RIOMET- metformin hydrochloride solution

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06-12-2018

Δραστική ουσία:
METFORMIN HYDROCHLORIDE (UNII: 786Z46389E) (METFORMIN - UNII:9100L32L2N)
Διαθέσιμο από:
Sun Pharmaceutical Industries, Inc.
INN (Διεθνής Όνομα):
METFORMIN HYDROCHLORIDE
Σύνθεση:
METFORMIN HYDROCHLORIDE 500 mg in 5 mL
Οδός χορήγησης:
ORAL
Τρόπος διάθεσης:
PRESCRIPTION DRUG
Θεραπευτικές ενδείξεις:
RIOMET is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus.
Περίληψη προϊόντος:
Flavor Appearance Size NDC Cherry clear, colorless solution 4 ounce (118 mL) 10631-206-01 16 ounce (473 mL) 10631-206-02 Strawberry clear, colorless to light yellow solution 4 ounce (118 mL) 10631-238-01 16 ounce (473 mL) 10631-238-02
Καθεστώς αδειοδότησης:
New Drug Application
Αριθμό άδειας:
10631-206-01, 10631-206-02, 10631-238-01, 10631-238-02

RIOMET- metformin hydrochloride solution

Sun Pharmaceutical Industries, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use RIOMET safely and effectively. See full

prescribing information for RIOMET.

RIOMET (metformin hydrochloride) solution, for oral use

Initial U.S. Approval: 1995

WARNING: LACTIC ACIDOSIS

See full prescribing information for complete boxed warning

INDICATIONS AND USAGE

RIOMET is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric

patients 10 years of age and older with type 2 diabetes mellitus. (1) (1)

DOSAGE AND ADMINISTRATION

Adult Dosage for RIOMET: (2)

Pediatric Dosage for RIOMET: (2)

Renal Impairment: (2)

Discontinuation for Iodinated Contrast Imaging Procedures: (2)

DOSAGE FORMS AND STRENGTHS

Oral Solution: 500 mg per 5 mL (100 mg/mL) in cherry and strawberry flavor (3) (3)

CONTRAINDICATIONS

®

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia,

hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory

distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate

levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >

5 mcg/mL. (5.1)

Risk factors include renal impairment, concomitant use of certain drugs, age ≥ 65 years old,

radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol

intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic

acidosis in these high risk groups are provided in the Full Prescribing Information. (5.1)

If lactic acidosis is suspected, discontinue RIOMET and institute general supportive measures in a

hospital setting. Prompt hemodialysis is recommended. (5.1)

Starting dose: 500 mg (5 mL) orally twice a day or 850 mg (8.5 mL) once a day, with meals (2.1)

Increase the dose in increments of 500 mg (5 mL) weekly or 850 mg (8.5 mL) every 2 weeks, up to a maximum dose

of 2,550 mg (25.5 mL) per day, given in divided doses

(2.1)

Doses above 2,000 mg (20 mL) may be better tolerated given in divided doses 3 times a day with meals (2.1)

Starting dose: 500 mg (5 mL) orally twice a day, with meals (2.2)

Increase dosage in increments of 500 mg (5 mL) weekly up to a maximum of

2,000 mg (20 mL) per day, given in divided doses twice daily (2.2)

Prior to initiation, assess renal function with estimated glomerular

filtration rate (eGFR) (2.3)

Do not use in patients with eGFR below 30 mL/minute/1.73 m (2.3)

Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m (2.3)

Assess risk/benefit of continuing RIOMET if eGFR falls below 45 mL/minute/1.73 m (2.3)

Discontinue if eGFR falls below 30 mL/minute/1.73 m (2.3)

RIOMET may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4)

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

The most common adverse reactions are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal

discomfort, and headache. (6.1) (6)

To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555

or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch (6)

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: LACTIC ACIDOSIS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage

2.2 Pediatric Dosage

2.3 Recommendations for Use in Renal Impairment

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

5.2 Vitamin B

Deficiency

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

5.4 Macrovascular Outcomes

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

Severe renal impairment (eGFR below 30 mL/min/1.73 m ) (4, 5.1)

Hypersensitivity to metformin (4)

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. (4)

Lactic acidosis: See boxed warning. (5.1)

Vitamin B deficiency: Metformin may lower vitamin B levels. Measure hematological parameters annually and

vitamin B at 2 to 3 year intervals and manage any abnormalities. (5.2)

12

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Increased risk of hypoglycemia when

used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be

required (5.3)

Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring (7)

Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase

the accumulation of metformin. Consider the benefits and risks of concomitant use (7)

Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake

Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended

pregnancy. (8.3)

Geriatric Use: Assess renal function more frequently. (8.5)

Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Storage

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have resulted in death,

hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin

associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such

as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin

associated lactic acidosis was characterized by elevated blood lactate levels (>5

mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased

lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and

Precautions (5.1)].

Risk factors for metformin-associated lactic acidosis include renal impairment,

concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate),

age 65 years old or greater, having a radiological study with contrast, surgery and other

procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake,

and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high

risk groups are provided [see Dosage and Administration (2.3), Contraindications (4), Warnings

and Precautions (5.1)].

