Rinformin® Long is produced in a special drug form with a delayed release of the active substance for reception once a day, which prevents the appearance of peaks in the concentration of metformin in the blood.
This drug is a prescribed medicine. It can be dispensed on a doctor's prescription only. There are contraindications. Please read the patient information leaflet. Do not use the medicinal agent if it was not prescribed by your treating physician. Always follow the patient information leaflet and your doctor’s recommendations.
Pharmacokinetics
Absorption
After an oral dose of the prolonged release tablet, metformin absorption is significantly delayed compared to the immediate release tablet.
For 500 mg tablet, the average time to peak metformin concentration in blood plasma (TCmax) is 7 hours. While TCmax for immediate release tablet is 2.5 hours.
Following a single oral administration of 1500 mg of Glucophage SR 750 mg, a mean peak plasma concentration of 1193 ng/ml is achieved with a median value of 5 hours and a range of 4 to 12 hours.
At steady state, similar to the immediate release formulation, Cmax and AUC are not proportionally increased to the administered dose. The AUC after a single oral administration of 2000mg of metformin prolonged release tablets is similar to that observed after administration of 1000mg of metformin immediate release tablets twice a day.
Intrasubject variability of Cmax and AUC of metformin prolonged release is comparable to that observed with metformin immediate release tablets.
Mean metformin absorption from the prolonged release formulation is almost not altered by meal composition.
No accumulation is observed after repeated administration of up to 2000mg of metformin as prolonged release tablets.
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean Vd ranged between 63-276 L.
Metformin penetrates into red blood cells. Probably, red blood cells represent a secondary compartment of metformin distribution.
Metabolism
No metabolites have been identified in humans.
Excretion
Metformin is excreted unchanged in the urine. Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
Commercial name Rinformin® Long
International Non-Proprietary Name (INN): metformin
Pharmaceutical form: prolonged release tablets
Composition
1 tablet 500 mg contains:
active ingredient: metformin hydrochloride 500.0 mg;
excipients: hypromellose, carmellose sodium, carbopol, magnesium stearate, pregelatinised starch, colloidal anhydrous silica.
1 tablet 750 mg contains:
active ingredient: metformin hydrochloride 750.0 mg;
excipients: hypromellose, carmellose sodium, carbopol, magnesium stearate, pregelatinised starch, colloidal anhydrous silica.
Description
Oval-shaped white to almost white tablets, mottling on the surface of tablets is allowed. With “g Ph” engraved on one side and “750” engraved on the other side for 750 mg dosage; with “500” engraved on one side for 500 mg dosage.
Pharmacotherapeutic group
Hypoglycaemic agent for oral ingestion of biguanides group.
ATC Code: A10BA02
Pharmacological properties
Pharmacodynamics
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia. Metformin increases insulin sensitivity of peripheral receptors and peripheral glucose uptake and utilisation (especially in muscle tissue). It reduces hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis. Metformin delays intestinal absorption of glucose.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of all types of membrane glucose transporters.
Patient’s body weight either remains stable or decreases moderately when taking metformin.
Metformin has a positive effect on lipid metabolism: it reduces concentration of total cholesterol, LDL cholesterol and triglyceride levels.
Contraindications
- hypersensitivity to metformin or to any of the excipients;
- diabetic ketoacidosis, diabetic pre-coma, coma;
- severe renal failure (GFR < 30 mL/min);
- acute conditions with the potential to alter renal function: dehydration (chronic or severe diarrhea, repeated vomiting), severe infectious diseases (e. g. respiratory infections, urinary tract infections), shock;
- clinically apparent manifestations of acute or chronic diseases which may cause tissue hypoxia (incl. acute heart failure, chronic heart failure with unstable hemodynamic parameters, respiratory failure, acute myocardial infarction);
- major surgeries and injuries where insulin therapy is indicated (see “Special precautions”);
- hepatic insufficiency, hepatic impairment;
- alcoholism, acute alcohol intoxication;
- pregnancy;
- lactic acidosis (including medical history);
- use less than 48 hours before and within 48 hours after radioisotope or radiological studies with the administration of iodine-containing contrast agent (e. g. intravenous urography, angiography) (see “Interaction with other medicinal products”);
- adherence to a hypocaloric diet (less than 1,000 kcal/day);
- children under 18 years old due to lack of data on the use.
