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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use GLUCOPHAGE and GLUCOPHAGE XR safely and effectively. See full prescribing information for GLUCOPHAGE and GLUCOPHAGE XR.
GLUCOPHAGE ^ (metformin hydrochloride) tablets, for oral use GLUCOPHAGE ^ XR (metformin hydrochloride) extended-release tablets, for oral use Initial U.S. Approval: 1995 WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.
- Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally > mcg/mL. (5.1)
- Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, 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. (5.1)
- If lactic acidosis is suspected, discontinue GLUCOPHAGE/ GLUCOPHAGE XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1) ---------------------------INDICATIONS AND USAGE--------------------------- GLUCOPHAGE is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. (1) GLUCOPHAGE XR is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1) ------------------------DOSAGE AND ADMINISTRATION--------------------- Adult Dosage for GLUCOPHAGE:
- Starting dose: 500 mg orally twice a day or 850 mg once a day, with meals (2.1)
- Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks, up to a maximum dose of 2550 mg per day, given in divided doses (2.1)
- Doses above 2000 mg may be better tolerated given 3 times a day with meals (2.1) Adult Dosage for GLUCOPHAGE XR:
- Swallow GLUCOPHAGE XR tablets whole and never crush, cut or chew (2.1)
- Starting dose: 500 mg orally once daily with the evening meal (2.1)
- Increase the dose in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal (2.1)
- Patients receiving GLUCOPHAGE may be switched to GLUCOPHAGE XR once daily at the same total daily dose, up to 2000 mg once daily (2.1) Pediatric Dosage for GLUCOPHAGE:
- Starting dose: 500 mg orally twice a day, with meals (2.2)
- Increase dosage in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses twice daily (2.2)
Renal Impairment:
- Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.3) o Do not use in patients with eGFR below 30 mL/minute/1.73 m^2 (2.3) o Initiation is not recommended in patients with eGFR between 30- mL/minute/1.73 m^2 (2.3) o Assess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m^2 (2.3) o Discontinue if eGFR falls below 30 mL/minute/1.73 m^2 (2.3) Discontinuation for Iodinated Contrast Imaging Procedures:
- GLUCOPHAGE/GLUCOPHAGE XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4) ----------------------DOSAGE FORMS AND STRENGTHS--------------------
- GLUCOPHAGE Tablets: 500 mg, 850 mg, and 1000 mg (3)
- GLUCOPHAGE XR Extended-Release Tablets: 500 mg and 750 mg (3) ------------------------------CONTRAINDICATIONS------------------------------
- Severe renal impairment (eGFR below 30 mL/min/1.73 m^2 ) (4, 5.1)
- Hypersensitivity to metformin (4)
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. (4) ------------------------WARNINGS AND PRECAUTIONS----------------------
- Lactic Acidosis: See boxed warning. ( 5.1)
- Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. (5.2)
- Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required (5.3) -------------------------------ADVERSE REACTIONS----------------------------- For GLUCOPHAGE/GLUCOPHAGE XR, the most common adverse reactions (>5.0%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch --------------------------------DRUG INTERACTIONS----------------------------
- Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring (7)
- Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use (7)
- Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake (7) ------------------------USE IN SPECIFIC POPULATIONS----------------------
- Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3)
- Geriatric Use: Assess renal function more frequently. (8.5)
- Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling Revised: 05/
FULL PRESCRIBING INFORMATION: CONTENTS WARNING: LACTIC ACIDOSIS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION* 2.1 Adult Dosage 2.2 Pediatric Dosage for GLUCOPHAGE 2.3 Recommendations for Use in Renal Impairment 2.4 Discontinuation for Iodinated Contrast Imaging Procedures 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Lactic Acidosis 5.2 Vitamin B 12 Deficiency 5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues 5.4 Macrovascular Outcomes
6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 1
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12.3 Pharmacokinetics NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES
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16.1 How Supplied 16.2 Storage PATIENT COUNSELING INFORMATION
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14.1 GLUCOPHAGE 14.2 GLUCOPHAGE XR HOW SUPPLIED/STORAGE AND HANDLING
*Sections or subsections omitted from the full prescribing information are not listed.
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- Doses above 2000 mg may be better tolerated given 3 times a day with meals.
GLUCOPHAGE XR
- Swallow GLUCOPHAGE XR tablets whole and never crush, cut or chew.
- The recommended starting dose of GLUCOPHAGE XR is 500 mg orally once daily with the evening meal.
- Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg once daily with the evening meal.
- If glycemic control is not achieved with GLUCOPHAGE XR 2000 mg once daily, consider a trial of GLUCOPHAGE XR 1000 mg twice daily. If higher doses are required, switch to GLUCOPHAGE at total daily doses up to 2550 mg administered in divided daily doses, as described above.
- Patients receiving GLUCOPHAGE may be switched to GLUCOPHAGE XR once daily at the same total daily dose, up to 2000 mg once daily.
2.2 Pediatric Dosage for GLUCOPHAGE
- The recommended starting dose of GLUCOPHAGE for pediatric patients 10 years of age and older is 500 mg orally twice a day, given with meals.
- Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg per day, given in divided doses twice daily.
2.3 Recommendations for Use in Renal Impairment
- Assess renal function prior to initiation of GLUCOPHAGE/GLUCOPHAGE XR and periodically thereafter.
- GLUCOPHAGE/GLUCOPHAGE XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m^2.
- Initiation of GLUCOPHAGE/GLUCOPHAGE XR in patients with an eGFR between 30
- 45 mL/minute/1.73 m^2 is not recommended.
- In patients taking GLUCOPHAGE/GLUCOPHAGE XR whose eGFR later falls below 45 mL/min/1.73 m^2 , assess the benefit risk of continuing therapy.
- Discontinue GLUCOPHAGE/GLUCOPHAGE XR if the patient’s eGFR later falls below 30 mL/minute/1.73 m^2 [see Warnings and Precautions (5.1) ].
2.4 Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue GLUCOPHAGE/GLUCOPHAGE 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^2 ; in patients with
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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 GLUCOPHAGE/GLUCOPHAGE XR if renal function is stable.
3 DOSAGE FORMS AND STRENGTHS
GLUCOPHAGE is available as:
- Tablets: 500 mg round, white to off-white, film-coated debossed with "BMS 6060" around the periphery on one side and "500" debossed across the face of the other side.
- Tablets: 850 mg round, white to off-white, film-coated debossed with "BMS 6070" around the periphery on one side and "850" debossed across the face of the other side.
- Tablets: 1000 mg white, oval, biconvex, film-coated with "BMS 6071" debossed on one side and "1000" debossed on the opposite side and with a bisect line on both sides.
GLUCOPHAGE XR is available as:
- Extended-release tablets: 500 mg white to off-white, capsule shaped, biconvex, with "BMS 6063" debossed on one side and "500" debossed across the face of the other side.
- Extended-release tablets: 750 mg pale red and may have a mottled appearance, capsule shaped, biconvex, with "BMS 6064" debossed on one side and "750" debossed on the other side.
4 CONTRAINDICATIONS
GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions
(5.1) ].
- Hypersensitivity to metformin.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
5 WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis
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, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver
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cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
- Radiologic 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 GLUCOPHAGE/GLUCOPHAGE 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^2 ; 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 GLUCOPHAGE/GLUCOPHAGE 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. GLUCOPHAGE/GLUCOPHAGE 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 cause prerenal azotemia. When such an event occurs, discontinue GLUCOPHAGE/GLUCOPHAGE XR.
- Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving GLUCOPHAGE/GLUCOPHAGE XR.
- Hepatic impairment — Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of GLUCOPHAGE/GLUCOPHAGE XR in patients with clinical or laboratory evidence of hepatic disease.
5.2 Vitamin B 12 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 B12-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
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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:
- Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
- Vitamin B12 Deficiency [see Warnings and Precautions (5.2)]
- Hypoglycemia [see Warnings and Precautions (5.3)]
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.
GLUCOPHAGE
In 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%
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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 the insulin secretagogue or insulin.^ of 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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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Limited data with GLUCOPHAGE/GLUCOPHAGE XR 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 mellitus in pregnancy [see Clinical Considerations].
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- and 5 times, respectively, a 2550 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 mellitus with an 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 mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, 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
Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
8.2 Lactation
Risk Summary
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8.6 Renal Impairment
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. GLUCOPHAGE/GLUCOPHAGE XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m^2 [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3) ].
8.7 Hepatic Impairment
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. GLUCOPHAGE/GLUCOPHAGE XR is not recommended in patients with hepatic impairment. [see Warnings and Precautions (5.1) ].
