Metformin Hydrochloride

Class: Biguanides
ATC Class: A10BA02
VA Class: HS502
Chemical Name: 1,1-Dimethylbiguanide monohydrochloride
Molecular Formula: C₄H₁₁N₅•HCl
CAS Number: 1115-70-4
Brands: Actoplus Met, Avandamet, Fortamet, Glucophage, Glucophage XR, Glucovance, Glumetza, Metaglip, Riomet

Special Alerts:

[UPDATED 02/04/2011] FDA notified healthcare professionals and patients that information on the cardiovascular risks (including heart attack) of rosiglitazone has been added to the physician labeling and patient Medication Guide. This information was first announced by FDA on September 23, 2010 as part of new restrictions for prescribing and use of this drug.

Rosiglitazone is sold as a single-ingredient product under the brand name Avandia. Rosiglitazone is also sold as a combination product under the brand name Avandamet (contains rosiglitazone and metformin) and under the brand name Avandaryl (contains rosiglitazone and glimepiride).

In addition to describing the cardiovascular risks, the drug labels have been revised to state that rosiglitazone and rosiglitazone-containing medicines should only be used:

• 
  

  In patients already being treated with these medicines

  
  


• 
  

  In patients whose blood sugar cannot be controlled with other anti-diabetic medicines and who, after consulting with their healthcare professional, do not wish to use pioglitazone-containing medicines (Actos, Actoplus Met, Actoplus Met XR, or Duetact).

  
  

For more information visit the FDA website at: and .

[Posted 09/23/2010] ISSUE: FDA notified healthcare professionals and patients that it will significantly restrict the use of the diabetes drug rosiglitazone (Avandia) to patients with Type 2 diabetes who cannot control their diabetes on other medications. These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with rosiglitazone

BACKGROUND: Rosiglitazone is in a class of drugs known as thiazolidinediones, or TZDs. It is intended to be used in conjunction with diet and exercise to improve glucose (blood sugar) control in patients with Type 2 diabetes mellitus. Rosiglitazone also is available in combination with other diabetes medications, metformin under the brand name Avandamet or glimepiride under the brand name Avandaryl.

RECOMMENDATION: FDA will require that GSK develop a restricted access program for rosiglitazone under a risk evaluation and mitigation strategy, or REMS. Under the REMS, rosiglitazone will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take pioglitazone (Actos), the only other drug in this class. Current users of rosiglitazone who are benefiting from the drug will be able to continue using the medication if they choose to do so.

Doctors will have to attest to and document their patients' eligibility; patients will have to review statements describing the cardiovascular safety concerns associated with this drug and acknowledge they understand the risks. The agency anticipates that the REMS will limit use of rosiglitazone significantly. For more information visit the FDA website at: and .

• 
  

  Lactic acidosis rare but potentially fatal.^{1 6 18 20 27 29 30 62 89 96 158} Increased risk of lactic acidosis in patients with renal impairment, advanced age, metformin plasma concentrations >5 mcg/mL.^{1 2 62 96 119}

  
  


• 
  

  Generally has occurred in diabetic patients with severe renal insufficiency who frequently had concomitant medical and/or surgical problems and were receiving multiple drugs.^{1 2 3 20 50 62 64 76 96 123 158 164 165}

  
  


• 
  

  Periodically monitor renal function and use the minimum effective dosage.^{1 32 62 63 65 76 85 91 93 96 123 124 158 164 165} Withhold promptly in patients with any condition associated with hypoxemia, sepsis, or dehydration.^{1 2 62 63 93} Avoid use in patients with clinical or laboratory evidence of hepatic impairment.^{1 2 63 65 85 91 93 156 158} Discontinue therapy temporarily in patients undergoing surgery or receiving parenteral iodinated radiographic contrast media.^{1 2 30 62 63 93 158} Drugs that may affect renal function or alter metformin elimination should be used with caution.¹

  
  


• 
  

  Advise patients not to consume excessive amounts of alcohol.^{1 2 63 76 91 93 158}

  
  


• 
  

  If lactic acidosis occurs, discontinue metformin.^{1 30} Immediate hospitalization and treatment required.¹

  
  

Introduction

Antidiabetic agent; a biguanide, chemically and pharmacologically unrelated to sulfonylurea antidiabetic agents.^{1 2 3 4 18 20 22 23 27 28 29 30 33 72 146 243 245 246}

Uses for Metformin Hydrochloride

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.

