Drug Interaction:
Interacting drugs - Sulfonyl ureas - summary
Metformin +
Gluburide (Glibenclamide)
Following coadministration of single doses, decrease in glyburide
AUC and Cmax were observed. Clinical significance uncertain
+Metformin
Alcohol
Alcohol potentiates the effect of metformin on lactate metabolism.
Warn patients against excessive alcohol intake.while receiving metaformin.
Cationic drugs
Cationic drugs( eg amiloride, digoxin, morphine, procainamide,
quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin)
eliminated by renal tubular secretion, have the potential for interaction with
metformin. dose adjustment of metformin is recommended
Cimetidine
Cimetidine caused a 60% increase in peak metformin plasma and
whole blood concentrations and a 40% increase in plasma and
whole blood AUC
Furosemide + Metformin
Furosemide increased the metformin plasma and blood Cmax and
blood AUC , without any significant change in metformin renal
Metformin + Furosemide
When administered with metformin, the Cmax and AUC of
furosemide were smaller than administered alone, and the terminal
half-life decreased, without any significant change in furosemide
renal clearance.
Iodinated contrast media
Parentral contrast studies with iodinated materials can lead to
acute renal failure with lactic acidosis in patients receiving metformin
. Therefore withhold metformin for at least 48 hours prior to procedure
Nifedipine
Co-administration increased plasma metformin Cmax and AUC
respy, and increased the amount excreted in the urine. Nifedipine
enhance the absorption of metformin
Indication:
U.S FDA APPROVED DRUGS FROM 01-01-08 TO 31-12-08
Drug name Indication Date of Approval
32. Metformin HCL ER 500mg 25-01-08
+ Fenofibrate 80mg /160mg tablet)
For the treatment of Type II diabetes associated
with mixed dyslipdemia
Metformin ER Tablets 750mg (Additional Strength)
Indication-
As an adjunct to diet and excercise to improve glycemic control in adult with
Type II Diabetes
Approved by FDA on 25-09-2014 (Ref- FDA approved List- 2014)
Non-insulin-dependent diabetes mellitus)NIDDM).
Patent Expiry Date of drugs (Ref - IDMA Publication)
Chemical Category Manufacturer/ US Patent
Ingredient- Marketer Expiration Date
Metformin Diabetes Bristol-Myers Squibb 03-09-2000
Approved by (DCI) Drug Controller GENERAL - India For Marketing
(Ref- IDMA Publication)
Name of Drug Indication Date of Approval
1.Metformin Er 1000mg/500mg 19-09-2011
+ Saxagliptin 2.5mg/5mg tablets
As an adjunct to diet and excercise to improve glycemic control in
patients with Type 2 Diabetes mellitus when treatment with Metformin
and Saxagliptin is in appropiate
2.Metformin ER Tablet 750mg 25-09-14
(addl.Stgth.)
As an adjunct to diet and excercise to improve glycemic control
in adult with patients with Type II diabetes
3.Metformin 500/500mg 20.08-2010
+ Repaglinide 1/2mg
Indicated as an adjunct to diet and excercise to improve glycemic
control in adults with Type II Diabetes Mellitus who are already treated
with Meglotinide & Metformin or who have inadequate glycemic control on
Meglotinide alone or Metformin
4.Metformin 500/850/1000mg 02-08-2010
+ Sitagliptin Phosphate 50/50/50mg
(Addl.Indcn.)
i.FDC is indicated as triple Combination Therapy with a PPARY agonist
(i.e. A thiazolidionone ) as an adjunct to diet and excecise in patients
inadequately controlled on their maximal tolerated dose of Metformin
and a PPARY agonist
ii. FDC is also indicated as an add on to insulin (i.e. triple combination
therapy ) as an adjunct to diet and excercise to improve glycemic
control in patients with stable dosage of Insulin and Metformin alone
do not provide adequate control.
