PRANDIMET (repaglinide 2 mg metformin hydrochloride 500 mg) Dailymed

• •Instruct patients to take PRANDIMET within 30 minutes before meals. Instruct patients to skip the scheduled dose of PRANDIMET if a meal is skipped. (2.1)
• •For patients inadequately controlled on metformin, start with 1 mg repaglinide/500 mg metformin twice daily and gradually titrate dose based on glycemic response. (2.1)
• •For patients inadequately controlled on repaglinide, start with 1 mg repaglinide/500 mg metformin or 2 mg repaglinide/500 mg metformin twice daily and gradually titrate dose to reduce gastrointestinal side effects (2.1)
• •For patients taking repaglinide and metformin, start PRANDIMET at the dose of repaglinide and metformin similar to (but not exceeding) the patient’s current doses. Titrate as needed to achieve glycemic control (2.1)
• •Do not exceed 10 mg repaglinide/2500 mg metformin daily or 4 mg repaglinide/1000 mg metformin per meal. (2.1)
• •Assess renal function with estimated glomerular filtration rate (eGFR) before initiation of PRANDIMET and periodically thereafter (2.2)
  • oContraindicated in patients with eGFR below 30 mL/minute/1.73 m²
  • oInitiation is not recommended in patients with eGFR between 30 – 45 mL/minute/1.73 m²
  • oAssess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m²
  • oDiscontinue if eGFR falls below 30 mL/minute/1.73 m2
• •PRANDIMET may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.3)
• •Dose modifications are required when used concominantly with some medications. (2.4, 7)

2.1 Recommended Dosage and Administration

General Dosage and Administration information

Administer PRANDIMET orally 2 to 3 times a day with meals up to a maximum daily dose of 10 mg repaglinide/2500 mg metformin. No more than 4 mg repaglinide/1000 mg metformin should be taken per meal.

Instruct patients to take PRANDIMET within 30 minutes before meals. In patients who skip meals, instruct patients to skip the scheduled dose of PRANDIMET to reduce the risk of hypogylcemia. In patients who experience hypoglycemia, the dose of PRANDIN should be reduced [see Warnings and Precautions (5.2)].

Patients Inadequately Controlled with Metformin Monotherapy

The recommended starting dose of PRANDIMET 1 mg repaglinide/500 mg metformin twice daily with meals. Gradually increase dose based on glycemic response to reduce the risk of hypoglycemia with repaglinide.

Patients Inadequately Controlled with Glinide Monotherapy

The recommended starting dose of metformin component of PRANDIMET is 500 mg metformin twice daily with meals. Gradually increase dose based on glycemic response to reduce gastrointestinal side effects associated with metformin.

Patients Currently Using Repaglinide and Metformin Concomitantly

Initiate PRANDIMET at the dose of repaglinide and metformin similar to (but not exceeding) the patient’s current doses. Titrate as needed to achieve glycemic control up to the maximum daily dose.

2.2 Recommended Dosage for Patients with Renal Impairment

Assess renal function with an estimated glomerular filtration rate (eGFR) prior to initiation of PRANDIMET and periodically thereafter.

PRANDIMET is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2.

Initiation of PRANDIMET in patients with an eGFR between 30 – 45 mL/min/1.73 m2 is not recommended.

In patients taking PRANDIMET whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit-risk of continuing therapy.

Discontinue PRANDIMET if the patient’s eGFR later falls below 30 mL/min/1.73 m2 [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )].

2.3 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue PRANDIMET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart PRANDIMET if renal function is stable [See Warnings and Precautions (5.1)].

2.4 Dose Modifications for Drug Interactions

Concomitant use with gemfibrozil is contraindicated [see Contraindications (4)].

Avoid concomitant use of PRANDIMET with clopidogrel. If concomitant use can not be avoided, initiate repaglinide at 0.5 mg before each meal. Although PRANDIMET is not available in that strength, repaglinide 0.5 mg tablets are available. Do not exceed a total daily dose of 4 mg of repaglinide [see Drug Interactions (7), Clinical Pharmacology (12.3)].

Do not exceed a total daily dose of 6 mg of repaglinide in patients receiving cyclosporine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

Dosage adjustments are recommended in patients taking concomitant strong CYP3A4 or CYP2C8 inhibitors or strong CYP3A4 or CYP2C8 inducers [see Drug Interactions (7), Clinical Pharmacology (12.3)].

3 Dosage Forms And Strengths

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

Tablets:

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

4 Contraindications

PRANDIMET is contraindicated in patients with:

• • Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)]
• • Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions (5.1)].
• • Concomitant use of gemfibrozil [see Drug Interactions (7.2)]
• • Known hypersensitivity to repaglinide, metformin or any inactive ingredients

• •Severe renal impairment (eGFR below 30 mL/min/1.73 m2). (4, 5.1)
• •Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
• •Concomitant use with gemfibrozil. (4, 7.2, 12.3)

5 Warnings And Precautions

• • Lactic acidosis: See boxed warning. (4, 5.1)
• • Hypoglycemia: PRANDIMET may cause hypoglycemia. Skip the scheduled dose if a meal is skipped to reduce the risk of hypoglycemia. Reduce the dose if hypoglycemia occurs. (5.2)
• • Vitamin B₁₂ deficiency: Metformin can lower vitamin B₁₂ levels. Monitor hematological parameters annually. (5.3)
• • Serious Cardiovascular Adverse Reactions with Concomitant NPH-insulin: PRANDIMET is not indicated for use with NPH-insulin. (5.4)
• • Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with PRANDIMET. (5.5)

5.1 Lactic Acidosis

There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.

Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of PRANDIMET.

