Metformin

 Generic name: metformin (met FOR min)

Brand name: Fortamet, Glucophage, Glucophage XR, Glumetza. Riomet
Drug class: Non-sulfonylureas

What is metformin?

Metformin is an oral diabetes medicine that helps control blood sugar levels.

Metformin is used together with diet and exercise to improve blood sugar control in adults with type 2 diabetes mellitus.

Metformin is sometimes used together with insulin or other medications, but it is not for treating type 1 diabetes.

Metformin is also used off-label to treat polycystic ovary syndrome (PCOS).

Warnings

You should not use metformin if you have severe kidney disease, metabolic acidosis, or diabetic ketoacidosis (call your doctor for treatment).

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

Though extremely rare, you may develop lactic acidosis, a dangerous build-up of lactic acid in your blood. Call your doctor or get emergency medical help if you have unusual muscle pain, trouble breathing, stomach pain, dizziness, feeling cold, or feeling very weak or tired.

Metformin (Glucophage) is an antidiabetic medicine that improves glycemic control by reducing hepatic glucose production and increasing insulin sensitivity.

It is used for the management of type 2 Diabetes Mellitus as an adjunct to diet and exercise. It is considered to be the preferred initial treatment if tolerated and no contraindications to treatment exist.

• It is also used as an off-label treatment in adults in the following conditions:

  • Antipsychotic-induced weight gain

  • Prevention of Type 2 Diabetes Mellitus

  • Treatment of Gestational Diabetes Mellitus

  • Polycystic ovary syndrome (PCOS)

  • For the treatment of oligomenorrhea due to PCOS

  • For the prevention of ovarian hyperstimulation syndrome (OHSS) in females with PCOS.

Dose in the treatment of Antipsychotic-induced weight gain:

• Immediate-release:

  • 750 mg – 2000 mg orally daily in 2 – 3 divided doses.
  • It should be initiated in a dose of 250 mg two times a day and gradually increased at a weekly interval to minimize gastrointestinal side effects.

• Extended-release:

  • 1 – 2 gm orally once a day.
  • It may be initiated as 500 mg orally once a day and titrated upwards in 500 mg increments every 2 – 6 weeks if tolerated.

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Dose in the prevention of type 2 Diabetes mellitus (as off-label use):

Note:

It is advised in selected patients with prediabetes. Individuals who may benefit from therapy include:

• • Those with a BMI of more than 35 kg/m²
  • Age less than 60 years
  • Women with a history of gestational diabetes mellitus in whom modification in diet and lifestyle interventions fail to improve glycemic indices

• Immediate-release:

  • 850 mg orally once a day for one month, then increase to 850 mg two times a day.

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Dose in the treatment of type 2 Diabetes mellitus:

• Immediate-release tablets:

  • • 500 mg orally once or twice a day or
    • 850 mg orally once a day

  • Dosage adjustments:

    • The dose should be gradually increased to minimize gastrointestinal adverse effects in increments of 500 or 850 mg every 7 days.

  • Usual maintenance dosage:

    • 1 g orally two times a day or
    • 850 mg orally two times a day.

  • Maximum:

    • The usual maximum dose is 2.55 g/day.
    • Doses of more than 2 gms should be administered in three divided doses.

• Extended-release tablets:

  • • 500 mg – 1 g orally once a day

• Dosage adjustments:

  • The dose should be gradually increased in increments of 500 mg every week to minimize Gastrointestinal adverse effects.

• Maximum dose:

  • 2 g/day.
  • The maximum dose may be given in two divided doses if glycemic control is not achieved.

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Off label use as an alternative agent in the treatment of Gestational diabetes mellitus:

• Immediate-release:

  • 500 mg orally once or two times a day
  • The dose may be increased gradually over one to two weeks to a maximum dose of 2.5 gm daily in 2 – 3 divided doses.
  • If target glycemic control is not achieved, insulin may be added to metformin.

Note: The preferred therapy in gestational diabetes mellitus is insulin as it does not cross the placenta.