10 OVERDOSAGE
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1) ]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
11 DESCRIPTION
GLUCOPHAGE/GLUCOPHAGE XR contain the antihyperglycemic agent metformin, which is a biguanide, in the form of monohydrochloride. The chemical name of metformin hydrochloride is N,N -dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown below:
Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula
of C 4 H11N 5 • HCl and a molecular weight of 165.63. It is freely soluble in water and is practically
insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride, which is equivalent to 389.93 mg, 662.88 mg, 779.86 mg metformin base, respectively. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the
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500 mg and 850 mg tablets contains hypromellose and the coating for the 1000 mg tablet contains hypromellose and polyethylene glycol.
GLUCOPHAGE XR contains 500 mg or 750 mg of metformin hydrochloride, which is equivalent to 389.93 mg, 584.90 mg metformin base, respectively.
GLUCOPHAGE XR 500 mg tablets contain the inactive ingredients hypromellose, microcrystalline cellulose, sodium carboxymethyl cellulose, and magnesium stearate.
GLUCOPHAGE XR 750 mg tablets contain the inactive ingredients hypromellose, sodium carboxymethyl cellulose, magnesium stearate and iron oxide pigment red.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.
12.3 Pharmacokinetics
Absorption
The absolute bioavailability of a GLUCOPHAGE 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of GLUCOPHAGE 500 to 1500 mg and 850 to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of GLUCOPHAGE, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL.
Following a single oral dose of GLUCOPHAGE XR, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of GLUCOPHAGE, however, the extent of absorption (as measured by AUC) is comparable to GLUCOPHAGE.
At steady state, the AUC and Cmax are less than dose proportional for GLUCOPHAGE XR within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from GLUCOPHAGE XR at a 2000 mg once-daily dose is similar to the same total daily dose administered as GLUCOPHAGE tablets 1000 mg twice daily. After repeated administration of GLUCOPHAGE XR, metformin did not accumulate in plasma.
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Geriatrics
Limited data from controlled pharmacokinetic studies of GLUCOPHAGE in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged,
and Cmax is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 4). [See Warnings and Precautions (5.1) and Use in Specific Populations (8.5) ].
Table 4: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of GLUCOPHAGE
Subject Groups: GLUCOPHAGE dosea (number of subjects)
C (^) max b (mcg/mL)
Tmax c (hrs)
Renal Clearance (mL/min) Healthy, nondiabetic adults: 500 mg single dose (24) 850 mg single dose (74)d 850 mg three times daily for 19 dosese^ (9)
1.03 (±0.33) 1.60 (±0.38) 2.01 (±0.42)
2.75 (±0.81) 2.64 (±0.82) 1.79 (±0.94)
600 (±132) 552 (±139) 642 (±173) Adults with type 2 diabetes mellitus: 850 mg single dose (23) 850 mg three times daily for 19 dosese^ (9)
1.48 (±0.5) 1.90 (±0.62)
3.32 (±1.08) 2.01 (±1.22)
491 (±138) 550 (±160) Elderly f, healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) Renal-impaired adults: 850 mg single dose Mild (CLcrg^61 - 90 mL/min) (5) Moderate (CLcr 31 - 60 mL/min) (4) Severe (CLcr 10 - 30 mL/min) (6)
1.86 (±0.52)
4.12 (±1.83) 3.93 (±0.92)
3.20 (±0.45)
3.75 (±0.50) 4.01 (±1.10)
384 (±122)
108 (±57) 130 (±90) a (^) All doses given fasting except the first 18 doses of the multiple dose studies b (^) Peak plasma concentration c (^) Time to peak plasma concentration d (^) Combined results (average means) of five studies: mean age 32 years (range 23-59 years) e (^) Kinetic study done following dose 19, given fasting f (^) Elderly subjects, mean age 71 years (range 65-81 years) g (^) CLcr = creatinine clearance normalized to body surface area of 1.73 m 2
Pediatrics
After administration of a single oral GLUCOPHAGE 500 mg tablet with food, geometric mean
metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12- years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.
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Gender
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16).
Race
No studies of metformin pharmacokinetic parameters according to race have been performed.