- by patients over 60 years old involved in intense physical work, which is associated with an increased risk of lactic acidosis progression;
- by patients with renal insufficiency (GFR 45 - 59 mL/min);
- by lactating women.
Administer with special care
The drug shall be taken with caution:
Use during pregnancy and lactation
Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality.
A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities.
When planning to become pregnant and during pregnancy, it is recommended that impaired glycaemic control or diabetes are not treated with metformin. For diabetes it is recommended that insulin should be used to maintain blood glucose levels as close to normal as possible to reduce the risk of malformations of the foetus.
Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment. A decision on whether to discontinue breast-feeding should be made, taking into account the benefit of breast-feeding and the potential risk to adverse effect on the child.
Method of administration and dosages
Prolonged release tablets of Rinformin® Long should be administered per os. Tablets shall be swallowed whole, without chewing, with a small amount of liquid, once a day with supper. Rinformin® Long should be adjusted on the basis of blood glucose measurements on an individual basis for each patient.
Monotherapy and combination with other oral antidiabetic agents
Rinformin® Long, prolonged release tablets, 500 mg
For naive patients, recommended starting dose of Rinformin® Long is 500 mg once daily with the evening meal.
Depending on the blood plasma glucose concentration slow dose increase (by 500 mg) every 10–15 days is allowed to reach the maximum daily dose (2,000 mg). Slow dose increase contributes to mitigation of side effects in the gastrointestinal tract.
In patients already treated with metformin tablets, starting dose of Rinformin® Long shall be equivalent to a daily dose of immediate release tablets.
Patients taking immediate release tablets of metformin in a dose above 2,000 mg are not recommended to switch to Rinformin® Long.
Rinformin® Long, prolonged release tablets, 750 mg
For naive patients, recommended starting dose of Rinformin® Long is 750 mg once daily with the evening meal.
After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastro-intestinal tolerability.
The recommended dose of Rinformin® Long is 2 tablets of 750 mg once daily. If the recommended dose does not help to reach an adequate glycaemic control, it is allowed to increase the dose to the maximum – 3 tablets of 750 mg once a day.
In patients already treated with metformin tablets, starting dose of Rinformin® Long shall be equivalent to a daily dose of immediate release tablets.
Patients taking immediate release tablets of metformin in a dose above 2,000 mg are not recommended to switch to Rinformin® Long.
In order to switch from any other hypoglycaemic agent patients should discontinue taking that agent and start taking Rinformin® Long as mentioned above.
Combination with insulin
Metformin and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose of Rinformin® Long is 500 mg or 750 mg once daily with evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements.
Daily dose
Rinformin® Long, prolonged release tablets, 500 mg
Maximum recommended dose of Rinformin® Long 500 mg is 4 tablets of 500 mg per day (2,000 mg).
If taking the maximum recommended dose once daily with evening meal fails to provide an adequate glycaemic control this dose can be divided: 2 tablets of 500 mg with morning meal and 2 tablets of 500 mg with evening meal.
If glycaemic control is not achieved by taking 2,000 mg of Rinformin® Long, prolonged release tablets, patients may be switched to immediate release metformin tablets to a maximum dose of 3000 mg daily.
Rinformin® Long, prolonged release tablets, 750 mg
Maximum recommended dose of Rinformin® Long 750 mg is 3 tablets of 750 mg per day (2,250 mg).
If glycaemic control is not achieved by taking 2,250 mg of Rinformin® Long, prolonged release tablets, patients may be switched to immediate release metformin tablets to a maximum dose of 3000 mg daily.
Renal impairment
Metformin can be used by patients with renal impairment (CFR of 30–59 mL/min) only in the absence of conditions/risk factors that may increase the risk of lactic acidosis.
A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at an increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.
In patients with GFR of 45–59 mL/min GFR should be assessed every 3–6 months; or otherwise every 3 months if GFR is 30–44 mL/min.