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Dose in the treatment of Polycystic ovary syndrome (PCOS):

Note: It is no longer recommended for anovulatory infertility in women with PCOS.

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Off label use as an alternative treatment agent in patients with oligomenorrhea due to PCOS:

• Immediate-release:

  • 1.5 – 2 g orally daily in 2 – 3 divided doses to minimize gastrointestinal adverse effects.
  • The dose should be initiated with 500 mg once or twice daily and gradually increased at weekly intervals by 500 mg.

Note: Until regular cycles are established, cyclic progestin therapy may be added for the first 6 months of metformin treatment.

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Off label use in the prevention of Ovarian hyperstimulation syndrome due to in vitro fertilization or intracytoplasmic sperm injection in women with PCOS:

• Immediate-release:

  • 1 – 2.55 g orally daily in 2 to 3 divided doses.

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Metformin conversion recommendations:

• • Conversion from immediate-release to extended-release tablets:

    • Patients receiving immediate-release metformin may be switched to extended-release metformin once a day at the same total daily dose, up to 2 gm once a day.

 

Dose in the treatment of type 2 Diabetes mellitus:

Note:

• • A low initial starting dose is recommended by most experts to avoid gastrointestinal side effect.
  • The dose should be gradually titrated upwards at 1 – 2 weeks.
    

    ---

• Immediate-release tablets or solution:

  • Children older than 10 years and Adolescents:
    • 500 – 1,000 mg orally once a day or 500 mg orally twice a day.
    • The dose may be increased the dose every 1 – 2 weeks as tolerated in 500 – 1,000 mg increments to a maximum dose of 1,000 mg twice a day or 850 mg orally thrice daily

• Extended-release tablets:

  • Children older than 10 years and Adolescents:
    • 500 – 1,000 mg orally once a day for 7 – 14 days.
    • The dose may be increased in 500 – 1,000 mg increments every 1 – 2 weeks to a maximum daily dose of 2,000 mg/day.

Dose in the Treatment of Severe Obesity as an adjunct to lifestyle interventions:

The AACE has not recommended its use in the treatment of obesity. A modest reduction in weight ( about 3%) has been observed in studies.

• Immediate-release tablets:

  • Children older than 6 years and Adolescents:
    • 500 mg orally once a day initially
    • The dose should be titrated at weekly intervals by 500 mg/day to the maximum dose of 1000 mg twice daily.

• Extended-release tablets:

  • Metformin XR:
    • 500 mg orally once a day initially with the evening meal for 2 weeks.
    • The dose may be increased to 1,000 mg once a day for 2 weeks, and then 2,000 mg once a day.
    • The dose should be slowly titrated to reduce the gastrointestinal side effects.

 

Pregnancy Risk Factor: B

• • Metformin crosses over the placenta but there have been no adverse fetal outcomes when it is used to treat gestational diabetes mellitus.
  • Hyperglycemia can lead to adverse outcomes for fetal health. Glycated hemoglobin should be maintained as close as possible to the target without causing hypoglycemia.
  • Insulin has been the most popular treatment for patients suffering from gestational diabetes mellitus.

Metformin use during breastfeeding:

• • Breast milk contains Metformin.
  • Metformin can be used while breastfeeding. Women should encourage breastfeeding during therapy.
  • However, the manufacturer recommends that you weigh the benefits and risks of breastfeeding treatment.

 

 

Metformin dose in Renal disease:

• eGFR of more than 45 mL/minute/1.73 m²:

  • Dose adjustment is not required.
  • Renal functions should be monitored periodically.
  • Annual monitoring may be sufficient, however, individuals with an eGFR of 45 – 60 ml/min/1.73m², more frequent monitoring should be done (every 3 – 6 months).
  • The dose should also not exceed in patients with an eGFR of 45 – 60 ml/min/1.73 m².

• eGFR of 30 – 45 mL/minute/1.73 m² :

  • • Patients with an existing impairment:

      • If there are no other risk factors, such as heart failure or dehydration, it may be used in low dosages.
      • You should start slowly and increase the dose gradually until you reach a maximum of 1 gm/day.

