Riomet

Name: Riomet

What should i avoid while taking metformin (fortamet, glucophage, glucophage xr, glumetza, riomet)?

Avoid drinking alcohol. It lowers blood sugar and may increase your risk of lactic acidosis while taking metformin.

Riomet Interactions

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • beta-blockers
  • cough and cold products containing decongestants
  • calcium channel blockers
  • cimetidine (Tagamet)
  • corticosteroids
  • digoxin (Lanoxin)
  • diuretics such as furosemide (Lasix)
  • estrogens
  • insulins or other medicines for diabetes
  • isoniazid (INH, Nydrazid)
  • morphine
  • niacin (nicotinic acid, Niaspan)
  • nifedipine
  • oral contraceptives
  • oral steroids
  • phenothiazines such as promethazine (Phenergan)
  • phenytoin (Dilantin)
  • procainamide
  • quinidine
  • quinine
  • ranitidine
  • thyroid medicines such as levothyroxine (Levothroid, Levoxyl, Synthroid, Tirosint)
  • triamterene
  • trimethoprim
  • vancomycin

This is not a complete list of Riomet drug interactions. Ask your doctor or pharmacist for more information.

Uses of Riomet

  • It is used to lower blood sugar in patients with high blood sugar (diabetes).

What are some things I need to know or do while I take Riomet?

  • Do not drive if your blood sugar has been low. There is a greater chance of you having a crash.
  • Check your blood sugar as you have been told by your doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • It may be harder to control your blood sugar during times of stress like when you have a fever, an infection, an injury, or surgery. A change in level of physical activity or exercise and a change in diet may also affect your blood sugar. Talk with your doctor.
  • Follow the diet and workout plan that your doctor told you about.
  • Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
  • If you are 65 or older, use Riomet with care. You could have more side effects.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Riomet - Clinical Pharmacology

Mechanism of Action

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.

Pharmacokinetics

Absorption and Bioavailability

Two pharmacokinetic studies have been performed in healthy volunteers to evaluate the bioavailability of Riomet in comparison with the commercially available metformin tablets under fasting and fed conditions (study 1 and study 2). A third pharmacokinetic study (study 3) assessed effects of food on absorption of Riomet.

The rate and extent of absorption of Riomet was found to be comparable to that of Metformin tablets under fasting or fed conditions (see Table 1).

T-test product (Riomet)
R-reference product (metformin tablets)

Table 1. Select Mean (± S.D.) Pharmacokinetic Parameters Following Single Oral Doses of 1000 mg Riomet and Metformin tablets in healthy, nondiabetic adults (n = 36) under fed and fasting conditions

Formulation

Cmax (ng/mL)

AUC0-∞ (ng.h/mL)

tmax (h)

Study 1- Fasting state

Riomet

1540.1 ± 451.1

9069.6 ± 2593.6

2.2 ± 0.5

Metformin Tablets

1885.1 ± 498.5

11100.1 ± 2733.1

2.5 ± 0.6

T/R Ratio X 100 (90% confidence interval)

81.2 (76.3 - 86.4)

81.2 (76.9 - 85.6)

-

Study 2- Fed State

Riomet

1235.3 ± 177.7

8950.1 ± 1381.2

4.1 ± 0.8

Metformin Tablets

1361 ± 298.8

9307.7 ± 1839.8

3.7 ± 0.8

T/R Ratio X 100 (90% confidence interval)

91.8 (87.4 - 96.5)

97.0 (92.9 - 101.2)

-

The food-effect study (study 3) assessed the effects of a high fat/high calorie meal and a low fat/low calorie meal on the bioavailability of Riomet in comparison with administration in the fasted state, in healthy volunteers. The extent of absorption was increased by 21% and 17% with the low fat/low calorie meal and the high fat/high calorie meal, respectively, compared with the administration in the fasted state. The rate and extent of absorption with high fat/high calorie and low fat/ low calorie meal were similar. The mean tmax was 2.5 hours under fasting conditions as compared to 3.9 hours with both low fat/ low calorie meal and high fat/high calorie meals (see Table 2).

Table 2. Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single Oral Doses of 1000 mg Riomet in healthy, nondiabetic adults (n = 33) under fed (high fat/high calorie meal and low fat/low calorie meal) and fasting conditions (study 3)

Meal type

Cmax

(ng/mL)

AUC0-∞ (ng.h/mL)

tmax

(h)

Fasting (F)

1641.5 ± 551.8

9982.9 ± 2544.5

2.5 ± 0.9

Low fat/ low calorie meal (L)

1525.8 ± 396.7

11542.0 ± 2947.5

3.9 ± 0.6

High fat/high calorie meal (H)

1432.5 ± 346.8

11184.5 ± 2446.1

3.9 ± 0.8

L/F Ratio X 100 (90% confidence interval)

94.6 (84.0 - 106.5)

115.6 (103.6 - 128.9)

-

H/F Ratio X 100 (90% confidence interval)

89.4 (79.4 - 100.6)

112.6 (100.9 - 125.6)

-

L/H Ratio X 100 (90% confidence interval)

105.8 (94.0 - 119.2)

102.7 (92.0 - 114.6)

-

Studies using single oral doses of metformin tablet formulations 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.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin 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, steady state plasma concentrations of metformin are reached within 24 to 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.