If metformin-associated lactic acidosis is suspected, immediately discontinue RIOMET and

institute general supportive measures in a hospital setting. Prompt hemodialysis is

recommended [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

RIOMET is indicated as an adjunct to diet and exercise to improve glycemic control in adults and

pediatric patients 10 years of age and older with type 2 diabetes mellitus.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage

2.2 Pediatric Dosage

2.3 Recommendations for Use in Renal Impairment

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

3 DOSAGE FORMS AND STRENGTHS

Oral solution: 500 mg per 5 mL (100 mg/mL) clear solution in cherry and strawberry flavor

4 CONTRAINDICATIONS

Measure the RIOMET dose in the RIOMET specific dosing cup.

The recommended starting dose of RIOMET is 500 mg (5 mL) orally twice a day or 850 mg (8.5

mL) once a day, given with meals.

Increase the dose in increments of 500 mg (5 mL) weekly or 850 mg (8.5 mL) every 2 weeks on

the basis of glycemic control and tolerability, up to a maximum dose of 2,550 mg (25.5 mL) per

day, given in divided doses.

Doses above 2,000 mg (20 mL) may be better tolerated given in divided doses 3 times a day with

meals.

Measure the RIOMET dose in the RIOMET specific dosing cup.

The recommended starting dose of RIOMET for pediatric patients 10 years of age and older is

500 mg (5 mL) orally twice a day, given with meals.

Increase dosage in increments of 500 mg (5 mL) weekly on the basis of glycemic control and

tolerability, up to a maximum of 2,000 mg (20 mL) per day, given in divided doses twice daily.

Assess renal function prior to initiation of RIOMET and periodically thereafter.

RIOMET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below

30 mL/minute/1.73 m .

Initiation of RIOMET in patients with an eGFR between 30 to 45 mL/minute/1.73 m is not

recommended.

In patients taking RIOMET whose eGFR later falls below 45 mL/min/1.73 m , assess the benefit

risk of continuing therapy.

Discontinue RIOMET if the patient’s eGFR later falls below 30 mL/minute/1.73 m [see Warnings

and Precautions (5.1)].

Discontinue RIOMET at the time of, or prior to, an iodinated contrast imaging procedure in

patients with an eGFR between 30 and 60 mL/min/1.73 m ; in patients with a history of liver

disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial

iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart RIOMET if

renal function is stable.

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

RIOMET is contraindicated in patients with:

Severe renal impairment (eGFR below 30 mL/min/1.73 m ) [see Warnings and Precautions (5.1)].

Hypersensitivity to metformin.

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal

cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as

malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however,

hypotension and resistant bradyarrhythmias have occurred with severe acidosis.

Metformin associated lactic acidosis was characterized by elevated blood lactate concentrations

(> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased

lactate: pyruvate ratio; metformin plasma levels were generally > 5 mcg/mL. Metformin decreases

liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic

acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be

instituted promptly in a hospital setting, along with immediate discontinuation of RIOMET. In

RIOMET treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt

hemodialysis is recommended to correct the acidosis and remove accumulated metformin

(metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good

hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms

occur, instruct them to discontinue RIOMET and report these symptoms to their healthcare

provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis,

recommendations to reduce the risk of and manage metformin-associated lactic acidosis are

provided below:

Before initiating RIOMET, obtain an estimated glomerular filtration rate (eGFR).

RIOMET is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m [see

Contraindications (4)].

Initiation of RIOMET is not recommended in patients with eGFR between 30 to 45 mL/min/1.73

Obtain an eGFR at least annually in all patients taking RIOMET. In patients at risk for the

development of renal impairment (e.g., the elderly), renal function should be assessed more

frequently.

In patients taking RIOMET whose eGFR falls below 45 mL/min/1.73 m , assess the benefit and

risk of continuing therapy.

Renal impairment—The postmarketing metformin-associated lactic acidosis cases primarily

occurred in patients with significant renal impairment.

The risk of metformin accumulation and metformin-associated lactic acidosis increases with the

severity of renal impairment because metformin is substantially excreted by the kidney. Clinical

recommendations based upon the patient’s renal function include [see Dosage and Administration

(2.3), Clinical Pharmacology (12.3)]:

Before initiating RIOMET, obtain an estimated glomerular filtration rate (eGFR).

RIOMET is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m [see

Contraindications (4)].

Initiation of RIOMET is not recommended in patients with eGFR between 30 to 45 mL/min/1.73

5.2 Vitamin B

Deficiency

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. RIOMET may

increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue.

Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of

Initiation of RIOMET is not recommended in patients with eGFR between 30 to 45 mL/min/1.73

Obtain an eGFR at least annually in all patients taking RIOMET. In patients at risk for the

development of renal impairment (e.g., the elderly), renal function should be assessed more

frequently.

In patients taking RIOMET whose eGFR falls below 45 mL/min/1.73 m , assess the benefit and

risk of continuing therapy.

Drug interactions — The concomitant use of RIOMET with specific drugs may increase the risk

of metformin-associated lactic acidosis: those that impair renal function, result in significant

hemodynamic change, interfere with acid-base balance, or increase metformin accumulation.

Consider more frequent monitoring of patients [see Drug Interactions (7)].

Age 65 or greater — The risk of metformin-associated lactic acidosis increases with the patient’s

age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac

impairment than younger patients. Assess renal function more frequently in elderly patients.

Radiologic studies with contrast — Administration of intravascular iodinated contrast agents in

metformin-treated patients has led to an acute decrease in renal function and the occurrence of

lactic acidosis. Stop RIOMET at the time of, or prior to, an iodinated contrast imaging procedure

in patients with an eGFR between 30 and 60 mL/min/1.73 m ; in patients with a history of hepatic

impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial

iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart RIOMET

if renal function is stable.