Diabetes Mellitus

Used as monotherapy for the management of patients with type 2 diabetes mellitus that cannot be controlled by diet alone.^{1 3 4 6 8 15 16 17 18 19 20 27 29 95 166}

Used in combination with a sulfonylurea, repaglinide, or thiazolidinedione antidiabetic agent for the management of patients with type 2 diabetes who do not achieve adequate glycemic control on monotherapy with metformin or any of these drugs.^{1 3 6 15 18 20 22 27 29 30 48 59 78 88 95 97 99 112 134 166 191 234 237 238 239 241 242 243 245 246 249 250} Used concomitantly with nateglinide in patients who no longer respond adequately to metformin despite appropriate diet, exercise, and metformin monotherapy.²⁴⁸

May be used with insulin to improve glycemic control and/or decrease the required dosage of insulin.^{1 3 6 88 90 94 95 146}

Commercially available in fixed combination with glyburide or glipizide for use as initial therapy in the management of patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone.^{234 254}

Fixed combinations with glyburide or glipizide used as second-line therapy in patients who do not achieve adequate control of hyperglycemia despite therapy with diet, exercise, and initial treatment with a sulfonylurea antidiabetic agent or metformin.^{234 254}

Add a thiazolidinedione antidiabetic agent to metformin in fixed combination with glyburide in patients who have inadequate glycemic control with the fixed combination.²³⁴

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.

Commercially available in fixed combination with rosiglitazone for use when treatment with rosiglitazone and metformin is appropriate (i.e., as initial therapy in patients whose hyperglycemia cannot be controlled by diet and exercise alone and as second-line therapy in patients who do not achieve adequate control of hyperglycemia despite therapy with diet, exercise, and treatment with rosiglitazone or metformin).^a

Metformin is the preferred initial oral antidiabetic agent for patients with type 2 diabetes mellitus.²⁶⁴

Not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma.^{1 6 30 146 191 192}

Metformin Hydrochloride Dosage and Administration

General

• 
  

  Sulfonylurea agent may be abruptly discontinued (no transition period generally required) when therapy is transferred from most sulfonylurea antidiabetic agents to metformin.^{1 2}

  
  


• 
  

  Patients whose therapy is transferred from chlorpropamide to metformin should be monitored closely for hypoglycemia during the initial 2 weeks following transfer.^{1 2 30}

  
  


• 
  

  Goal of therapy should be to reduce both fasting glucose and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) values to normal or near normal using the lowest effective dosage of metformin hydrochloride, either when used as monotherapy or combined with another oral antidiabetic agent (e.g., sulfonylurea, acarbose).^{1 8 13 14 78 85 88 105 134 146 166 234 235 243 245 246}

  
  

Administration

Oral Administration

Administer orally with meals to reduce adverse GI effects.^{1 2 3 18 53 85}

Administer conventional tablets 2 or 3 times daily.¹ Administer in 2 divided doses if total dosage ≤2 g daily or in 3 divided doses if total dosage is >2 g daily.¹

Administer extended-release tablets once daily with the evening meal.¹

Dosage

Available as metformin hydrochloride; dosage expressed in terms of the salt.¹

Individualize dosage carefully based on patient’s glycemic response and tolerance.^{1 4 243 245 246}

Pediatric Patients

Diabetes Mellitus

Oral

Conventional tablets or oral solution in children 10–16 years of age: Initially, 500 mg twice daily with meals as monotherapy.^{1 257 258} Titrate dosage in increments of 500 mg daily at weekly intervals to a maximum of 2 g daily given in divided doses.^{1 257 258}

Adults

Diabetes Mellitus

Initial Dosage in Previously Untreated Patients

Oral

Conventional tablets or oral solution: Initially, 500 mg twice daily with the morning and evening meal.^{1 4 134 243 245 246 257 259} Titrate dosage by 500 mg daily at weekly intervals to a total of 2 g daily^{1 2 14 18 21 30 85 134 257} or to 850 mg twice daily after 2 weeks.^{1 257} Clinically important responses generally not observed at dosages <1.5 g daily.^{1 257} Usual maintenance dosage is 850 mg twice daily.^{1 259}

