Lactic Acidosis:
Lactic acidosis is a rare, but serious, metabolic complicationthat can occur due to metformin accumulation during treatment with GLUCOPHAGEor GLUCOPHAGE XR; when it occurs, it is fatal in approximately 50% of cases.Lactic acidosis may also occur in association with a number of pathophysiologicconditions, including diabetes mellitus, and whenever there is significanttissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevatedblood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbanceswith an increased anion gap, and an increased lactate/pyruvate ratio. Whenmetformin is implicated as the cause of lactic acidosis, metformin plasmalevels >5 µg/mL are generally found.
The reported incidence of lactic acidosis in patients receivingmetformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years,with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000patient-years exposure to metformin in clinical trials, there were no reportsof lactic acidosis. Reported cases have occurred primarily in diabetic patientswith significant renal insufficiency, including both intrinsic renal diseaseand renal hypoperfusion, often in the setting of multiple concomitant medical/surgicalproblems and multiple concomitant medications. Patients with congestive heartfailure requiring pharmacologic management, in particular those with unstableor acute congestive heart failure who are at risk of hypoperfusion and hypoxemia,are at increased risk of lactic acidosis. The risk of lactic acidosis increaseswith the degree of renal dysfunction and the patient's age. The risk of lacticacidosis may, therefore, be significantly decreased by regular monitoringof renal function in patients taking GLUCOPHAGE or GLUCOPHAGE XR and by useof the minimum effective dose of GLUCOPHAGE or GLUCOPHAGE XR. In particular,treatment of the elderly should be accompanied by careful monitoring of renalfunction. GLUCOPHAGE or GLUCOPHAGE XR treatment should not be initiated inpatients ≥80 years of age unless measurement of creatinine clearance demonstratesthat renal function is not reduced, as these patients are more susceptibleto developing lactic acidosis. In addition, GLUCOPHAGE and GLUCOPHAGE XR shouldbe promptly withheld in the presence of any condition associated with hypoxemia,dehydration, or sepsis. Because impaired hepatic function may significantlylimit the ability to clear lactate, GLUCOPHAGE and GLUCOPHAGE XR should generallybe avoided in patients with clinical or laboratory evidence of hepatic disease.Patients should be cautioned against excessive alcohol intake, either acuteor chronic, when taking GLUCOPHAGE or GLUCOPHAGE XR, since alcohol potentiatesthe effects of metformin hydrochloride on lactate metabolism. In addition,GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued prior to anyintravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).
The onset of lactic acidosis often is subtle, and accompaniedonly by nonspecific symptoms such as malaise, myalgias, respiratory distress,increasing somnolence, and nonspecific abdominal distress. There may be associatedhypothermia, hypotension, and resistant bradyarrhythmias with more markedacidosis. The patient and the patient's physician must be aware of the possibleimportance of such symptoms and the patient should be instructed to notifythe physician immediately if they occur (see also PRECAUTIONS).GLUCOPHAGE and GLUCOPHAGE XR should be withdrawn until the situation is clarified.Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactatelevels, and even blood metformin levels may be useful. Once a patient is stabilizedon any dose level of GLUCOPHAGE or GLUCOPHAGE XR, gastrointestinal symptoms,which are common during initiation of therapy, are unlikely to be drug related.Later occurrence of gastrointestinal symptoms could be due to lactic acidosisor other serious disease.
Levels of fasting venous plasma lactate above the upperlimit of normal but less than 5mmol/L in patientstaking GLUCOPHAGE or GLUCOPHAGE XR do not necessarily indicate impending lacticacidosis and may be explainable by other mechanisms, such as poorly controlleddiabetes or obesity, vigorous physical activity, or technical problems insample handling. (See also PRECAUTIONS.)
Lactic acidosis should be suspected in any diabetic patientwith metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treatedin a hospital setting. In a patient with lactic acidosis who is taking GLUCOPHAGEor GLUCOPHAGE XR, the drug should be discontinued immediately and generalsupportive measures promptly instituted. Because metformin hydrochloride isdialyzable (with a clearance of up to 170mL/min under goodhemodynamic conditions), prompt hemodialysis is recommended to correct theacidosis and remove the accumulated metformin. Such management often resultsin prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.)