Surgery and other procedures — Withholding of food and fluids during surgical or other

procedures may increase the risk for volume depletion, hypotension, and renal impairment.

RIOMET should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic states — Several of the postmarketing cases of metformin-associated lactic acidosis

occurred in the setting of acute congestive heart failure (particularly when accompanied by

hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction,

sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis

and may cause prerenal azotemia. When such an event occurs, discontinue RIOMET.

Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism.

Patients should be warned against excessive alcohol intake while receiving RIOMET.

Hepatic impairment — Patients with hepatic impairment have developed cases of metformin-

associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher

lactate blood levels. Therefore, avoid use of RIOMET in patients with clinical or laboratory

evidence of hepatic disease.

12

In clinical trials of 29-week duration with metformin hydrochloride (HCl) tablets, a decrease to

subnormal levels of previously normal serum vitamin B

levels was observed in approximately

7% of patients. Such decrease, possibly due to interference with B

absorption from the B

intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with

discontinuation of metformin or vitamin B

supplementation. Certain individuals (those with

inadequate vitamin B

or calcium intake or absorption) appear to be predisposed to developing

subnormal vitamin B

levels. Measure hematologic parameters on an annual basis and vitamin B

at 2 to 3 year intervals in patients on RIOMET and manage any abnormalities [see Adverse

Reactions (6.1)].

hypoglycemia when used in combination with RIOMET [see Drug Interactions (7)].

5.4 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction

with RIOMET.

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

(n = 145)

The following adverse reactions are also discussed elsewhere in the labeling:

Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]

Vitamin B

Deficiency [see Warnings and Precautions (5.2)]

Hypoglycemia [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates

observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials

of another drug and may not reflect the rates observed in practice.

In a U.S. clinical trial of metformin HCl tablets in patients with type 2 diabetes mellitus, a total of

141 patients received metformin HCl tablets up to 2,550 mg per day. Adverse reactions reported

in greater than 5% of patients treated with metformin HCl tablets and that were more common than

in placebo-treated patients, are listed in Table 1.

Table 1: Adverse Reactions from a Clinical Trial of Metformin HCl Tablets Occurring >5%

and More Common than Placebo in Patients with Type 2 Diabetes Mellitus

Metformin HCl Tablets (n =

141)

Placebo

Diarrhea

Nausea/Vomiting

Flatulence

Asthenia

Indigestion

Abdominal Discomfort

Headache

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

Diarrhea led to discontinuation of metformin HCl tablets in 6% of patients. Additionally, the

following adverse reactions were reported in ≥ 1% to ≤ 5% of patients treated with metformin

HCl tablets and were more commonly reported than placebo: abnormal stools, hypoglycemia,

myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest

discomfort, chills, flu syndrome, flushing, palpitation.

Pediatric Patients

In clinical trials with metformin HCl tablets in pediatric patients with type 2 diabetes mellitus, the

profile of adverse reactions was similar to that observed in adults.

Laboratory Tests

Vitamin B

Concentrations

12

In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels

of previously normal serum vitamin B

levels was observed in approximately 7% of patients.

The following adverse reactions have been identified during post approval use of metformin.

Because these reactions are reported voluntarily from a population of uncertain size, it is not

always possible to reliably estimate their frequency or establish a causal relationship to drug

exposure.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with

postmarketing use of metformin.

Table 2 presents clinically significant drug interactions with RIOMET.

Table 2: Clinically Significant Drug Interactions with RIOMET

Carbonic Anhydrase Inhibitors

Clinical Impact:

Carbonic anhydrase inhibitors frequently cause a decrease in serum

bicarbonate and induce non-anion gap, hyperchloremic metabolic

acidosis. Concomitant use of these drugs with RIOMET may increase

the risk for lactic acidosis.

Intervention:

Consider more frequent monitoring of these patients.

Examples:

Topiramate, zonisamide, acetazolamide or dichlorphenamide.

Drugs that Reduce RIOMET Clearance

Clinical Impact:

Concomitant use of drugs that interfere with common renal tubular

transport systems involved in the renal elimination of metformin (e.g.,

organic cationic transporter-2 [OCT ] / multidrug and toxin extrusion

[MATE] inhibitors) could increase systemic exposure to metformin

and may increase the risk for lactic acidosis [see Clinical

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pharmacology (12.3)].

Intervention:

Consider the benefits and risks of concomitant use with RIOMET.

Examples:

Ranolazine, vandetanib, dolutegravir, and cimetidine.

Alcohol

Clinical Impact:

Alcohol is known to potentiate the effect of metformin on lactate

metabolism.

Intervention:

Warn patients against excessive alcohol intake while receiving

RIOMET.

Insulin Secretagogues or Insulin

Clinical Impact:

Coadministration of RIOMET with an insulin secretagogue (e.g.,

sulfonylurea) or insulin may increase the risk of hypoglycemia.

Intervention:

Patients receiving an insulin secretagogue or insulin may require

lower doses of the insulin secretagogue or insulin.

Drugs Affecting Glycemic Control

Clinical Impact:

Certain drugs tend to produce hyperglycemia and may lead to loss of

glycemic control.

Intervention:

When such drugs are administered to a patient receiving RIOMET,

observe the patient closely for loss of blood glucose control. When

such drugs are withdrawn from a patient receiving RIOMET, observe

the patient closely for hypoglycemia.

Examples:

Thiazides and other diuretics, corticosteroids, phenothiazines,

thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic

acid, sympathomimetics, calcium channel blockers, and isoniazid.