5.Metformin HCL ER 500mg 25-01-2008
+ Fenofibrate 80mg/160mg tablet
For the treatment of Type II Diabetes Associated with mixed Dyslipdemia
6.Metformin HCL IP 500mg 05-01-2011
+Alpha Lipoic acid
USP 200mg tablet
For the treatment of Patients with Diabetic Polyneuropathy
7.Metformin SR 500mg/500mg 28-05-2010
+ Gliclazide SR 60mg/30mg
+ Pioglitazone 15mg/15mg tablets
As 3rd line treatment of Type II Diabetes Mellitus when Diet, excercise
and single agents and second line therapy with two drugs do not result
in adequate Glycemic control
FIXED DOSE COMBINATIONS APPROVED BY DCG(I)
FROM JANUARY 1961 TILL NOVEMBER 2014
Name of Drug Indication Date of Approval
1.Metformin 500mg CR + 17-12-2003
Glipizide 5mg CR tablet
2.Metformin Hcl 500mg/850mg/1000mg + 22-10-2013
Vidalgliptin 50mg/50mg/50mg film coated tablet
For the treatment of type 2 Diabetes Mellitus having
HbA 1c >8% where diabetes is not adequately
controlled by diet and excercise alone
3.Metformin Hcl 850mg + 15-12-2009
Sitalgliptin Phosphate 50mg tablet
As an adjunct to diet & excercise to improve glycemic
control in patients with type 2 diabetes mellitus
4. Metformin SR 500mg/500mg + 28-05-2010
Gliclazide SR 60mg/30mg +
Pioglitazone 15mg/15mg tablets
As 3rd line treatment of type II diabetes mellitus when
diet, excrcise, andthe single agents and the second line
therapy with two drugs do not result in adequate glycemic
control
Adverse Reaction:
GI- Most common- diarrhea, nausea, vomiting, abdominal bloating, flatulenceanorexia These symptoms are generally transcient and resolve spontaneously during continued treatment. Occasionally temporary dose reduction may be useful.
Special senses- during initiation of therapy about 3% of patients may complain of an unpleasant or metallic taste, which usually resolves spontaneously.
Hermatologic- monitor serum B12 levels or consider periodic parentral B12 supplementation. Miscellaneous- lactic acidosis.
Contra-Indications:
Diabetic coma,severe ketoacidosis,severe renal or hepatic insufficiency,cardiac failure.
Recent M.I.,alcoholism, conditions associated with hypoxemia.
Special precautuions:
Pregnancy, decompensation, serious infections, trauma, surgery, avoid alcohol.
Monitoring- before initiation of therapy and at least annually thereafter, assess renal function and verify as normal. In patients in whom development of renal dysfunction is anticipated, assess renal function more frequently and discontinue the drug if evidence of renal impairment is absent.
Hypoxic states- cardiovascular collapse (shock) acute CHF, acute Mi and other conditions characterised by hypoxemia have been associated with lactic acidosis and may cause prerenal
azotemia.
Special procedures- temporary suspend metformin for surgical procedures (unless minor and associated with restricted intake of food and fluids) Do not restart until the parients oral intake has resumed and renal function is normal.
Vitamin B12 levels- certain individuals with inadequate Vitamin B12 or calcium intake or absorption appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2 to 3 year interevals may be useful.
Hypoglycemia- hypoglycemia does not occur in patients receiving metformin alone under usual circumstances, but could occur with deficient calorie intake. Elderly, debilated or malnourished patients and those with adrenal or pituitary effects. Hypoglycemia may be difficult to recongnize in the elderly and in people who are taking beta-adrenergic blocking drugs.
Loss of control of blood glucose- when a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur.
At such times it may necesary to with hold metformin and and temporarily administer insulin.
Drug/food interactions- food decreases the extent and slightly delays the absorption of a single 850mg dose of metformin.
