Expiration date: 01/2025

The composition and form of issue: 

Tablets, film-coated. 1 tablet contains:

glimepiride 1 mg

Metformin 250 mg

excipients: lactose monohydrate sodium carboximetilkrahmal povidone K30, MCC crospovidone magnesium stearate 

film shell: hypromellose macrogol 6000 titanium dioxide (E171) Carnauba wax 

in packages contour cell 10 PCs per cartons 3 packages.

Tablets, film-coated. 1 tablet contains:

glimepiride 2 mg

Metformin 500 mg

excipients: lactose monohydrate sodium carboximetilkrahmal povidone K30 MCC crospovidone magnesium stearate 

film shell: hypromellose macrogol 6000 titanium dioxide (E171) Carnauba wax 

in packages contour cell 10 PCs per cartons 3 packages.

Description pharmaceutical form:

1 tablets+250 mg: oval, biconvex, film-coated white color, with engraving "HD125" on one side.

2 tablets+500 mg: oval, biconvex, film-coated white color, with an engraving of "HD25" on one side and scored on the other.

Feature:

Combined hypoglycemic drug, which includes glimepiride and Metformin.

Pharmacokinetics:

The pharmacokinetics of glimepiride

For multiple doses in a daily dose of 4 mg Cmax in plasma is reached after about 2.5 h after oral administration and is 0,309 µg/ml. Between dose, Cmax in plasma and AUC, there is a linear relationship. Glimepiride has a complete oral bioavailability. The meal did not substantially affect the absorption, only slightly reduces its speed.

The glimepiride very small Vd (about 8.8 l), approximately equal to the Vd of albumin, a high degree of binding to blood plasma proteins (99%) and low clearance (approximately 48 ml/min).

After a single oral dose of glimepiride is excreted by the kidneys 58% of the drug (in the form of metabolites) and 35% — through the intestines. T1/2 in plasma concentrations in the serum corresponding to multiple reception is 5-8 hours After taking the drug in high doses showed an elongation of T1/2.

In the urine and feces revealed 2 inactive metabolites resulting from metabolism in the liver, one of them is hydroxy and the second carboxyperitoneum. After oral administration of glimepiride terminal T1/2 of these metabolites were 3 to 5 and 5-6 h, respectively.

Glimepiride is excreted in breast milk and crosses the placental barrier. Penetrates through the BBB bad.

Comparison of single and multiple (2 times a day) ingestion of glimepiride did not reveal any significant differences in pharmacokinetic parameters, their variability in different patients was different.

Patients of different sex and different age groups pharmacokinetic parameters are the same. When impaired renal function (low creatinine clearance) tended to increase clearance and decrease in average plasma concentrations of glimepiride, due to its more rapid elimination because of lower protein binding blood plasma. Thus, the risk of drug accumulation in these patients is not.

Pharmacokinetics of Metformin

After oral administration, Metformin is absorbed from the gastrointestinal tract adequately. The absolute bioavailability of Metformin is 50-60%. Cmax (approximately 2 µg/ml or 15 µmol) in plasma achieved through 2.5 h At simultaneous food intake and reduced absorption of Metformin is delayed.

Metformin is rapidly distributed in tissue, there is not associated with plasma proteins. Metabolized in very low extent and excreted by the kidneys. Clearance in healthy subjects is 440 ml/min (4 times more than that of creatinine), indicating active tubular secretion. After taking the dose inside the terminal T1/2 is approximately 6.5 h. When renal failure is increasing, there is a risk of drug accumulation.

Description pharmacological action:

Pharmacodynamics of glimepiride

Glimepiride is the oral hypoglycemic drug derived sulfonylureas of the III generation. Used in diabetes type 2.

Stimulates the secretion and release of insulin from the beta cells of the pancreas (patrioticheskoe action), improves sensitivity of peripheral tissues (muscle and fat) to the action of endogenous insulin (extrapancreatic action).

Effect on insulin secretion

Sulfonylureas increase insulin secretion by closing ATP-dependent potassium channels located in the plasma membrane of the beta cells of the pancreas. Closing the potassium channels, they cause depolarization of the beta cells that contributes to the opening of calcium channels and increase the amount of calcium inside cells.