8.2 Lactation

Risk Summary

Limited data with RIOMET in pregnant women are not sufficient to determine a drug-associated

risk for major birth defects or miscarriage. Published studies with metformin use during

pregnancy have not reported a clear association with metformin and major birth defect or

miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly

controlled diabetes mellitus in pregnancy [see Clinical Considerations].

No adverse developmental effects were observed when metformin was administered to pregnant

Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5

times, respectively, a 2,550 mg clinical dose, based on body surface area [see Data].

The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational

diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20 to 25% in women

with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is

unknown. In the U.S. general population, the estimated background risk of major birth defects and

miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic

ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery

complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects,

stillbirth, and macrosomia related morbidity.

Data

Human Data

Published data from post-marketing studies have not reported a clear association with metformin

and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was

used during pregnancy. However, these studies cannot definitely establish the absence of any

metformin-associated risk because of methodological limitations, including small sample size and

inconsistent comparator groups.

Animal Data

Metformin hydrochloride did not adversely affect development outcomes when administered to

pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and

5 times a 2,550 mg clinical dose based on body surface area comparisons for rats and rabbits,

respectively. Determination of fetal concentrations demonstrated a partial placental barrier to

metformin.

Risk Summary

Limited published studies report that metformin is present in human milk [see Data]. However,

there is insufficient information to determine the effects of metformin on the breastfed infant and

no available information on the effects of metformin on milk production. Therefore, the

developmental and health benefits of breastfeeding should be considered along with the mother’s

clinical need for RIOMET and any potential adverse effects on the breastfed child from RIOMET

or from the underlying maternal condition.

Data

Published clinical lactation studies report that metformin is present in human milk which resulted

in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a

milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to

definitely establish the risk of use of metformin during lactation because of small sample size and

limited adverse event data collected in infants.

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

Discuss the potential for unintended pregnancy with premenopausal women as therapy with

RIOMET may result in ovulation in some anovulatory women.

The safety and effectiveness of RIOMET for the treatment of type 2 diabetes mellitus have been

established in pediatric patients 10 to 16 years old. Safety and effectiveness of RIOMET have not

been established in pediatric patients less than 10 years old.

Use of RIOMET in pediatric patients 10 to 16 years old for the treatment of type 2 diabetes

mellitus is supported by evidence from adequate and well-controlled studies of metformin HCl

tablets in adults with additional data from a controlled clinical study of metformin HCl tablets in

pediatric patients 10 to 16 years old with type 2 diabetes mellitus, which demonstrated a similar

response in glycemic control to that seen in adults [see Clinical Studies (14)]. In this study, adverse

reactions were similar to those described in adults. A maximum daily dose of 2,000 mg of

RIOMET is recommended. [See Dosage and Administration (2.2).]

Controlled clinical studies of metformin HCl tablets did not include sufficient numbers of elderly

patients to determine whether they respond differently from younger patients. In general, dose

selection for an elderly patient should be cautious, usually starting at the low end of the dosing

range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of

concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal

function more frequently in elderly patients [see Warnings and Precautions (5.1)].

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and

lactic acidosis increases with the degree of renal impairment. RIOMET is contraindicated in

severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30

mL/min/1.73 m [see Dosage and Administration (2.3), Contraindications (4), Warnings and

Precautions (5.1), and Clinical Pharmacology (12.3)].

Use of metformin in patients with hepatic impairment has been associated with some cases of

lactic acidosis. RIOMET is not recommended in patients with hepatic impairment. [see Warnings

and Precautions (5.1)].

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than

50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association

with metformin has been established. Lactic acidosis has been reported in approximately 32% of

metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a

clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may

be useful for removal of accumulated drug from patients in whom metformin overdosage is

suspected.

RIOMET oral solution contains the biguanidine antihyperglycemic agent metformin in the form of

monohydrochloride salt. Metformin hydrochloride, is N,N-dimethylimidodicarbonimidic diamide

hydrochloride. The structural formula is shown as:

Metformin hydrochloride, USP is a white crystalline powder with a molecular formula of C

H N HCl and a molecular weight of 165.62. Metformin hydrochloride, USP 2.0 g is soluble in 20

mL of water. The pK of metformin is 12.4. The pH of a 1% aqueous solution of metformin

hydrochloride is 6.68. It is freely soluble in water; slightly soluble in alcohol; practically insoluble in

acetone and in methylene chloride.

RIOMET (Cherry Flavor) contains 500 mg of metformin hydrochloride (the equivalent of 389.93 mg

metformin) per 5 mL and the following inactive ingredients: Artificial cherry flavor, hydrochloric acid,

potassium bicarbonate, purified water, saccharin calcium, and xylitol.

RIOMET (Strawberry Flavor) contains 500 mg of metformin hydrochloride (the equivalent of 389.93

mg metformin) per 5 mL and the following inactive ingredients: Hydrochloric acid, N&A strawberry

flavor (propylene glycol and glycerin), potassium bicarbonate, purified water, sucralose, and xylitol.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2

diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases

hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin

sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin

secretion remains unchanged while fasting insulin levels and day-long plasma insulin response

may decrease.