Warnings-
Lactic acidosis- lactic acidosis is rare, but serious metabolic complications that can occur due to metabolic accumulation during treatment when it occurs, it is fatal in 50% of the cases. In a patient with lactic acidosis who is taking metformin .discontinue the drug immediately, and promptly institute general supportive measures.
Diet- in initiating treatment for NIDDM emphasise diet as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic ptient.
Glusose control- if after a suitable trial of such tratments, glucose control still has not been acheived , give consideration to the use of Insulin.
Increased risk of cardiovascular mortality- administration of oral antidiabetic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin.
Renal/hepatic function impairment- since impaired hepatic function has been associated with some cases of lactic acidosis, generally avoid metformin in patients with clinical or laboratory evidence of hepatic disease.
Elderly- generally elderly patients should not be titrated with maximum dose of metformin.
Pregnancy- safety in pregnant women has not been established. Balance any decison to use the drug against the benefits and risks.
Lactation- Use with caution and decide whetherto discontinue nursing or discontune the drug taking into account the importance of the drug to the mother.
Children- safety and efficacy inchildrn have not been established.
Dosages/ Overdosage Etc:
Indication-
As an adjunct to diet and excercise to improve glycemic control in adult with
Type II Diabetes
Dosage-
There is no fixed dosage for the management of hyperglycemia in diabetes mellitus with metformin.
Maximum recommended daily dose is 2g . Give individed doses with meals and start at a low dose, with gradual dose escalation
Overdosage-
Symptoms
Hypoglycemia has not been seen even with ingestion of up to 85g of metformin, although lactic acidosis has occured in such circumstances.
Metformin is dialiazable with a clearance of of up to 170ml/min under good hemodynamic conditions
Treatment
1. Hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected
Missed dose-
1. If you miss a dose of this medicine, take it as soon as possible.
2. However, if it is time for your next dose, skip the missed dose and go back to your regular dosing schedule.
3. Do not double doses.
Other Information:
For Availability/supplies
Contact -
1.Indian Drug Manufacturers Association (IDMA)
Phone- 022- 24944624/ 24974308
Fax- 022- 24950723
Email- idma@vsnl.com
Website: www.idma-assn.org
2.Bulk Drug Manufacturers Association (India)(BDMA)
Phone - 040-23703910/ 23706718
Fax- 040-23704804
Email- info@bdmai.org
Website: www.info@bdmai.org
Patient Information:
1. Inform patients of the potentail risks of metformin and of alternative modes of therapy
2. Inform them about the importance of adherence to dietary instructions, of a regular excercise program and regular testing of blood glucose, glycosylated hemoglobin, renal function and hematologic parameters
3. Expain the risk of lactic acidosis, its symptoms, and conditions that predispose to its development.
4. Advice patients to discontinue metformin immediately and to promptly notify their health practioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence,or other nonspecific symptoms occur
5. One a patient is stabilised on metformin, GI symptoms , which are common during initiation of therapy, are likely to be drug related. Later occurance of GI symptoms could be due to lactic acididosis or other serious disease.
6. Counsel patients excessive alcohol intake while receiving metformin
7. Metformin alone dose not usually cause hypoglycemia, although it may occur when metformin is used in conjunction with oral sulfonylureas. When initiating combination therapy, explain the risk of hypoglycemia, its symptoms and treatment, and conditions that predipose to its development
8.Allergies- tell your doctor if you have ever had any unusual or allergic reaction to metformin. Also tell your doctor if you are allergic to any other substances, such as foods, presrvatives or dyes.
9.Pregnancy - metformin has not shown to cause birth defects or problems in humans. However, metformin is not used in pregnancy
10.Breast feeding- metformin passes into breast milk. It has not been shown to cause problems in nursing babies
11.Children - no specific information comparing use of metformin in children with use in other age groups
12. Elderly- if you have blood disorrdeers or kidney problems your doctor may adjust your dose or tell you to stop taking this medicine.