    • Therapy: eGFR should be between 30 and 45 mL/minute/1.73m2:

      • It is important to weigh the risks and benefits of therapy.
      • To achieve a maximum daily dose of 1 gm, the dose should be decreased by 50%
      • At least once every three months, it is important to monitor the function of your kidneys.

• eGFR of less than 30 mL/minute/1.73 m² :

  • Its use is contraindicated.

 

Due to the risk of lactic acidosis, metformin should be avoided in patients with moderate or severe liver disease.

Lactic acidosis is more common in patients with concomitant renal or heart disease, as well as alcoholics.

It may also be associated with survival benefits in mild hepatic dysfunction.

 

Common Side Effects of Metformin Include:

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Vomiting
  • Flatulence

• Infection:

  • Infection

Less Common Side Effects Of Metformin Include:

• Cardiovascular:

  • Chest Discomfort
  • Flushing
  • Palpitations

• Central Nervous System:

  • Headache
  • Chills
  • Dizziness
  • Taste Disorder

• Dermatologic:

  • Diaphoresis
  • Nail Disease
  • Skin Rash

• Endocrine & Metabolic:

  • Decreased Vitamin B Serum Concentrate
  • Hypoglycemia

• Gastrointestinal:

  • Nausea
  • Dyspepsia
  • Abdominal Distress
  • Abdominal Pain
  • Abdominal Distention
  • Abnormal Stools
  • Constipation
  • Heartburn

• Neuromuscular & Skeletal:

  • Weakness
  • Myalgia

• Respiratory:

  • Rhinitis
  • Dyspnea
  • Flu-Like Symptoms
  • Upper Respiratory Tract Infection

• Miscellaneous:

  • Accidental Injury

 

Contraindication to Metformin Include:

• Allergic reactions to metformin or any component of the formulation.
• Severe renal dysfunction with an eGFR of less than 30 mL/minute/1.73 m²
• Acute or chronic metabolic acidosis including diabetic ketoacidosis.
• Cardiogenic shock
• Acute myocardial infarction
• Sepsis
• Type 1 Diabetes Mellitus or unstable insulin-dependent diabetes mellitus.
• History of lactic acidosis
• Excessive alcohol intake
• Severe/ advanced liver disease
• Diseases associated with hypoxemia
• Stress conditions like severe infection, trauma, and surgery
• Severe dehydration
• Pregnancy
• Breastfeeding

Warnings & Precautions

·         Lactic acidosis: [US Boxed Warning]:

• • Metformin-induced lactic acidosis can be life-threatening. It can cause death, hypothermia and hypotension, as well as cardiac bradyarrhythmias.
  • Non-specific symptoms of lactic acidosis include malaise, myalgias and somnolence.
  • It is characterised by high blood lactate levels (more that 5 mmol/L), anion gaps metabolic acidosis and increased lactate:pyruvate ratio. Plasma metformin levels are more than 5 mg/ml.
  • These patients are at high risk for developing lactic acidosis:
    • Patients with severe renal impairment
    • Use of other drugs, such as topiramate or Acetazolamide, in conjunction with certain drugs
    • Over 65
    • Radiocontrast study of patients
    • Major surgeries and diagnostic procedures are performed on patients undergoing major surgery.
    • Hypoxic states, such as heart failure, can be hypoxic.
    • Hepatic impairment
    • Alcohol intake that is excessive
  • Patients with lactic acidosis must stop treatment immediately. They may need hemodialysis.

·         Vitamin B – 12 concentrations:

• • Metformin long-term use is linked to vitamin B-12 deficiency.
  • Patients with anemia or peripheral neuropathy should have their serum levels of vitamin A 12 levels monitored regularly.

·         Heart failure:

• • Patients suffering from unstable heart failure may be at high risk for lactic acidosis secondary hypoperfusion.
  • It can be used for patients with stable heart disease and associated with reduced hospital admissions and mortality.