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

1000 mg RIOMET and Metformin HCl tablets in healthy, nondiabetic adults (n = 36)

under fed and fasting conditions

Formulation

C

(ng/mL)

AUC

(ng.h/mL)

T

(h)

Study 1- Fasting state

RIOMET

1540.1 ± 451.1

9069.6 ± 2593.6

2.2 ± 0.5

Metformin HCl 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 to 86.4)

81.2

(76.9 to 85.6)

Study 2- Fed State

RIOMET

1235.3 ± 177.7

8950.1 ± 1381.2

4.1 ± 0.8

Metformin HCl Tablets

1361 ± 298.8

9307.7 ± 1839.8

3.7 ± 0.8

T/R Ratio X 100 (90%

confidence interval)

91.8

(87.4 to 96.5)

97.0

(92.9 to 101.2)

Table 4: Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single

Oral Doses of 1,000 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

C

(ng/mL)

AUC

(ng.h/mL)

t

(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 to 106.5)

115.6

(103.6 to 128.9)

H/F Ratio X 100 (90% confidence

interval)

89.4

(79.4 to 100.6)

112.6

(100.9 to 125.6)

L/H Ratio X 100 (90% confidence

interval)

105.8

(94.0 to 119.2)

102.7

(92.0 to 114.6)

Two pharmacokinetic studies performed in healthy volunteers to evaluate the bioavailability of

RIOMET in comparison with metformin HCl tablets under fasting and fed conditions showed that

the rate and extent of absorption of RIOMET was found to be comparable to that of metformin HCl

tablets under fasting or fed conditions (see Table 3).

max

0 -∞

max

T-test product (RIOMET)

R-reference product (immediate release metformin HCl tablets)

Studies using single oral doses of metformin HCl tablets 500 mg to 1,500 mg, and 850 mg to

2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due

to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing

schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to

48 hours and are generally < 1 mcg/mL.

Effect of food: The food-effect study 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 approximately 16%

and 13% 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 t

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 4).

max

0 -∞

max

interval)

(94.0 to 119.2)

(92.0 to 114.6)

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin

HCl 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin

partitions into erythrocytes, most likely as a function of time.

Metabolism

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.

Elimination

Renal clearance (see Table 5) 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

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 5) [See Dosage and Administration (2.3),

Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Hepatic Impairment

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

[See Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

Geriatrics

Limited data from controlled pharmacokinetic studies of metformin HCl tablets 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. It appears that the change in metformin

pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table

5). [See Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].

Table 5: Select Mean (±S.D.) Metformin Pharmacokinetic ParametersFollowing Single or

Multiple Oral Doses of Metformin HCl Tablets

Subject Groups:

Metformin HCl dose

a

(number of subjects)

Cmax

b

(mcg/mL)

Tmax

c

(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)

1.60 (±0.38)

2.64 (±0.82)

552 (±139)

850 mg three times daily for 19

doses (9)

2.01 (±0.42)

1.79 (±0.94)

642 (±173)

Adults with type 2 diabetes

mellitus :

850 mg single dose (23)

1.48 (±0.5)

3.32 (±1.08)

491 (±138)

850 mg three times daily for 19

doses (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 (CL g 61 to 90 mL/min)

1.86 (±0.52)

3.20 (±0.45)

384 (±122)

Moderate (CL 31 to 60

mL/min) (4)

4.12 (±1.83)

3.75 (±0.50)

108 (±57)

Severe (CL 10 to 30 mL/min)

3.93 (±0.92)

4.01 (±1.10)

130 (±90)

a All doses given fasting except the first 18 doses of the multiple dose studies

bPeak plasma concentration

cTime to peak plasma concentration

d Combined results (average means) of five studies: mean age 32 years (range 23 to 59 years)

e Kinetic study done following dose 19, given fasting

f Elderly subjects, mean age 71 years (range 65 to 81 years)

g CLcr = creatinine clearance normalized to body surface area of 1.73 m

Pediatrics

After administration of a single oral metformin HCl 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.

Gender

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and

patients with type 2 diabetes mellitus when analyzed according to gender (males = 19, females =

16).

16).

Race

No studies of metformin pharmacokinetic parameters according to race have been performed.

Drug Interactions

In VivoAssessment of Drug Interactions

Table 6: Effect of Coadministered Drug on Plasma Metformin SystemicExposure

Coadminis tered

Drug

Dose of

Coadminis tered

Drug

Dose of

Metformin

HCl

Geometric Mean Ratio

(ratio with/without

coadministered drug) No Effect

= 1.00

AUC

C

max

No dosing adjustments required for the following:

Glyburide

5 mg

850 mg

metformin

0.91

0.93

Furosemide

40 mg

850 mg

metformin

1.09

1.22

Nifedipine

10 mg

850 mg

metformin

1.16

1.21

Propranolol

40 mg

850 mg

metformin

0.90

0.94

Ibuprofen

400 mg

850 mg

metformin

1.05

1.07

Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [See

Warnings and Precautions (5.1) and Drug Interactions (7).]

Cimetidine

400 mg

850 mg

metformin

1.40

1.61

Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions

(5.1) and Drug Interactions (7).]

