India’s apex drug regulator has granted conditional approval for producing and selling five fixed-dose combination (FDC) medicines which were previously under consideration for a ban.
These drugs include antidepressants, cough syrups, cold and flu medicines and headache or body pain relievers. Some of the known brands include D Cold Total, Saridon Triple Action, Piriton Syrup and Dolo Cold.
The regulator has asked drug manufacturers to provide post-marketing safety and efficacy data for three combinations. Additionally, changes to the dosage and information labels are required for the remaining two combinations. The regulator has also suggested conducting phase IV clinical trials to generate safety and clinical data for some combinations.
FDC, or cocktail medicines, combine more than one drug in a single pill, and have increasingly come under the government lens as combinations of drugs, such as antibiotics, can result in resistance to the drug in the disease-causing organism.
Of the 19 FDCs, in June, the Union government — on orders of the drug regulatory agency Central Drugs Standard Control Organisation (CDSCO) — announced the ban on 14 FDCs after they were found to lack therapeutic relevance.
These drugs have been under the scanner because a lax regulatory framework allowed several unscientific combinations to flood the market. There are also fears that this may increase drug resistance in people.
The drug regulator has ordered every manufacturer — permitted to manufacture the given five FDCs — to submit the periodic safety update reports (PSURs) as per New Drugs and Clinical Trial Rules, 2019, to the Central Licensing Authority.
“Failure to submit the PSURs shall be considered as contravention of these rules,” according to the order undersigned by the Drug Controller General of India, Rajeev Singh Raghuvanshi, who heads the CDSCO.
What these five combinations will be changing
1. Paracetamol IP 500mg + Phenylephrine Hydrochloride IP 10mg + Caffeine Anhydrous IP 32mg tablets
The combination is used to relieve fever, congestion and body pain. Some of the medicines using the same combination include D Cold Total and Dolopar.
The committee recommended continued manufacturing and marketing of the FDC with the condition of generating safety and efficacy data by way of conducting Phase IV Clinical Trial.
Accordingly, a Phase VI Clinical Trial is required to be conducted to generate the data within the time frame of one year.
2. Caffeine Anhvdrous IP + Paracetamol IP + Phenylephrine Hydrochloride IP + Chlorpheniramine Maleate IP tablets
This combination is also used to treat cough and cold. Micro Labs’ Dolo Cold and Cipla’s NoCold are part of this category.
The condition is that the medicine shall be sold by retail on the prescription of a registered medical practitioner only. The package insert should also mention caution for patients suffering from cardiovascular diseases.
“Dose of Paracetamol in the FDC should be a minimum 500mg,” the order said.
Also, the committee recommended conducting a randomised comparative, phase IV clinical trial comparing the FDC with the individual ingredients present in the FDC. This trial is required to be conducted to generate the data “within a time frame of one year”.
3. Paracetamol IP 250mg + Propyphenazone 150mg + Caffeine 30mg tablets
This combination belongs to a class of painkillers called non-steroidal anti-inflammatory drugs (NSAIDs). This combination is used to manufacture Saridon Triple Action.
The committee recommended continued manufacturing and marketing of the FDC for “mild to moderate headache” but with conditions.
Firstly, this combination shall not be taken for more than 5-7 days and must be sold by retail on prescription only.
Also, the manufacturers must conduct an active post-marketing study to generate safety and efficacy data within the time frame of one year.
4. Imipramine Hydrochloride IP plus Diazepam IP (25mg +2mg &25mg +continued manufacturing and 5mg) tablets
The combination is used to manufacture anti-depressant medicines. “FDC shall be indicated for co-morbid anxiety conditions and duration of the treatment should not exceed 6 to 8 weeks,” the order stated.
5. Chlorpheniramine Maleate IP Ammonium Chloride IP + Sodium Citrate IP Syrup
This includes a list of popular cough syrups, including Piriton and Redikuf.
The committee noted that the firms are manufacturing the FDC in different strengths. The committee also noted that as per the literature available, sodium citrate is administrated 0.3gm to 1gm in divided doses in a day and chlorpheniramine maleate is administered 4mg to 16mg in divided doses in a day.
The government order recommended for continued manufacturing and marketing of the FDC with the condition that “the firm should modify the prescribing information or label by clearly mentioning the dosing schedule for adults and children keeping given the above-stated dose range without exceeding the maximum permissible dose”.
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