DCGI Approved Fixed-Dose Combinations for Diabetes Management

DCGI Approved Fixed-Dose Combinations for Diabetes Management
by new_pharma

DCGI Approved Fixed-Dose Combinations for Diabetes Management

Fixed-dose combinations (FDCs) are gaining popularity worldwide, considering their importance in disease management and better efficacy and safety profile.

It has always been a great topic of deliberation in the pharmaceutical industry, drug regulatory agency, pharmaceutical trade and public health point of view.

The increased therapeutic activity of FDC shows new possibilities in the treatment of almost every human disease. Fixed-dose combinations have been utilized in several disciplines of medicine, based on their convenience rate, and improved adherence rates.

What are Fixed-dose combinations (FDC)?

Fixed-dose combinations (FDC) can be defined as medications that contain two or more active ingredients combined in a fixed-dose in a single formulation. They exhibit similar bioequivalence, rates and therefore, similar pharmacokinetic and pharmacodynamic properties as separate tablets.

What are the advantages of using FDC Products over monotherapy?

1 . Better treatment

FDC’s can lead to better treatment outcomes by improving patient adherence rates. It also helps to     avoid treatment failure due to relapse.

2 . Improves patient compliance

FDC’s may improve patient compliance by taking fewer tablets daily. It significantly reduces pill burden of patients.

3 . Simple dosage schedule

FDC’s may reduce the confusion and complexity of dose schedule in treatment of some diseases such as tuberculosis that may require 5-16 tablets per day.

4 . Greater efficacy compared to monotherapy

FDC’s are more efficient than monotherapies, as per the data obtained from various research studies and clinical trials.

5. Reduced risk of adverse events

FDC’s have been reported to cause less adverse effects as compared to those of two drugs given independently.

6 . Synergistic effect

FDC’s creates a perfect combination that exhibits a synergistic effect. For instance, a fixed-dose combination of Paracetamol and Tramadol shows a synergistic effect with a quick onset of action and prolonged analgesic effect.

7 . Inhibition of microbial resistance

FDC’s are more effective in eliminating or slowing down antimicrobial resistance as compared to monotherapy as infectious pathogens at developing antimicrobial resistance against drugs.

Inhibition of microbial resistance

Regulation of FDC Products In India

Any new drug to be authorized and marketed in India is regulated by Drug Control General of India (DCGI), under the guidelines of Drugs and Cosmetic Act 1940. Before drug approval, Central Drugs Standard Control Organization (CDSCO) undergoes a clinical examination and monitors the drug formulations from the angle of quality, efficacy, safety and rationality.

1 . The marketing approval and rights to manufacture/import FDC’s are entirely based on the FDA guidelines. As per Rule 122 (E) of Drugs and Cosmetics Act 1940 and their Rules 1945, FDC’s are considered as a complete pharmaceutical product and a new drug.

2 . The approval of FDC’s is based on the appropriate therapeutic rationale of the particular combination of active substances. Confirmation can also be obtained from the scientific literature of scientific value.

3 . Comparative clinical trials of FDC’s with reference treatment may also be essential when the therapeutic explanation shows the superiority of FDC’s over a reference treatment.

4 . The application for marketing authorization should include original data, scientific literature and a combination of both. Chemical and pharmaceutical data should always be completely innovative unless there is enough explanation with literature when partial data can be in-original.

Fixed-Dose Combinations (FDC’s) and Diabetes

Diabetes mellitus is a chronic disease, with a growing prevalence worldwide.
According to the World Health Organisation (WHO), 422 million adults were suffering from diabetes globally in 2014. The estimated prevalence of diabetes in India was recorded to be 72 million cases in 2017. These figures are expected to double by 2025.

The first-line management of diabetes includes the use of biguanides, metformin. It is the most commonly used anti-diabetic drug. The potential of metformin as an effective drug is explained by its ability to lower blood glucose levels by decreasing glucose production, stimulating glucose uptake by muscles and increased fatty acid oxidation.

The exact mechanism of action is not fully understood yet. It is contraindicated or intolerable as the initial treatment in some patients. Therefore another class of anti-hyperglycemic agent are used.

Management of diabetes is also complicated because many barriers affect glycemic control. These barriers include risk of hypoglycemia, weight gain and complicated dosing schedules.