Glimepiride replacement with high speed connects and detaches from the protein of the beta cells of the pancreas (mol. weight of 65 KD/SURX), which is associated with ATP-dependent potassium channels, but different from the binding sites of the normal derivatives of sulfonilmocevina (a protein with mol. a mass of 140 CD/SUR1).

This process leads to the release of insulin by exocytosis, the secreted amount of insulin is much less than the customary (traditionally used) sulfonylurea derivatives (e.g. glibenclamide). The minimum stimulating effect of glimepiride on insulin secretion and provides less risk of hypoglycemia.

Extrapancreatic activity

As traditional sulfonylureas, but to a much greater extent, glimepiride has a pronounced extrapancreatic effects (reduction of insulin resistance, the lesser the effect on the cardiovascular system, antiatherogenic, antiplatelet, and antioxidant action).

Disposal of glucose from the blood by peripheral tissues (muscle and adipose) is derived with the help of special transport proteins (GLUT1 and GLUT4) located in cell membranes. Glucose transport in these tissues in diabetes type 2 is limited by the speed stage of glucose utilization. Glimepiride very rapidly increases the number and activity of molecules to transport glucose (GLUT1 and GLUT4), which leads to an increase of glucose uptake by peripheral tissues.

Glimepiride has a weaker inhibitory effect on ATP-dependent K+channels of cardiomyocytes. When taking glimepiride retained the ability of metabolic adaptation of the myocardium to ischemia.

Glimepiride increases the activity of phospholipase C, which in isolated muscle and fat cells can correlate the drug-induced lipogenesis and glycogenes.

Glimepiride inhibits the glucose in your liver, increasing the intracellular concentration of fructose-2,6-diphosphate, which in turn, inhibits glycogenes.

Glimepiride selectively ingibiruet COX and reduces the transformation of arachidonic acid to thromboxane A2, which promotes platelet aggregation, thus exerting antithrombotic effect.

Glimepiride reduces the content of lipids, reduces lipid peroxidation, which contributes to the antiatherogenic effect of the drug.

Glimepiride increases the amount of endogenous alpha-tocopherol, catalase, glutathione peroxidase and superoxide dismutase, thereby reducing the severity of oxidative stress in the patient, which is always present in diabetes mellitus type 2.

Pharmacodynamics of Metformin

Hypoglycemic agents from the group of biguanides. Its hypoglycemic action is possible only under condition of preservation of insulin secretion (although reduced). Metformin has no effect on the beta cells of the pancreas and increases insulin secretion at therapeutic doses, does not cause hypoglycemia in humans.

Mechanism of action not fully elucidated. It is assumed that Metformin can potentiate the effects of insulin or increase these effects in areas peripheral receptors. Metformin increases tissue sensitivity to insulin by increasing the number of insulin receptors on cell surface membranes. In addition, Metformin inhibits hepatic gluconeogenesis, reduces the formation of free fatty acids and fat oxidation, reduces the concentration of triglycerides (TG) and LDL and VLDL in the blood. Metformin slightly reduces appetite and reduces the absorption of carbohydrates in the intestine. It improves fibrinolytic properties of blood due to the suppression of plasminogen activator inhibitor tissue-type.

Indications:

Treatment of diabetes mellitus type 2:

• in the case when glycemic control cannot be achieved with a combination of diet, exercise, weight loss and monotherapy with glimepiride or Metformin
  
• when replacing a combination therapy with glimepiride and Metformin in one combination drug.
  

Contraindications:

• hypersensitivity auxiliary substances, sulfonylurea, sulphonamides or biguanides
  
• diabetes mellitus type 1
  
• diabetic ketoacidosis (including in history), diabetic coma and prekomatosnoe condition, acute or chronic metabolic acidosis
  
• severe liver dysfunction (lack of experience with the drug, to ensure that adequate glycemic control requires treatment with insulin)
  
• the impairment of renal function, including patients on hemodialysis (creatinine concentration in the serum — 1, 5 mg/DL in men and 1.4 mg/DL in women or decrease in creatinine clearance — increased risk of lactic acidosis and other side effects of Metformin)
  
• susceptibility to the development of lactic acidosis, lactic acidosis in history
  
• stressful situations (severe infections with fever, severe trauma, burns, surgical operations, septicemia)
  
• heart failure, collapse (shock), acute myocardial infarction
  
• exhaustion, starvation, dehydration, adherence to a reduced-calorie diet (less than 1000 cal/day)
  
• malabsorption of food and drugs in the gastrointestinal tract (intestinal obstruction, intestinal paralysis, diarrhea, vomiting)
  
• pituitary or adrenal insufficiency
  
• severe impairment of pulmonary function, other hypoxic States, including tissue hypoxia (cardiac and respiratory insufficiency, acute myocardial infarction, etc.)
  
