Calciu Masticabil may be available in the countries listed below.
Calcium Carbonate is reported as an ingredient of Calciu Masticabil in the following countries:
International Drug Name Search
GLUCOPHAGE® (metformin hydrochloride) Tablets and GLUCOPHAGE® XR (metformin hydrochloride) Extended-Release Tablets are oral antihyperglycemic drugs 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 is a white to off-white crystalline compound with a molecular formula of C4H11N5 • HCl and a molecular weight of 165.63. Metformin hydrochloride 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. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 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 as the active ingredient.
Glucophage XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, microcrystalline cellulose, and magnesium stearate.
Glucophage XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, and magnesium stearate.
System Components and Performance–Glucophage XR comprises a dual hydrophilic polymer matrix system. Metformin hydrochloride is combined with a drug release controlling polymer to form an "inner" phase, which is then incorporated as discrete particles into an "external" phase of a second polymer. After administration, fluid from the gastrointestinal (GI) tract enters the tablet, causing the polymers to hydrate and swell. Drug is released slowly from the dosage form by a process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass.
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 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 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. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) 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.
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 similar 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 µg/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.
Within-subject variability in Cmax and AUC of metformin from Glucophage XR is comparable to that with GLUCOPHAGE.
Although the extent of metformin absorption (as measured by AUC) from the Glucophage XR tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of Glucophage XR.
The apparent volume of distribution (V/F) of metformin following single oral doses of GLUCOPHAGE 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 GLUCOPHAGE, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 µg/mL. During controlled clinical trials of GLUCOPHAGE, 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.
The pharmacokinetics of Glucophage XR in patients with type 2 diabetes are comparable to those in healthy normal adults.
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 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. 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). GLUCOPHAGE (metformin hydrochloride) Tablets and Glucophage XR (metformin hydrochloride) Extended-Release Tablets 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).
| Subject Groups: GLUCOPHAGE dosea (number of subjects) | Cmaxb (µg/mL) | Tmaxc (hrs) | Renal Clearance (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 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 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 GLUCOPHAGE 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 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 GLUCOPHAGE was comparable in males and females.
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of GLUCOPHAGE 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 US 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 GLUCOPHAGE (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2).
| GLUCOPHAGE (n=141) | Placebo (n=145) | p-Value | |
|---|---|---|---|
| * All patients on diet therapy at Baseline | ** Not statistically significant | ||
| FPG (mg/dL) Baseline Change at FINAL VISIT | 241.5 –53.0 | 237.7 6.3 | NS** 0.001 |
| Hemoglobin A1c (%) Baseline Change at FINAL VISIT | 8.4 –1.4 | 8.2 0.4 | NS** 0.001 |
| Body Weight (lbs) Baseline Change at FINAL VISIT | 201.0 –1.4 | 206.0 –2.4 | NS** NS** |
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 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 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) followed the same titration schedule. 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. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to GLUCOPHAGE (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of GLUCOPHAGE and glyburide was effective in reducing FPG, PPG, and HbA1c 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).
| 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 glucose concentration following the institution of GLUCOPHAGE (metformin hydrochloride) Tablets therapy was 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, GLUCOPHAGE, 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).
| GLUCOPHAGE vs Placebo | Combined GLUCOPHAGE/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) | |||||
| Baseline Mean % Change at FINAL VISIT | 39.0 2% | 40.5 –1% | 37.2 5% | 39.0 3% | 37.0 1% |
In contrast to sulfonylureas, body weight of individuals on GLUCOPHAGE tended to remain stable or even decrease somewhat (see Tables 2 and 3).
A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE 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 GLUCOPHAGE plus insulin achieved a reduction in HbA1c of 2.10%, compared to a 1.56% reduction in HbA1c 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, GLUCOPHAGE plus insulin versus insulin plus placebo, respectively, p=0.04.
| GLUCOPHAGE/ 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 Change at FINAL VISIT | 8.95 –2.10 | 9.32 –1.56 | –0.54 ± 0.43a |
| Insulin Dose (U/day) | |||
| Baseline Change at FINAL VISIT | 93.12 –0.15 | 94.64 15.93 | –16.08± 7.77b |
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 HbA1c of 7.46 ± 0.97%, the addition of GLUCOPHAGE maintained similar glycemic control (HbA1c 7.15 ± 0.61 vs 6.97 ± 0.62 for GLUCOPHAGE plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 vs an increase of 0.43 ± 25.20 units for GLUCOPHAGE plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of GLUCOPHAGE 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.
