The Ministry of Health and Family Welfare, Government of India has recently prohibited the manufacture for sale, sale or distribution for human use of 328 fixed dose combinations (FDCs) with immediate effect, including FDCs in diabetes.
All of us have read the Government’s notification on FDCs and it has generated some confusion and also raised several questions as to what is allowed and what is not allowed.
Let us talk about the rationality of use of FDCs in diabetes.
Type 2 diabetes is a progressive disease, characterized by insulin resistance and β-cell dysfunction. As the disease runs its course, the initial oral hypoglycemic agent (OHA) prescribed may lose its efficacy leading to inadequate glycemic control, which requires sequential addition of a second or even a third drug belonging to a different class of OHAs, to achieve target or desired glycemic control.
Combination therapy administered as separate medications may deter patient from adhering to the prescribed treatment.
Combining two or more OHAs as a single-dose fixed-dose combinations (FDCs) therefore improves treatment adherence by minimizing medication burden to the patient and also reduces costs of treatment, which is a very important consideration, given that out of pocket expenditure on health is amongst the highest in India.
A widely used FDC in diabetes is the combination of glimepiride, metformin and pioglitazone in two strengths: lower strength (7.5 mg) & higher strength (15 mg).
Triple drug combinations reduced A1c to a greater extent than two drugs in a systematic review and meta-analysis of randomized controlled trials, which examined the addition of a third agent after dual therapy failure in patients inadequately controlled with two agents (predominantly metformin and a sulfonylurea or metformin and a thiazolidinedione),. In trials lasting 52 to 54 weeks, addition of thiazolidinediones, GLP-1 receptor agonists, or SGLT2 inhibitors to metformin and sulfonylurea reduced A1c to a similar extent (Diabetes Obes Metab. 2018 Apr;20(4):985-997).
It is important to note that the Govt. notification also says, “It has also “restricted” the manufacture, sale or distribution of six FDCs“subject to certain conditions”.
The Govt. of India’s notification has recommended the discontinuation of only the FDCs containing lower strength of pioglitazone because of inadequate published international literature, but has allowed the FDC of glimepiride and metformin with pioglitazone in higher strength (15mg).
The notification has not questioned the safety and efficacy of the three molecules. The only issue raised is use of a particular strength of the molecule.
Anti-diabetic triple FDCs containing glimepiride, metformin with high dose pioglitazone are approved by DCGI and all patients can be continued on the existing medication.
In case a patient happens to be on the FDC containing the lower strength of pioglitazone (7.5mg), he should be evaluated again.
Status of FDCs for diabetes
Strength | Status |
Glimepiride (1mg/2mg) + Pioglitazone (15mg) + Metformin 500mg (Immediate Release/Sustained Release/ Extended Release) Tablet | Allowed |
Pio 7.5 + Met 500/1000 | Prohibited |
Glimepiride 1/2/3 + Pio 15 + Met 1000 | Prohibited |
Glimepiride 1mg/ 2mg + Pioglitazone 15mg/ 15mg + Metformin 850mg/ 850mg v | Prohibited |
Metformin 850mg + Pioglitazone 7.5 mg + Glimepiride 2mg | Prohibited |
Metformin 850mg + Pioglitazone 7.5 mg + Glimepiride 1mg | Prohibited |
Metformin 500mg/ 500mg + Gliclazide SR 30mg/ 60mg + Pioglitazone 7.5mg/ 7.5mg | Prohibited |
Voglibose + Pioglitazone + Metformin | Prohibited |
Pioglitazone 30 mg + Metformin 500 mg | Prohibited |
Pioglitazone 15 mg + Metformin 850 mg | Prohibited |
Metformin + Gliclazide + Pioglitazone + Chromium Polynicotinate | Prohibited |
Metformin (sustained release) 500mg + Pioglitazone 15 mg + Glimepride 3mg | Prohibited |
Metformin (SR) 500mg + Pioglitazone 5mg | Prohibited |
The relevant section of the notification is reproduced as below:
NOTIFICATION New Delhi, the 7th September, 2018 S.O. 4711(E).—Whereas, the Central Government in exercise of the powers conferred by section 26 A of the Drugs and Cosmetics Act, 1940 (23 of 1940) prohibited the manufacture for sale, sale and distribution for human use of drug fixed dose combination of Glimepiride + Pioglitazone + Metformin vide S.O. number 815 (E) published in the Gazette of India: Extraordinary Part II- Section 3(ii), Dated the 10th March, 2016; And whereas, in compliance with the directions given by the Supreme Court of India in its judgement dated the 15th December, 2017 in Union of India and Anr. v/s Pfizer Ltd. and Ors. Civil Appeal No. 22972 of 2017 (Arising out of SLP (c) No.7061 of 2017), the matter was examined by Drugs Technical Advisory Board constituted under section 5 of the Drugs and Cosmetics Act, 1940 (23 of 1940) which furnished its report on the 31st July, 2018 in respect of above drug to the Central Government. And whereas, the Drugs Technical Advisory Board recommended that “FDC of Glimepiride + Pioglitazone + Metformin may be restricted under section 26A for the following strengths: 1. Glimepiride (1mg/2mg) + Pioglitazone (15mg) + Metformin 500mg (Immediate Release/Sustained Release/ Extended Release) Tablet for "Treatment of type-2 diabetes mellitus (T2DM) when diet, exercise along with monotherapy and dual therapy does not achieve glycaemic target" as this FDC with the said strengths is rational for the defined patient population. Further, the label and all the promotional literature including the package insert shall mention the precautions for individual drugs. Any other strength of FDC of Glimepiride + Pioglitazone + Metformin except above mentioned strengths is not recommended”. Now, therefore, in supersession of the notification of the Government of India, Ministry of Health and Family Welfare (Department of Health and Family Welfare) published in the Gazette of India, Extraordinary, Part II, Section 3, Sub-section (ii), vide number S.O. 815 (E) dated the 10th March, 2016 and in exercise of the powers conferred by section 26A of the Drugs and Cosmetics Act, 1940 the Central Government hereby, restricts the manufacture, sale or distribution of the drug Fixed Dose Combination of Glimepiride + Pioglitazone + Metformin subject to the following conditions,- - the manufacture, sale or distribution of the said drug shall be in the strength of Glimepiride (1mg/2mg) + Pioglitazone (15mg) + Metformin 500mg (Immediate Release or Sustained Release or Extended Release) Tablet only;
- the said drug shall be used for treatment of type-2 diabetes mellitus (T2DM) when diet, exercise along with monotherapy and dual therapy does not achieve glycaemic target; and
- in respect of the said drug, the label and all the promotional literature including the package insert shall mention the precautions for individual drugs respectively.
This notification shall come into force with immediate effect. [F. No. X.11035/53/2014-DFQC (Pt. II)] SUDHIR KUMAR, Jt. Secy. |
Dr KK Aggarwal
Padma Shri Awardee
Vice President CMAAO
Group Editor-in-Chief IJCP Publications
President Heart Care Foundation of India
Immediate Past National President IMA