Drug Interactions
In Vivo Assessment of Drug Interactions
Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug
Dose of Coadministered Drug *
Dose of Metformin *
Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1. AUC †^ C^ max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin (^) 0.91‡^ 0.93‡ Furosemide 40 mg 850 mg metformin (^) 1.09‡^ 1.22‡ Nifedipine 10 mg 850 mg metformin 1.16 1. Propranolol 40 mg 850 mg metformin 0.90 0. Ibuprofen 400 mg 850 mg metformin (^) 1.05‡^ 1.07‡ Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [See Warnings and Precautions (5.9) and Drug Interactions (7.2). ] Cimetidine 400 mg 850 mg metformin 1.40 1. Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions (5.1) and Drug Interactions (7.1). ] Topiramate (^) 100 mg §^ 500 mg §^ metformin (^) 1.25§^ 1.
- All metformin and coadministered drugs were given as single doses † (^) AUC = AUC(INF) ‡ (^) Ratio of arithmetic means
§ (^) At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h
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14 CLINICAL STUDIES
14.1 GLUCOPHAGE
Adult Clinical Studies
A double-blind, placebo-controlled, multicenter US clinical trial involving obese patients with type 2 diabetes mellitus whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL) was conducted. Patients were treated with GLUCOPHAGE (up to 2550 mg/day) or placebo for 29 weeks. The results are presented in Table 7.
Table 7: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing GLUCOPHAGE vs Placebo in Patients with Type 2 Diabetes Mellitus
GLUCOPHAGE (n=141)
Placebo (n=145)
p-Value
FPG (mg/dL) Baseline Change at FINAL VISIT
–53.
NS*
Hemoglobin A (^) 1c (%) Baseline Change at FINAL VISIT
–1.
NS*
- Not statistically significant
Mean baseline body weight was 201 lbs and 206 lbs in the GLUCOPHAGE and placebo arms, respectively. Mean change in body weight from baseline to week 29 was -1.4 lbs and -2.4 lbs in the GLUCOPHAGE and placebo arms, respectively.A 29-week, double-blind, placebo-controlled study of GLUCOPHAGE and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes mellitus who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL). Patients randomized to the combination arm started therapy with GLUCOPHAGE 500 mg and glyburide 20 mg. At the end of each week of the first 4 weeks of the trial, these patients had their dosages of GLUCOPHAGE increased by 500 mg if they had failed to reach target fasting plasma glucose. After week 4, such dosage adjustments were made monthly, although no patient was allowed to exceed GLUCOPHAGE 2500 mg. Patients in the GLUCOPHAGE only arm (metformin plus placebo) discontinued glyburide and followed the same titration schedule. Patients in the glyburide arm continued the same dose of glyburide. At the end of the trial, approximately 70% of the patients in the combination group were taking GLUCOPHAGE 2000 mg/glyburide 20 mg or GLUCOPHAGE 2500 mg/glyburide 20 mg. The results are displayed in Table 8.
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Table 8: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing GLUCOPHAGE/Glyburide (Comb) vs Glyburide (Glyb) vs GLUCOPHAGE (GLU): in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Glyburide
Comb (n=213)
Glyb (n= )
GLU (n=210)
p-Values Glyb vs Comb GLU vs Comb GLU vs Glyb
Fasting Plasma Glucose (mg/dL) Baseline 250.5 247.5 253.9 NS* NS* NS* Change at FINAL VISIT – 63.5 13.7 – 0.9 0.001 0.001 0. Hemoglobin A (^) 1c (%) Baseline 8.8 8.5 8.9 NS* NS* 0. Change at FINAL VISIT – 1.7 0.2 – 0.4 0.001 0.001 0.
- Not statistically significant
Mean baseline body weight was 202 lbs, 203 lbs, and 204 lbs in the GLUCOPHAGE/glyburide, glyburide, and GLUCOPHAGE arms, respectively. Mean change in body weight from baseline to week 29 was 0.9 lbs, -0.7 lbs, and -8.4 lbs in the GLUCOPHAGE/glyburide, glyburide, and GLUCOPHAGE arms, respectively.
Pediatric Clinical Studies
A double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), treatment with GLUCOPHAGE (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) was conducted. The results are displayed in Table 9.
Table 9: Mean Change in Fasting Plasma Glucose at Week 16 Comparing GLUCOPHAGE vs Placebo in Pediatric Patientsa^ with Type 2 Diabetes Mellitus
GLUCOPHAGE Placebo p-Value FPG (mg/dL) Baseline Change at FINAL VISIT
(n=37)
(n=36)
21.4 <0. a (^) Pediatric patients mean age 13.8 years (range 10- 16 years)
Mean baseline body weight was 205 lbs and 189 lbs in the GLUCOPHAGE and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the GLUCOPHAGE and placebo arms, respectively.
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