A 24-week, double-blind, placebo-controlled study of Glucophage XR, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7.0%-10.0%, FPG 126-270 mg/dL). Patients entering the study had a mean baseline HbA1c of 8.0% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with Glucophage XR 1000 mg once daily. Subsequently, the treatment dose was increased to 1500 mg once daily if HbA1c was≥7.0% but <8.0% (patients with HbA1c ≥8.0% were discontinued from the study). At the final visit (24-week), mean HbA1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with Glucophage XR.
A 16-week, double-blind, placebo-controlled, dose-response study of Glucophage XR, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7.0%-11.0%, FPG 126-280 mg/dL). Changes in glycemic control and body weight are shown in Table 6.
| Glucophage XR | Placebo | |||||
|---|---|---|---|---|---|---|
| 500 mg Once Daily | 1000 mg Once Daily | 1500 mg Once Daily | 2000 mg Once Daily | 1000 mg Twice Daily | ||
| * All patients on diet therapy at Baseline | ||||||
| a All comparisons versus Placebo | ||||||
| ** Not statistically significant | ||||||
| Hemoglobin A1c (%) | (n=115) | (n=115) | (n=111) | (n=125) | (n=112) | (n=111) |
| Baseline | 8.2 | 8.4 | 8.3 | 8.4 | 8.4 | 8.4 |
| Change at FINAL VISIT | –0.4 | –0.6 | –0.9 | –0.8 | –1.1 | 0.1 |
| p-valuea | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | – |
| FPG (mg/dL) | (n=126) | (n=118) | (n=120) | (n=132) | (n=122) | (n=113) |
| Baseline | 182.7 | 183.7 | 178.9 | 181.0 | 181.6 | 179.6 |
| Change at FINAL VISIT | –15.2 | –19.3 | –28.5 | –29.9 | –33.6 | 7.6 |
| p-valuea | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | – |
| Body Weight (lbs) | (n=125) | (n=119) | (n=117) | (n=131) | (n=119) | (n=113) |
| Baseline | 192.9 | 191.8 | 188.3 | 195.4 | 192.5 | 194.3 |
| Change at FINAL VISIT | –1.3 | –1.3 | –0.7 | –1.5 | –2.2 | –1.8 |
| p-valuea | NS** | NS** | NS** | NS** | NS** | – |
Compared with placebo, improvement in glycemic control was seen at all dose levels of Glucophage XR (metformin hydrochloride) Extended-Release Tablets and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for GLUCOPHAGE and Glucophage XR).
A 24-week, double-blind, randomized study of Glucophage XR, taken once daily with the evening meal, and GLUCOPHAGE (metformin hydrochloride) Tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with GLUCOPHAGE 500 mg twice daily for at least 8 weeks prior to study entry. The GLUCOPHAGE dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA1c was≤8.5% and FPG was ≤200 mg/dL. Changes in glycemic control and body weight are shown in Table 7.
| GLUCOPHAGE 500 mg Twice Daily | Glucophage XR | ||
|---|---|---|---|
| 1000 mg Once Daily | 1500 mg Once Daily | ||
| * All patients on GLUCOPHAGE 500 mg twice daily at Baseline | |||
| a n=68 | |||
| Hemoglobin A1c (%) | (n=67) | (n=72) | (n=66) |
| Baseline | 7.06 | 6.99 | 7.02 |
| Change at 12 Weeks | 0.14 | 0.23 | 0.04 |
| (95% CI) | (–0.03, 0.31) | (0.10, 0.36) | (–0.08, 0.15) |
| Change at FINAL VISIT | 0.14a | 0.27 | 0.13 |
| (95% CI) | (–0.04, 0.31) | (0.11, 0.43) | (–0.02, 0.28) |
| FPG (mg/dL) | (n=69) | (n=72) | (n=70) |
| Baseline | 127.2 | 131.0 | 131.4 |
| Change at 12 Weeks | 12.9 | 9.5 | 3.7 |
| (95% CI) | (6.5, 19.4) | (4.4, 14.6) | (–0.4, 7.8) |
| Change at FINAL VISIT | 14.0 | 11.5 | 7.6 |
| (95% CI) | (7.0, 21.0) | (4.4, 18.6) | (1.0, 14.2) |
| Body Weight (lbs) | (n=71) | (n=74) | (n=71) |
| Baseline | 210.3 | 202.8 | 192.7 |
| Change at 12 Weeks | 0.4 | 0.9 | 0.7 |
| (95% CI) | (–0.4, 1.5) | (0.0, 2.0) | (–0.4, 1.8) |
| Change at FINAL VISIT | 0.9 | 1.1 | 0.9 |
| (95% CI) | (–0.4, 2.2) | (–0.2, 2.4) | (–0.4, 2.0) |
After 12 weeks of treatment, there was an increase in mean HbA1c in all groups; in the Glucophage XR 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION).
