METFORMIN HYDROCHLORIDE | METFORMIN HYDROCHLORIDE

10:17 EDT 31st October 2014 | BioPortfolio
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Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 µg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride tablets, USP is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin hydrochloride tablets, USP treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin hydrochloride tablets, USP since alcohol potentiates the effects of metformin hydrochloride tablets, USP on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS). The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). Metformin hydrochloride tablets, USP should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, 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 acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity or technical problems in sample handling. (See also PRECAUTIONS.)

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride tablets, USP are dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS AND PRECAUTIONS).

Metformin hydrochloride, USP is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride ( N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:

Metformin hydrochloride, USP is a white to off-white crystalline compound with a molecular formula of CHN•HCl and a molecular weight of 165.63. Metformin hydrochloride, USP is freely soluble in water and is practically insoluble in acetone, ether and chloroform. The pK of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride, USP is 6.68.

Metformin hydrochloride tablets, USP contain 500 mg, 850 mg, and 1000 mg of metformin hydrochloride, USP. Each tablet contains the inactive ingredients povidone, polyethylene glycol and magnesium stearate. In addition, the coating for 500 mg, 850 mg and 1000 mg contains: lactose, polyethylene glycol, hydroxypropyl methylcellulose, titanium dioxide, and sodium citrate dihydrate.

IMAGE metformin-structure.jpg

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin hydrochloride tablets, USP of 500 mg to 1500 mg, and 850 mg 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. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (T) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins in contrast to sulfonylureas which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, USP steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 µg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum doses.

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 1) is approximately 3.5 times greater than creatinine clearance which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

In the presence of normal renal function, there are no differences between single or multiple dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.

In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also see WARNINGS).

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced. (See WARNINGS and DOSAGE AND ADMINISTRATION).

Table 1. Select Mean (±S.D) Metformin Pharmacokinetic Parameter Following
Single or Multiple Oral Doses of Metformin Hydrochloride Tablets, USP
Subject Groups:
Metformin dosea
(number of subjects)
Cmax b
(µg/mL)
Tmax c
(hrs)
Renal Clearence
(mL/min)
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 yrs).
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 m2.
Healthy, nondiabetic adults:
500 mg single dose (24) 1.03 (±0.33) 2.75 (±0.81) 600 (±132)
850 mg single dose (74)d 1.60 (±0.38) 2.64 (±0.82) 552 (±139)
850 mg three times daily for 19 dosese (9) 2.01 (±0.42) 1.79 (±0.94) 642 (±173)
Adults with type 2 diabetes:
850 mg single dose (23) 1.48 (±0.5) 3.32 (±1.08) 491 (±138)
850 mg three times daily for 19 dosese (9) 1.90 (±0.62) 2.01 (±1.22) 550 (±160)
Elderlyf, 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) 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)

After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin C and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets, USP was comparable in males and females.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin hydrochloride tablets, USP in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and hispanics (n=24).

In a double-blind placebo-controlled, multicenter U.S. clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with metformin hydrochloride tablets, USP (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A (HbA) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to placebo group (see Table 2).

A 29-week, double-blind, placebo-controlled study of metformin and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes patients who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with metformin hydrochloride 500 mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had their dosages of metformin hydrochloride increased by 500 mg if they had failed to reach target fasting plasma glucose. After week four, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin hydrochloride 2500 mg. Patients in the metformin hydrochloride only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking metformin hydrochloride 2000 mg/glyburide 20 mg or metformin hydrochloride 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG and HbA of 14 mg/dL, 3 mg/dL and 0.2%, respectively. In contrast, those randomized to metformin (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG and HbA of 1 mg/dL, 6 mg/dL and 0.4%, respectively. The combination of metformin and glyburide was effective in reducing FPG, PPG and HbA levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were -77 mg/dL, -68 mg/dL and -1.9%, respectively (see Table 3).

The magnitude of the decline in fasting blood glucose concentration following the institution of metformin hydrochloride tablets, USP therapy is proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin.

In clinical studies, metformin, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol and LDL cholesterol levels and had no adverse effects on other lipid levels (see Table 4).

In contrast to sulfonylureas, body weight of individuals on metformin tended to remain stable or even decrease somewhat (see Tables 2 and 3).

A 24-week, double blind, placebo-controlled study of metformin hydrochloride tablets, USP plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to receive metformin hydrochloride plus insulin achieved a reduction in HbA of 2.10%, compared to a 1.56% reduction in HbA achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs 110.6 U/day, metformin hydrochloride tablets, USP plus insulin versus insulin plus placebo, respectively, p=0.04.

A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA of 7.46 ± 0.97%, the addition of metformin hydrochloride tablets, USP maintained similar glycemic control (HbA 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin hydrochloride tablets, USP plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for metformin hydrochloride tablets, USP plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of metformin hydrochloride tablets, USP plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01.

