Drug Safety-related Labeling Changes (SrLC)

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JANUMET XR (NDA-202270)

(METFORMIN HYDROCHLORIDE; SITAGLIPTIN PHOSPHATE)

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

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06/21/2022 (SUPPL-26)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined

…

Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome; upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1)]; worsening renal function, including acute renal failure (sometimes requiring dialysis) and tubulointerstitial nephritis; severe and disabling arthralgia; bullous pemphigoid; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus; mouth ulceration; stomatitis; cholestatic, hepatocellular, and mixed hepatocellular liver injury; rhabdomyolysis.

12/04/2020 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Acute Renal Failure

(Additions and/or revisions underlined)

There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with JANUMET XR and at least annually thereafter, renal function should be assessed. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET XR discontinued if evidence of renal impairment is present. JANUMET XR is contraindicated in patients with severe renal impairment [see Contraindications (4) and Warnings and Precautions (5.1)].

5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues

(Additions and/or revisions underlined)

JANUMET XR may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue (e.g., sulfonylurea) [see Adverse Reactions (6)]. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with JANUMET XR [see Drug Interactions (7)].

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are also discussed elsewhere in the labeling:

• Lactic Acidosis [see Warnings and Precautions (5.1)]

• Pancreatitis [see Warnings and Precautions (5.2)]

• Heart Failure [see Warnings and Precautions (5.3)]

• Acute Renal Failure [see Warnings and Precautions (5.4)]

• Vitamin B12 Deficiency [see Warnings and Precautions (5.5)]

• Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.6)]

• Hypersensitivity Reactions [see Warnings and Precautions (5.7)]

• Severe and Disabling Arthralgia [see Warnings and Precautions (5.8)]

• Bullous Pemphigoid [see Warnings and Precautions (5.9)]

7 Drug Interactions

(Newly added Table – please refer to label)

Table 4: Clinically Significant Drug Interactions with JANUMET XR

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of JANUMET XR have not been established in pediatric patients.

Three 20-week double-blind, placebo-controlled studies each with 34-week extensions were conducted to evaluate the efficacy and safety of sitagliptin in 410 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes, with or without insulin therapy (HbA1c 6.5-10% for patients not on insulin, HbA1c 7-10% for patients on insulin). At study entry, patients in study 1 were not treated with oral antihyperglycemic agents; patients in studies 2 and 3 were on maximally tolerated metformin therapy. The primary efficacy endpoint was the change from baseline in HbA1c after 20 weeks of therapy. The pre-specified primary efficacy analyses included data from study 1 and pooled data from studies 2 and 3, regardless of glycemic rescue or treatment discontinuation.

In both efficacy analyses, the effect of treatment with sitagliptin was not significantly different from placebo. In study 1, the mean baseline HbA1c was 7.5%, and 12% of patients were on insulin therapy. At week 20, the change from baseline in HbA1c in patients treated with sitagliptin (N=95) was 0.06% compared to 0.23% in patients treated with placebo (N=95), a difference of -0.17% (95% CI: -0.62, 0.28). In studies 2 and 3, the mean baseline HbA1c was 8.0%, 15% of patients were on insulin and 72% were on metformin HCl doses of greater than 1,500 mg daily. At week 20, the change from baseline in HbA1c in patients treated with sitagliptin (N=107) was -0.23% compared to 0.09% in patients treated with placebo (N=113), a difference of -0.33% (95% CI: -0.70, 0.05).

8.5 Geriatric Use

(Additions and/or revisions underlined)

JANUMET XR

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 concomitant disease or other drug therapy and the higher risk of lactic acidosis. Renal function should be assessed more frequently in elderly patients. [See Contraindications (4); Warnings and Precautions (5.1, 5.4); Clinical Pharmacology (12.3).]

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Lactic Acidosis

Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue JANUMET XR immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about the importance of regular testing of renal function while receiving JANUMET XR. Instruct patients to inform their doctor that they are taking JANUMET XR prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1)].

Vitamin B12 Deficiency

Inform patients about the importance of regular monitoring of hematological parameters while receiving JANUMET XR [see Warnings and Precautions (5.5)].

Hypoglycemia

Inform patients that the incidence of hypoglycemia is increased when sitagliptin with or without metformin is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy. Explain to patients receiving JANUMET XR in combination with these medications the risks of hypoglycemia., its symptoms and treatment and conditions that predispose to its development [see Warnings and Precautions (5.6)].

08/12/2019 (SUPPL-19)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

History of a serious hypersensitivity reaction to JANUMET, sitagliptin, or metformin, such as anaphylaxis or angioedema.

5 Warnings and Precautions

Additions and/or revisions underlined:

Vitamin B12 Deficiency

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 measurements at 2- to 3-year intervals in patients on JANUMET and manage any abnormalities.

6 Adverse Reactions

Clinical Trials Experience

Additions and/or revisions underlined:

In an additional, 30-week placebo-controlled, study of patients with type 2 diabetes inadequately controlled with metformin comparing the maintenance of sitagliptin 100 mg versus withdrawal of sitagliptin when initiating basal insulin therapy, the event rate and incidence of documented symptomatic hypoglycemia (blood glucose measurement ?70 mg/dL) did not differ between the sitagliptin and placebo groups.

