Fixed Dose Combinations

Fixed Dose Combinations Contents… F D C         Definition Need of FDCs Schedule Y Then why BAN? A case study Present scenario :INDIA Summary References Definition F D C A fixed dose combination (FDC) is a formulation of two or more active ingredients combined in a single dosage form available in certain fixed doses. NOTE: FDCs are treated as NEW DRUGS as per Drugs & Cosmetics Act (RULE 122E) Cocktail Drugs Need Of FDCs F D C To prevent drugresistant strains Patient Compliance FDC NEED REASON SCHEDULE Y : APPENDIX VI FIXED DOSE COMBINATIONS F D C 1ST criteria New +New/ Approved 4 Groups of FDCs Approved + Approved Marketed FDC Marketed + Marketed ONLY convenience 2nd criteria 3rd criteria 1st Category APPROVED / F D C • Marketing data to be submitted will be similar to the data required for any new drug (including clinical trials) + nd 2 Category + APPROVED ACTIVE INGREDIENT • Combination is 1st time. • Perticular theraputic claim • The ingredients are likely to have significant interaction of a pharmacodynamic or pharmacokinetic nature.  F D C + APPROVED ACTIVE INGREDIENT 3 Criteria's F D C 1st criteria: If clinical trials have been carried out with the FDC in other countries If FDC is marketed abroad Reports of such trials should be submitted. Regulatory status in other countries should be stated 2nd criteria : • These drugs are already in use concomitantly (not as an FDC but individually) for the said claim. F D • But a combination is not marketed anywhere in the world Then following should be submitted ….. C Chemical and pharmaceutical data Data showing the stability of the proposed dosage form 3rd criteria: : Any other such FDCs, clinical trials may be required ….. F D C • Then following should submitted A summary of available pharmacological, toxicological & clinical data on individual ingredients.  The rationale for combining them in proposed ratio.  Acute toxicity data (LD 50) & pharmacological data on individual ingredients as well as their combination in proposed ratio. 3rd Category F D C  The ratio of active ingredients change or  To make a new therapeutic claim. .  For such FDCs, appropriate rationale including published reports (if any) should be submitted to obtain marketing permission.  Permission will be granted depending upon nature of claim & data submitted. 4th Category + F D C +  Widely used in a particular indication(s) for years.  Their concomitant use is often necessary.  No claim is proposed to be made other than convenience.  It will have to be demonstrated that the proposed dosage form is stable  NO significant interaction of a pharmacodynamic or pharmacokinetic nature. Applications Submitted for FDCs – Guidelines by FDA F D C • Data showing lack of Interaction between Active Ingredients • Appropriate Quality Standards for each Active Ingredient and for the Dosage Form • Assurance of Reproducible Drug Release from the Dosage Form • Stability Data • References or Data Supporting Safety of Excipients • Demonstration that Manufacturing Processes for Active Ingredients & Dosage Form are Defined & Understood • Selection of Packaging Then Why BAN ……. Reasons F D C • Useless • Increase financial burden • Increase in unwanted effects • Fall in bioavailability • Instability of formulations • Difficult to understand responsible agent for adverse reaction • An ineffective dosage Cont…. F D C = 2 Trimethoprim + Sulphonamide  Antibacterial activity = -2 Carbamazepine + Diuretics  Effect =3 Streptomycin + Kanamycin  toxicity Cont…. F D C Treatment Difficult +Expensive A CASE STUDY ……… Of an irrational FDC F D C • • Stamlobeta Treatment by her doctor Atenolol 50mg + Amlodipine 5mg more susceptible to infections 54 years old Hypertension Solution : • Amlodipine  Diarrhea F D C • Atenolol  Indigestion. • Best solution o Atenolol 50mg in the morning o Amlodipine 5mg in the evening NOTE: Bigger problem is not combination but FIXED dose combination Disadvantages of FDCs: F D C Disadvantages are, 1) Fall in BA of Rifampicin. 