·         Hepatic impairment:

• • Metformin may be recommended for patients with mild to moderate liver dysfunction. However, individuals with advanced liver disease or unstable liver function may need to be careful.
  • Patients with advanced liver disease should avoid it.

·         Renal impairment:

• • Metformin is excreted through the kidneys.
  • Before initiating treatment, patients should have their renal function checked and again periodically thereafter.
  • Patients with a lower eGFR than 30 ml/min/1.73m2 should not use it.
  • Patients with an eGFR of 30 to 45 ml/min or less should have their dose reduced.
  • Patients suffering from acute renal dysfunction or dehydration should not use it.

·         Stress-related states:

• • Patients suffering from acute stress such as trauma, fever, infection, or surgery should not use insulin. Instead, they should be prescribed insulin.

 

 

Metformin: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)
Abemaciclib	May increase the serum concentration of MetFORMIN.
Alpha-Lipoic Acid	May enhance the hypoglycemic effect of Antidiabetic Agents.
Androgens	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol.
Bictegravir	May increase the serum concentration of MetFORMIN.
Carbonic Anhydrase Inhibitors	May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Exceptions: Brinzolamide; Dorzolamide.
Cephalexin	May increase the serum concentration of MetFORMIN.
Dalfampridine	MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN.
Direct Acting Antiviral Agents (HCV)	May enhance the hypoglycemic effect of Antidiabetic Agents.
Dofetilide	MetFORMIN may increase the serum concentration of Dofetilide.
Glycopyrrolate (Systemic)	May increase the serum concentration of MetFORMIN.
Guanethidine	May enhance the hypoglycemic effect of Antidiabetic Agents.
Hyperglycemia-Associated Agents	May diminish the therapeutic effect of Antidiabetic Agents.
Hypoglycemia-Associated Agents	Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents.
Isavuconazonium Sulfate	May increase the serum concentration of MetFORMIN.
LamoTRIgine	May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended.
Maitake	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Monoamine Oxidase Inhibitors	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Ombitasvir, Paritaprevir, and Ritonavir	May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased.
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir	May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased.
Ondansetron	May increase the serum concentration of MetFORMIN.
Pegvisomant	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Prothionamide	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Quinolones	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use.
Ritodrine	May diminish the therapeutic effect of Antidiabetic Agents.
Salicylates	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Selective Serotonin Reuptake Inhibitors	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Thiazide and Thiazide-Like Diuretics	May diminish the therapeutic effect of Antidiabetic Agents.
Topiramate	May enhance the adverse/toxic effect of MetFORMIN.
Trimethoprim	May increase the serum concentration of MetFORMIN.
Trospium	MetFORMIN may decrease the serum concentration of Trospium.
Vandetanib	May increase the serum concentration of MetFORMIN.
Verapamil	May diminish the therapeutic effect of MetFORMIN.
Risk Factor D (Consider therapy modification)
Cimetidine	May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis).
Dolutegravir	May increase the serum concentration of MetFORMIN. Management: Limit the daily metformin dose to 1,000 mg when used with dolutegravir. Monitor for increased metformin effects/toxicities during concomitant use.
Iodinated Contrast Agents	May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Exceptions: Diatrizoate Meglumine; Diatrizoate Sodium; Ethiodized Oil.
Patiromer	May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer.
Ranolazine	May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1700 mg/day when used together with ranolazine 1000 mg twice daily.
Tafenoquine	May increase the serum concentration of MATE1 Substrates. Management: Avoid use of MATE substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the MATE substrate and consider a reduced dose of the MATE substrate according to that substrate’s labeling.
Tafenoquine	May increase the serum concentration of OCT2 Substrates. Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate’s labeling.
Risk Factor X (Avoid combination)
Alcohol (Ethyl)	May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis

 

How to administer Metformin?

To reduce gastrointestinal side effects, it is taken orally along with food.

Extended-release tablets must be taken whole. You should not chew, crush, or chew the extended-release tablets.