DESCRIPTION
GLUCOPHAGE® (metforminhydrochloride) Tablets and GLUCOPHAGE® XR (metforminhydrochloride) Extended-Release Tablets are oral antihyperglycemic drugs usedin the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidicdiamide hydrochloride) is not chemically or pharmacologically related to anyother classes of oral antihyperglycemic agents. The structural formula isas shown:
Metformin hydrochloride is a white to off-white crystallinecompound with a molecular formula of C4H11N5 •HCl and a molecular weight of 165.63. Metformin hydrochloride is freely solublein water and is practically insoluble in acetone, ether, and chloroform. ThepKa of metformin is 12.4. The pH of a 1% aqueous solutionof metformin hydrochloride is 6.68.
GLUCOPHAGE tabletscontain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tabletcontains the inactive ingredients povidone and magnesium stearate. In addition,the coating for the 500 mg and 850 mg tablets contains hypromellose and thecoating for the 1000mg tablet contains hypromellose andpolyethylene glycol.
GLUCOPHAGE XR contains 500 mgor 750 mg of metformin hydrochloride as the active ingredient.
GLUCOPHAGEXR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose,hypromellose, microcrystalline cellulose, and magnesium stearate.
GLUCOPHAGEXR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose,hypromellose, and magnesium stearate.
SystemComponents and Performance–GLUCOPHAGE XR comprises a dual hydrophilicpolymer matrix system. Metformin hydrochloride is combined with a drug releasecontrolling polymer to form an "inner" phase, which is then incorporated asdiscrete particles into an "external" phase of a second polymer. After administration,fluid from the gastrointestinal (GI) tract enters the tablet, causing thepolymers to hydrate and swell. Drug is released slowly from the dosage formby a process of diffusion through the gel matrix that is essentially independentof pH. The hydrated polymer system is not rigid and is expected to be brokenup by normal peristalsis in the GI tract. The biologically inert componentsof the tablet may occasionally remain intact during GI transit and will beeliminated in the feces as a soft, hydrated mass.
CLINICAL PHARMACOLOGY
Mechanism of Action
Metformin is an antihyperglycemic agentwhich improves glucose tolerance in patients with type 2 diabetes, loweringboth basal and postprandial plasma glucose. Its pharmacologic mechanisms ofaction are different from other classes of oral antihyperglycemic agents.Metformin decreases hepatic glucose production, decreases intestinal absorptionof glucose, and improves insulin sensitivity by increasing peripheral glucoseuptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemiain either patients with type 2 diabetes or normal subjects (except in specialcircumstances, see PRECAUTIONS) and doesnot cause hyperinsulinemia. With metformin therapy, insulin secretion remainsunchanged while fasting insulin levels and day-long plasma insulin responsemay actually decrease.
Pharmacokinetics
Absorption and Bioavailability
The absolute bioavailability of a GLUCOPHAGE500 mg tablet given under fasting conditions is approximately 50% to 60%.Studies using single oral doses of GLUCOPHAGE 500 to 1500mg,and 850 to 2550 mg, indicate that there is a lack of dose proportionalitywith increasing doses, which is due to decreased absorption rather than analteration in elimination. Food decreases the extent of and slightly delaysthe absorption of metformin, as shown by approximately a 40% lower mean peakplasma concentration (Cmax), a 25% lower area underthe plasma concentration versus time curve (AUC), and a 35-minute prolongationof time to peak plasma concentration (Tmax) followingadministration of a single 850 mg tablet of metformin with food, comparedto the same tablet strength administered fasting. The clinical relevance ofthese decreases is unknown.
Following a single oraldose of GLUCOPHAGE XR, Cmax is achieved with a medianvalue of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately20% lower compared to the same dose of GLUCOPHAGE, however, the extent ofabsorption (as measured by AUC) is similar to GLUCOPHAGE.
