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Drug Safety-related Labeling Changes (SrLC)

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ACTOPLUS MET (NDA-021842)

(METFORMIN HYDROCHLORIDE; PIOGLITAZONE HYDROCHLORIDE)

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

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12/21/2017 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

Metformin

Cholestatic, hepatocellular, and mixed hepatocellular liver injury.

7 Drug Interactions

7.4 Drugs that Reduce Metformin Clearance

(additions underlined)

Concomitant use of drugs that common renal tubular transport systems involved in the renal 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.

7.8 Topiramate

(new subsection added)

A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate. The clinical relevance of this decrease is unknown; however, when ACTOPLUS MET and topiramate are used concomitantly, monitor patients for adequate glycemic control.

12/12/2016 (SUPPL-20)

Approved Drug Label (PDF)

4 Contraindications

 (addition underlined)

•         Severe renal impairment (eGFR below 30 mL/min/1.73 m2)

5 Warnings and Precautions

5.4 Hypoglycemia

 (addition underlined)

Patients receiving ACTOPLUS MET in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia. Hypoglycemia can also occur when caloric intake is deficient or when strenuous be necessary to reduce the risk of hypoglycemia exercise is not compensated by caloric supplement. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

5.6 Urinary Bladder Tumors

(addition underlined)

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In addition, during the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; [95% CI: 0.59–1.72]).

Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did.

A  large prospective10-year observational cohort study conducted in the United States found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone, compared to those never exposed to pioglitazone (HR=1.06 [95% CI 0.89–1.26]).

 

A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone and bladder cancer (HR: 1.63; [95% CI: 1.22–2.19]).

Associations between cumulative dose or cumulative duration of exposure to pioglitazone and bladder cancer were not detected in some studies including the 10- year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data.

Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors.

Consequently, ACTOPLUS MET should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with ACTOPLUS MET should be considered in patients with a prior history of bladder cancer.

5.9 Vitamin B12 Levels

  (additions underlined)

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. Such decrease, possibly due to interference with B12 absorption from the B12 -intrinsic factor complex, is, however, very 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 ACTOPLUS MET 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 two- to three-year intervals may be useful.

6 Adverse Reactions

6.1 Clinical Trials Experience

 (additions underlined)

Pioglitazone

In six pooled 16- to 26-week placebo-controlled monotherapy and 16- to 24-week add- on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%).

 Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. During the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time

of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; 95% CI: 0.59-1.72)

7 Drug Interactions

7.3 Carbonic Anhydrase Inhibitors

(additions underlined)

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 ACTOPLUS MET may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients..

7.4 Drugs that Reduce Metformin Clearance

(additions underlined)

Drugs that are eliminated by renal tubular secretion (e.g., cationic drugs such as cimetidine) have the potential for interaction with metformin by competing for common renal tubular transport systems, and may increase the accumulation of metformin and the risk for lactic acidosis ]. Consider more frequent monitoring of these patients.

7.5 Alcohol

(additions underlined)

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

7.6 Insulin Secretagogues or Insulin

(additions underlined)

If hypoglycemia occurs in a patient coadministered ACTOPLUS MET and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient coadministered ACTOPLUS MET and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Limited data with ACTOPLUS MET or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

 

In animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5- and 35-times the 45 mg clinical dose, respectively, based on body surface area. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- to 6-times, respectively, a 2000 mg clinical dose, based on body surface area [see Data].

 

The estimated background risk of major birth defects is 6-10% in women with pre- gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a 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 2-4% and 15-20%, 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, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

 

Data

Human Data

Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.


Animal Data

Pioglitazone and Metformin hydrochloride

Animal reproduction studies were not conducted with the combined products in ACTOPLUS MET. The following data are based on studies conducted with the individual components of ACTOPLUS MET.

 

Pioglitazone

Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (approximately 5-times the 45 mg clinical dose), but delayed parturition and reduced embryofetal viability at 40 and 80 mg/kg, or greater than or equal to 9-times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at

80 mg/kg (approximately 35-times the 45 mg clinical dose), but reduced embryofetal viability at 160 mg/kg, or approximately 69-times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or greater than or equal to 2-times the 45 mg clinical dose, by body surface area.

 

Metformin hydrochloride

Metformin hydrochloride did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- to 6 -times a 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.

8.2 Lactation

 (PLLR conversion)

Risk Summary

There is no information regarding the presence of ACTOPLUS MET or pioglitazone in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone is present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ACTOPLUS MET and any potential adverse effects on the breastfed infant from ACTOPLUS MET or from the underlying maternal condition.

 

Data

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

8.3 Females and Males Reproductive Potential

(PLLR conversion)

Discuss the potential for unintended pregnancy with premenopausal women as therapy with ACTOPLUS MET, may result in ovulation in some anovulatory women.

8.5 Geriatric Use

(additions underlined)

Metformin hydrochloride

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. 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

(additions underlined)

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. ACTOPLUS MET is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m(squared)

8.7 Hepatic Impairment

(additions underlined)

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. ACTOPLUS MET 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)

•         Explain to patients the risks of lactic acidosis, its symptoms and conditions that predispose to its development, as noted in the Warnings and Precautions (5.2) section. Advise patients to discontinue ACTOPLUS MET immediately and to promptly notify their healthcare professional if unexplained hyperventilation, myalgia, gastrointestinal symptoms, malaise, unusual somnolence, or other nonspecific symptoms occur. Instruct patients to inform their doctor that they are taking ACTOPLUS MET prior to any surgical or radiological procedure, as temporary discontinuation of ACTOPLUS MET may be required until renal function has been confirmed to be normal.

•         Inform female patients that treatment with ACTOPLUS MET may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation.

MEDICATION GUIDE

 (additions underlined)

Do not take ACTOPLUS MET if you:

•         have severe kidney problems

What should I tell my doctor before taking ACTOPLUS MET?

•         are pregnant or plan to become pregnant. It is not known if ACTOPLUS MET can harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant about the best way to control your blood glucose levels while pregnant

•         are breastfeeding or plan to breastfeed. It is not known if ACTOPLUS MET passes into your milk and if it can harm your baby. Talk to your doctor about the best way to control your blood glucose levels while breastfeeding.

12/12/2016 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Lactic Acidosis Metformin hydrochloride Lactic Acidosis

(additions  underlined)

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 (greater than 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 ACTOPLUS MET. In ACTOPLUS MET-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/min 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 ACTOPLUS MET 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.

•         Before initiating ACTOPLUS MET, obtain an eGFR.

•         ACTOPLUS MET is contraindicated in patients with an eGFR less than

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

•         Obtain an eGFR at least annually in all patients taking ACTOPLUS MET. 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 ACTOPLUS MET 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 ACTOPLUS MET 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 (e.g. cationic drugs). 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 ACTOPLUS MET 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 ACTOPLUS MET 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. ACTOPLUS MET 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 ACTOPLUS MET.

 

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 ACTOPLUS MET.

 

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 ACTOPLUS MET in patients with clinical or laboratory evidence of hepatic disease.