• chronic alcoholism, acute alcohol poisoning
  
• in/in the introduction iodocetylic drugs because they can cause acute impairment of renal function (the drug is not administered for 48 h before and for 48 hours after the study)
  
• lactase deficiency, lactose intolerance, glucose-galactose malabsorption
  
• pregnancy, pregnancy planning
  
• the breast-feeding period
  
• children up to age 18 years (no clinical data).
  

With caution:

• a condition in which increased risk of hypoglycemia (patients who do not wish or are not able to cooperate with the doctor, often older patients are malnourished, eating irregularly, skipping meals in case of discrepancy between physical exercise and carbohydrate intake modify diet, use of alcohol, especially in combination with skipped meals in the liver and kidneys in some of decompensated endocrine disorders — violation of thyroid function, a deficiency of hormones of the anterior pituitary and of the adrenal cortex that affect the metabolism of carbohydrates and activation of mechanisms aimed at increasing the concentration of glucose in the blood hypoglycemia — these patients require more careful monitoring of the concentration of glucose in the blood and signs of hypoglycemia)
  
• the simultaneous use of certain other drugs (see "Interactions")
  
• the decline in renal function (in the elderly, with collapse, shock — increased risk of lactic acidosis and other side effects of Metformin)
  
• when performing heavy physical work (it increases the risk of lactic acidosis while taking Metformin)
  
• smoothness or absence of symptoms of hypoglycemia that are associated with the activation of the sympathetic nervous system in elderly patients, with neuropathic lesions of the autonomic nervous system or concurrently with the therapy of beta-blockers, clonidine, guanetidin, and other simpatoliticescoe means — such patients need more careful monitoring of glucose levels in the blood.
  

If one of the above diseases or conditions before using the drug should consult a doctor.

Application of pregnancy and breast-feeding:

Pregnancy. Contraindicated in pregnancy because of possible adverse effects on fetal development. Pregnant women and women planning a pregnancy, must inform the doctor. During pregnancy, women with disorders of carbohydrate metabolism, correctisimo diet and exercise should to insulin therapy.

Lactation. In order to avoid contact of the drug with breast milk into the baby's body, nursing women should not take this drug. If necessary, the patient should be transferred to insulin therapy or to stop breast-feeding.

Side effects:

Glimepiride

Based on the experience with glimepiride and known data on other derivatives sulfonylureas may develop the following side effects of the drug.

From the metabolic and nutrition: hypoglycemia, which may be protracted (as with other sulfonylurea derivatives). The symptoms of developing hypoglycemia include: headache, acute hunger, nausea, vomiting, confusion, lethargy, sleep disturbances, anxiety, aggressiveness, poor concentration, reduced alertness, slower psychomotor reactions, depression, confusion, slurring of speech, aphasia, blurred vision, tremor, paresis, sensory disorders, dizziness, helplessness, loss of self-control, delirium, convulsions, somnolence and loss of consciousness up to coma, shallow breathing, bradycardia. In addition, there may be signs of development of adrenergic responses to hypoglycemia: sweating, stickiness of the skin, increased anxiety, tachycardia, increased blood pressure, feeling tachycardia, angina and arrhythmia. The clinical picture of severe hypoglycemia attack may resemble an acute violation of cerebral circulation. The symptoms almost always resolve after elimination of glucose.

On the part of the organ of vision: blurred vision (especially at the beginning of treatment due to fluctuations in the concentration of glucose in the blood).

From the digestive tract: nausea, vomiting, fullness of stomach, abdominal pain, and diarrhea.

The liver and biliary tract: increased activity of liver enzymes and impaired liver function (e.g. cholestasis and jaundice) and hepatitis which can progress to liver failure.

