Treating young children afflicted by drug-sensitive TB disease will no longer be the same. After years of neglect, the availability of flavoured, easily dissolvable first-line TB drugs in correct doses marks a watershed moment as the special needs of these children will be met. The tablets, which are a combination of two and more medicines in a fixed dose (FDC), are meant for children weighing less than 25 kg.
At this momentous time, it is a matter of pride that India has gone beyond being the “pharmacy of the South” with the Mumbai-based Macleods Pharmaceuticals Limited supplying the paediatric TB medicines to the entire world. “Our capacities are sufficient to meet the global demand”, said Vijay Agarwal, Business Development Director of Macleods Pharmaceuticals in an email to The Hindu . Lupin Pharmaceuticals, also based in Mumbai, is expected to produce the combinations later in 2016.
“The Revised National Tuberculosis Control Program in India has made the child TB program a priority. India expects to roll out the new FDCs in a pilot project in 100 districts”, Dr. Cherise Scott, head of paediatric programs at TB Alliance, Geneva said in an email to The Hindu .
According to the World Health Organisation, at least 1 million children become ill with TB each year and 140,000 children die each year. It’s an irony that despite the high demand, children around the world have not had access to appropriate TB medicines.
Young children, who have relatively greater mass of liver in proportion to total bodyweight, absorb and eliminate drugs faster than adults. Children are not little adults but need higher doses of the medicines than what they were receiving and what is prescribed for adults.
Recognizing this, the WHO issued the dosing guidelines for children in 2010 and recommended the composition of the fixed-dose combination in 2012.
But pharmaceutical companies did not rise to the occasion due to several reasons. Difficulty in diagnosing childhood TB led to underestimation of the number of paediatric TB cases. “It’s a vicious circle, no demand, no market, no innovation. If there is no one to support the development and no market, no company will invest in developing such kind of drugs”, said Dr. Philippe Duneton, Deputy Executive Director, UNITAID, Geneva in an email to The Hindu . UNITAID and USAID provided upfront funding and TB Alliance worked across all areas — researchers, manufacturers, regulators, governments and advocates — to bring these products to the market.
In the absence of medicines of correct dosages, parents and caregivers were forced to crush or cut medicines meant for adults to achieve correct dosing. Very often, the crude method of crushing adult tablets resulted in imprecise dosing, not to mention the bitter taste when tablets were broken. “It is likely that cutting and crushing of adult pills could have contributed to drug resistance as caregivers were never fully sure to give the right dosages”, Dr. Malgorzata Grzemska, Coordinator, Technical Support Coordination, Global TB programme, WHO, Geneva said in an email to The Hindu .
The availability of child-friendly drugs of correct dosages will have many advantages — dramatically simplify and improve adherence, improve overall treatment, stop the growth of drug-resistant TB, and save lives. “The FDCs will prove to be a game changer”, said Dr. Duneton.
“In India, children are treated with many disparate regimens. Having fixed-dose combinations in the correct doses and that are easy for providers to give and for children to take could dramatically improve treatment”, said Dr. Scott.
The fixed-dose drugs are already available and countries can place an order, which can take 2-3 months for delivery. “These drugs will be primarily distributed through WHO’s Global Drug Facility (GDF). We will supply within 10 weeks of receipt of orders from GDF. Also, these products can be purchased [by countries] directly from Macleods”, said Mr. Agarwal.
The FDCs are priced at approximately $15.54 for a six-month course of treatment. “They cost approximately 20 per cent more than today’s improperly-dosed products,” said Dr. Scott.
Macleods Pharmaceuticals has already submitted its applications for approval of these products to the Drugs Controller General of India (DCGI). “We have requested the DCGI to expedite the approval process”, said Dr. K.S. Sachdeva, Additional Deputy Director General, Central TB Division, Ministry of Health and Family Welfare.
Bioequivalence studies of the new combinations have already been done, based on which the products were approved by the WHO’s Expert Review Panel. “No other trials need to be undertaken to start using these products”, said Mr. Agarwal.
Children will be treated with two fixed-dose combinations — rifampicin, isoniazid and pyrazinamide for the first two months (intensive phase), and then isoniazid and pyrazinamide for the remaining four months (continuation phase).
Due to HIV infection and isoniazid resistance in the country, India advocates four drugs, including ethambutol to treat TB. “Ethambutol has to be given separately as it cannot be combined with other three drugs”, said Dr. Soumya Swaminathan, Director General of ICMR.
“A new formulation of Ethambutol 100 mg dispersible is under development. It will be made available as soon as possible”, said Mr. Agarwal.