Atsteady state, the AUC and Cmax are less than dose proportionalfor 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 µg/mL for 500,1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metforminabsorption (as measured by AUC) from GLUCOPHAGE XR at a 2000 mg once-dailydose is similar to the same total daily dose administered as GLUCOPHAGE tablets1000 mg twice daily. After repeated administration of GLUCOPHAGE XR, metformindid not accumulate in plasma.
Within-subject variabilityin Cmax and AUC of metformin from GLUCOPHAGE XR iscomparable to that with GLUCOPHAGE.
Although the extentof metformin absorption (as measured by AUC) from the GLUCOPHAGE XR tabletincreased by approximately 50% when given with food, there was no effect offood on Cmax and Tmax of metformin.Both high and low fat meals had the same effect on the pharmacokinetics ofGLUCOPHAGE XR.
Distribution
The apparent volume of distribution (V/F) of metformin followingsingle oral doses of GLUCOPHAGE 850 mg averaged 654 ± 358 L. Metformin isnegligibly bound to plasma proteins, in contrast to sulfonylureas, which aremore than 90% protein bound. Metformin partitions into erythrocytes, mostlikely as a function of time. At usual clinical doses and dosing schedulesof GLUCOPHAGE, steady state plasma concentrations of metformin are reachedwithin 24 to 48 hours and are generally <1 µg/mL. During controlled clinicaltrials of GLUCOPHAGE, maximum metformin plasma levels did not exceed 5 µg/mL,even at maximum doses.
Metabolism and Elimination
Intravenous single-dose studies in normal subjects demonstratethat metformin is excreted unchanged in the urine and does not undergo hepaticmetabolism (no metabolites have been identified in humans) nor biliary excretion.Renal clearance (see Table 1) isapproximately 3.5 times greater than creatinine clearance, which indicatesthat tubular secretion is the major route of metformin elimination. Followingoral administration, approximately 90% of the absorbed drug is eliminatedvia the renal route within the first 24 hours, with a plasma elimination half-lifeof approximately 6.2 hours. In blood, the elimination half-life is approximately17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Special Populations
Patients with Type 2 Diabetes
In the presence of normal renal function, there are no differencesbetween single- or multiple-dose pharmacokinetics of metformin between patientswith type 2 diabetes and normal subjects (see Table1), nor is there any accumulation of metformin in either groupat usual clinical doses.
The pharmacokinetics of GLUCOPHAGE XR in patients with type 2 diabetesare comparable to those in healthy normal adults.
Renal Insufficiency
In patients with decreased renal function (based on measured creatinineclearance), the plasma and blood half-life of metformin is prolonged and therenal clearance is decreased in proportion to the decrease in creatinine clearance(see Table 1; also see WARNINGS).
Hepatic Insufficiency
No pharmacokinetic studies of metformin have been conducted inpatients with hepatic insufficiency.
Geriatrics
Limited data from controlled pharmacokineticstudies of GLUCOPHAGE in healthy elderly subjects suggest that total plasmaclearance of metformin is decreased, the half-life is prolonged, and Cmax isincreased, compared to healthy young subjects. From these data, it appearsthat the change in metformin pharmacokinetics with aging is primarily accountedfor by a change in renal function (see Table 1).GLUCOPHAGE (metformin hydrochloride) Tablets and GLUCOPHAGE XR (metforminhydrochloride) Extended-Release Tablets treatment should not be initiatedin patients ≥80 years of age unless measurement of creatinine clearance demonstratesthat renal function is not reduced (see WARNINGS and DOSAGE AND ADMINISTRATION).