Topiramate

100 mg

500 mg

metformin

1.25

1.17

All metformin HCl and coadministered drugs were given as single doses

AUC = AUC (INF)

Ratio of arithmetic means

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours;

AUC = AUC

0-12h

Table 7: Effect of Metformin on Coadministered Drug Systemic Exposure

Coadminis tered

Drug

Dose of

Coadminis tered

Drug

Dose of

Metformin

HCl

Geometric Mean Ratio (ratio

with/without metformin) No

Effect = 1.00

AUC

C

max

No dosing adjustments required for the following:

Glyburide

5 mg

850 mg

glyburide

0.78

0.63

Furosemide

40 mg

850 mg

furosemide

0.87

0.69

Nifedipine

10 mg

850 mg

nifedipine

1.10

1.08

Propranolol

40 mg

850 mg

propranolol

1.01

1.02

Ibuprofen

400 mg

850 mg

ibuprofen

0.97

1.01

Cimetidine

400 mg

850 mg

cimetidine

0.95

1.01

All metformin HCl and coadministered drugs were given as single doses

AUC = AUC

unless otherwise noted

Ratio of arithmetic means, p-value of difference < 0.05

reported

0-24 hr

Ratio of arithmetic means

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks)

and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500

mg/kg/day, respectively. These doses are both approximately 3 times the maximum recommended

human daily dose of 2,550 mg based on body surface area comparisons. No evidence of

carcinogenicity with metformin was found in either male or female mice. Similarly, there was no

tumorigenic potential observed with metformin in male rats. There was, however, an increased

incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

14 CLINICAL STUDIES

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames

test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test

(human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high

as 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose of

2,550 mg based on body surface area comparisons.

Adult Clinical Studies

A double-blind, placebo-controlled, multicenter US clinical trial involving obese patients with

type

2 diabetes mellitus whose hyperglycemia was not adequately controlled with dietary management

alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL) was conducted.

Patients were treated with metformin HCl tablets (up to 2,550 mg/day) or placebo for 29 weeks.

The results are presented in Table 8.

Table 8: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29Comparing

Metformin HCl Tablets vs Placebo in Patients with Type 2Diabetes Mellitus

Metformin HCL

Tablets (n=141)

Placebo

(n=145)

p-Value

FPG (mg/dL)

Baseline

Change at FINAL VISIT

241.5

–53.0

237.7

0.001

Hemoglobin A (%)

1c

Baseline

Change at FINAL VISIT

–1.4

0.001

* Not statistically significant

Mean baseline body weight was 201 lbs and 206 lbs in the metformin HCl tablet and placebo arms,

respectively. Mean change in body weight from baseline to week 29 was -1.4 lbs and -2.4 lbs in

the metformin HCl tablet and placebo arms, respectively.

A 29-week, double-blind, placebo-controlled study of metformin HCl tablet and glyburide, alone

and in combination, was conducted in obese patients with type 2 diabetes mellitus who had failed

to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of

approximately 250 mg/dL). Patients randomized to the combination arm started therapy with

metformin HCl tablet 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 metformin HCl 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 metformin HCl 2,500 mg. Patients in the

metformin only arm (metformin HCl plus placebo) discontinued glyburide and followed the same

titration schedule. Patients in the glyburide arm continued the same dose of glyburide. At the end

of the trial, approximately 70% of the patients in the combination group were taking metformin

HCl 2,000 mg/glyburide 20 mg or metformin HCl 2,500 mg/glyburide 20 mg. The results are

Comb

(n = 213)

Glyb

(n = 209)

GLU

(n = 210)

p-Values

Glyb vs Comb

GLU vs

Comb

GLU

vs

Glyb

0.001

0.001

0.025

0.001

0.001

0.007

0.001

192.3

21.4

displayed in Table 9.

Table 9: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29Comparing

Metformin HCl Tablets/Glyburide (Comb) vs Glyburide (Glyb) vs Metformin HCl Tablets

(GLU): in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on

Glyburide

Fasting Plasma

Glucose (mg/dL)

Baseline

Change at FINAL

VISIT

250.5

–63.5

247.5

13.7

253.9

–0.9

Hemoglobin A

(%)

1c

Baseline

Change at FINAL

VISIT

–1.7

–0.4

Not statistically significant

Mean baseline body weight was 202 lbs, 203 lbs, and 204 lbs in the metformin HCl

tablet/glyburide, glyburide, and metformin HCl tablet arms, respectively. Mean change in body

weight from baseline to week 29 was 0.9 lbs, -0.7 lbs, and -8.4 lbs in the metformin HCl

tablet/glyburide, glyburide, and metformin HCl tablet arms, respectively.

Pediatric Clinical Studies

A double-blind, placebo-controlled study was conducted in pediatric patients aged 10 to 16 years

with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), where patients were treated with metformin

HCl tablets (up to 2,000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks). The

results are displayed in Table 10.

Table 10: Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin HCl

Tablets vs Placebo in Pediatric Patientsa with Type 2Diabetes Mellitus

Metformin HCl

Tablets

Placebo

p-Value

FPG (mg/dL)

Baseline

Change at FINAL VISIT

(n = 37)

162.4

–42.9

(n = 36)

<0.001

aPediatric patients mean age 13.8 years (range 10 to16 years)

Mean baseline body weight was 205 lbs and 189 lbs in the metformin HCl tablet and placebo arms,

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Flavor

Appearance

Size

NDC

Cherry

clear, colorless solution

4 ounce (118 mL)

10631-206-01

16 ounce (473 mL)

10631-206-02

Strawberry clear, colorless to light yellow

solution

4 ounce (118 mL)

10631-238-01

16 ounce (473 mL)

10631-238-02

Storage

17 PATIENT COUNSELING INFORMATION

respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in

the metformin HCl tablet and placebo arms, respectively.

RIOMET 500 mg per 5 mL (100 mg/mL) oral solution is supplied in bottles with child-resistant

caps and a dosing cup as follows:

Store at 15 - 30 C (59 - 86 F) [See USP Controlled Room Temperature].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Administration:

Instruct patients or caregivers to use the supplied dosing cup to measure the prescribed amount of

medication. Inform patients that additional RIOMET dosing cups or oral dosing syringes may be

obtained from their pharmacy.