Changes in lipid parameters in the previously described placebo-controlled dose-response study of Glucophage XR are shown in Table 8.
| Glucophage XR | Placebo | |||||
|---|---|---|---|---|---|---|
| 500 mg Once Daily | 1000 mg Once Daily | 1500 mg Once Daily | 2000 mg Once Daily | 1000 mg Twice Daily | ||
| * All patients on diet therapy at Baseline | ||||||
| Total Cholesterol (mg/dL) | (n=120) | (n=113) | (n=110) | (n=126) | (n=117) | (n=110) |
| Baseline | 210.3 | 218.1 | 214.6 | 204.4 | 208.2 | 208.6 |
| Mean % Change at FINAL VISIT | 1.0% | 1.7% | 0.7% | –1.6% | –2.6% | 2.6% |
| Total Triglycerides (mg/dL) | (n=120) | (n=113) | (n=110) | (n=126) | (n=117) | (n=110) |
| Baseline | 220.2 | 211.9 | 198.0 | 194.2 | 179.0 | 211.7 |
| Mean % Change at FINAL VISIT | 14.5% | 9.4% | 15.1% | 14.9% | 9.4% | 10.9% |
| LDL-Cholesterol (mg/dL) | (n=119) | (n=113) | (n=109) | (n=126) | (n=117) | |
Directions For Use: To assure effectiveness, treated birds must consume enough medicated water to provide a therapeutic dosage.
Indications Dosage of Erythromycin Phosphate
Chronic Respiratory Disease 1/2 g/gal of drinking water for 5 days
Infectious Coryza 1/2 g/gal of drinking water for 7 days
Bluecomb 1/2 g/gal of drinking water for 7 days
(Non-specific Infectious Enteritis)
MIXING INSTRUCTIONS FOR DRINKING WATER:
Add one (1) package (250 g) per 130 gallons and mix thoroughly. For proportioners which meter 1 oz/gal, add one (1) package (250 g) to each gallon of stock solution.
In chickens, this dosage provides 5.0 to 17.8 mg/lb and, in turkeys, 3.1 to 34.2 mg/lb body weight per bird per day of erythromycin activity depending upon age, class of chicken (or turkey), feed conversion, environmental temperature, and relative humidity during medication period.
WARNING:
Do not use in chickens or turkeys producing eggs for human consumption.
Do not use in replacement pullets over 16 weeks of age.
Withdraw on (1) day before slaughter.
Important: Solutions older than 3 days should not be used.
Gallimycin PFC
(Erythromycin)
Poultry Formula Concentrated Water Soluble
| Gallimycin PFC erythromycin powder, for solution | ||||||||||||||||||||
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| NADA | NADA035157 | 01/23/1974 | |
| Labeler - Bimeda, Inc. Division of Cross Vetpharm Group (043653216) |
| Registrant - Bimeda, Inc. Division of Cross Vetpharm Group (043653216) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Bimeda, Inc. Division of Cross Vetpharm Group | 043653216 | manufacture | |
Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Chemical Name: 1-(Aminomethyl)-cyclohexaneacetic acid
Molecular Formula: C9H17NO2
CAS Number: 60142-96-3
Brands: Neurontin
Special Alerts:
[UPDATE 05/05/2009] FDA notified healthcare professionals that it approved updated labeling for antiepileptic drugs used to treat epilepsy, psychiatric disorders, and other conditions (e.g., migraine and neuropathic pain syndromes). FDA also required development of a medication guide, to be issued to patients each time the product is dispensed. Since issuing safety alerts on December 16, 2008 and January 31, 2008, FDA has been working with the manufacturers of drugs in this class to better understand the suicidality risk. Eleven antiepileptic drugs were included in a pooled analysis of placebo-controlled clinical studies in which these drugs were used to treat epilepsy as well as psychiatric disorders and other conditions. The increased risk of suicidal thoughts or behavior was generally consistent among the eleven drugs, with varying mechanisms of action and across a range of indications. This observation suggests that the risk applies to all antiepileptic drugs used for any indication.
