People are forced to use more than one medicine for treatment of either single ailment or multiple co-morbid conditions. If some of the fixed drug combinations (FDCs) are useful, a large number available in the country are irrational and useless and potentially dangerous. On many occasions manufacturers go for FDCs with the objective of generating prescriptions and to make profits. Ideally drugs have to be administered as individual items based on the specific requirement of each patient. It enables the prescriber to select specific drugs in specific doses for specific durations to individual patients in certain specific conditions. However, on certain special occasions or situations we may have to unite together certain drugs for better results, convenience and certain other benefits. When two or more drugs are combined together in a fixed ratio into a single dosage, it is known as Fixed Dose Combinations or FDCs. Maximum FDC preparations comprise vitamins, cough suppressants, anti-diarrhoeal, iron preparations, antacids, analgesics and tonics.
Clinical studies and research find that combination medicines are useful and effective in the management of certain diseases. In certain cases FDCs help to improve the quality of life and also the efficacy of the medicine. They also help to reduce te number of pills taken by the patient at a time. FDCs available for the treatment of various ailments range from nutritional deficiency to cardiovascular diseases. In certain cases FDCs help to simplify treatment regimens, improve patient adherence and facilitate implementation of interventional programs and prevent the development of drug resistance. Most effective treatment against malaria is a combination of drugs using artemisinin derivatives. Artemisinin-based combination therapy is the quickest and most reliable way of clearing malaria infection. Here use of a combination of drugs shortens the treatment course. WHO has recommended phasing out monotherapy in the treatment of malaria.
Certain situations where FDCs are beneficial to the patients
(i) Where two or more drugs have a synergistic action. It means that the combination acts to have a better therapeutic response than the individual drugs if used separately.
(ii) Where there is a corrective action. That is, one drug may act to reduce the incidence, intensity or severity of adverse effects caused by the other.
(iii) Where the combination helps for enhancing therapeutic efficacy.
(iv) Where combination will enhance patient compliance.
(v) Where the combination can reduce the dose of individual drug.
(vi) Where it decreases the development of drug resistance.
(vii) Where the combination drug is cheaper than individual drugs because of reduced cost from packaging to distribution and sales.
The Bad and the ugly
Take the case of antihypertensive drug atenolol. There is an allegation that when atenolol could not generate enough sales, it was mixed with alprazolam (used to treat anxiety and panic disorders) to create an expensive 'novel' product. The same is the case with combinations like nimesulide (anti-inflammatory) with paracetamol. The non-steroidal anti-inflammatory diclofenac is generally taken three times a day. Why is it mixed with famotidine (used to treat ulcers) which is usually given once in a day (bet time)? Mebendazole (anti-worm) is taken either two or three times a day for three days as an anthelmintic (destroyer of parasitic worms). Pyrantel is another anthelmintic taken as a single dose. Why these two are mixed and marketed as FDC? Whether clinical studies were conducted either at the time of approval or in post-marketing stages in the country?
Ampicillin and cloxacillin combinations are available in plenty in various dosage forms like capsules, dry syrups, injections or kid tablets in the country. Both of them belong to the same group of penicillin and act by same mechanism without any synergism. The fixed ratio takes the flexibility of changing one or other antibiotic. The two can be concurrently used wherever needed. Similarly many FDCs of amoxicillin and cloxacillin are available in the market. Is there any rationale in promoting, marketing and prescribing such FDCs?
Drugs like ibuprofen, ketoprofen, diclofenac and paracetamol belong to a single category of drugs - Non-Steroidal Anti Inflammatory Drugs (NSAIDS). Paracetamol has both analgesic and antipyretic actions equally. Ibuprofen and diclofenac have mainly anti-inflammatory action in addition to their analgesic and antipyretic effects. All these effects are produced by inhibition of synthesis of prostaglandins. Since the mechanism of action is same, there is no synergism.
There is a need to weed out irrational and unethical combinations for the safety of patients. Drug authorities, particularly at the state-level, had endorsed approval for the production and marketing of FDCs. India needs an effective mechanism to assess and prove that the FDC is rational and genuinely necessary.
Pharma policy 2017: Impact on FDCs
The draft of the Centre’s Pharmaceutical Policy 2017 published recently does not specifically mention the issue of FDCs. However, the policy takes up issues of generic prescription and dispensing, which has an indirect impact on FDCs. The new policy prescribes bioavailability and bioequivalence (BA 7BE) tests to ensure quality of medicines. The Central Drug Regulator will conduct regular annual audit of laboratories which are accredited to conduct BA/BE tests and certify results. Besides, the Central Drug Regulator shall also get all manufacturing units inspected at least once annually through an accredited network of third party inspectors/agencies (national/international) empanelled by it. Self-certification of manufacturing units can also be considered as an effective mechanism till such time that Central Drug Regulator develops capacity for annual inspections.
Parliamentary committee report and its impact on fixed combinations
The 59th Standing Parliamentary Committee that investigated the functioning of Central Drugs Standard Control Organization (CDSCO) in 2012 observed that the CDSCO “had skewed priorities, according primacy to the propagation and facilitation of the drugs industry, due to which, the interest of the biggest stakeholder, i.e. the consumer has never been ensured.” The committee pointed out that some State Licensing Authorities (SLAs) have been issuing manufacturing licenses for FDCs without prior clearance from the Drugs Control General. About two-thirds of FDCs are manufactured and marketed without the license of DCGI. Medicines banned or used under strict regulations were also found widely used as FDCs.
In September 2014, the Ministry of Health and Family Welfare constituted a committee under the chairmanship of Dr C.K.Kokate for examining applications for rationality, safety, and efficacy of the FDCs.
The Committee classified FDCs under 4 categories
Category “a” – FDCs considered as irrational.
Category “b” – FDCs requiring further deliberations with subject experts;
Category “c” – FDCs considered as rational.
Category “d” – FDCs requiring further generation of data.
The Committee submitted its final report – “Evaluation of cases of FDCs” to the Centre in February 2016. The Centre banned 344 FDCs under Section 26A of the Drugs and Cosmetics Act 1940 the next month. Out of them over 60 are combinations of antibiotics. The ban of 344 combinations affected about 7,000 brands of many firms, including major manufacturers like Abbott Healthcare, Macleods Pharma, Pfizer, Mankind, Alkem, IPCA, Medly, Glenmark, Franco Indian, Woekhardt and Aristo.
The ban dented annual sales to the tune of Rs 500 crore to Rs 100 crore to certain firms. In December 2016, the Delhi High Court stayed the ban of 344 FDCs citing technical reasons. The subsequently directed all High Courts to stop hearing all cases against the ban of the 344 FDCs and forward the cases to Supreme Court. The Supreme Court has directed the Centre to classify FDCs and submit it to the Court.
(Dr. K.G. Revikumar is well known pharmacist)...