2) Instability of formulation. 3) Hepatotoxicity leading to Hepatitis. • Eg:TB treatment: Rifampicin + Ethambutol + Pyrazinamide + Isoniazid Present Scenario: India F D C • The World Health Organization (WHO) lists 325 essential drugs, including only 19 FDCs. • The national list of essential medicines have 354 essential drugs, including 14 FDCs . ESSENTIAL 14 FDCs (National list) F D C 1) Acriflavin+Glycerin 2) Al(OH)3 +Mg(OH)2 3) Benzoic + Salicylic Acid 1) Trimethoprim + Sulphamethoxazole 2) Ethinylestradiol + Levonorgesterol 6) Ethinylestradiol + Norethisterone 7) Lamivudine + Zidovudine 8) Lamivudine +Nevirapine + Stavudine 9) Levodopa+ Carbidopa 10) Levodopa+ Carbidopa 11) Lignocaine Hydrochloride + Adrenaline 12) Neomycin + Bacitracin 13) Sulfadoxine +Pyrimethamine 14) Thiacetazone + Isoniazid ESSENTIAL 19 FDCs ( WHO list) F D C • • • • • • • • • • Neomycin + Bacitracin Amoxicillin + Clavulanic Imipenem + Cilastatin Sulfamethoxazole + Trimethoprim Sulfamethoxazole + Trimethoprim Isoniazid + Ethambutol Rifampicin + Isoniazid Rifampicin + Isoniazid + Pyrazinamide Thiacetazone + Isoniazid Benzoic acid + Salicylic acid • Ethinylestradiol + Levonorgestrel • Ethinylestradiol + Levonorgestrel • Ethinylestradiol + Norethisterone • Levodopa + Carbidopa 15. Ferrous salt + Folic acid • Sulfadoxine + Pyrimethamine • Lidocaine + Epinephrine • Oral Rehydration Salts: Sodium chloride + • Trisodium citrate dihydrate + Glucose +Potassium chloride Combination vaccines: F D C Currently in use are • DTP • DTaP (diphtheria- tetanus –pertussis ) • Trivalent IPV ( three strains of inactivated polio vaccine) • MMR (measles mumps & rubella) • DTaP-Hib • Hib +HepB (hepatitis B) Entire list of banned FDCs in India F D C Fixed dose combinations of Penicillin with Sulphonamides. Fixed dose combinations of Vitamins with Analgesics • http://www.pharmabiz.com/default.asp (Saturday , 16th February ,2008 Pharmabiz online issue ) • http://cdsco.nic.in/ Recently approved FDCs F D C • • • • Niacin & Simvastatin 3/5/08 Aliskiren & Hydrochlorothiazide 2/6/08 Amlodipine & Olmesartan 11/7/07 Acetaminophen, Dextromethorphan, Phenylephrine (new formulation) 6/7/07 • Amlodipine & Valsartan 6/7/07 • Sitagliptan & Metformin 4/7/07 • Atropine & Pralidoxime 2/7/07 ONGOING CLINICAL TRIAL F D C Tuberculosis Research Centre (TRC) • Four month regimen for TB by using Fluroquinolone as a combined therapy. • Conducting a clinical trial to study the efficacy of treatment in patients with both HIV & TB. FAILURE CLINICAL TRIAL FOR FDC Pfizer F D C  Torcetrapib - drug being developed to treat hyper cholesterolemia in combination with Atorvastatin (Lipitor)  1990 - Development of the drug began  1999- first administered in humans  2004 trial -Torcetrapib could increase HDL and lower LDL  2006 , Phase III trial- a 60% increase in deaths among patients taking Torcetrapib and Atorvastatin versus taking Atorvastatin alone  December 2, 2006 - cut off Torcetrapib's trial MAJOR PLAYERS TO BAN IRRATIONAL FDCs F D C DCGI IRRATIONAL FDC BAN CONTRIBUTORS INTERNATIONAL REGULATORY BODIES IDMA DOCTORS Steps to remove irrational FDCs: F D C Summary: F D C • Schedule Y considers FDCs as NEW Drugs. • FDCs are very much needed as a new drug therapy for various serious health conditions like Tuberculosis, HIV, etc. • Some irrational FDCs are useless & sometimes harmful. • DCGI has taken an initiative to remove these FDCs from the market. References F • http://content.nejm.org/ D C • • • • • • http://medind.nic.in/ibi/ibim.shtml http://www.expresspharmaonline.com/ http://www.pharmabiz.com/ http://www.fda.gov/ http://www.icmr.nic.in/pinstitute/trc.htm http://economictimes.indiatimes.com/