti-diabetic drug. (5.15)

ADVERSE REACTIONS

Hypoglycemia and headache were the most common adverse reactions (≥10%) reported among patients treated with repaglinide in combination with metformin HCl, occurring more frequently than among patients treated with repaglinide alone or metformin HCl alone. (6.2)
Gastrointestinal reactions (e.g., diarrhea, nausea and vomiting) are the most common adverse reactions with metformin HCl treatment and are more frequent at higher metformin HCl doses. (6.1, 6.2)
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Cationic drugs eliminated by renal tubular secretion may interfere with metformin elimination: use with caution. (7.1)
Repaglinide is partly metabolized by CYP2C8 and CYP3A4. Use caution in patients taking inhibitors and/or inducers of CYP2C8 and CYP3A4. (7.2)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 4/2012

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: LACTIC ACIDOSIS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

5.2 Impaired Renal Function

5.3 Radiologic Studies with Intravascular Iodinated Contrast Materials

5.4 Impaired Hepatic Function

5.5 Alcohol Intake

5.6 Combination with NPH-insulin

5.7 Drug Interactions

5.8 Hypoglycemia

5.9 Vitamin B12 Levels

5.10 Surgical Procedures

5.11 Loss of Control of Blood Glucose

5.12 Use of Concomitant Medications Affecting Renal Function or Metformin Disposition

5.13 Hypoxic States

5.14 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes

5.15 Macrovascular Outcomes

6 ADVERSE REACTIONS

6.1 Most Frequently Observed Adverse Reactions

6.2 Clinical Trial Experience

6.3 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Cationic Drugs

7.2 CYP2C8 and CYP3A4 Inhibitors/Inducers

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Patients with Inadequate Glycemic Control on Metformin HCl Monotherapy

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Physician Instructions

17.2 Laboratory Tests

*: Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

PrandiMet is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a meglitinide and metformin HCl or who have inadequate glycemic control on a meglitinide alone or metformin HCl alone.

Important Limitations of Use:

PrandiMet should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

2 DOSAGE AND ADMINISTRATION

Recommended Dosing

The dosage of PrandiMet should be individualized on the basis of the patient's current regimen, effectiveness and tolerability. PrandiMet can be administered 2 to 3 times a day up to a maximum daily dose of 10 mg repaglinide/2500 mg metformin HCl. No more than 4 mg repaglinide/1000 mg metformin HCl should be taken per meal. Initiation and maintenance of combination therapy with PrandiMet should be individualized to the patient, and at the discretion of the health care provider. Blood glucose monitoring should be performed to determine the therapeutic response to PrandiMet.

PrandiMet doses should usually be taken within 15 minutes prior to the meal but the timing can vary from immediately preceding the meal up to 30 minutes before the meal. Patients who skip a meal should be instructed to skip the PrandiMet dose for that meal.

Patients Inadequately Controlled with Metformin HClMonotherapy

If therapy with a combination tablet containing repaglinide and metformin HCl is considered appropriate for a patient with type 2 diabetes mellitus inadequately controlled with metformin HCl alone, the recommended starting dose of PrandiMet is 1 mg repaglinide/500 mg metformin HCl administered twice daily with meals, with gradual dose escalation (based on glycemic response) to reduce the risk of hypoglycemia with repaglinide.

Patients Inadequately Controlled with MeglitinideMonotherapy

If therapy with a combination tablet containing repaglinide and metformin HCl is considered appropriate for a patient with type 2 diabetes mellitus inadequately controlled with repaglinide alone, the recommended starting dose of the metformin HCl component of PrandiMet should be 500 mg metformin HCl twice a day, with gradual dose escalation (based on glycemic response) to reduce gastrointestinal side effects associated with metformin HCl.

Patients Currently Using Repaglinide and Metformin HCl Concomitantly

For patients switching from repaglinide co-administered with metformin HCl, PrandiMet can be initiated at the dose of repaglinide and metformin HCl similar to (but not exceeding) the patient's current doses, then may be titrated to the maximum daily dose as necessary to achieve targeted glycemic control.

No studies have been performed examining the safety and efficacy of PrandiMet in patients previously treated with other oral antihyperglycemic agents and switched to PrandiMet. Any change in therapy should be undertaken with care and with appropriate monitoring as changes in glycemic control can occur.

3 DOSAGE FORMS AND STRENGTHS

1 mg repaglinide /500mg metformin HCl tablets are yellow, biconvex, debossed with Novo Nordisk (Apis) bull symbol on one side, and strength indicated on the other side
2 mg repaglinide /500mg metformin HCl tablets are pink, biconvex, debossed with Novo Nordisk (Apis) bull symbol on one side, and strength indicated on the other side

4 CONTRAINDICATIONS

PrandiMet is contraindicated in:

Renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance) [see Warnings and Precautions (5.2)].