Table 1: Select Mean (±S.D.) Metformin Pharmacokinetic ParametersFollowing Single or Multiple Oral Doses of GLUCOPHAGE
SubjectGroups: GLUCOPHAGE dosea
(number ofsubjects) |
Cmaxb
(µg/mL) |
Tmaxc
(hrs) |
RenalClearance
(mL/min) |
|
a All doses givenfasting except the first 18 doses of the multiple dose studies |
|
bPeak plasma concentration |
|
cTime to peak plasmaconcentration |
|
dCombinedresults (average means) of five studies: mean age 32 years (range 23-59 years) |
|
eKinetic study donefollowing dose 19, given fasting |
|
fElderly subjects,mean age 71 years (range 65-81 years) |
|
gCLcr =creatinine clearance normalized to body surface area of 1.73 m2 |
|
Healthy, nondiabetic adults: |
|
|
|
|
500mg single dose (24) |
1.03 (±0.33) |
2.75 (±0.81) |
600 (±132) |
|
850mg single dose (74)d |
1.60 (±0.38) |
2.64 (±0.82) |
552 (±139) |
|
850mg three times daily for 19 dosese (9) |
2.01 (±0.42) |
1.79 (±0.94) |
642 (±173) |
|
Adults with type 2 diabetes: |
|
|
|
|
850mg single dose (23) |
1.48 (±0.5) |
3.32 (±1.08) |
491 (±138) |
|
850mg three times daily for 19 dosese (9) |
1.90 (±0.62) |
2.01 (±1.22) |
550 (±160) |
|
Elderlyf,healthy nondiabetic adults: |
|
|
|
|
850mg 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) |
1.86 (±0.52) |
3.20 (±0.45) |
384 (±122) |
|
Moderate (CLcr 31-60 mL/min) (4) |
4.12 (±1.83) |
3.75 (±0.50) |
108 (±57) |
|
Severe (CLcr 10-30 mL/min) (6) |
3.93 (±0.92) |
4.01 (±1.10) |
130 (±90) |
Pediatrics
After administration of a single oralGLUCOPHAGE 500 mg tablet with food, geometric mean metformin Cmax andAUC differed less than 5% between pediatric type 2 diabetic patients (12-16years of age) and gender- and weight-matched healthy adults (20-45 years ofage), all with normal renal function.
Gender
Metformin pharmacokinetic parameters did not differ significantlybetween normal subjects and patients with type 2 diabetes when analyzed accordingto gender (males = 19, females = 16). Similarly, in controlled clinical studiesin patients with type 2 diabetes, the antihyperglycemic effect of GLUCOPHAGEwas comparable in males and females.
Race
No studies of metformin pharmacokinetic parameters according torace have been performed. In controlled clinical studies of GLUCOPHAGE inpatients with type 2 diabetes, the antihyperglycemic effect was comparablein whites (n=249), blacks (n=51), and Hispanics (n=24).
Clinical Studies
GLUCOPHAGE
In a double-blind, placebo-controlled,multicenter US clinical trial involving obese patients with type 2 diabeteswhose hyperglycemia was not adequately controlled with dietary managementalone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL),treatment with GLUCOPHAGE (up to 2550 mg/day) for 29 weeks resulted in significantmean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobinA1c (HbA1c) of 59 mg/dL, 83mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2).
Table 2: GLUCOPHAGE vs Placebo Summary of Mean Changes from Baseline*in Fasting Plasma Glucose, HbA1c, and Body Weight,at Final Visit (29-week study)
|
|
GLUCOPHAGE
(n=141) |
Placebo
(n=145) |
p-Value |
|
* All patients on diet therapy at Baseline |
** Not statistically significant |
FPG (mg/dL)
Baseline
Changeat FINAL VISIT |
241.5
–53.0 |
237.7
6.3 |
NS**
0.001 |
Hemoglobin A1c (%)
Baseline
Changeat FINAL VISIT |
8.4
–1.4 |
8.2
0.4 |
NS**
0.001 |
Body Weight (lbs)
Baseline
Changeat FINAL VISIT |
201.0
–1.4 |
206.0
–2.4 |
NS**
NS** |
A 29-week, double-blind, placebo-controlled study of GLUCOPHAGEand glyburide, alone and in combination, was conducted in obese patients withtype 2 diabetes who had failed to achieve adequate glycemic control whileon maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combinationarm started therapy with GLUCOPHAGE 500 mg and glyburide 20 mg. At the endof each week of the first 4 weeks of the trial, these patients had their dosagesof GLUCOPHAGE increased by 500mg if they had failed to reachtarget fasting plasma glucose. After week 4, such dosage adjustments weremade monthly, although no patient was allowed to exceed GLUCOPHAGE 2500 mg.Patients in the GLUCOPHAGE only arm (metformin plus placebo) followed thesame titration schedule. At the end of the trial, approximately 70% of thepatients in the combination group were taking GLUCOPHAGE 2000 mg/glyburide20 mg or GLUCOPHAGE 2500 mg/glyburide 20 mg. Patients randomized to continueon glyburide experienced worsening of glycemic control, with mean increasesin FPG, PPG, and HbA1c of 14 mg/dL, 3mg/dL,and 0.2%, respectively. In contrast, those randomized to GLUCOPHAGE (up to2500mg/day) experienced a slight improvement, with meanreductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL,and 0.4%, respectively. The combination of GLUCOPHAGE and glyburide was effectivein reducing FPG, PPG, and HbA1c levels by 63 mg/dL,65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatmentalone, the net differences with combination treatment were –77 mg/dL, –68mg/dL, and –1.9%, respectively (see Table 3).