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

PATIENT INFORMATION

Additions and/or revisions underlined:

Lactic Acidosis

Inform patients of the risks of lactic acidosis due to the metformin component, its symptoms, and conditions that predispose to its development, as noted in Warnings and Precautions (5.1). Advise patients to discontinue JANUMET XR immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heart beat, 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 JANUMET XR therapy; however, inform patients to 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. Instruct patients to inform their doctor that they are taking JANUMET XR prior to any surgical or radiological procedure, as temporary discontinuation of JANUMET XR may be required until renal function has been confirmed to have returned to its prior level.

Counsel patients against excessive alcohol intake, either acute or chronic, while receiving JANUMET XR.

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

Pancreatitis

Inform patients that acute pancreatitis has been reported during postmarketing use of JANUMET XR. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to promptly discontinue JANUMET XR and contact their physician if persistent severe abdominal pain occurs.

Heart Failure

Inform patients of the signs and symptoms of heart failure. Before initiating JANUMET XR, ask patients about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their health care provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet.

Hypoglycemia

Inform patients that the incidence of hypoglycemia is increased when JANUMET XR is added to a sulfonylurea or insulin and that a lower dose of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions

Inform patients that allergic reactions have been reported during postmarketing use of sitagliptin, one of the components of JANUMET XR. If symptoms of allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking JANUMET XR and seek medical advice promptly.

Severe and Disabling Arthralgia

Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs.

Bullous Pemphigoid

Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur.

Administration Instructions

Inform patients that the tablets must never be split or divided before swallowing.

Incompletely Dissolved Tablets in Feces

Inform patients that incompletely dissolved JANUMET XR tablets may be eliminated in the feces. Tell patients that, if they repeatedly see tablets in feces, they should report this finding to their health care provider. Assess adequacy of glycemic control if a patient reports repeatedly observing tablets in feces.

Overdosage

Advise patients to notify their health practitioner or call the Poison Control Center immediately in case of JANUMET XR overdose.

07/01/2019 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(addition underlined)

… rhabdomyolysis.

02/09/2018 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of the following to adverse reactions:

mouth ulceration; stomatitis.

7 Drug Interactions

7.6 Digoxin

Newly added subsection:

There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the coadministration of 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUMET is recommended.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions underlined:

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to JANUMET XR during pregnancy. Health care providers are encouraged to report …

Risk Summary

The limited available data with JANUMET XR in pregnant women are not sufficient to inform a drug- associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy. No adverse developmental effects were observed when sitagliptin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 30­times and 20-times, respectively, the 100 mg clinical dose, based on AUC. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during organogenesis at doses up to 2- and 6-times, respectively, a 2000 mg clinical dose, based on body surface area.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a Hemoglobin A1c greater than 7% and has been reported to be as high as 20-25% in women with a Hemoglobin A1c greater than 10%. 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 do not report a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Animal Data

Sitagliptin and Metformin

No animal reproduction studies were conducted with the coadministration of sitagliptin and metformin.

Sitagliptin

In embryo-fetal development studies, sitagliptin administered to pregnant rats and rabbits during organogenesis (gestation day 6 to 20) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (30-times the 100 mg clinical dose) and 125 mg/kg (20-times the 100 mg clinical dose), respectively, based on AUC. Higher doses in rats associated with maternal toxicity increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100-times the clinical dose, based on AUC. Placental transfer of sitagliptin was observed in pregnant rats and rabbits.

Sitagliptin administered to female rats from gestation day 6 to lactation day 21 caused no functional or behavioral toxicity in offspring of rats at doses up to 1000 mg/kg.

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- and 6-times a 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.

8.2 Lactation

PLLR conversion; additions underlined:

Risk Summary

There is no information regarding the presence of JANUMET XR in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk. There are no reports of adverse effects on breastfed infants exposed to metformin. There is no information on the effects of metformin on milk production. Sitagliptin is present in rat milk and therefore possibly present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for JANUMET XR and any potential adverse effects on the breastfed infant from JANUMET XR or from the underlying maternal condition.

Data

Sitagliptin

Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1.

Metformin hydrochloride

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 of Reproductive Potential

 PLLR conversion; additions underlined:

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

8.6 Renal Impairment

Additions and/or revisions underlined:

JANUMET XR

The dose of the sitagliptin component should be limited to 50 mg once daily if eGFR falls below 45 mL/min/1.73 m2. JANUMET XR is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2.

Sitagliptin

Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased in patients with renal impairment. Lower dosages are recommended in patients with eGFR less than 45 mL/min/1.73 m2 (moderate and severe renal impairment, as well as in ESRD patients requiring dialysis).

Metformin hydrochloride

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment.

08/10/2017 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Heart Failure

(Newly added subsection)

An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.

Consider the risks and benefits of JANUMET XR prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of JANUMET XR.

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

17 PATIENT COUNSELING INFORMATION

17.1       Instructions

(Additions and/or revisions are underlined)

Patients should be informed of the signs and symptoms of heart failure. Before initiating JANUMET XR, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Patients should be instructed to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet.