The drugs included in the analyses include (some of these drugs are also available in generic form):
Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
Felbamate (marketed as Felbatol)
Gabapentin (marketed as Neurontin)
Lamotrigine (marketed as Lamictal)
Levetiracetam (marketed as Keppra)
Oxcarbazepine (marketed as Trileptal)
Pregabalin (marketed as Lyrica)
Tiagabine (marketed as Gabitril)
Topiramate (marketed as Topamax)
Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
Zonisamide (marketed as Zonegran)
For more information visit the FDA website at: and .
[UPDATE 12/16/2008] The FDA has completed its analysis of reports of suicidality (suicidal behavior or ideation [thoughts]) from placebo-controlled clinical trials of drugs used to treat epilepsy, psychiatric disorders, and other conditions. Based on the outcome of this review, FDA is requiring that all manufacturers of drugs in this class include a Warning in their labeling and develop a Medication Guide to be provided to patients prescribed these drugs to inform them of the risks of suicidal thoughts or actions.
For more information visit the FDA website at: and .
[Posted 01/31/2008] FDA informed healthcare professionals that the Agency has analyzed reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies of eleven drugs used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.
Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.
The drugs included in the analyses include (some of these drugs are also available in generic form):
Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
Felbamate (marketed as Felbatol)
Gabapentin (marketed as Neurontin)
Lamotrigine (marketed as Lamictal)
Levetiracetam (marketed as Keppra)
Oxcarbazepine (marketed as Trileptal)
Pregabalin (marketed as Lyrica)
Tiagabine (marketed as Gabitril)
Topiramate (marketed as Topamax)
Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
Zonisamide (marketed as Zonegran)
Although the 11 drugs listed above were the ones included in the analysis, FDA expects that the increased risk of suicidality is shared by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly. For more information visit the FDA website at: and .
REMS:
FDA approved a REMS for gabapentin to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().
Anticonvulsant; structurally related to the inhibitory CNS neurotransmitter GABA.1 4 6 7 8 9
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Management (in combination with other anticonvulsants) of partial seizures with or without secondary generalization in adults and children >12 years of age.1 2 8 9
Management (in combination with other anticonvulsants) of partial seizures in children 3–12 years of age.1
Management of postherpetic neuralgia in adults.1 20 21 22 23 24 38 39 40
Treatment of pain associated with diabetic neuropathy†.20 21 22 23 24 25 40 41 42 43 44 45 40% of patients who receive gabapentin for pain associated with diabetic neuropathy obtain good pain relief.40
Some evidence of benefit for the relief of chronic neurogenic pain† in a variety of conditions including trigeminal neuralgia†,20 21 46 47 pain and control of paroxysmal symptoms of multiple sclerosis†,20 21 48 49 complex regional pain syndromes†,20 52 53 HIV-related peripheral neuropathy†,20 21 50 and neuropathic pain associated with cancer†.20 21 51 Also has been used in the treatment of restless legs syndrome†.26 27 28 Additional study needed to further elucidate precise role in the management of these conditions.
Has been used for the management of vasomotor symptoms (e.g., hot flashes) in women with breast cancer†.30
Has been used for the management of vasomotor symptoms (e.g., hot flashes) associated with menopause†.31 34 54
Monitoring of plasma gabapentin concentrations is not necessary to optimize therapy.1 Because addition of gabapentin to existing anticonvulsant therapy does not appreciably alter steady-state plasma concentrations of concomitantly administered anticonvulsants, additional monitoring of plasma concentrations of anticonvulsants generally is not necessary.1 (See Specific Drugs under Interactions.)