 

Mechanism of action of Metformin:

Metformin improves the glycemic control of patients with type 2 Diabetes Mellitus through the following mechanisms:

• • It reduces the production of hepatic glucose.
  • It decreases glucose absorption from the intestines.
  • Metformin increases insulin sensitivity by increasing glucose uptake in peripheral tissues.

W is the moment of the onset of action.It can take up to two weeks. Maximum effect can last up to 2 weeks. The drug is bound to proteins in very small quantities.

It has been abioavailabilityFasting state: 50% to 60%, and it is not metabolized by the liver.

It has been aEliminating half-lifeThe plasma is kept for between 4 and 9 hours, and blood for 17.6 hours. TheTime to achieve peak serum concentrationThe immediate-release tablet lasts 2 – 3 hours, while the extended-release tablet takes 7 hours. This ranges from 4 – 8 hours.

90% of the drug’s ingredients are natural.ExcretedIn the urine as an unchanged drug

 

International Brands:

• ACT MetFORMIN
• APO-MetFORMIN
• APO-MetFORMIN ER
• Auro-Metformin
• DOM-MetFORMIN
• ECL-MetFORMIN
• Glucophage
• Glumetza
• Glycon
• JAMP-MetFORMIN
• JAMP-MetFORMIN Blackberry
• Mar-MetFORMIN
• MetFORMIN FC
• MINT-MetFORMIN
• MYLAN-MetFORMIN
• PHL-MetFORMIN
• PMS-MetFORMIN
• PRO-MetFORMIN
• Q-MetFORMIN
• RAN-MetFORMIN
• RATIO-MetFORMIN
• RIVA-MetFORMIN
• SANDOZ MetFORMIN FC
• Septa-MetFORMIN
• TEVA-MetFORMIN
• Adecco
• Alexodiab
• Amophage
• Ansures
• Bentic
• Biguax
• Dabex
• Dainipron
• Deson
• DH-Metglu 850
• DH-Metglu XR 1000
• Diabemet
• Diabetmin
• Diabetmin Retard
• Diabetmin XR
• Diabetol
• Diabex XR
• Diafat
• Diaformin
• Diaformin XR
• Diaformina LP
• Dialon
• Diamet
• Dianben
• Diaslim
• Diformin
• Diformin Retard
• Dimefor
• Dimet
• Euform Retard
• Fordica 500 XR
• Formet
• Formin
• Formit
• Fornidd
• Glafornil
• Glibudon
• Glicenex
• Glicophage
• Glifage
• Gliformin
• Glikos
• Glisulin XR
• Gluciophage XR
• Gluco
• Glucodown
• Glucofage
• Glucofor
• Glucoform
• Glucogen
• Glucoles
• Glucomet
• Glucomin
• Glucomine
• Glucon
• Glucophage
• Glucophage Forte
• Glucophage Retard
• Glucophage SR
• Glucophage XR
• Glucophage-Mite
• Glucotika
• Glucotin
• Glufor
• Glumet
• Glumet DC
• Glumet Forte
• Glumet XR
• Glumin XR
• Glunor
• Glupa
• Glustress
• Glutamet
• Glutomin
• Glycomet
• Glycomin
• Glyformin
• Glymet
• Guamet
• Heskopaq
• Humamet
• Humamet XR
• I-Max
• Indform
• Insufor
• Insumed
• Islotin
• Lucomet
• Maformin
• Medfort
• Mefarmil
• Meglucon
• Melbin
• Merckformin
• Mescorit
• Metchek
• Metdia
• Metex XR
• Metfar
• Metfin
• Metfogamma
• Metfor
• Metfor XR
• Metforal
• Metformax
• Metgluco
• Metgreen-SR
• Metophage
• Metta SR
• Neoform
• Normax
• Omformin
• Orabet
• Panfor SR
• Quexel
• Risidon
• Siamformet
• Siofor
• Stagid
• Sukkarto SR
• Thiabet
• Walaphage
• Xmet
• Yaltormin

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