If GFR is below 30 mL/min administration of metformin shall be discontinued immediately.
| GFR (mL / min) | Maximum daily dose (divided into 2–3 doses per day) | Additional information |
| 60–89 | 3,000 mg | Consider reduced metformin dose because of renal insufficiency. |
| 45–59 | 2,000 mg | Before starting metformin therapy check if any factors increasing the risk of lactic acidosis (see “Administer with special care”) are present; Initial dose shall be one half of maximum daily dose. |
| 30–44 | 1,000 mg | |
| < 30 | – | Metformin is contraindicated |
Elderly patients
Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary regularly twice a year (see “Special precautions”).
Duration of treatment
Rinformin® Long should be administered every day without interruptions. If treatment is discontinued inform your physician.
Missed dose
If a dose is missed, take the next dose as usual. Do not take a double dose of Reinformin® Long.
Undesirable effects
Frequencies of undesirable effects are defined as follows:
- very common: ≥ 1/10;
- common: ≥ 1/100, < 1/10;
- uncommon: ≥ 1/1,000, < 1/100;
- rare: ≥ 1/10,000, < 1/1,000;
- very rare: < 1/10,000.
Metabolism and nutrition disorders
Very rare:
Lactic acidosis (see “Special precautions”).
Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such an aetiology is recommended if a patient presents with megaloblastic anaemia.
Nervous system disorders:
Common: taste disturbance (metallic taste in the mouth).
Gastrointestinal disorders:
Very common: nausea, vomiting, diarrhoea, abdominal pain and loss of appetite.
These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. A slow increase of the dose may also improve gastrointestinal tolerability.
Hepatobiliary disorders:
Very rare: abnormal hepatic function and hepatitis; once metformin is discontinued such adverse events completely disappear.
Skin and subcutaneous tissue disorders
Very rare: skin reactions such as erythema (skin redness), itching, urticaria.
If any of the undesirable effects specified herein are worsening, or any other undesirable effects not specified herein have been observed, inform your physician.
Overdose
Hypoglycaemia has not been seen with metformin doses of up to 85 g (42.5-fold the maximum daily dose), although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis (see “Special precautions”).
Treatment: if lactic acidosis symptoms occur, treatment with the metformin should be discontinued immediately, the patient should be urgently hospitalized and diagnosis should be clarified based on lactate concentration. The most effective method to remove lactate and metformin is haemodialysis. Symptomatic treatment shall be provided as well.
Interaction with other medicinal products
Contraindicated combinations
Iodinated contrast agents: in patients with diabetes mellitus with renal insufficiency radiological study with the use of iodinated contrast agents may cause lactic acidosis. Rinformin® Long must be discontinued depending on renal function at least 48 hours after or for the period of the radiological study with the use of iodinated contrast agents and restarted no earlier than within 48 hours after, provided that renal function has been re-evaluated and found to be stable.
Concomitant use not recommended
Alcohol: acute alcohol intoxication increases the risk of lactic acidosis, particularly in case of:
- malnutrition, adherence to hypocaloric diet;
- hepatic impairment.
Alcohol intake and ethanol-containing drugs shall be avoided during treatment.
Combinations requiring precautions for use
Medicinal products with intrinsic hyperglycaemic activity (e. g. glucocorticosteroids and tetracosactide (systemic and local effect), beta2 agonists, danazol, chlorpromazine when taken in large doses (100 mg per day) and diuretics): more frequent monitoring of blood glucose concentration may be required, especially at the beginning of treatment. If necessary, the dose of Rinformin® Long can be adjusted during treatment and after discontinuation based on glycaemia level.
Diuretics: concomitant use of loop diuretics may result in lactic acidosis progression due to potential renal insufficiency.
Concomitant use of Rinformin® Long with sulfonylureas, insulin, acarbose, salicylates may result in hypoglycaemia.
Nifedipine increases metformin absorption and Cmax.
Cationic medicinal products (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) secreted in renal tubules compete with metformin for tubular transport systems and may result in an increase in its Cmax.
Colesevelam when used concurrently with prolonged release tablets of metformin increases the metformin concentration in blood plasma (increase in AUC without a significant increase in Cmax).