Discontinuance of gabapentin and/or addition of an alternative anticonvulsant drug to therapy should be done gradually over ≥1 week.1
Administer orally without regard to meals.1
If Neurontin film-coated scored tablets containing 600 or 800 mg of gabapentin are to be used in patients requiring a 300- or 400-mg dose, divide the tablet in half to allow administration of the appropriate dose.1 Instruct patients to take one-half tablet and to use the remaining half-tablet for the next dose.1 Half-tablets that are not used within several days should be discarded.1
Administer orally 3 times daily.1 The interval between doses in this schedule should not exceed 12 hours.1
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Children 3–12 years of age: Initially, 10–15 mg/kg daily in 3 divided doses.1 Maintenance dosage of 40 mg/kg daily in 3 divided doses for children 3 or 4 years of age and 25–35 mg/kg daily in 3 divided doses for children 5–12 years of age.1
Children >12 years of age: Initially, 300 mg 3 times daily.1 Maintenance dosage of 900 mg to 1.8 g daily in 3 divided doses.1
Initially, 300 mg 3 times daily.1 Maintenance dosage of 900 mg to 1.8 g daily in 3 divided doses.1
300 mg on the first day, 300 mg twice daily on the second day, and 300 mg 3 times daily on the third day.1 Increase dosage as needed for relief of pain up to a total daily dosage of 1.8 g in 3 divided doses.1 No evidence of additional benefit with dosages >1.8 g daily.1
Dosages of 900 mg to 3.6 g daily have been used; however, pain relief generally observed in patients receiving dosages >1.8 g daily.24 25
300 mg 3 times daily has been effective; higher dosages may provide additional benefit.30 31 37
Children 3–12 years of age: Dosages up to 50 mg/kg daily in divided doses have been tolerated as adjunctive therapy in the management of partial seizures.1
Children >12 years of age: Dosage of 3.6 g daily has been tolerated as adjunctive therapy in the management of partial seizures.1
Dosage of 3.6 g daily has been tolerated as adjunctive therapy in the management of partial seizures.1
Not studied in children <12 years of age with renal impairment.1
In adults and children ≥12 years of age, base dosage on measured or estimated Clcr:1 16
aIn patients with Clcr <15 mL/min, reduce dosage proportionally (e.g., a patient with a Clcr of 7.5 mL/min should receive one-half the dosage that a patient with a Clcr of 15 mL/min should receive).
bGive maintenance doses based on Clcr, with supplemental doses (125–350 mg) given after each 4-hour hemodialysis session.1
Clcr (mL/min) | Total Daily Dosage (mg/day) | Dosage Regimen |
|---|---|---|
≥60 | 900–3600 | 300 –1200 mg 3 times daily |
30–59 | 400–1400 | 200 –700 mg twice daily |
15–29 | 200–700 | 200 –700 mg once daily |
15a | 100–300 | 100 –300 mg once daily |
ESRD patients undergoing hemodialysis | — | 125–350 mgb |
Select dosage carefully, usually initiating therapy at the low end of the dosage range.1 Adjust dosage based on Clcr.1
Known hypersensitivity to gabapentin or any ingredient in the formulation.1
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Emotional lability (primarily behavioral problems), hostility (including aggressive behaviors), thought disorders (including concentration and school performance changes), and hyperkinesia (primarily restlessness and hyperactivity) associated with use in children 3–12 years of age with epilepsy.1
Abrupt withdrawal may result in increased seizure frequency; withdraw gabapentin gradually and reduce dosage slowly over ≥1 week.1
Not established whether incidence of status epilepticus (1.5% in controlled and uncontrolled trials of gabapentin) is higher or lower than would be expected in patients with epilepsy not treated with the drug.1
Unexpectedly high incidence of pancreatic acinar adenocarcinomas in male but not female rats.1 Clinical relevance unknown.1
Higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with epilepsy or refractory epilepsy.1
Category C.1
Distributed into milk; use only if potential benefits outweigh the risks.1
Safety and efficacy as adjunctive therapy in the management of partial seizures not established in children <3 years of age.1
Safety and efficacy for the management of postherpetic neuralgia not established in children.1
Insufficient experience with gabapentin for the management of partial seizures in patients ≥65 years of age to determine whether they respond differently than younger adults.1 Select dosage carefully.1 (See Geriatric Patients under Dosage and Administration.)
Appeared to be more effective for the management of postherpetic neuralgia in patients >75 years of age than in younger patients; apparent difference in efficacy may be related to decreased renal function in older patients.1
Adverse effects in older patients with postherpetic neuralgia generally similar to those in younger adults; however, the incidence of peripheral edema and ataxia appears to increase with age.1
Geriatric patients may have decreased hepatic, renal, or cardiac function, with increased risk of adverse effects.1 16 Use with caution; renal function monitoring may be useful.1
Clearance decreased; adjust dosage in adults and children ≥12 years of age with renal impairment.1 (See Renal Impairment under Dosage and Administration.)
