GLUCOPHAGE (Page 2 of 6)

5.2 Vitamin B12 Deficiency

In GLUCOPHAGE clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of GLUCOPHAGE or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on GLUCOPHAGE/GLUCOPHAGE XR and manage any abnormalities [see Adverse Reactions ( 6.1)].

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. GLUCOPHAGE/GLUCOPHAGE XR may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with GLUCOPHAGE/GLUCOPHAGE XR [see Drug Interactions ( 7)].

5.4 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUCOPHAGE/GLUCOPHAGE XR.

6 ADVERSE REACTIONS

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

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely 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 practice.

GLUCOPHAGEIn a U.S. clinical trial of GLUCOPHAGE in patients with type 2 diabetes mellitus, a total of 141 patients received GLUCOPHAGE up to 2550 mg per day. Adverse reactions reported in greater than 5% of GLUCOPHAGE treated patients and that were more common than in placebo-treated patients, are listed in Table 1.

Table 1: Adverse Reactions from a Clinical Trial of GLUCOPHAGE Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus
GLUCOPHAGE (n=141) Placebo (n=145)
Diarrhea 53% 12%
Nausea/Vomiting 26% 8%
Flatulence 12% 6%
Asthenia 9% 6%
Indigestion 7% 4%
Abdominal Discomfort 6% 5%
Headache 6% 5%

Diarrhea led to discontinuation of GLUCOPHAGE in 6% of patients. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of GLUCOPHAGE treated patients and were more commonly reported with GLUCOPHAGE than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.
In GLUCOPHAGE clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.
Pediatric Patients
In clinical trials with GLUCOPHAGE in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults.
GLUCOPHAGE XRIn placebo-controlled trials, 781 patients were administered GLUCOPHAGE XR. Adverse reactions reported in greater than 5% of the GLUCOPHAGE XR patients, and that were more common in GLUCOPHAGE XR- than placebo-treated patients, are listed in Table 2.

Table 2: Adverse Reactions from Clinical Trials of GLUCOPHAGE XR Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus
GLUCOPHAGE XR (n=781) Placebo (n=195)
Diarrhea 10% 3%
Nausea/Vomiting 7% 2%

Diarrhea led to discontinuation of GLUCOPHAGE XR in 0.6% of patients. Additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of GLUCOPHAGE XR patients and were more commonly reported with GLUCOPHAGE XR than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

7 DRUG INTERACTIONS

Table 3 presents clinically significant drug interactions with GLUCOPHAGE/GLUCOPHAGE XR.

Table 3: Clinically Significant Drug Interactions with GLUCOPHAGE/GLUCOPHAGE XR
Carbonic Anhydrase Inhibitors

Clinical Impact:

Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with GLUCOPHAGE/GLUCOPHAGE XR may increase the risk for lactic acidosis.

Intervention:

Consider more frequent monitoring of these patients.

Examples:

Topiramate, zonisamide, acetazolamide or dichlorphenamide.

Drugs that Reduce GLUCOPHAGE/GLUCOPHAGE XR Clearance

Clinical Impact:

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) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology ( 12.3)].

Intervention:

Consider the benefits and risks of concomitant use with GLUCOPHAGE/GLUCOPHAGE XR.

Examples:

Ranolazine, vandetanib, dolutegravir, and cimetidine.

Alcohol

Clinical Impact:

Alcohol is known to potentiate the effect of metformin on lactate metabolism.

Intervention:

Warn patients against excessive alcohol intake while receiving GLUCOPHAGE/GLUCOPHAGE XR.

Insulin Secretagogues or Insulin

Clinical Impact:

Coadministration of GLUCOPHAGE/GLUCOPHAGE XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia.

Intervention:

Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.

Drugs Affecting Glycemic Control

Clinical Impact:

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.

Intervention:

When such drugs are administered to a patient receiving GLUCOPHAGE/GLUCOPHAGE XR, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving GLUCOPHAGE/GLUCOPHAGE XR, observe the patient closely for hypoglycemia.

Examples:

Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

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