Alternatively, give initial dosage of 500–850 mg once daily in the morning.^{1 2 3 4 23 30 146 243 245 246} If initial dosage is 850 mg daily, titrate dosage by 850 mg daily every other week to a total of 2 g daily.^{1 2 3 4 18 22 85 243 245 246}

For additional glycemic control, administer up to a maximum daily dosage of 2.55 g given in divided doses.^{1 257}

Extended-release tablets (Glucophage XR) in patients ≥17 years of age: Initially, 500 mg once daily with the evening meal.^{1 259} Titrate dosage by 500 mg daily at weekly intervals to a maximum of 2 g daily.^{1 259} If glycemic control is not achieved with 2 g once daily, consider administering 1 g twice daily.^{1 259} If >2 g daily is required, switch to conventional tablet formulation and increase dosage up to 2.55 g daily in divided doses (preferably 3 doses for daily dosages >2 g).^{1 259}

Extended-release tablets (Fortamet) in patients ≥17 years of age: Initially, 1 g daily with the evening meal; 500 mg daily may be used when clinically appropriate.²⁵⁸ Titrate dosage by 500 mg daily at weekly intervals to a maximum of 2.5 g daily with the evening meal.²⁵⁸

Initial Dosage of Metformin Hydrochloride in Fixed Combination with Glipizide (Metaglip)

Oral

Initially, 250 mg of metformin hydrochloride and 2.5 mg of glipizide once daily with a meal.²⁵⁴ For more severe hyperglycemia (fasting plasma glucose concentrations of 280–320 mg/dL), 500 mg of metformin hydrochloride and 2.5 mg of glipizide twice daily.²⁵⁴ Titrate in increments of one tablet (using the tablet strength at which therapy was initiated) daily at 2-week intervals until adequate blood glucose control is achieved or maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glipizide is reached.^{254 256}

Efficacy of metformin hydrochloride and glipizide in fixed combination not established in patients with fasting plasma glucose concentrations >320 mg/dL.²⁵⁴ No experience with total initial daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide.²⁵⁴

Initial Dosage of Metformin Hydrochloride in Fixed Combination with Glyburide (Glucovance)

Oral

Initially, 250 mg of metformin hydrochloride and 1.25 mg of glyburide once daily with a meal.²³⁴ For more severe hyperglycemia (i.e., fasting plasma glucose concentrations >200 mg/dL or glycosylated hemoglobin >9%), 250 mg of metformin hydrochloride and 1.25 mg of glyburide twice daily with the morning and evening meal.²³⁴ Titrate dosage in increments of 250 mg of metformin hydrochloride and 1.25 mg of glyburide daily at 2-week intervals adequate control of blood glucose is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glyburide.²³⁴

The fixed combination of metformin hydrochloride 500 mg and glyburide 5 mg should not be used as initial therapy due to an increased risk of hypoglycemia.²³⁴

Initial Dosage of Metformin Hydrochloride in Fixed Combination with Rosiglitazone (Avandamet)

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.

Oral

Initially, 500 mg of metformin hydrochloride and 2 mg of rosiglitazone once or twice daily.^a For more severe hyperglycemia (i.e., HbA_1c >11% or fasting plasma glucose concentrations >270 mg/dL), consider 500 mg of metformin hydrochloride and 2 mg of rosiglitazone twice daily.^a If additional glycemic control needed after 4 weeks, titrate dosage upward in increments of 500 mg of metformin hydrochloride and 2 mg of rosiglitazone per day until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 8 mg of rosiglitazone is reached.^a

Initial Dosage in Patients Transferred to Metformin Hydrochloride in Fixed Combination with Glipizide (Metaglip)

Oral

In previously treated patients, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glipizide twice daily with the morning and evening meals.²⁵⁴ The initial dosage of glipizide and metformin hydrochloride in fixed combination should not exceed the daily dosage of metformin hydrochloride or glipizide (or the equivalent dosage of another sulfonylurea) previously received.²⁵⁴ Titrate dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glipizide until adequate control of blood glucose is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.²⁵⁴