Use in children <12 years of age with renal impairment has not been studied.1
Children 3–12 years of age receiving gabapentin as adjunctive therapy for partial seizures: viral infection, fever, nausea and/or vomiting, somnolence, hostility.1
Adults and children >12 years of age receiving gabapentin as adjunctive therapy for partial seizures with or without secondary generalization: somnolence, dizziness, ataxia, fatigue, nystagmus.1
Adults receiving gabapentin for management of postherpetic neuralgia: dizziness, somnolence, peripheral edema.1
Not metabolized by CYP isoenzymes.1 Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro; causes slight inhibition of CYP2A6 at high concentrations.1
Drug | Interaction | Comments |
|---|---|---|
Antacids | Reduced bioavailability of gabapentin1 | Administer gabapentin at least 2 hours after antacid1 |
Anticonvulsants | Plasma concentrations of carbamazepine, phenytoin, valproic acid, phenobarbital, and diazepam in existing treatment regimens not affected by gabapentin;1 3 12 13 14 pharmacokinetics of gabapentin not affected by these drugs1 6 12 15 | |
Cimetidine | Possible decrease in gabapentin clearance 1 | Not likely to be clinically important1 |
Hydrocodone | Possible dose-dependent decrease in plasma concentrations of hydrocodone; possible increase in plasma concentrations of gabapentin1 | |
Morphine | Increase in plasma concentrations of gabapentin1 | Decrease in dosage of morphine or gabapentin may be required in patients with symptoms of CNS depression (e.g., somnolence)1 |
Naproxen | Increased bioavailability of gabapentin at subtherapeutic dosages of both drugs1 | Extent of interaction at usual therapeutic dosages is unknown1 |
Oral Contraceptives | Possible increase in peak plasma concentrations of norethindrone1 | Not likely to be clinically important1 |
Probenecid | No pharmacokinetic interaction observed1 |
Bioavailability of 60–27% for doses ranging from 900 mg to 4.8 g daily.1 Bioavailability is not dose proportional.1
Food increases extent of absorption and peak plasma concentration by 14%.1
Readily crosses the blood-brain barrier and concentrates in brain tissue.29 Distributed into breast milk.1 Not known whether gabapentin crosses the placenta.1
<3%.1
Not appreciably metabolized.1
Excreted renally as unchanged drug.1
5–7 hours.1
In children <5 years of age, clearance normalized for weight is higher than in adults and children ≥5 years of age.1
In patients with renal impairment, plasma clearance is decreased and half-life is prolonged.1 In patients with Clcr <30 mL/minute, half-life of 52 hours reported.1 In anuric patients, half-life reported to be 132 hours on nondialysis days and 3.8 hours during hemodialysis.1
25°C (may be exposed to 15–30°C).1
2–8°C.1
Mechanism of anticonvulsant action is unknown.1 4 5 7 8 9 Does not bind to GABA receptors,1 4 5 6 7 17 affect GABA reuptake or metabolism, 1 6 7 17 or act as a precursor of GABA or other substances active at GABA receptors.1 17
Mechanism of analgesic action is unknown.1 20 21 22 23 Prevents allodynia (pain-related behavior in response to normally innocuous stimuli) and hyperalgesia (exaggerated response to painful stimuli) in several animal models of neuropathic pain.1 20 Decreases pain-related responses after peripheral inflammation in animals; however, has not altered immediate pain-related behaviors.1 Clinical relevance of these findings is not known.1
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Importance of taking gabapentin exactly as prescribed.1 Importance of not abruptly discontinuing therapy.1
Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1
Importance of informing patients of other important precautionary information. (See Cautions.)1
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 100 mg* | Gabapentin Capsules | Actavis, Apotex, Mutual, Ranbaxy, Sandoz, Teva |
Neurontin | Pfizer | |||
300 mg* | Gabapentin Capsules | Actavis, Apotex, Mutual, Ranbaxy, Sandoz, Teva | ||