To reduce these barriers and achieve glycemic control targets, fixed-dose combinations of oral hyperglycaemic agents with metformin has been licensed for use in the management of diabetes mellitus.
The combination therapy using a second agent with a different mechanism of action is also favoured when monotherapy fails to achieve the glycemic goal.

There are six major classes of anti-diabetic agents that can be combined with metformin. They are sulfonylureas (SU), thiazolidinediones (TZDs), dipeptidyl peptidase-4 inhibitors (DPP4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), Alpha-glucosidase inhibitors (AGIs), and Meglitinide analogues.

Sulfonylureas

This class of medications includes a group of anti-hyperglycemic agents used as a combination therapy with metformin, a sulfonylurea or other anti-hyperglycemic agent. They are usually divided into first and second generations.
Examples of first-generation sulfonylureas include chlorpropamide, tolazamide, and tolbutamide, while second-generation sulfonylureas include glipizide, gliclazide, glyburide and glimepiride.

Sulfonylureas act by increasing the release of insulin through the stimulation of pancreatic beta cells. They have remained a frequently prescribed medication despite potential hypoglycemic risks.

CDSCO Approved fixed-dose combination of Sulfonylureas

1. Glipizide and Metformin: For non-insulin dependent diabetes mellitus

2. Glimepiride and Metformin: For the treatment of patients with type II diabetes mellitus, when diet, exercise and single-agent do not result in adequate glycemic control

3. Glimepiride, Pioglitazone and Metformin: Used as 3rd line treatment of type-II diabetes mellitus when diet, exercise and the single agents and second-line therapy with two drugs do not result in adequate glycemic control

4. Glimepiride, Metformin and Atorvastatin: For the treatment of type II diabetes mellitus associated with dyslipidemia

5. Gliclazide and Metformin: For the management of type-II diabetes, and non-insulin dependent diabetes (Type-II) in adult patients where single-drug therapy, diet and exercise do not result in adequate glycemic control

6. Gliclazide, Metformin and Rosiglitazone: For the management of all types of diabetes

7. Gliclazide, Metformin and Pioglitazone: Used as 3rd line treatment of type II diabetes mellitus when diet, exercise and the single agents and the second-line therapy with two drugs do not result in adequate glycemic control

8. Glibenclamide and Metformin: For the management of non-insulin dependent diabetes mellitus patients poorly controlled with sulphonylurea or biguanide alone and when single-drug therapy, diet and exercise do not result in adequate glycemic control

9. Glibenclamide, Pioglitazone and Metformin: Used as 3rd line treatment of type II diabetes mellitus when diet, exercise and the single agents and the second-line therapy with two drugs do not result in adequate glycemic control

Thiazolidinediones

Thiazolidinediones are a novel class of agents, which has been introduced to improve pancreatic β-cell function and insulin sensitivity. Two thiazolidinediones (rosiglitazone and pioglitazone) has been used in combinations for achieving glycemic control in patients with type II diabetes.
They act by regulating glucose and lipid metabolism in the body. They also exhibits anti-inflammatory, beneficial effects on cardiovascular risk factors, and also decreases blood pressure. The efficacy of these agents has been determined in clinical trials.

CDSCO Approved fixed-dose combination of Thiazolidinediones

1. Pioglitazone and Metformin: Used as second-line therapy in patients with type II diabetes mellitus when diet, exercise & the single agent do not result in adequate glycemic control

2. Pioglitazone and Glimepiride: For the treatment of type-II diabetes as 2nd line therapy when diet, exercise & initial therapy with glitazone or urea do not result in adequate glycemic control

3. Rosiglitazone and Metformin: For the treatment of patients with type-II diabetes when diet, exercise, and the single agent do not result in adequate glycemic control

4. Rosiglitazone and Glimepiride: For type II diabetes mellitus where diet, exercise and single-agent do not result in adequate glycemic control

Gliptins or Dipeptidyl peptidase-4 inhibitors (DPP-4s)
Gliptins are a new class of drugs that have revolutionized the treatment of type II diabetes. It includes alogliptin, anagliptin, sitagliptin, teneligliptin, vildagliptin, saxagliptin, and linagliptin.

These agents act by increasing insulin secretion, with an increase in blood sugar. They also suppress glucagon production in response to a carbohydrate-containing meal. They also decrease the risk of hyperglycemia and weight gain.
The efficacy of gliptins in monotherapy and combination with various type II diabetes medications has been demonstrated in multiple clinical trials.

