Metformin long prolonged release film-coated tablets 850 mg and 1000 mg

Metformin long prolonged release film-coated tablets 850 mg and 1000 mg

International nonproprietary name

Metformin

Pharmacological group

Гипогликемические средства

Composition

Active substance:

Metformin hydrochloride
(equivalent to 100% substance)                                - 850 mg        - 1000 mg
Excipients of the core:
povidone (К 30)                                                         - 120 mg         - 140 mg
hypromellose                                                             - 160.8 mg      - 187.6 mg
calcium stearate                                                        - 12 mg           - 14 mg
lactose monohydrate (lactobiose)                             - 57.2 mg        - 58.4 mg
Excipients of the coating:
opadry® II blue,                                                         - 35 mg           - 40 mg
including:
lactose monohydrate                                                             - 40 %                    
hypromellose(hydroxypropylmethyl cellulose 2910)             - 28 %                                
titanium dioxide                                                                     - 22.78 %
triacetin                                                                                 - 8 %
brilliant blue dye FCF, Е 133, aluminum lake                       - 0.98 %
black ferric oxide dye, Е 172                                                - 0.22 %
yellow ferric oxide dye, Е 172                                               - 0.02 %

Pharmacological action

Metformin is a biguanide with a hypoglycemic effect, which reduces both basal and postprandial glucose levels in blood plasma. It does not stimulate secretion of insulin and therefore does not cause hypoglycemia. The drug increases sensitivity of peripheral receptors to insulin and utilization of glucose by cells. Metformin reduces production of glucose by the liver by inhibiting gluconeogenesis and glycogenolysis. The drug delays absorption of glucose in the intestine. Metformin stimulates the synthesis of glycogen, affecting glycogen synthase. The drug increases the transport capacity of all types of glucose transporters. After administration of metformin the patient's body weight either remains stable or moderately decreases.
Metformin has a beneficial effect on lipid metabolism: it reduces the content of total cholesterol, low-density lipoproteins and triglycerides.

Pharmacokinetics

Absorption

The average time to the maximum plasma concentration of metformin after meals is 2.5 hours after single oral administration of 1 tablet 850 mg and 5 hours after single oral administration of 1 tablet at dose 1000 mg (within the range from 4 to 10 hours).
In an equilibrium state identical to the equilibrium state of metformin with conventional release, the maximum concentration and area under the concentration-time curve increase in proportion to the administered dose. After single oral administration of metformin in the form of prolonged-release tablets at a dose of 2000 mg, the area under the concentration-time curve is similar to that observed after ingestion of metformin in the form of tablets with the conventional release at dose 1000 mg twice per day.
The intra-individual variability of the maximum concentration and area under the "concentration-time" curve after administration of metformin in the form of prolonged-release tablets is similar to that observed after administration of metformin in the form of tablets with conventional release.
After administration of metformin in the form of prolonged-release tablets at dose 1000 mg after meals, the area under the concentration-time curve increases by 77% (the maximum concentration increases by 26% and the average time to the maximum plasma concentration of metformin increases by approximately 1 hour).
Absorption of metformin from the prolonged-release tablets does not depend on the composition of the food taken.
Repeated administration of metformin in the form of prolonged-release tablets at dose 2000 mg does not cause accumulation.
Distribution
Binding with the plasma proteins is insignificant. The maximum concentration in the blood is less than the maximum plasma concentration and is achieved approximately after the same time. The average volume of distribution ranges from 63 to 276 liters.
Metabolism
Metabolites in humans were not found.
Recovery
Metformin is excreted unchanged by the kidneys. The renal clearance of metformin is more than 400 ml/min, which indicates that metformin is excreted due to the renal blood flow and tubular secretion. After oral administration, the elimination half-life is about 6.5 hours.
In patients with renal dysfunction, the clearance of metformin decreases in proportion to the creatinine clearance, the half-life increases increasing the plasma concentration of metformin.

Indications for Use

Diabetes mellitus type 2 in adults, especially in patients with obesity, when diet and exercises are ineffective:
- as a monotherapy;
- in combination with other oral hypoglycemic agents or insulin.