13. Other medicines - Let your doctor know what other medicines you are taking, so that he can advice you accordingly. Alcohol- large amount of alcohol taken in one sitting without any food can increase the effect of metformin. This can keep the blood pressure down for a longer period of time. Amiloride or Calcium channel blockers or Cimetidine or Digoxin or Furosemide or Morphine or Procainamide or Qunidine or Quinine or Ranitidine or Triamterene or Vancomycin - use with metformin may cause high blood levels of metformin which may increase the chance of low blood sugar or side effects
14. Other medical problems - Tell your doctor if you have any other medical problems especially - Acid in blood or Burns or Dehydration or Diabetic coma or Diarrhea or Female hormone changes during pregnancy, puberty etc or High fever or Infection or Injury or Ketones in urine or Mental sress or Overactive adrenal gland or Problems with intestines or Slow stomach emptying or Surgery or Vomiting or Any other condition that causes problems with eating or absorbing food or Any other condition in which blood sugar changes rapidly - metformin in many cases will be replaced by your doctor with insulin , possibly for a short time.
Heart or blood vesel dosorders or Kidney disease or kidney problems or Liver disease - lactic acidosis can occur in these conditions Kidney , heart or other problems requiring medical tests - metformin should be stopped 2 days before medical examination or diagnostic tests that might cause less urine than normal
Overactive thyroid or Under active thyroid - until the thyroid condition is controlled it may change the amount or the type of antidiabetic medicine that you need Underactive adrenal gland or Underactive pituitary gland or Undernourished condition or Weakened physical condition or Any other condition that causes low blood pressure - patients with these conditions are more likely to develop low blood sugar which can affect the dose of metformin you need
11. Missed dose - If you miss a dose of this medicine, take it as soon as possible. however, if it is almost time for the next dose, skip the missed dose. Do not double doses. 12. Storage - Keep out of reach of children. Store away from heat or direct sunlight. Do not store the capsule in bathroom, near the kitchen sink, or in other damp places.
13. Outdated medicines - Do not keep outdated medicine or medicine no longer needed. Be sure that any discarded medicine is out of reach of children.
Pharmacology/ Pharmacokinetics:
Ref- Drug Facts And comparisons(2010)
Pharmacology:
Metformin is an oral antihyperglycemic drug used in the management of non-insulin-dependent diabetes mellitus)NIDDM). It is not chemically or pharmacologically related to the oral sulfonylureas. Metformin improves glucose tolerance in NIDDM subjects.
Pharmacokinetics:
The absolute bioavailability of 500mg metaformin giving under fasting conditions is about 50% to 60%. Food decreases the extent and slightly delays the absorption of metformin.
In a multiple-dose cross over study 23 patients with type 2 diabetes mellites were
administered either Fortamet 2000mg once daily (after dinner ) or metformin 1000mg IR
twice daily (after breakfast and after dinner) .
After 4 weeks treatment steady-state pharmacokinetic parameters , AUC, Tmax, and Cmax were evaluated. Results are presented below-
Fortamet vs Metformin IR Steady-state pharmacokinetic Parameters
at 4 weeks
Phamacokinetic Fortamet Metformim IR
parameters 2000mg 2000mg
(mean (+/- SD) ( Administered (1000mg twice daily)
once daily after
dinner)
AUC 0-24h(ng*h/mL 26811+/- 7055 27371+/- 5781
Tmax (h) 6 (3 to 10) 3 (1 to 8)
Cmax (ng/mL) 2849+/- 797 1829+/- 370
Interaction with Food:
Food decreases the extent and slightly delays the absorption of metformin.
Pregnancy and lactation:
Pregnancy-
Safety in pregnant women has not been established. Balance any decison to use the drug against the benefits and risks.
Lactation-
Use with caution and decide whether to discontinue nursing or discontune the drug takinginto account the importance of the drug to the mother.
Children-
Safety and efficacy in children have not been established.
Manufacturer Details