Fixed Dose Combinations & Rational Pharmacotherapeutics

1. Fixed Dose Combinations &Rational Pharmacotherapeutics DR VIJAY THAWANI vijaythawani@rediffmail.com vijaythawani.blogspot.com http://groups.yahoo.com/group/netrum

2. Background > 70,000 formulations From about750 API Domestic retail market = 70,000 crores p.a. FDCs account for 10% = 7,000 crores p.a. If 50% FDCs irrational = 3,500 crores p.a. going down the drain Only few FDCs have textual evidence. Manufacturers interested in economic gains. Improper implementation of regulations.

3. Rational therapeutics √Medicine √Manner (dose, route, frequency, duration) √ Patient √ Cost When necessary

4. Basis for rationality of FDCs • Constituent medicines in FDC should act by different mechanisms. • Pharmacokinetics must not vary widely. • Should not have supra-additive toxicity of the ingredients. • Must target a single disease like AIDS, TB, malaria.

5. The WHO Model List Some rational FDCs : • Sulfamethoxazole + Trimethoprim • Rifampicin + Isoniazid • Isoniazid + Ethambutol • Levodopa + Carbidopa • ORS • Estrogen + Progesterone

6. Advantages of FDCs • Simplify therapy •  Patient compliance • ↓ Total daily dose • ↓ ADRs • ↓ Cost of therapy

7. Advantages of FDCs (contd.) • Simpler dosage schedules improve compliance and T/t outcomes. • ↓ inadvertent medication errors. • Prevents / slows attainment of AM resistance by eliminating monotherapy. • Synergism e.g. Trimethoprim + Sulfamethoxazole: each selectively interferes with successive steps in bacterial folate metabolism. • One drug ↓ side effects of other. • One drug ↓ abuse potential of other e.g.excessive use of antidiarrheal narcotic Diphenoxylate is discouraged by SE of atropine in the FDC.

8. Where FDCs are useful ? CV diseases : FDCs with agents having complementary MOA • Increase patient adherence • Effectiveness of T/t. Combination therapy recommended for mgt of HT: • ACE inhibitors with CCBs, • ACE inhibitors with diuretics, • ARBs with diuretics, • ARBs with beta-blockers, • Centrally acting drugs with diuretics, • Diuretics with diuretics.

9. Non-therapeutic advantages of FDCs • Simplify medicine procurement,management, storage and handling • ↓ packing and shipping costs • ↓ risk of being “out of stock” • Single expiry date

10. Credits: VHAI, Banned and bannable drugs.

12. Disadvantages of FDCs • Dosage alteration of one medicine is not possible without alteration of the other. • Differing pharmacokinetics of constituent medicines pose problem of frequency of administration. • ↑ risk of ADRs & DI when compared to both medicines given individually.

13. Drawbacks of irrational FDCs • Impose unnecessary financial burden • ↑ ADRs • ↑ Episodes of hospitalization • ↓ QOL of consumers

14. Promotional gimmickry The ‘combined ’ pills are marketed with slogans like: • ‘ Ibuprofen for pain and Paracetamol for fever ’ • ‘ Ibuprofen for peripheral action and Paracetamol for central action ’

15. Evaluation study • In 33 / 44 FDCs the clinical evidence on safety and efficacy was established. • For remaining 11, no published evidence could be found. Panda J, Tiwari P, Uppal R. Evaluation of the rationality of some FDCs: Focus on antihypertensive drugs. Ind J Pharm Sci 2006;68:649-53 . 

16. Criteria for evaluating rationality of FDCs • Each API of FDC should be in the EML / NEML. • Dose of each API present in FDC should be appropriate for the intended use for the defined population group. • Combo should have advantage of established evidence of efficacy and safety over single compounds administered separately. • Overall cost of the FDC should be < cost of the individual components. • FDC should either ↓ dose of individual drugs or their ADRs. • The Pk parameters of each API should not be affected. There should be no unfavorable Pk interaction between the APIs. • Individual drugs should have different MOA.

17. Irrational FDCs in market • FDCs of Nimesulide + Paracetamol : Nimesulide alone is more antipyretic than paracetamol, more anti-inflammatory than aspirin, and equivalent in analgesia to any of the NSAIDS alone. Efficacy gains unlikely with added Paracetamol and pts are subjected to increased hepatotoxic effects from the combo. • FDCs of Diclofenac + Serratiopeptidase: No advantage over individual drugs despite the claim that Serratiopeptidase promotes more rapid resolution of inflammation. Pts exposed to greater risk of GI irritation and bleeding from peptic ulceration. • FDCs of Quinolones + Nitroimidazoles (e.g. Norfloxacin + Metronidazole; Ciprofloxacin + Tinidazole; Ofloxacin + Ornidazole) not recommended in any std text book.

