Fixed Dose Combinations &

Rational Pharmacotherapeutics

DR VIJAY THAWANI

vijaythawani@rediffmail.com

vijaythawani.blogspot.com

http://groups.yahoo.com/group/netrum

Background• > 70,000 formulations• From about 750 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.

Rational therapeutics

√ Medicine

√ Manner (dose, route, frequency, duration)

√ Patient

√ Cost

When necessary

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.

The WHO Model List

Some rational FDCs : • Sulfamethoxazole + Trimethoprim• Rifampicin + Isoniazid• Isoniazid + Ethambutol• Levodopa + Carbidopa • ORS• Estrogen + Progesterone

Advantages of FDCs

• Simplify therapy

• Patient compliance • ↓ Total daily dose

• ↓ ADRs

• ↓ Cost of therapy

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.

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.

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

Credits: VHAI, Banned and bannable drugs.

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.

Drawbacks of irrational FDCs

• Impose unnecessary financial burden

• ↑ ADRs • ↑ Episodes of hospitalization

• ↓ QOL of consumers

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 ’

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 . 

Criteria for evaluating rationality of FDCs

1. Each API of FDC should be in the EML / NEML. 2. Dose of each API present in FDC should be

appropriate for the intended use for the defined population group.

3. Combo should have advantage of established evidence of efficacy and safety over single compounds administered separately.

4. Overall cost of the FDC should be < cost of the individual components.

5. FDC should either ↓ dose of individual drugs or their ADRs.

6. The Pk parameters of each API should not be affected. There should be no unfavorable Pk interaction between the APIs.

7. Individual drugs should have different MOA.

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.

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.

Criticism of some FDCs

• 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.

Fluconazole + TinidazoleDoxycycline + 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.

• 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.

• 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.

• 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.

Domperidone + Rabeprazole Domperidone + EsomeprazoleIncreased incidence of rhabdomyolysis.

Simvastatin + Nicotinic acidAtorvastatin + Nicotinic acid Probability of myopathy is increased.

Enalapril + Losartan Combining two drugs affecting same pathway is irrational as it does not add to efficacy.

4. Domperidone + Rabeprazole; Domperidone + Esomeprazole Increased incidence of rhabdomyolysis.

• 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 ↑

• 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.

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.

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.

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.

Can WE change FDC scenario & bring in Rational Pharmacotherapeutics?