Medication Guide

(Additions and/or revisions are underlined)

What is the most important information I should know about JANUMET XR?

Serious side effects can happen in people taking JANUMET XR, including:

3. Heart failure. Heart failure means that your heart does not pump blood well enough.

Before you start taking JANUMET XR, tell your doctor if you have ever had heart failure or have problems with your kidneys. Contact your doctor right away if you have any of the following symptoms:

• increasing shortness of breath or trouble breathing, especially when you lie down
• swelling or fluid retention, especially in the feet, ankles or legs
• an unusually fast increase in weight
• unusual tiredness

These may be symptoms of heart failure.

01/18/2017 (SUPPL-15)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

Postmarketing 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 lactate levels (greater than 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally greater than 5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase 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 JANUMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

4 Contraindications

(Additions and/or revisions are underlined)

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

5 Warnings and Precautions

5.1 Lactic Acidosis

(Additions and/or revisions are underlined)

Metformin hydrochloride

There have been postmarketing 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 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally 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 JANUMET XR. In JANUMET XR- 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 JANUMET XR 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 JANUMET XR, obtain an estimated glomerular filtration rate (eGFR).

•         JANUMET XR is contraindicated in patients with an eGFR below 30 mL/min/1.73 m (squared).

•         Initiation of JANUMET XR is not recommended in patients with eGFR between 30 and 45 mL/min/1.73 m(squared).

•         In patients taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.

•         Obtain an eGFR at least annually in all patients taking JANUMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions

The concomitant use of JANUMET XR 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. 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 JANUMET XR 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 m(squared); 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 JANUMET XR 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. JANUMET XR 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 JANUMET XR.

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 JANUMET XR.

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 JANUMET XR in patients with clinical or laboratory evidence of hepatic disease.

5.3 Assessment of Renal Function

(Additions and/or revisions are underlined)

Metformin hydrochloride

JANUMET XR is contraindicated in patients with severe renal impairment.

Sitagliptin

... In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET XR discontinued if evidence of renal impairment is present.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Additional adverse reactions have been identified during postapproval use of JANUMET XR, sitagliptin, or metformin.

…Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome; upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis; worsening renal function, including acute renal failure (sometimes requiring dialysis) severe and disabling arthralgia; bullous pemphigoid; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus; cholestatic, hepatocellular, and mixed hepatocellular liver injury.

7 Drug Interactions

7.1 Carbonic Anhydrase Inhibitors

(Additions and/or revisions are underlined)

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

7.2 Drugs that Reduce Metformin Clearance

(Revised subsection title; additions and/or revisions are underlined)

Concomitant use of drugs that interfere with 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.

7.3 Alcohol

(Newly added subsection)

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

7.4 Insulin Secretagogues or Insulin

(Newly added subsection)

Coadministration of JANUMET XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

JANUMET XR

Because sitagliptin and metformin are substantially excreted by the kidney, and because aging can be associated with reduced renal function, renal function should be assessed more frequently in elderly patients.

Metformin hydrochloride

…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

(Newly added subsection)

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. JANUMET XR is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m(squared). JANUMET XRis not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m(squared) because these patients require a lower dosage of sitagliptin than what is available in the fixed dose combination JANUMET XR product.

8.7 Hepatic Impairment

(Newly added subsection)

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

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

17.1 Instructions

…Instruct patients to inform their doctor that they are taking JANUMET XR prior to any surgical or radiological procedure, as temporary discontinuation of JANUMET XR may be required until renal function has been confirmed to have returned to its prior level.

Medication Guide JANUMET® XR (JAN-you-met XR) (sitagliptin and metformin hydrochloride extended-release) Tablets

(Additions and/or revisions are underlined)

Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with JANUMET XR:

• have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye

The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your JANUMET XR for a while if you have any of these things.

JANUMET XR can have other serious side effects. See “What are the possible side effects of JANUMET XR ?”

Who should not take JANUMET XR? Do not take JANUMET XR if:

• you have severe kidney problems.

What should I tell my doctor before taking JANUMET XR? Before you take JANUMET XR, tell your doctor if you:

• have severe kidney problems

01/18/2017 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Bullous Pemphigoid

(Newly added subsection)

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving JANUMET XR. If bullous pemphigoid is suspected, JANUMET XR should be discontinued  and  referral  to  a  dermatologist should  be  considered  for  diagnosis  and appropriate treatment.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

…Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome; upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and non­fatal hemorrhagic and necrotizing pancreatitis; worsening renal function, including acute renal failure (sometimes requiring dialysis); severe and disabling arthralgia; bullous pemphigoid…

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

17.1 Instructions

Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur.

Medication Guide JANUMET® XR (JAN-you-met) (sitagliptin and metformin hydrochloride extended release) Tablets

(Additions and/or revisions are underlined)

What are the possible side effects of JANUMET XR?  Serious side effects have happened in people taking JANUMET XR or the individual medicines in JANUMET XR.

• Skin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines in JANUMET XR, may develop a skin reaction called bullous pemphigoid that can require treatment in a hospital. Tell your doctor right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your doctor may tell you to stop taking JANUMET XR.