Table 2. Metformin Hydrochloride Tablets, USP vs Placebo
Summary of Mean Changes from Baseline* in Fasting Plasma Glucose
HbA1c and Body Weight, at Final Visit (29-week study)
Metformin hydrochloride tablets, USP
(n = 141)
Placebo
(n = 145)
P-value
* All patients on diet therapy at baseline
* * Not statistically significant
FPG (mg/dL)
Baseline 241.5 237.7 NS* *
Change at FINAL VISIT -53.0 6.3 0.001
Hemoglobin A1c (%)
Baseline 8.4 8.2 NS* *
Change at FINAL VISIT -1.4 0.4 0.001
Body Weight (lbs)    
Baseline 201.0 206.0  NS* *
Change at FINAL VISIT -1.4 -2.4 NS* *
Table 3. Combined Metformin Hydrochloride Tablets, USP / Glyburide (Comb) vs Glyburide (Glyb)
or Metformin Hydrochloride Tablets, USP (Met) Monotherapy: Summary of Mean Changes from Baseline*
in Fasting Plasma Glucose, HBA1c and Body Weight at Final Visit (29-week study)
p-values
Comb
(n = 213)
Glyb
(n = 209)
Met
(n = 210)
Glyb
Vs Comb
Met
Vs comb
Met
Vs Glyb
*All patients on glyburide, 20 mg/day, at Baseline
* * Not statistically significant
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 0.025
Hemoglobin A1c (%)
Baseline 8.8 8.5 8.9 NS* * NS* * 0.007
Change at FINAL VISIT -1.7 0.2 -0.4 0.001 0.001 0.001
Body Weight (lbs)
Baseline 202.2 203.0 204.0 NS* * NS* * NS* *
Change at FINAL VISIT 0.9 -0.7 -8.4 0.011 0.001 0.001
Table 4. Summary of Mean Percent Change from Baseline
of Major Serum Lipid Variables at Final Visit (29-week studies)
Metformin Vs Placebo Combined Metformin/Glyburide
Vs Monotherapy
Metformin
(N = 141)
Placebo
(N = 145)
Metformin
(n = 210)
Metformin/Glyburide
(n = 213)
Glyburide
(n = 209)
Total Cholestrol (mg/dL)
Baseline 211.0 212.3 213.1 215.6 219.6
Mean % change
at FINAL VISIT
-5% 1% -2% -4% 1%
Total Triglycerides (mg/dL)
Baseline 236.1 203.5 242.5 215.0 266.1
Mean % change
at FINAL VISIT
-16% 1% -3% -8% 4%
LDL-Cholestrol (mg/dL)
Baseline 135.4 138.5 134.3 136.0 137.5
Mean % change
at FINAL VISIT
-8% 1% -4% -6% 3%
HDL-Cholestrol (mg/dL)
Baseline 39.0 40.5 37.2 39.0 37.0
Mean % change
at FINAL VISIT
2% -1% 5% 3% 1%
Table 5. Combined Metformin Hydrochloride Tablets, USP/Insulin vs Placebo/Insulin
Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose
Metformin Hydrochloride tablets, USP/Insulin
n=26
Placebo/Insulin
n=28
Treatment difference
Mean ± SE
a Statistically significant using analysis of covariance with baseline as covariate (p=0.04)
Not significant using analysis of variance (values shown in table)
b Statistically significant for insulin (p=0.04)
Hemoglobin A1c (%)
Baseline 8.95 9.32
Change at FINAL VISIT - 2.10 - 1.56 - 0.54 ± 0.43a
Insulin Dose (U/day)
Baseline 93.12 94.64
Change at FINAL VISIT - 0.15 15.93 - 16.08 ± 7.77b

In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with metformin hydrochloride tablets, USP (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 6).

Table 6. Metformin Hydrochloride Tablets, USP vs Placebo (Pediatricsa)
Summary of Mean Changes from Baseline* in
Plasma Glucose and Body Weight at Final Visit
Metformin hydrochloride tablets, USP Placebo P-Value
FPG (mg/dL) (n = 37) (n = 36)
a Pediatric patients mean age 13.8 years (range 10-16 yeas)
* All patients on diet therapy at Baseline
* * Not statistically significant
Baseline 162.4 192.3
Change at FINAL VISIT - 42.9 21.4 <0.001
Body Weight (lbs) (n = 39) (n = 38)
Baseline 205.3 189.0
Change at FINAL VISIT -3.3 -2.0 NS* *

Metformin hydrochloride tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.

Metformin hydrochloride tablets are contraindicated in patients with:

Metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS.)

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin or any other anti-diabetic drug.

Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive metformin. In patients with advanced age, metformin should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥ 80 years of age, renal function should be monitored regularly and, generally, metformin should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION).

Before initiation of metformin therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and metformin discontinued if evidence of renal impairment is present.

Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: Drug Interactions), should be used with caution.

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, metformin should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on metformin therapy, the drug should be promptly discontinued.

Metformin therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving metformin.

Since impaired hepatic function has been associated with some cases of lactic acidosis, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

In controlled clinical trials of metformin hydrochloride of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B absorption from the B -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets, USP or vitamin B supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests).

Certain individuals (those with inadequate vitamin B or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B levels. In these patients, routine serum vitamin B measurements at two- to three-year intervals may be useful.

A patient with type 2 diabetes previously well controlled on metformin hydrochloride tablets, USP who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs, metformin must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).

Hypoglycemia does not occur in patie

Manufacturer

State of Florida DOH Central Pharmacy

Active Ingredients

Source

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40-8868 Revised — May 2004

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