Transcript Fixed Dose Combinations & Rational Pharmacotherapeutics DR

Fixed Dose Combinations
&
Rational Pharmacotherapeutics
DR VIJAY THAWANI
[email protected]
vijaythawani.blogspot.com
http://groups.yahoo.com/group/netrum
Background
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> 70,000 formulations
From about 750 API
Domestic retail market =
FDCs account for 10% =
If 50% FDCs irrational =
70,000 crores p.a.
7,000 crores p.a.
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
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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 :
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Sulfamethoxazole + Trimethoprim
Rifampicin + Isoniazid
Isoniazid + Ethambutol
Levodopa + Carbidopa
ORS
Estrogen + Progesterone
Advantages of FDCs
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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
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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.
Irrational FDCs in market
• FDCs of Nimesulide + Paracetamol : Nimesulide alone is
more antipyretic than paracetamol, more antiinflammatory 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
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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 + 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.
• 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 + Esomeprazole
Increased incidence of rhabdomyolysis.
Simvastatin + Nicotinic acid
Atorvastatin + Nicotinic acid
Probability of myopathy is increased.
4. Domperidone + Rabeprazole; Domperidone + Esomeprazole Increased incidence of
rhabdomyolysis.
Enalapril + Losartan
Combining two drugs affecting same pathway
is irrational as it does not add to efficacy.
• 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 ↑
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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?