Neurontin | Pfizer | |||
400 mg* | Gabapentin Capsules | Actavis, Apotex, Mutual, Ranbaxy, Sandoz, Teva | ||
Neurontin | Pfizer | |||
Solution | 250 mg/5 mL | Neurontin | Pfizer | |
Tablets | 100 mg* | Gabapentin Tablets | Greenstone, Ranbaxy, Teva | |
300 mg* | Gabapentin Tablets | Greenstone, Ranbaxy, Teva | ||
400 mg* | Gabapentin Tablets | Greenstone, Ranbaxy, Teva | ||
600 mg | Gabapentin Tablets | Teva | ||
800 mg | Gabapentin Tablets | Teva | ||
Tablets, film-coated | 600 mg | Gabapentin Tablets | Actavis | |
Neurontin | Pfizer | |||
800 mg | Gabapentin Tablets | Actavis | ||
Neurontin | Pfizer |
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Gabapentin 100MG Capsules (AMNEAL PHARMACEUTICALS): 90/$43.99 or 270/$115.97
Gabapentin 250MG/5ML Solution (HI-TECH): 470/$139.99 or 1410/$399.96
Gabapentin 300MG Capsules (AMNEAL PHARMACEUTICALS): 90/$18.99 or 270/$170.96
Gabapentin 400MG Capsules (AMNEAL PHARMACEUTICALS): 90/$74.99 or 270/$209.98
Gabapentin 600MG Tablets (GLENMARK PHARMACEUTICALS): 90/$97.99 or 270/$248.97
Gabapentin 800MG Tablets (GLENMARK PHARMACEUTICALS): 90/$99.99 or 100/$107.97
Neurontin 100MG Capsules (PFIZER U.S.): 100/$93.99 or 300/$269.97
Neurontin 250MG/5ML Solution (PFIZER U.S.): 470/$172.99 or 1410/$475.97
Neurontin 300MG Capsules (PFIZER U.S.): 30/$69.99 or 90/$199.96
Neurontin 400MG Capsules (PFIZER U.S.): 30/$83.99 or 90/$245.97
Neurontin 600MG Tablets (PFIZER U.S.): 90/$396.98 or 100/$435.99
Neurontin 800MG Tablets (PFIZER U.S.): 90/$481.00 or 270/$1,399.96
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
1. Parke-Davis. Neurontin (gabapentin) capsules prescribing information. New York, NY; 2005 Dec.
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3. Anon. Warner Lambert’s Neurontin approved for adjunctive therapy in epilepsy patients Dec 30; “1P” drug does not interact with other anticonvulsants. F-D-C Rep. 1994 Jan:11.
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28. Thorp MK, Morris DC, Bagby SP. A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients. Am J of Kidney Diseases. 2001;38:104-8.
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36. Reviewers’ comments (personal observations).
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39. Rowbotham M, Harden N, Stacey B et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998; 280:1837-42. [PubMed 9846778]
40. Wiffen PJ, McQuay HJ, Edwards JE et al. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev. 2005; 3:CD005452. [PubMed 16034978]
41. Gorson KC, Schott C, Herman R, Ropper AH. Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol Neurosurg Psychiatry. 1999; 66 :251-2. (Letter) [PubMed 10071116]
42. Pérez HE, Sánchez GF. Gabapentin therapy for diabetic neuropathic pain. Am J Med. 2000; 108; 689. (Letter)
43. Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromusc Dis. 2001; 3:53-62.
44. Dallocchio C, Buffa C, Mazzarello P et al. Gabapentin vs. amitriptyline in painful diabetic neuropathy: an open-label pilot study. J Pain Symptom Manage. 2000; 20:280-5. [PubMed 11027910]
45. Morello CM, Leckband SG, Stoner CP et al. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med. 1999; 159:1931-7. [PubMed 10493324]
46. Khan OA. Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients. Neurology. 1998; 51:611-4. [PubMed 9710050]
47. Cheshire WP. Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study. J Pain. 2002; 3:137-42. [PubMed 14622800]
48. Solaro C, Lunardi GL, Capello E et al. An open-label trial of gabapentin treatment of paroxysmal symptoms in multiple sclerosis patients. Neurology. 1998; 51:609-11. [PubMed 9710049]
49. Yetimalar Y, Gürgör N, Basoglu M. Clinical efficacy of gabapentin for paroxysmal symptoms in multiple sclerosis. Acta Neurol Scand. 2004; 109; 430-1. (Letter) [PubMed 15147470]
50. Hahn K, Arendt G, Braun JS et al. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol. 2004; 251:1260-6. [PubMed 15503108]
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