Contraindications

·         increased sensation to metformin or to any excipients;
·         diabetic ketoacidosis, diabetic precoma, coma;
·         renal failure (creatinine clearance less than 45 ml/min);
·       acute conditions with the risk of renal dysfunction: dehydration (with chronic or severe diarrhea, repeated attacks of vomiting), severe infectious diseases (for example, respiratory infections, urinary tract infections), shock;
·         significant symptoms of acute or chronic diseases causing tissue hypoxia (including cardiac or respiratory failure, acute myocardial infarction);
·         extensive surgery and trauma, when insulin therapy is administered (see section "Precautions");
·         hepatic failure, liver dysfunction;
·         chronic alcoholism, acute alcohol poisoning;
·         pregnancy;
·         lactoacidosis (including in the past medical history);
·      administration within less than 48 hours before and within 48 hours after radioisotope or X-ray examinations with introduction of iodine-containing contrast medium (for example intravenous urography, angiography) (see section "Interaction with other drugs");
·         hypocaloric diet (less than 1000 kcal/day);
·         lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
·         children under 18 years old due to the lack of clinical data about administration.
With care
Administer the drug:
in persons over 60 years old performing heavy physical work, which is associated with increased risk of lactic acidosis;
in patients with renal failure (creatinine clearance 45 - 59 ml/min);
during lactation period.
Administration during pregnancy and lactation period
Decompensated diabetes mellitus during pregnancy is associated with increased risk of congenital malformations and perinatal mortality.
Limited data suggests that administration of metformin in pregnant women does not increase the risk of congenital malformations in children.
When planning pregnancy, as well as in case of pregnancy during the period of administration of metformin, the drug shall be withdrawn and replaced by insulin therapy . Maintain the level of glucose in the blood plasma at the level closest to the norm in order to reduce the risk of fetal malformations.
Metformin penetrates into the breast milk. Adverse effects in infants breastfed by mothers receiving metformin were not observed. However, due to the limited data, administration of the drug during breastfeeding is not recommended. Discontinuation of breastfeeding shall be considered based on the benefits of breastfeeding and the potential risk of adverse effects in the infant.

 

Cautions

Lactic acidosis

Lactic acidosis is rare but serious (high mortality in case of lack of  emergency treatment) complication, which can be caused by cumulation of metformin. Cases of lactic acidosis caused by administration of metformin were developed mainly in patients with diabetes mellitus with severe renal failure.
Other associated risk factors, such as decompensated diabetes mellitus, ketosis, prolonged fasting, alcoholism, liver failure and any condition associated with severe hypoxia, shall be considered. This can help to reduce the incidence of lactic acidosis.
The risk of lactic acidosis in case of nonspecific signs appear, such as muscle cramps associated with dyspeptic disorders, abdominal pain and severe asthenia shall be considered.
Lactoacidosis is characterized by severe malaise with general weakness, acidotic dyspnea, vomiting, abdominal pain, muscle cramps and hypothermia followed by coma. Diagnostic laboratory indicators include decreased blood pH (less than 7.25), the plasma concentration of lactate exceeding 5 mmol/l, increased anion gap and the lactate / pyruvate ratio. In case of suspected lactic acidosis, discontinue administration of the drug and consult a doctor immediately.
Surgical operations
Administration of metformin shall be discontinued 48 hours before planned surgery and can be continued no earlier than 48 hours after it, provided that during the examination the renal function is consifdered as normal.
Kidney function
Since metformin is excreted by the kidneys, before starting the treatment and regularly later on, creatinine clearance shall be determined: at least once per year in patients with normal renal function and 2 - 4 times per year in elderly patients, as well as in patients with creatinine clearance at the lower limit.
Special care shall be taken in cases of possible renal dysfunction in elderly patients in case of simultaneous administration of antihypertensive drugs, diuretics or non-steroidal anti-inflammatory drugs.
Other precautions
Patients are recommended to continue keeping a diet with even intake of carbohydrates throughout the day. Patients with excessive body weight shall continue keeping hypocaloric diet (but not less than 1000 kcal/day). Patients shall also exercise regularly.
Patients shall inform a physician about any ongoing treatment and any infectious diseases such as a cold, an infection of the respiratory tract or the urinary tract infection.
Regular laboratory testing is recommended to be conducted on a regular basis to control diabetes mellitus.
Metformin does not cause hypoglycemia in patients with monotherapy, but care shall be taken for administration in combination with insulin or other oral hypoglycemic agents (for example, sulfonylureas or repaglinide derivatives, etc.).
Symptoms of hypoglycemia include weakness, headache, dizziness, increased sweating, heart palpitations, impaired vision or impaired concentration of attention.
The patient shall be warned that inactive components of the drug Metformin Long can be excreted unchanged through the intestine, which does not affect the therapeutic activity of the drug.
Effects on ability to drive and use machines
Monotherapy with the drug Metformin Long does not cause hypoglycemia, therefore does not affect the ability to drive vehicles and mechanisms.
Nevertheless, hypoglycemia can develop after administration of metformin in combination with other hypoglycemic drugs (sulfonylureas, insulin, repaglinide, etc.). In case of symptoms of hypoglycemia avoid driving vehicles and mechanisms.