Metabolism and Elimination

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 3) 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.

Specific Populations

Patients with Type 2 Diabetes

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 3), nor is there any accumulation of metformin in either group at usual clinical doses.

Renal Impairment

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 3; also see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Hepatic Impairment

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

Geriatrics

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 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 3) (See WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

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

Table 3. Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin

Subject Groups: Metformin dosea (number of subjects)

Cmaxb(µg/mL)

Tmaxc(hrs)

Renal Clearance (mL/min)

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)

Renally-impaired adults:

 

 

 

850 mg single dose

 

 

 

Mild (CLcrg 61 - 90mL/min) (5)

1.86 (± 0.52)

3.20 (± 0.45)

384 (± 122)

Moderate (CLcr31 - 60mL/min) (4)

4.12 (± 1.83)

3.75 (± 0.50)

108 (± 57)

Severe (CLcr10 - 30mL/min) (6)

3.93 (± 0.92)

4.01 (± 1.10)

130 (± 90)

Pediatrics

After administration of a single oral metformin 500 mg dose with food, geometric mean metformin Cmax 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.

Gender

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 was comparable in males and females.

Race

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

Clinical Studies

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 (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 4).

*-All patients on diet therapy at Baseline
**-Not statistically significant

Table 4. Metformin vs Placebo

Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study)

 

Metformin (n = 141)

Placebo (n = 145)

p-Value

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**

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 who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 5). Patients randomized to the combination arm started therapy with metformin 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 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 2500 mg. Patients in the metformin 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 2000 mg/glyburide 20 mg or metformin 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 metformin (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 metformin 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 5).

* All patients on glyburide, 20 mg/day, at Baseline;
**-Not statistically significant

Table 5. Combined Metformin/Glyburide (Comb) vs Glyburide (Glyb) or Metformin (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

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

The magnitude of the decline in fasting blood glucose concentration following the institution of metformin 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, 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 6).

Table 6. 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 Cholesterol (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-Cholesterol (mg/dL)

Baseline

135.4

138.5

134.3

136.0

137.5

Mean % Change at FINAL VISIT

-8%

1%

-4%

-6%

3%

HDL-Cholesterol (mg/dL)

Baseline

39.0

40.5

37.2

39.0

37.0

Mean % Change at FINAL VISIT

2%

-1%

5%

3%

1%

In contrast to sulfonylureas, body weight of individuals on metformin tended to remain stable or even decrease somewhat (see Tables 4 and 5).

A 24-week, double-blind, placebo-controlled study of metformin 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 7). Patients randomized to receive metformin 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, metformin plus insulin versus insulin plus placebo, respectively, p = 0.04.

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)

Table 7. Combined Metformin/Insulin vs Placebo/Insulin Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose

 

Metformin/Insulin (n = 26)

Placebo/Insulin (n = 28)

Treatment Difference Mean ± SE

Hemoglobin A1c (%)

 

 

 

Baseline

8.95

9.32

  -0.54 ± 0.43a

Change at FINAL VISIT

-2.10

-1.56

Insulin Dose (U/day)

 

 

 

Baseline

93.12

94.64

  -16.08 ± 7.77b

Change at FINAL VISIT

-0.15

15.93

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 metformin maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin 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 plus insulin and placebo plus insulin, p < 0.01). In addition, this study demonstrated that the combination of metformin 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.

Pediatric Clinical Studies

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 (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 8).

a-Pediatric patients mean age 13.8 years (range 10 - 16 years)
*- All patients on diet therapy at Baseline
**-Not statistically significant

Table 8. Metformin vs Placebo (Pediatricsa) Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit

 

Metformin

Placebo

p-value

FPG (mg/dL)

(n = 37)

(n = 36)

< 0.001

Baseline

162.4

192.3

Change at FINAL VISIT

-42.9

21.4

Body Weight (lbs)

(n = 39)

(n = 38)

NS**

Baseline

205.3

189.0

Change at FINAL VISIT

-3.3

-2.0

Overdosage

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no casual association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Package/Label Display Panel

10631-206-01

Riomet®(metformin hydrochloride oral solution)

500 mg/5 mL

Each 5 mL contains: 500 mg of metformin hydrochloride, USP.

Cherry Flavor

Rx only

4 fl. Oz. 118 mL

What is Riomet?

Riomet (metformin oral solution) is an oral diabetes medicine that helps control blood sugar levels.

Riomet oral soution is used to improve blood sugar control in people with type 2 diabetes.

Riomet is sometimes used in combination with insulin or other medications, but metformin is not for treating type 1 diabetes.

Important information

You should not use Riomet if you have severe kidney disease, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking Riomet.

Riomet may cause a serious condition called lactic acidosis. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of metformin may cause lactic acidosis, which may be fatal.

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