CDSCO Approved fixed-dose combination of Gliptins

1. Vildagliptin and Metformin: For the treatment of type II diabetes mellitus when single-drug therapy along with diet, exercise do not result in adequate glycemic control

2. Sitagliptin and Metformin: Used as an adjunct to diet & exercise to improve glycemic control in patients with type- II diabetes mellitus. It is also indicated as an add-on to insulin(i.e. triple combination therapy) in patients when the stable dosage of insulin and metformin alone do not provide adequate control

3. Saxagliptin and Metformin: Used as an adjunct to diet and exercise to improve glycemic control in adults patients with type II diabetes mellitus when treatment with both Saxagliptin and Metformin is appropriate

4. Linagliptin and Metformin: Used as an adjunct to diet and exercise to improve glycemic control in adults with type II diabetes Mellitus when treatment with Linagliptin and Metformin is appropriate

5. Teneligliptin and Metformin: Used as an adjunct to diet and exercise to improve glycemic control in adults with type II diabetes mellitus when treatment with both teneligliptin and metformin is appropriate

Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors represent another class of anti-diabetic medication. It includes canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin.

These drugs block glucose reabsorption by the kidneys resulting in increased urinary excretion of glucose. These drugs also promote weight loss, and remain hypoglycemic-neutral and also shoes cardiovascular benefit.

CDSCO Approved fixed-dose combination of SGLT2 inhibitors

1. Dapagliflozin and Metformin: Indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type II diabetes mellitus when treatment with both Dapagliflozin and Metformin is appropriate.

2. Empagliflozin and Linagliptin: Used as an adjunct to diet and exercise to improve glycaemic control in adults with type II diabetes mellitus

3. Empagliflozin and Metformin: Used as an adjunct to diet and exercise to improve glycaemic control in adult patients with type II diabetes mellitus who are not adequately controlled on a regimen containing Empagliflozin or Metformin, or in patients already being treated with both Empagliflozin and Metformin.

4. Canagliflozin and Metformin: Indicated as an adjunct to diet and exercise to improve glycaemic control in the adult with type II diabetes mellitus when treatment with both Canagliflozin and metformin is appropriate. It is not used for the treatment of type 1 diabetes or diabetic ketoacidosis

5. Remogliflozin Etabonate and Metformin:

1 . Indicated in adults aged 18 years and older with type II diabetes mellitus as an adjunct to diet and exercise to improve glycemic control

2 . In patients insufficiently controlled on their maximally tolerated dose of metformin alone

3 . In patients already being treated with the combination of Remogliflozin and metformin as separate tablets

Alpha-glucosidase inhibitors (AGIs)

Alpha-glucosidase inhibitors (AGIs) are a class of anti-diabetic drugs derived from bacteria. It includes acarbose and voglibose. These oral drugs are enzyme inhibitors which work by delaying carbohydrate absorption in the gastrointestinal tract with improved cardiovascular benefit. They have been used in the early stages of type II diabetes to reduce postprandial hyperglycaemia.

CDSCO Approved fixed-dose combination of Alpha-glucosidase inhibitors (AGIs)

1. Acarbose and Metformin: For the treatment of patients with type II diabetes mellitus, when diet, exercise and single-agent do not result in adequate glycemic control

2. Voglibose and Metformin: Used as 2nd line treatment of type II diabetes mellitus when diet, exercise and the single agent do not result in adequate glycemic control

Meglitinide analogues

Meglitinide analogues are a class of oral hypoglycaemic agents that causes an increase in insulin secretion. It includes repaglinide and nateglinide. These agents increase insulin secretion by regulating ATP sensitive potassium channels in pancreatic beta cells.

CDSCO Approved fixed-dose combination of Meglitinide analogues

1. Repaglinide and Metformin: Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type II diabetes mellitus who are already treated with a meglitinide & metformin or who have inadequate glycemic control on a meglitinide alone or metformin

2. Nateglinide and Metformin: Used in patients with type-II diabetes in adequately controlled by diet, exercise and maximally tolerated dose of Metformin alone

By now, you must be aware of various fixed-dose combinations for treatment of diabetes mellitus licensed in India. These fixed-dose combinations are highly effective in controlling your blood sugar levels with a reduced rate of side effects and simple dosing schedules.

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