Dosing and Administration

For oral administration.
Tablets are swallowed in a whole, without chewing, with enough liquid amount, once per day during or after dinner.
The dose of the drug is set by the doctor on an individual basis for each patient based on the results of measuring the concentration of glucose in the blood.
Monotherapy and combined therapy together with other hypoglycemic agents
Recommended dose:
- 1000 mg tablets - 1 tablet (1000 mg) once per day during or after dinner.
-850 mg tablets - 2 tablets (1700 mg) once per day.
If the recommended dose does not allow achieving adequate glycemic control, the dose can be increased up to the maximum dose.
Maximum recommended dose:
- 850 mg tablets - 3 tablets once per day (2550 mg);
- 1000 mg tablets - 2 tablets once per day (2000 mg).
If the maximum recommended dose once per day can not be adequately controlled glycemia, the maximum dose (for Metformin Long 1000 mg) can be divided into two administrations: one tablet 1000 mg - at breakfast and one tablet 1000 mg - at dinner time. If adequate glycemic monitoring is not achieved, and in this case transition to normal release metformin with  maximum daily dose 3000 mg is possible.
For patients who do not receive metformin, the recommended initial dose of prolonged action metformin is 500 mg (similar drugs are available at this dosage) or 850 mg of Metformin Long once per day during dinner. Every 10 -15 days, it is recommended to adjust the dose based on the results of measuring the concentration of glucose in the blood. Slow dose increase contributes to better tolerability of the gastrointestinal tract.
In case of transition from another hypoglycemic agent, the dose shall be selected as described above, starting from administration of prolonged release metformin at dose 500 mg (similar drugs are available at this dose) or 850 mg of the drug Metformin Long with possible subsequent transition to the drug Metformin Long at dose 1000 mg .
The drug Metformin Long is administered as a suppoting therapy for patients receiving metformin in the form of normal release tablets at dose 1000 mg or 2000 mg. To switch to a prolonged release drug, the daily dose shall be equivalent to the daily dose of normal release metformin.
For patients receiving metformin in the form of normal release tablets at dose exceeding 2000 mg transition to Metformin Long is not recommended.
Combination with insulin
To achieve better glycemic control, metformin and insulin can be used as a combined therapy. The usual initial dose of prolonged release metformin is 500 mg (similar drugs are available at this dose) or 850 mg of Metformin Long once per day during dinner, while the insulin dose is selected based on the results of measuring the blood glucose concentration. Further, replacement by Metformin Long at dose 1000 mg is possible.
Patients with renal failure:
Metformin can be administered in patients with moderate renal failure (creatinine clearance 45 - 59 ml/min) only in the absence of conditions that can increase the risk of lactic acidosis.
The initial dose of prolonged action metformin is 500 mg (similar drugs are available at this dosage) or 850 mg of Metformin Long once per day during dinner. The maximum dose is 1000 mg per day.
The renal function should be carefully monitored every 3 to 6 months.
If the creatinine clearance is less than 45 ml/min, the drug shall be immediately withdrawn.
Elderly patients
In elderly patients the dose shall be adjusted based on the renal function assessment, which shall be performed on a regular basis (see "Precautions").
Duration of the treatment
Metformin Long shall be administered on a daily basis, without interruption. In case of discontinuation of the treatment, the patient shall inform the physician about this.
Dose missing
In case of missed next dose, the patient shall take the next dose at the usual time. Do not administer a double dose of Metformin Long.