From the blood system and lymphatic system: thrombocytopenia in some cases — leukopenia, hemolytic anemia or erythropenia, granulocytopenia, agranulocytosis or pancytopenia. Requires careful monitoring of the patient, as during treatment with sulphonylurea there were cases of aplastic anemia and pancytopenia. If you experience these phenomena the drug should stop and start appropriate treatment.

The immune system: allergic and pseudoallergic reactions (such as itching, hives or rashes). These reactions almost always occur in the form of light, but can go severe, with shortness of breath or a decrease in blood pressure, until the development of anaphylactic shock. If you experience hives, you should immediately consult a doctor. Possible cross-Allergy with other sulfonylureas, sulfonamides or similar substances. Allergic vasculitis.

Other: photosensitivity, hyponatremia.

Metformin

From the metabolism and nutrition: lactic acidosis (see "Special indications"), hypoglycemia.

On the part of the digestive tract: diarrhea, nausea, abdominal pain, vomiting, flatulence, lack of appetite are the most frequent reactions in monotherapy with Metformin. These symptoms occur almost 30% more frequently than in patients taking placebo, especially at the beginning of treatment. These symptoms are mostly transient and disappear on their own. In some cases, it may be useful to temporarily reduce the dose. In clinical studies, Metformin was cancelled almost 4% of patients because of the occurrence of reactions from the gastrointestinal tract.

Because the development of symptoms of the gastrointestinal tract at the beginning of treatment was dose-dependent, their expression can be reduced by gradual increase in dose and taking the drug at mealtime.

As the diarrhea and/or vomiting can cause dehydration and prerenal renal failure, when they occur, the drug should be suspended.

At the beginning of treatment with Metformin in approximately 3% of patients, possible occurrence of an unpleasant or metallic taste in the mouth, which usually resolves on its own.

The skin: erythema, pruritus, rash.

From the blood system and lymphatic system: anemia, thrombocytopenia or leukocytopenia. Approximately 9% of patients who received monotherapy with the drug Amaryl M, and 6% of patients who received treatment with Metformin or Metformin/drug from the group of sulfonylurea, is an asymptomatic decrease in the level of vitamin B12 in the blood plasma (the level of folic acid in blood plasma were not significantly decreased). Despite this, during the drug Amaryl M was was only megaloblastic anemia, increase in the incidence of neuropathy not revealed. Therefore, it is necessary to conduct an appropriate control of the level of vitamin B12 in blood plasma (may require periodic parenteral administration of vitamin B12).

Hepatic: abnormal liver function.

All cases of the occurrence of the above adverse reactions or other unwanted reactions the patient should inform the doctor. Due to the fact that some adverse reactions, including hypoglycemia, haematological disorders, severe allergic and pseudoallergic reactions, and liver failure can threaten the patient's life, during their development, the patient should immediately report them to the doctor and stop taking the drug until you have instructions from the doctor. Unexpected adverse reactions to Amaryl M, with the exception of already known reactions to glimepiride and Metformin, during clinical trials of the first phase and open phase III studies were observed.

Drug interactions:

Glimepiride

If a patient who takes glimepiride, at the same time appoint or cancel the other drug is possible as an unwanted gain, and the weakening of the hypoglycemic action of glimepiride. Based on the experience with glimepiride and other sulfonylurea derivatives, consider the following drug interactions.

With drugs that are inducers or inhibitors of CYP2C9

Glimepiride is metabolized via cytochrome P450 CYP2C9. It is known that its metabolism is affected by the simultaneous use of inducers of CYP2C9 such as rifampicin (risk of decrease in hypoglycemic effect of glimepiride in coadministration with inducers of CYP2C9 and increases the risk of hypoglycemia in case of cancellation inducers of CYP2C9 without correction doses of glimepiride) and inhibitors of CYP2C9, such as fluconazole (increased risk of hypoglycemia and side effects of glimepiride when administered simultaneously with these drugs and the risk of a decrease of the hypoglycemic action of glimepiride in the abolition of CYP2C9 inhibitors without a dose adjustment of glimepiride).

Drugs that potentiate hypoglycemic effect

Insulin and oral hypoglycaemic agents, ACE inhibitors, allopurinol, anabolic steroids, male sex hormones, chloramphenicol, cumarin anticoagulants, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluoxetine, guanetidin, ifosfamide, MAO inhibitors, miconazole, fluconazole, aminosalicylic acid, pentoxifylline (when administered parenterally in high doses), phenylbutazone, probenecid, antimicrobial agents of the quinolone group, salicylates, sulfinpirazon, derivatives of sulfonamide, tetracyclines, tritoqualine, trofosfamide, azapropazon, oxyphenbutazone.