For patients switching from combined therapy with separate preparations, the initial dosage of the fixed-combination preparation of glipizide and metformin hydrochloride should not exceed the daily dosages of glipizide (or equivalent dosage of another sulfonylurea antidiabetic agent) and metformin hydrochloride currently being taken.²⁵⁴ Use clinical judgment regarding whether to switch to the nearest equivalent dosage or to titrate dosage.²⁵⁴ Titrate dosage in increments of not more than 5 mg of glipizide and 500 mg of metformin hydrochloride until adequate control of blood glucose is achieved or maximum daily dosage of 20 mg of glipizide and 2 g of metformin hydrochloride is reached.²⁵⁴

Initial Dosage in Patients Transferred to Metformin Hydrochloride in Fixed Combination with Glyburide (Glucovance)

Oral

Initially, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glyburide twice daily with the morning and evening meal.²³⁴ For patients previously receiving metformin hydrochloride or glyburide (or another sulfonylurea agent), the initial dosage of metformin hydrochloride or glyburide should not exceed the dosage (or equivalent dosage) received previously.²³⁴ For patients previously receiving both metformin hydrochloride and glyburide (or another sulfonylurea agent) separately, the initial dosage should not exceed the previous dosage of metformin hydrochloride and glyburide (or the equivalent dosage of the other sulfonylurea) administered separately.²³⁴ Titrate dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide until adequate control of blood glucose is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide is reached.^{158 234}

For patients whose hyperglycemia is not adequately controlled on therapy with metformin hydrochloride in fixed combination with glyburide, a thiazolidinedione (e.g., pioglitazone, rosiglitazone) may be added at its recommended initial dosage and the dosage of the fixed combination may be continued unchanged.²³⁴ In patients requiring further glycemic control, titrate thiazolidinedione dosage upward as recommended.²³⁴

Initial Dosage in Patients Transferred to Metformin Hydrochloride in Fixed Combination with Rosiglitazone (Avandamet)

Oral

In patients not adequately controlled on monotherapy with metformin hydrochloride or rosiglitazone, dosage of the fixed combination is based on the patient’s current dosages of metformin hydrochloride and/or rosiglitazone.²⁴⁷ (See Table.)

In patients inadequately controlled on metformin monotherapy, the usual initial dosage of rosiglitazone is 4 mg daily given with patient's existing dosage of metformin hydrochloride.^a

In patients inadequately controlled on rosiglitazone monotherapy, the usual initial dosage of metformin hydrochloride is 1 g daily given with patient's existing dosage of rosiglitazone.^a

Individualize therapy in patients already receiving metformin hydrochloride at dosages not available in the fixed combination (i.e., dosages other than 1 or 2 g).²⁴⁷

Table 1. Initial Dosage of the Fixed Combination of Metformin Hydrochloride and Rosiglitazone (Avandamet)a

Prior Therapy	Usual Initial Dosage of Avandamet
Total Daily Dosage	Tablet strength	Number of tablets
Metformin Hydrochloride
1 g	2 mg/500 mg	1 tablet twice daily
2 g	2 mg/1 g	1 tablet twice daily
Rosiglitazone
4 mg	2 mg/500 mg	1 tablet twice daily
8 mg	4 mg/500 mg	1 tablet twice daily

The tablet strength of the fixed combination that is selected should be the one that most closely provides the patient’s existing dosage of metformin hydrochloride or rosiglitazone, respectively.²⁴⁷ (See Table.)

If additional glycemic control is needed following transfer, titrate dosage upward in increments of 500 mg of metformin hydrochloride and/or 4 mg of rosiglitazone per day until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 8 mg of rosiglitazone is reached.^a Following increase in dosage of metformin hydrochloride, further dosage adjustment recommended if adequate glycemic control not achieved in 1–2 weeks.^a Following increase in dosage of rosiglitazone, further dosage adjustment recommended if adequate glycemic control not achieved in 8–12 weeks.^a

For patients switching from combined therapy with separate preparations, the initial dosage of the fixed-combination preparation of metformin hydrochloride and rosiglitazone should be the same as the daily dosage of metformin hydrochloride and rosiglitazone currently being taken.²⁴⁷

Initial Metformin Hydrochloride Dosage in Patients Transferred from Insulin

Oral

Initially, 500 mg once daily; increase dosage by 500 mg daily at weekly intervals adequate control of blood glucose is achieved or a maximum daily dosage of 2.5 g (conventional tablets) or 2 g (extended-release tablets) is reached.¹ Concurrent insulin dosage initially remains unchanged.¹ When fasting plasma glucose concentration decreases to <120 mg/dL, decrease insulin dosage by 10–25%.¹