Side effect

The frequency of adverse effects of the drug is classified as follows:

Very common: ≥ 1/10
Common (frequent): ≥ 1/100, < 1/10
Uncommon (infrequent): ≥ 1/1000, < 1/100
Rare: ≥ 1/10,000, < 1/1000
Very rare: < 1/10 000
Adverse metabolism and digestive  effects: very rare - lactic acidosis (see "Precautions").
Long-term administration of metformin can decrease absorption of vitamin B12. In case of diagnosed megaloblastic anemia,consider the possibility of such etiology.
Adverse nervous system effects:: common (frequent) - taste disorders (metallic taste in the mouth).
Adverse gastrointestinal effects: very common - nausea, vomiting, diarrhea, abdominal pain and lack of appetite. Most often they occur during the initial period of treatment and in most cases pass spontaneously. To prevent symptoms, it is recommended to administer metformin during or after a meal. Slow dose increase may improve gastrointestinal tolerance.
Adverse liver and biliary tract effects: very rare: liver dysfunction and hepatitis; after withdrawal of metformin, these adverse events disappearcompletely.
Adverse skin and subdermal tissue effects: very rare - skin reactions such as erythema (redness of the skin), itching, rash.
If any of the adverse effects listed in the patient information leaflet are aggravated, or in case of any other adverse effects not listed in the leaflet, inform immediately your doctor.
 
Overdose
Administration of metformin at dose 85 g (42.5 times maximum daily dose) does not cause development of hypoglycemia observed. However, lactoacidosis was observed in this case. Significant overdose or associated risk factors can cause lactic acidosis (see "Precautions").
Treatment: in case of signs of lactic acidosis the treatment with the drug shall be discontinued immediately, the patient shall be urgently hospitalized and, after determination of the lactate content, clarify the diagnosis. The most effective measure for elimination of lactate and metformin from the body is hemodialysis. Expectant treatment is also conducted.

Interaction with other medicines

 

Condradicted combinations
Iodine-containing radiopaque means in patients with functional renal failure associated with diabetes mellitus, a radiological examination using iodine-containing radiocontrast agents can cause lactic acidosis.
The treatment with Metformin Long shall be terminated based on the renal function 48 hours prior to or at the time of radiologic examination using iodine-containing radiopaque means and renewed no earlier than 48 hours after, provided that during the examination the renal function was found to be normal.
Unrecommended combinations
Alcohol: acute alcohol intoxication increases the risk of lactic acidosis, especially in case of malnutrition, low-calorie diet; hepatic failure.
During the treatment with the drug avoid drinking alcohol and administering the drugs containing ethanol.
Combinations requiring caution
The drugs with indirect hyperglycemic effect (for example, glucocorticosteroids and tetracosactides (systemic and topical), β2-adreno-mimetics, danazol, chlorpromazine administered at high doses (100 mg per day) and diuretics can require more frequent monitoring of glucose concentration in the blood, especially at the beginning of the treatment. If required, the dose of the drug Metformin Long can be adjusted during the treatment and after its termination, based on the level of glycemia.
Diuretics: simultaneous administration of loop diuretics can cause lactic acidosis because of possible functional renal failure. Do not administer Metformin Long if the creatinine clearance is less than 60 mL/min.
Simultaneous administration of the drug Metformin Long with derivatives of sulfonylurea, insulin, acarbose, salicylates can cause hypoglycemia.
Nifedipine increases absorption and maximum concentration of metformin.
Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) secreted in the renal tubules compete with metformin over the tubular transport systems and can increase its maximum concentration.
Combined administration of prolonged release metformin with kolesevelam can increase the level of metformin in the blood, at the same time dose correction or more stringent control of blood sugar levels for safe administration of both drugs. Immediately consult a doctor in case of worsens condition or adverse effects, such as nausea, vomiting, diarrhea, flatulence, dyspepsia. Immediately consult a doctor in case of developing weakness, muscle pain, chills, increased somnolency, abdominal pain or discomfort, slow or irregular heartbeats, shortness of breath and other unusual symptoms, as these may be early signs of such rare but serious adverse effect of metformin, as lactic acidosis.

Form release

Storage conditions

In a dry and dark place at temperature maximum 25 °С.

Expiration date

2 years