Lactic Acidosis:

Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its

development. Advise patients to discontinue RIOMET immediately and to promptly notify their

healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or

other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform

patients about importance of regular testing of renal function while receiving RIOMET. Instruct

patients to inform their doctor that they are taking RIOMET prior to any surgical or radiological

procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1)].

Hypoglycemia

Inform patients that hypoglycemia may occur when RIOMET is coadministered with oral

sulfonylureas and insulin. Explain to patients receiving concomitant therapy the risks of

hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see

Warnings and Precautions (5.3)].

Vitamin B12 Deficiency:

Inform patients about importance of regular hematological parameters while receiving RIOMET

[see Warnings and Precautions (5.2)].

Females of Reproductive Age:

Inform females that treatment with RIOMET may result in ovulation in some premenopausal

anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)].

RIOMET is a registered trademark of Sun Pharmaceutical Industries Limited.

Manufactured by:

Mikart, LLC

Patient Medication Information

Atlanta, GA 30318

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

November 2018 FDA-11

PATIENT INFORMATION

RIOMET (ree oh met)

(metformin hydrochloride)

oral solution

What is the most important information I should know about RIOMET?

RIOMET can cause serious side effects, including:

Lactic Acidosis. Metformin hydrochloride, the medicine in RIOMET, can cause a rare, but

serious side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause

death. Lactic acidosis is a medical emergency and must be treated in a hospital.

Stop taking RIOMET and call your healthcare provider right away if you get any of the

following symptoms of lactic acidosis:

feel very weak and tired

have unusual sleepiness or sleep longer than

usual

have unusual (not normal) muscle pain

feel cold, especially in your arms and legs

have trouble breathing

feel dizzy or lightheaded

have unexplained stomach or intestinal

problems with nausea and vomiting, or

diarrhea

have a slow or irregular heartbeat

You have a higher chance of getting lactic acidosis if you:

have moderate to severe kidney problems. See “Do not take RIOMET if you

have liver problems.

have congestive heart failure that requires treatment with medicines.

drink a lot of alcohol (very often or short-term “binge” drinking).

get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever,

vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise

and do not drink enough fluids.

have certain x-ray tests with injectable dyes or contrast agents.

have surgery.

have a heart attack, severe infection, or stroke.

are 65 years of age or older.

Tell your healthcare provider if you have any of the problems in the list above.

Tell your healthcare provider that you are taking RIOMET before you have surgery or x-ray

tests. Your healthcare provider may need to stop RIOMET for a while if you have surgery or

certain x-ray tests.

RIOMET can have other serious side effects. See “What are the possible side effects of

RIOMET?”

What is RIOMET?

RIOMET is a prescription medicine that contains metformin hydrochloride. RIOMET is used with

diet and exercise to help control high blood sugar (hyperglycemia) in adults and children 10 years

of age and older with type 2 diabetes.

It is not known if RIOMET is safe and effective in children under 10 years of age.

Do not take RIOMET if you:

have severe kidney problems.

are allergic to the metformin hydrochloride or any of the ingredients in RIOMET. See the end of

this Patient Information leaflet for a complete list of ingredients in RIOMET.

have a condition called metabolic acidosis including diabetic ketoacidosis (high levels of certain

acids called “ketones” in your blood or urine).

Before taking RIOMET tell your healthcare provider about all your medical conditions,

including if you:

have a history or risk for diabetic ketoacidosis. See “Do not take RIOMET if you?

have kidney problems.

have liver problems.

have heart problems, including congestive heart failure.

are 65 years or older.

drink alcohol very often or drink a lot of alcohol in short-term “binge” drinking.

are taking insulin or a sulfonylurea medicine.

are pregnant or plan to become pregnant. It is not known if RIOMET will harm your unborn baby.

If you are pregnant, talk with your healthcare provider about the best way to control your blood

sugar while you are pregnant.

are a premenopausal woman who does not have periods regularly or at all. RIOMET can cause the

release of an egg from an ovary in a woman (ovulation). This can increase your chance of getting

pregnant.

are breastfeeding or plan to breastfeed. RIOMET can pass into your breast milk. Talk with your

healthcare provider about the best way to feed your baby while you take RIOMET.

Tell your healthcare provider about all the medicines you take, including prescription and

over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep

a list of them to show your healthcare provider and pharmacist when you get a new medicine.

RIOMET may affect the way other medicines work, and other medicines may affect how RIOMET

works.

How should I take RIOMET?

Take RIOMET exactly as your healthcare provider tells you.

Use the Riomet dosing cup to measure your dose. Ask your pharmacist for a dosing cup if you do

not have one.

RIOMET should be taken with meals to help decrease an upset stomach.

When your body is under some types of stress, such as fever, trauma (such as a car accident),

infection, or surgery, the amount of diabetes medicine that you need may change. Tell your

healthcare provider right away if you have any of these problems.

Your healthcare provider should do blood tests to check how well your kidneys are working

before and during your treatment with RIOMET.

Your healthcare provider will check your diabetes with regular blood tests, including your blood

sugar levels and your hemoglobin A1C.

Low blood sugar (hypoglycemia) can happen more often when RIOMET is taken with certain

other diabetes medicines. Talk to your healthcare provider about how to prevent, recognize and

manage low blood sugar. See “What are the possible side effects of RIOMET?”

Check your blood sugar as your healthcare provider tells you to.