Prescribing Limits

Pediatric Patients

Oral

Children 10–16 years of age: Maximum 2 g daily as conventional tablets or oral solution.^{1 257}

Adults

Oral

Maximum 2.55 g daily (conventional tablets or oral solution; 2.5 g daily as Fortamet extended-release tablets; or 2 g daily as certain other extended-release tablets (e.g., Glucophage).^{1 2 3 4 14 18 22 85 257 258 259} Switch to conventional tablets for further dosage titration if required dosage exceeds 2 g daily while on extended-release tablets.^{1 259}

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.

For the fixed combination with glyburide, maximum daily dosage as second-line therapy is 2 g of metformin hydrochloride and 20 mg of glyburide.²³⁴ For the fixed combination with glipizide, maximum daily dosage is 2 g of metformin hydrochloride and 20 mg of glipizide.^{254 256} For the fixed combination with rosiglitazone, maximum daily dosage is 2 g of metformin hydrochloride and 8 mg of rosiglitazone.²⁴⁷

Special Populations

Geriatric Patients

Maintenance dosage generally should not be titrated to the maximum recommended for younger adults;^{1 2 3 4 165 1} limited data suggest reducing initial dosage by approximately 33% in geriatric patients.^{30 174}

Cautions for Metformin Hydrochloride

Contraindications

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  Sole therapy in patients with type 1 diabetes and in patients with diabetes complicated by acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.^{1 2 234 247}

  
  


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  Renal impairment (e.g., ≥1.5 or 1.4 mg/dL in men or women, respectively) or abnormal S_cr.^{1 2 18 20 91 234} Renal impairment may result from conditions such as cardiovascular collapse (shock), AMI, or septicemia.^{1 2 18 20 91 234}

  
  


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  Congestive heart failure requiring drug therapy (e.g., digoxin, furosemide).^{1 209 214 215}

  
  


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  Known hypersensitivity to metformin hydrochloride or any ingredient in the formulations.^{1 2 234 247 254}

  
  

Warnings/Precautions

Warnings

Lactic Acidosis

See Boxed Warning.

General Precautions

Hypoglycemia

Uncommon in patients receiving metformin as monotherapy.^{1 15 30 78 94 99} Debilitated, malnourished, or geriatric patients and patients with renal or hepatic impairment or adrenal or pituitary insufficiency may be particularly susceptible.^{1 2} Strenuous exercise, alcohol ingestion, insufficient caloric intake, or use in combination with other antidiabetic agents may increase risk.^{1 2} Hypoglycemia may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents.^{1 83 91 128 143 153 159} (See Specific Drugs under Interactions.)

Hematologic Effects

Decreased serum vitamin B₁₂ concentrations, ^{1 18} with or without clinical manifestations (e.g., anemia).¹

Symptoms rapidly reversible following discontinuation of metformin or supplementation with vitamin B₁₂.^{1 3 6 20 30 70 77 82 134} Monitor hematologic parameters (e.g., hemoglobin, serum vitamin B₁₂ concentrations)^{1 82 114 122 134 148} prior to initiation of therapy and at least annually during treatment and any abnormality properly investigated.

Consider periodic supplementation with parenteral vitamin B₁₂ in patients at high risk for developing subnormal serum vitamin B₁₂ concentrations (e.g., alcoholics, patients with low calcium or vitamin B₁₂ intake or absorption).^{1 82 114 122 134 148}

Cardiovascular Effects

Possible increased cardiovascular mortality associated with other biguanide antidiabetic agents (i.e., phenformin).^{1 191 192 200} The American Diabetes Association (ADA) and other clinicians do not recommend changing current guidelines regarding the use of metformin as monotherapy or in combination with sulfonylureas pending the results of further studies of metformin alone or in combination with sulfonylureas.^{220 221 224}

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.

Use of metformin in combination with rosiglitazone and insulin is not indicated; adverse cardiovascular events (e.g., edema, heart failure) have occurred with combined rosiglitazone and insulin therapy.²⁴⁷

Concurrent Illness

Evaluate serum electrolytes and ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate, and metformin concentrations for evidence of ketoacidosis or lactic acidosis.^{1 88 134 156 169}

Temporary withdrawal of metformin therapy and administration of insulin may be required to maintain glycemic control during periods of stress.¹

Use of Fixed Combinations

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.