Table 3: Combined GLUCOPHAGE/Glyburide (Comb) vs Glyburide (Glyb)or GLUCOPHAGE (GLU) Monotherapy: Summary of Mean Changes from Baseline* inFasting Plasma Glucose, HbA1c, and Body Weight, atFinal Visit (29-week study)
|
|
|
|
|
p-values |
|
|
Comb
(n=213) |
Glyb
(n=209) |
GLU
(n=210) |
Glyb vs
Comb |
GLU vs
Comb |
GLU vs
Glyb |
|
* All patients on glyburide, 20 mg/day, at Baseline |
** Not statistically significant |
|
Fasting Plasma Glucose (mg/dL) |
|
|
|
|
|
|
Baseline
Change at FINAL VISIT |
250.5
–63.5 |
247.5
13.7 |
253.9
–0.9 |
NS**
0.001 |
NS**
0.001 |
NS**
0.025 |
|
Hemoglobin A1c (%) |
|
|
|
|
|
|
Baseline
Change at FINAL VISIT |
8.8
–1.7 |
8.5
0.2 |
8.9
–0.4 |
NS**
0.001 |
NS**
0.001 |
0.007
0.001 |
|
Body Weight (lbs) |
|
|
|
|
|
|
Baseline
Change at FINAL VISIT |
202.2
0.9 |
203.0
–0.7 |
204.0
–8.4 |
NS**
0.011 |
NS**
0.001 |
NS**
0.001 |
The magnitude of the decline in fasting blood glucoseconcentration following the institution of GLUCOPHAGE (metformin hydrochloride)Tablets therapy was proportional to the level of fasting hyperglycemia. Patientswith type 2 diabetes with higher fasting glucose concentrations experiencedgreater declines in plasma glucose and glycosylated hemoglobin.
Inclinical studies, GLUCOPHAGE, alone or in combination with a sulfonylurea,lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterollevels, and had no adverse effects on other lipid levels (see Table 4).
Table 4: Summary of Mean Percent Change From Baseline of Major SerumLipid Variables at Final Visit (29-week studies)
|
|
GLUCOPHAGEvs Placebo |
CombinedGLUCOPHAGE/Glyburide
vs Monotherapy |
|
|
GLUCOPHAGE
(n=141) |
Placebo
(n=145) |
GLUCOPHAGE
(n=210) |
GLUCOPHAGE/
Glyburide
(n=213) |
Glyburide
(n=209) |
|
Total Cholesterol (mg/dL) |
|
|
|
|
|
Baseline
Mean % Change at FINAL VISIT |
211.0
–5% |
212.3
1% |
213.1
–2% |
215.6
–4% |
219.6
1% |
|
Total Triglycerides (mg/dL) |
|
|
|
|
|
Baseline
Mean % Change at FINAL VISIT |
236.1
–16% |
203.5
1% |
242.5
–3% |
215.0
–8% |
266.1
4% |
|
LDL-Cholesterol (mg/dL) |
|
|
|
|
|
Baseline
Mean % Change at FINAL VISIT |
135.4
–8% |
138.5
1% |
134.3
–4% |
136.0
–6% |
137.5
3% |
|
HDL-Cholesterol (mg/dL) |
|
|
|