Stay on your prescribed diet and exercise program while taking RIOMET.

If you take too much RIOMET, call your healthcare provider, or go to the nearest hospital

emergency room right away.

What should I avoid while taking RIOMET?

Do not drink a lot of alcoholic drinks while taking RIOMET. This means you should not binge

drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can

increase the chance of getting lactic acidosis.

What are the possible side effects of RIOMET?

RIOMET may cause serious side effects, including:

See “What is the most important information I should know about RIOMET?”

Low vitamin B

(vitamin B

deficiency). Using RIOMET may cause a decrease in the amount

of vitamin B

in your blood, especially if you have had low vitamin B

levels before. Your

healthcare provider may do blood tests to check your vitamin B

levels.

12

12

Low blood sugar (hypoglycemia). If you take RIOMET with another medicine that can cause

lower blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is

higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take

RIOMET. Signs and symptoms of low blood sugar may include:

headache

hunger

dizziness

drowsiness

fast heartbeat

sweating

weakness

confusion

irritability

shaking or feeling jittery

Common side effects of RIOMET include:

diarrhea

indigestion

nausea and vomiting

stomach-area (abdominal) discomfort

gassiness (flatulence)

headache

PACKAGE LABEL. PRINCIPAL DISPLAY PANEL

NDC 10631-238-02

Riomet

(metformin hydrochloride oral solution)

500 mg/5 mL

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

Strawberry Flavor

Rx only

16 fl. oz.473 mL

weakness or lack of energy (asthenia)

These are not all the possible side effects of RIOMET.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-

800-FDA-1088.

How should I store RIOMET?

Store at room temperature between 59°F to 86°F (15°C to 30°C). See insert.

Keep RIOMET and all medicines out of the reach of children.

General information about the safe and effective use of RIOMET.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information

leaflet. Do not use RIOMET for a condition for which it was not prescribed. Do not give

RIOMET to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about RIOMET that is written

for health professionals.

What are the ingredients of RIOMET?

Active ingredients: metformin hydrochloride.

Inactive ingredients (Cherry Flavor): Artificial cherry flavor, hydrochloric acid, potassium

bicarbonate, purified water, saccharin calcium, and xylitol.

Inactive ingredients (Strawberry Flavor): Hydrochloric acid, N&A strawberry flavor (propylene

glycol and glycerin), potassium bicarbonate, purified water, sucralose, and xylitol.

Manufactured by:

Mikart, LLC

Atlanta, GA 30318

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

®

Strawberry Flavor

Package/Label Display Panel

NDC 10631-206-02

Riomet

(metformin hydrochloride oral solution)

500 mg/5 mL

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

Cherry Flavor

Rx only

16 fl. oz.473 mL

®

Cherry Flavor

RIOMET

metformin hydrochloride solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:10 6 31-238

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

METFO RMIN HYDRO CHLO RIDE (UNII: 78 6 Z46 38 9 E) (METFORMIN -

UNII:9 10 0 L32L2N)

METFORMIN

HYDROCHLORIDE

50 0 mg

in 5 mL

Inactive Ingredients

Ingredient Name

Stre ng th

HYDRO CHLO RIC ACID (UNII: QTT1758 2CB)

PO TASSIUM BICARBO NATE (UNII: HM5Z15LEBN)

XYLITO L (UNII: VCQ0 0 6 KQ1E)

SUCRALO SE (UNII: 9 6 K6 UQ3ZD4)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

GLYCERIN (UNII: PDC6 A3C0 OX)

Product Characteristics

Color

S core

S hap e

S iz e

Flavor

STRAWBERRY

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:10 6 31-238 -0 1

118 mL in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/0 4/20 0 4

2

NDC:10 6 31-238 -0 2

473 mL in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/0 4/20 0 4

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 2159 1

0 1/0 4/20 0 4

RIOMET

metformin hydrochloride solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:10 6 31-20 6

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

METFO RMIN HYDRO CHLO RIDE (UNII: 78 6 Z46 38 9 E) (METFORMIN -

UNII:9 10 0 L32L2N)

METFORMIN

HYDROCHLORIDE

50 0 mg

in 5 mL

Inactive Ingredients

Ingredient Name

Stre ng th

HYDRO CHLO RIC ACID (UNII: QTT1758 2CB)

PO TASSIUM BICARBO NATE (UNII: HM5Z15LEBN)

XYLITO L (UNII: VCQ0 0 6 KQ1E)

SACCHARIN SO DIUM (UNII: SB8 ZUX40 TY)

Product Characteristics

Color

S core

S hap e

S iz e

Flavor

CHERRY

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:10 6 31-20 6 -0 1

118 mL in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/0 4/20 0 4

2

NDC:10 6 31-20 6 -0 2

473 mL in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/0 4/20 0 4

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 2159 1

0 1/0 4/20 0 4

Labeler -

Sun Pharmaceutical Industries, Inc. (146974886)

Registrant -

Sun Pharmaceutical Industries, Inc. (146974886)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Mikart, Inc.

0 1332238 7

MANUFACTURE(10 6 31-238 , 10 6 31-20 6 )

Sun Pharmaceutical Industries, Inc.

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Mikart, LLC.

0 30 0 348 47

PACK(10 6 31-238 , 10 6 31-20 6 ) , LABEL(10 6 31-238 , 10 6 31-20 6 )

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Farmhispania S.A.

46 20 38 145

API MANUFACTURE(10 6 31-238 , 10 6 31-20 6 )

Revised: 12/2018

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