In PRANDIMET treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue PRANDIMET and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment: The post-marketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Clinical Pharmacology (12.3)]:

• • Before initiating PRANDIMET, obtain an estimated glomerular filtration rate (eGFR).
• • PRANDIMET is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2 [see Contraindications (4)].
• • Initiation of PRANDIMET is not recommended in patients with eGFR between 30 – 45 mL/minute/1.73 m2.
• • Obtain an eGFR at least annually in all patients taking PRANDIMET. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
• • In patients taking PRANDIMET whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.

Drug Interactions: The concomitant use of PRANDIMET with specific drugs may increase the risk of metformin- associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop PRANDIMET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart PRANDIMET if renal function is stable.

Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. PRANDIMET should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting

of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue PRANDIMET.

Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving PRANDIMET.

Hepatic Impairment: Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of PRANDIMET in patients with clinical or laboratory evidence of hepatic disease.

5.2 Hypoglycemia

All glinides, including PRANDIMET, can cause hypoglycemia [see Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).

Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.

Factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content), changes in level of physical activity, changes to co-administered medication [see Drug Interactions (7)], and concomitant use with other antidiabetic agents. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].

Patients should administer PRANDIMET before meals and be instructed to skip the dose of PRANDIMET if a meal is skipped. In patients who experience hypoglycemia, the dose of PRANDIMET should be reduced [see Dosage and Administration (2.1)]. Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

5.3 Vitamin BLevels

In controlled clinical trials of metformin of 29 weeks’ duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels, without clinical manifestations, was observed in approximately 7% of patients. This finding, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, is rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on PRANDIMET and any apparent abnormalities should be appropriately investigated and managed.

Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. In these patients, routine serum vitamin B₁₂ measurements at 2- to 3-year intervals may be useful.

5.4 Serious Cardiovascular Adverse Reactions with Concomitant Use with NPH-insulin

Across seven controlled trials, there were six serious adverse events of myocardial ischemia in patients treated with repaglanide plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study [See Adverse Reactions (6.1)]. PRANDIMET is not indicated for use in combination with NPH-insulin.

5.5 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with PRANDIMET.

6 Adverse Reactions

The following adverse reactions are discussed in more detail in other sections of the labeling.

• •Lactic acidosis [see Warnings and Precautions (5.1)]
• •Hypoglycemia [see Warnings and Precautions ( 5.2 )]
• •Vitamin B₁₂ levels [see Warnings and Precautions ( 5.3 )]

• •Hypoglycemia and headache were the most common adverse reactions (≥10%) reported among patients treated with repaglinide in combination with metformin. (6.1)
• •Gastrointestinal reactions (e.g., diarrhea, nausea and vomiting) are the most common adverse reactions with metformin (6.1)
•   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.

6.1 Clinical Trial Experience

Because clinical trials are conducted under 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 clinical practice.

PRANDIMET was administered to 374 patients with type 2 diabetes during clinical trials. Table 1 summarizes the most common adverse reactions occurring in a 6-month randomized trial of repaglinide as add-on therapy to metformin in patients inadequately controlled on metformin alone.

Table 1: Adverse Reactions (%) occurring >10% in Patients Treated with Repaglinide and Metformin Together or Repaglinide and Metformin Monotherapy during a 6 Month Trial
	Repaglinide and Metformin	Metformin Monotherapy	Repaglinide Monotherapy
	N = 27	N = 27	N = 28
Diarrhea Nausea	19 15	30 7	7 4
Symptomatic Hypoglycemia*	33	0	11
Headache	22	15	11
Upper Respiratory Tract Infection	11	11	11
* Hypoglycemia with symptoms which included, but were not limited to, anxious feeling, dizziness, sweating, tremor, hunger and difficulty in concentration. None of the symptomatic hypoglycemia events uled in the table required the assistance of another person.

Hypoglycemia

In clinical trials with repaglinide, hypoglycemia is the most commonly observed adverse reaction. Mild or moderate hypoglycemia occurred in 31% of repaglinide treated patients and 7% of placebo treated patients.

Gastrointestinal Adverse Reactions

Gastrointestinal reactions (e.g., diarrhea, nausea, vomiting) are the most common adverse reactions (> 5%) with metformin treatment and are more frequent at higher metformin doses.

Weight Gain

In a clinical trial, 83 patients were randomized to add-on repaglinide, repaglinide monotherapy, or continued treatment with metformin monotherapy. A statistically significant weight gain was observed for the combination of repaglinide and metformin in a pairwise comparison with metformin monotherapy (see Table 2).

Table 2: Repaglinide as Add-on to Metformin: Mean Changes from Baseline in Body Weight After 4 to 5 Months of Treatment1
	Repaglinide add-on to Metformin	Repaglinide monotherapy	Metformin HCl monotherapy
N	27	28	27
Weight (kg)
Baseline	93	87	91
Change from Baseline	2.4#	3.0	-0.9
1: based on intent-to-treat analysis #: p< 0.05, for pairwise comparison with metformin monotherapy.

Cardiovascular Events in repaglinide monotherapy trials

•  The incidence of total serious cardiovascular adverse events, including ischemia, was higher for repaglinide (51/1228 or 4%) than for sulfonylurea drugs (13/498 or 3%) in controlled clinical trials.

Seven controlled clinical trials included repaglinide combination therapy with NPH-insulin (n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH-insulin or repaglinide plus metformin ) (n=120). There were six serious adverse events of myocardial ischemia in patients treated with repaglinide plus NPH-insulin (1.4%) from two studies, and one event in patients using insulin formulations alone from another study (0.3%) [see Warnings and Precautions (5.4)].

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or a causal relationship to drug exposure.

Repaglinide

Alopecia, hemolytic anemia, pancreatitis, Stevens-Johnson Syndrome, and severe hepatic dysfunction including jaundice and hepatitis.

Metformin

Cholestatic, hepatocellular, and mixed hepatocellular liver injury.