Drug Safety-related Labeling Changes (SrLC)

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PRANDIMET (NDA-022386)

(METFORMIN HYDROCHLORIDE; REPAGLINIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/08/2017 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hypoglycemia

Newly added information:

All glinides, including PRANDIMET, can cause hypoglycemia. 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), 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, and concomitant use with other antidiabetic agents. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.

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. 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.

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

Newly added subsection:

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

6 Adverse Reactions

6.1 Clinical Trial Experience

Additions and/or revisions underlined:

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.

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 (greater than 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.

7 Drug Interactions

Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with PRANDIMET and instructions for preventing or managing them.

Table 3: Clinically Important Drug Interactions with PRANDIMET; please refer to label for complete information.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Lactic Acidosis

Explain the risks of lactic acidosis due to the metformin component, its symptoms and conditions that predispose to its development. Advise patients to discontinue PRANDIMET immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heartbeat, sensation of feeling cold (especially in the extremities), or other nonspecific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of PRANDIMET therapy; however, patients should consult their physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease.

Counsel patients against excessive alcohol intake while receiving PRANDIMET.

Inform patients about the importance of regular testing of renal function and hematological parameters when receiving treatment with PRANDIMET.

Instruct patients to inform their doctor that they are taking PRANDIMET prior to any surgical or radiological procedure, as temporary discontinuation of PRANDIMET may be required until renal function has been confirmed to be normal.

Hypoglycemia

Inform patients that PRANDIMET can cause hypoglycemia and instruct patients and their caregivers on self-management procedures including glucose monitoring and management of hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as a result 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.

Administration

Instruct patients to take PRANDIMET within 30 minutes before meals. Instruct patients to skip their dose of PRANDIMET when a meal is skipped.

Drug Interactions

Discuss potential drug interactions with patients and inform them of potential drug-drug interactions with PRANDIMET.

04/05/2017 (SUPPL-18)

Approved Drug Label (PDF)

Boxed Warning

(additions underlined)

Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.   The onset of metformin-associated lactic acidosis is  often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin associated lactic acidosis was characterized by  - elevated blood lactateIf levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or   ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL 

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of   certain drugs (e.g., carbonic anyhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive   heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information.

If metformin-associated lactic acidosis is suspected, immediately discontinue PrandiMet and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

4 Contraindications

(addition underlined)

PrandiMet is contraindicated in:

- Severe renal impairment (GFR below 30 mL/min)

-Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin

-Patients receiving gemfibrozil

-Patients with known hypersensitivity to repaglinide, metformin HCl or any inactive ingredients in PrandiMet.

5 Warnings and Precautions

5.1 Lactic Acidosis

(subsection revised, additions underlined)

Metformin hydrochloride

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 hydrochloride 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 postmarketing 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:


  • 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

  •  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 frequentlyIn 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- associate lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation. 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.

    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 impairmentalcoholism, 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.

6 Adverse Reactions

(subsection added)

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

•         Lactic acidosis

•         Hypoglycemia

•         Vitamin B 12 levels

7 Drug Interactions

7.1 Carbonic Anhydrase Inhibitors

(subsection added)

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with PrandiMet may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

7.2 Drugs that reduce metformin clearance

(additions underlined)

Concomitant use of drugs that interfere with common renal tubular transport systems  involved in the elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis). Consider the benefits and risks of concomitant use.

7.3 Alcohol

 (subsection added)

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving PrandiMet.

8 Use in Specific Populations

8.5 Geriatric Use

(additions underlined)

Healthy volunteers treated with repaglinide 2 mg before each of 3 meals, showed no significant differences in repaglinide pharmacokinetics between the group of patients <65 years of age and those ?65 years of age.

In patients with advanced age, PrandiMet should be carefully titrated to establish the minimum dose for adequate glycemic effect. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients.

8.6 Renal Impairment

(subsection added)

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. PrandiMet is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2.

8.7 Hepatic Impairment

(subsection added)

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. PrandiMet is not recommended in patients with hepatic impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(additions underlined)

The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the Warnings and Precautions (5.1), should be explained to patients. Patients should be advised to… Instruct patients to inform their doctor that they are taking PrandiMet prior to any surgical or radiological procedure, as temporary discontinuation of PrandiMet may be required until renal function has been confirmed to be normal.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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