Special precautions
Lactic acidosis
Lactic acidosis, a very rare, but serious, metabolic complication (high mortality rate in the absence of emergency treatment) that can occur due to metformin accumulation. Lactic acidosis most often occurs in patients with diabetes mellitus with renal insufficiency.
Other associated risk factors such as decompensated diabetes mellitus, ketosis, prolonged fasting, alcoholism, liver failure and any condition associated with severe hypoxia shall be taken into account. This can help to reduce the incidence of lactic acidosis.
The risk of lactic acidosis shall be considered when non-specific symptoms occur such as muscle cramps accompanied by dyspeptic disorders, abdominal pain and apparent asthenia.
Lactic acidosis is characterised by severe malaise, fatigue, acidotic dyspnea, vomiting, abdominal pain, muscle cramps and hypothermia followed by coma. Diagnostic laboratory indicators are decrease in blood pH (less than 7.25), lactate concentration in blood plasma over 5 mmol/l, increased anion gap and lactate/pyruvate ratio. If lactic acidosis is suspected discontinue taking the drug and consult with a physician immediately.
Surgery
Metformin must be discontinued 48 hours before surgery and can be restarted no earlier than within 48 hours following surgery, provided that renal function has been re-evaluated and found to be stable.
Renal function
As metformin is excreted by the kidneys, GFR should be assessed before initiation of treatment with metformin containing products and at least annually for patients with normal renal function and 2–4 times a year for elderly patients and patients with creatinine clearance at the lower limit of normal thereafter.
If GFR is less than 45 mL/min the drug is contraindicated.
Particular caution is required in case of potential renal impairment in elderly patients, if using hypertensive medicinal products, diuretics or non-steroid anti-inflammatory agents.
Heart failure
Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, metformin may be used with a regular monitoring of cardiac and renal function.
Metformin administration in case of acute heart failure and chronic heart failure with unstable hemodynamic indicators is contraindicated.
Other precautions
All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet (but no less than 1,000 kcal/day). Patients shall also exercise on a regular basis.
Patients shall inform their physician of any treatment being given and any infectious diseases such as colds, respiratory infections or urinary tract infections.
The usual laboratory tests for diabetes monitoring should be performed regularly.
Metformin alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulphonylureas or meglitinides). Hypoglycaemia symptoms are weakness, headache, dizziness, increased sweating, palpitations, visual impairment or impaired concentration.
Inform the patient that inactive components of Rinfomin® Long can be excreted unchanged via faeces, which does not affect the therapeutic activity of the drug.
Effects on ability to drive and use machines
Rinfomin® Long monotherapy does not cause hypoglycaemia and therefore it does not affect the ability to drive vehicles and mechanisms.
Nevertheless, hypoglycaemia progression is possible when using metformin in combination with other hypoglycemic drugs (sulfonylureas, insulin, or meglinitides).
Nature and contents of container
Prolonged release tablets, 500 mg and 750 mg.
10 tablets per blister made of PVC or PVC/PCTFE film and aluminium foil.
30 tablets in a HDPE bottle.
3 or 6 blisters or one bottle along with the instruction for use in a carton pack.
Storage conditions
Store in a dark place at temperature below 25°C.
Keep out of reach of children!
Shelf life
3 years.
Do not use after shelf life expiration date indicated on the package.
Pharmacy prescription terms
Available on prescription.
Name and address of the drug manufacturer and the production site address
OOO GEROPHARM, Russia
9, ul. Zvenigorodskaya, Saint Petersburg, 191119
Tel.: +7(812) 703-79-75 (multiline), fax: +7(812) 703-79-76
Manufacturer’s production site:
13, Moskovskoye shosse, bldg VI, bldg VL, 196158 Saint Petersburg
Organisation authorized to receive claims from customers
OOO GEROPHARM, Russia
Postal address: 11 Degtyarniy per., lit. B, 191144, Saint Petersburg
Tel.: +7(812) 703-79-75 (multiline), fax: +7(812) 703-79-76
Hot Line: 8-800-333-4376 (free throughout Russia)
Please, send any information on adverse reactions by email to farmakonadzor@geropharm.com or to OOO GEROPHARM address mentioned above.