Increased risk of hypoglycemia with concomitant use of the above drugs glimepiride and risk for poor glycemic control in their cancellation without correction doses of glimepiride.

Drugs that reduce the hypoglycaemic effect

Acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine, or sympathomimetic agents, glucagon, laxatives (long-term use), nicotinic acid (in high doses), estrogens, progestogen, phenothiazines, phenytoin, rifampicin, thyroid hormones.

Increased risk of worsening glycemic control in a joint application of glimepiride with these medications and the risk of hypoglycemia in case of cancellation without correction doses of glimepiride.

Drugs that can both enhance and reduce the hypoglycemic effect

The histamine H2-receptors, clonidine and reserpine.

With simultaneous use may both the increase and decrease of hypoglycemic effect of glimepiride. Careful monitoring of the concentration of glucose in the blood.

With beta-blockers

Beta-blockers decrease glucose tolerance, which can disrupt metabolic regulation. In addition, in the blocking reactions of the sympathetic nervous system in response to hypoglycemia they can make hypoglycemia more noticeable to the patient and physician and thus increase the risk of its occurrence.

With simpatoliticescoe means

They are able to reduce or block the reaction of the sympathetic nervous system in response to hypoglycemia that can make hypoglycemia more noticeable to the patient and physician and thus increase the risk of its occurrence.

With alcohol

The consumption of alcohol can both relax, and enhance hypoglycemic effect of glimepiride.

With coumarin derivatives

Glimepiride can both reduce and enhance the effects of coumarin derivatives.

Metformin

With iodinated contrast agents, antibiotics, have a pronounced nephrotoxic effect (gentamicin)

Increase risk of development of lactic acidosis. In the case of the simultaneous use of these drugs requires careful monitoring of the patient.

Drugs that potentiate hypoglycemic effect of Metformin

Insulin, sulfonamides, sulfonylureas, anabolic steroids, guanetidin, salicylates (acetylsalicylic acid, etc.), beta-blockers (propranolol, etc.), MAO inhibitors.

While the use of these drugs with Metformin need to closely monitor the patient and control concentration of glucose in the blood, because. may increase hypoglycemic action.

With drugs that reduce hypoglycemic action of Metformin

Epinephrine, corticosteroids, thyroid hormones, estrogens, pyrazinamide, isoniazid, Niacin, phenothiazines, thiazide diuretics diuretics and other groups, oral contraceptives, phenytoin, sympathomimetics, BPC.

While the use of these drugs with Metformin need to closely monitor the patient and control concentration of glucose in the blood, because the weakening of the hypoglycemic action.

With glibenclamide

In a clinical study to investigate the interaction of Metformin and glibenclamide in single dose was not observed any changes in either the pharmacokinetics or the pharmacodynamics of Metformin in patients with diabetes mellitus type 2. However, there was a decrease in AUC and Cmax of glibenclamide, which was quite variable. Due to the fact that during the study were administered a one-time dose, but also due to the lack of correlation between the levels of glibenclamide in plasma and pharmacodynamic effects, clinical significance of this interaction is unclear.

With furosemide

In a clinical study to investigate the interaction of Metformin and furosemide in single dose to healthy volunteers it was shown that co-administration of these drugs affects their pharmacokinetic parameters. Furosemide increases the Cmax of Metformin in plasma and in the blood by 22% and blood AUC by 15%, without any significant change in Metformin renal clearance. When applying the indicators Metformin Cmax and AUC of furosemide decreased by 31 and 12%, respectively, compared to monotherapy with furosemide, and terminal T1/2 decreased by 32%, without any significant changes in renal clearance of furosemide. Information about the interaction of Metformin and furosemide long-term use is missing.

With nifedipine

In a clinical study to investigate the interaction of Metformin and nifedipine in their single dose to healthy volunteers it was shown that co-administration of nifedipine increases Cmax and AUC of Metformin in plasma by 20 and 9%, respectively, and increases the amount of drug extracted by the kidney. Metformin had minimal effect on the pharmacokinetics of nifedipine.

With cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin)

Cationic medications that are excreted via tubular secretion in the kidneys, is theoretically able to interact with Metformin as a result of competition at the common tubular transport system. Such interaction between Metformin and oral cimetidine was observed in healthy volunteers in clinical studies of interaction between Metformin and cimetidine in single and multiple use, where there was a 60% increase in Cmax in plasma and total concentration of Metformin in the blood and 40% increase in plasma and total AUC of Metformin. In single dose change in T1/2 was not. Metformin did not affect the pharmacokinetics of cimetidine. Although such interactions remain theoretical (except for cimetidine), should ensure close monitoring of patients and to dose adjustment of Metformin and/or interacting with the drug are taking cationic medications that are excreted from the body secretory system in the proximal tubules of the kidney.

With propranolol, ibuprofen

Healthy volunteers in studies on the interaction of Metformin and propranolol and Metformin and ibuprofen in a single application was not observed changes in their pharmacokinetic parameters.

Method of application and dose:

Inside, before or during a meal, 1-2 times a day.

Use in adult patients. The dosage of hypoglycemic drugs should be individualised, taking into account the concentration of glucose in the blood of the patient. As a rule, it is recommended to start treatment with the lowest effective dose and depending on the concentration of glucose in the blood of the patient to increase the dose. For this it is necessary to conduct appropriate monitoring of the concentration of glucose in the blood.

Use in pediatric patients. The study of the safety and efficacy of the drug in children with diabetes mellitus type 2 was conducted.

Use in elderly patients. It is known that Metformin is excreted primarily by the kidney and because the risk of severe adverse reactions to the drug in patients with impaired kidney function above, it can be used only in patients with normal renal function. Due to the fact that with age, kidney function declines, and Metformin in elderly patients should be used with caution. You must carefully select a dose and provide regular monitoring of renal function.

Overdose:

Symptoms: hypoglycemia (due to content in the drug of glimepiride), lactic acidosis (due to content in the drug Metformin). When getting Metformin into the stomach in an amount up to 85 g of hypoglycemia was not observed.

Treatment: mild hypoglycemia without loss of consciousness and neurological changes should be treated with oral glucose and correction doses of the drug and/or diet of the patient (intensive monitoring should continue until, until the doctor convinced that the patient is out of danger). Severe cases of hypoglycemia, accompanied by coma, convulsions and other neurological symptoms are frequent and urgent condition requiring immediate hospitalization of the patient. If hypoglycemic coma is diagnosed or suspect its occurrence, the patient must enter a concentrated (40%) solution of glucose in/in struino, and then carry out continuous infusion the introduction of a less concentrated (10%) glucose solution at a rate that ensures the maintenance of a stable level of blood glucose above 100 mg/DL. For patients need constant supervision for at least 24 to 48 hours, because after the improvement of the patient, hypoglycaemia may recur.

Metformin is able to output via dialysis with a clearance of up to 170 ml/min under good hemodynamic. So if you suspect an overdose, hemodialysis may be useful for removing accumulated in the body of the drug.

Special instructions:

The effectiveness of any hypoglycemic therapy should be monitored by periodic monitoring of glucose concentration and glycated hemoglobin in the blood. The goal of treatment is to normalize these indicators. The concentration of glycosylated hemoglobin, which allows assessing glycemic control.

In the first week of treatment requires careful monitoring because of the risk of hypoglycemia, particularly at elevated risk for its development (patients unwilling or unable to follow the doctor's recommendations, most elderly patients with poor nutrition, irregular meals when skipping meals in case of discrepancy between physical exercise and carbohydrate intake with changes in diet, alcohol consumption, especially in combination with skipped meals when impaired renal function severe impaired liver function overdose of the drug Amaryl M under certain uncompensated disorders of the endocrine system (e.g. dysfunction of the thyroid gland and failure of function of the anterior pituitary or adrenal) while the appointment of some other drugs that affect carbohydrate metabolism (see "Interactions"). In such cases, careful monitoring of the concentration of glucose in the blood. The patient should inform the doctor about these factors and the symptoms of hypoglycemia, if any. In the presence of risk factors of hypoglycemia may require correction doses of the drug or the entire therapy. This approach is used whenever during therapy develops any medical condition, and changes the lifestyle of the patient.