When used in fixed combination with glipizide, glimepiride, or rosiglitazone, consider the cautions, precautions, and contraindications associated with the concomitant agent.^{234 247 254}

Specific Populations

Pregnancy

Category B.¹

Most clinicians recommend use of insulin during pregnancy in diabetic patients to maintain optimum control of blood glucose concentrations.^{1 3 4 18 72 88 92}

Lactation

Distributed into milk in rats; not known if distributed into milk in humans.^{1 85} Discontinue nursing or the drug.^{1 3 4}

Pediatric Use

Safety and efficacy of metformin as conventional tablets or oral solution in children <10 years of age have not been established.^{1 257}

Safety and efficacy of metformin as extended-release tablets in children <17 years of age have not been established.^{1 258 259}

Safety and efficacy of metformin in fixed combination with glipizide or rosiglitazone in children have not been established.^{1 3 4 30 134 234 247 254} Data from a clinical trial in children 9–16 years of age comparing combined therapy with metformin and glyburide (Glucovance) with each drug as monotherapy did not reveal unexpected safety findings.²³⁴

Geriatric Use

Insufficient number of geriatric patients in controlled clinical trials of metformin hydrochloride conventional (Glucophage) and extended-release tablets (Glucophage XR) to determine if such patients respond differently than younger adults.¹ With another extended-release preparation of metformin hydrochloride (Fortamet), no overall differences in safety or efficacy in geriatric patients were observed compared with younger adults.²⁵⁸

Use with caution, since renal function declines with age.^{1 3 4 30 85 174}

Monitor renal function periodically.^{1 2 3 4 164 165}

Do not initiate in patients ≥80 years of age without confirmation of adequate renal function as measured by Cl_cr.^{1 209 214}

Geriatric patients particularly susceptible to hypoglycemia,^{1 2} which may be difficult to recognize.^{1 83 91 128 143 153 159}

Renal Impairment

Evaluate renal function prior to initiation of therapy and at least annually thereafter.^{1 2 77 85 234}

Monitor more frequently if development of impaired renal function is anticipated (e.g., those with blood glucose concentrations >300 mg/dL, those who may develop renal dysfunction as a result of polyuria and volume depletion).¹⁵⁶

Discontinue metformin if evidence of renal impairment is present.^{1 2 156 164}

Patients whose serum creatinine concentrations exceed the upper limit of normal for their age should not receive metformin.¹

Hepatic Impairment

Avoid use.^{1 165} Elimination of lactate may be substantially reduced.¹ (See Boxed Warning.)

Common Adverse Effects

Diarrhea,^{1 31 48 49 53 78 109 118 122 135} nausea,^{1 31 53 78 109 118 122} vomiting,^{1 118 122} abdominal bloating, abdominal cramping or pain,^{1 31 35 42 53 118 122} flatulence,¹ anorexia.^{1 3 6 18}

Interactions for Metformin Hydrochloride

Cationic Agents Secreted by Proximal Renal Tubules

Pharmacokinetic interaction with cimetidine (decreased excretion of metformin).^{1 75}

Potential pharmacokinetic interaction with other cationic drugs that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin).^{1 30}

Monitor carefully; consider dosage adjustment of either agent.¹

Protein-bound Drugs

Pharmacokinetic interaction unlikely.¹

Drugs That May Antagonize Hypoglycemic Effects

Calcium-channel blocking agents, corticosteroids, thiazide diuretics, estrogens and progestins (e.g., oral contraceptives), isoniazid, niacin, phenothiazines, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline); observe patient closely for evidence of altered glycemic control when such drugs are added to or withdrawn from therapy.^{1 30 80 85 91 120 121 134 139 143 151 152 153 154 159 160}

Specific Drugs

Drug	Interaction	Comments
ACE inhibitors	Potential risk of hypoglycemia/hyperglycemia when ACE inhibitor therapy is initiated/withdrawn131 132 134 152 155 160	Monitor blood glucose concentrations during dosage adjustments with either agent130 131 132 134 152 155 160
Alcohol	Increased risk of hypoglycemia and lactic acidosis1 2