18. Irrational FDCs • FDCs of NSAIDS / analgesics + antispasmodics Irrational & could be dangerous. • Antipyretic ↑ sweating • Anticholinergic antispasmodic ↓ sweating. Combining these two can result in dangerous elevation of the body temp.

19. Criticism of some FDCs

20. Norfloxacin + Metronidazole • Norfloxacin + Tinidazole • Norfloxacin +Tinidazole + Loperamide • Norfloxacin + Tinidazole + Dicyclomine • Norfloxacin + Ornidazole • Ciprofloxacin + Tinidazole • Ofloxacin + Tinidazole • Ofloxacin + Metronidazole • Ofloxacin + Ornidazole • Gatifloxacin + Ornidazole Though claimed to be broad spectrum, combining antiamoebic with antimicrobial is irrational because patients usually suffer from one type of diarrhea. Using FDCs  cost, ADRs and resistance.

21. Fluconazole + Tinidazole Doxycycline + Tinidazole Tetracycline + Metronidazole • Combining two AM to ↑ spectrum of activity is irrational, as the patient may need only one drug. The key point is to make a correct diagnosis.

22. Diazepam + Dried aluminium hydroxide gel + Aluminium glycinate + Oxyphenonium • Diazepam + Magaldrate + Oxyphenonium; • Diazepam + Dried aluminium hydroxide gel + Magnesium trisilicate + Dimethylpolysiloxane. Antacids ↑ gastric pH and ↓ absorption of benzodiazepines. • Cisapride + Omeprazole; • Mosapride + Pantoprazole ; • Ondansetron + Pantoprazole In patients with GERD, use of FDCs with addition of prokinetic drugs has shown no benefit.

23. Cetirizine + Phenylpropanolamine + Dextromethorphan • Cetirizine + Phenylpropanolamine + Paracetamol • Levocetirizine + Paracetamol + Phenylpropanolamine PPA is banned world over, but in India it is constituent of many cough - cold remedies. It has potential to cause stroke in hypertensive, aggravate DM, glaucoma and prostate enlargement.

24. Roxithromycin + Ambroxol • Ciprofloxacin + Ambroxol • Gatifloxacin + Ambroxol • Cefadroxil + Ambroxol • Cefixime + Ambroxol + Lactobacillus • Trials have failed to show superior efficacy of the FDC over Ambroxol alone in respiratory tract infection. Gatifloxacin has been withdrawn.

25. Domperidone + Rabeprazole Domperidone + Esomeprazole Increased incidence of rhabdomyolysis. Simvastatin + Nicotinic acid Atorvastatin + Nicotinic acid Probability of myopathy is increased. Enalapril + Losartan Combining two drugs affecting same pathway is irrational as it does not add to efficacy.

26. Amoxycillin + Cloxacillin Amoxycillin is inactive against staph, as most strains produce ß-lactamase and cloxacillin is not so active against strepto. For any given infection, one of the above components is useless and adds to cost & ADR. Since amount of each drug is halved, efficacy is ↓ and chances of selective resistant strains is ↑

27. Nimesulide + Diclofenac • Nimesulide + Dicyclomine + Simethicone • Nimesulide + Paracetamol • Nimesulide + Cetirizine + Pseudoephedrine • Nimesulide + Paracetamol + Tizanidine Nimesulide has been banned in many countries but available in India. Combining two NSAIDs may increase the SE of both. There is little documentary evidence that preparation containing > 1 analgesic is superior to a single ingredient preparation.

28. Limited Success story • Indian drug authorities banned some FDCs which did not have any therapeutic justification or were risky. e.g. FDCs of: Vitamins with anti-inflammatory agents and tranquilizers; Anti-histamines with anti-diarrhoeals.

29. What needs to be done? • Acknowledge irrational FDCs are a problem • Frame pro-people medicine policy • Implement that policy • Control FDC • approval, • production, • promotion, • availability and • use.

30. What needs to be done (contd.) • Irrational combinations should be replaced by formulations having rational and logical basis. • Careful monitoring and censorship of misleading claims. • CME / course for practitioners once in two years on newer FDCs, new drug molecules, introduced in the market.

32. Can WE change FDC scenario & bring in Rational Pharmacotherapeutics?