Toddlers across India infected with HIV or suffering from AIDS are not getting their doses of antiretroviral medicine. The National Aids Control Programme or NACO has, in March, completely run out of a syrup comprising the drugs lopinavir and ritonavir, which is given to children up to age of three with HIV and AIDS.
There are approximately 500 toddlers who depend on the medicine, said Dr RS Gupta, deputy director general of NACO. HIV and AIDS patients need to take their antiretroviral medicines at fixed times every day. Missing or skipping a dose escalates the chances of drug resistance with patients failing to respond to the drugs.
The antiretroviral syrup is normally administered in combination with two other drugs – lamivudine along with zidovudine or abacavir. Lamivudine in combination with zidovudine or abacavir is available in liquid formulations for children.
Cipla, which is the only producer of the syrup, had stopped manufacturing it in 2015. However, NACO issued tenders for the syrup only in October 2016, and then again in January 2017, when nobody bid for it in the previous round. NACO bought its last consignment of the drug in from Cipla in 2014, which ran out between January and February this year.
After about a month of the stockout, NACO placed “emergency” orders with a company in Haryana’s Ambala district, McNeil & Argus Pharmaceuticals, that has produced the medicine only twice so far – in 2013 for Bangladesh and in 2015 for Iran.
McNeil & Argus Pharmaceuticals chairman GD Chibber said that the company can manufacture the drug in 10-15 days.
Meanwhile, NACO has issued a notification informing antiretroviral centres across the country to advise parents to break tablets into parts to give to their children. NACO said that this stop gap measure can be performed with tablets normally prescribed for children or even the ones given to adults.
“The parent can dissolve part of the tablet in water and give the child,” said Gupta. “Or divide it into pieces. If you cannot do that, you can nicely grind it and make it into a powder and then use it.”
Timeline to a stock out
- 2014: NACO got a stock of lopinavir/ritonavir syrup from Cipla which is the sole maker of the drug in the country.
- 2015: Cipla stops manufacture of the syrup and switches over to pellets of the same formulation.
- October 2016: NACO issued tenders for syrup but no company bid.
- January 2017: NACO issued tenders for the syrup again. The activists working with HIV patients informed them that Cipla has stopped manufacturing the drug.
- January 2017: The stock of syrup acquired from Cipla in 2014 ran out.
- End of February 2017: NACO requests McNeil & Argus Pharmaceuticals to manufacture the syrup on an emergency basis.
“Not a good product”
Dr Denis Broun, director of public and government affairs for Cipla Global, has said that the company stopped producing the syrup in 2015 because it “was not a good product”.
“It had a high alcoholic content (equivalent to giving babies a shot of whisky twice a day), tasted extremely foul (experience showed that a lot of the syrup was spat by babies) and required refrigeration to be kept active,” said Broun.
Parents of children who have had this syrup agree that the syrup was not palatable. “My child used to vomit the syrup,” said a father of a two-and-half-year old from Durg district in Chhattisgarh. “It was too bitter.”
Cipla developed a different formulation that had no taste and no alcohol, and could be stored at room temperature. These were pellets of lopinavir and ritonavir, packaged as micro-tablets inside a capsule. The number of capsules a child has to take depends on the child’s weight and age. The capsule can be opened by the parents and the micro-tablets can be mixed with the child’s food.
In 2015, after the United States Food and Drug Administration approved the pellets, Cipla discontinued manufacture of the syrup.
“These pellets replace the syrup and are available in many countries,” said Broun. “In India, their availability will depend on their approval by Drugs Controller General of India. As soon as they are registered in India, they can be procured by NACO.”
Cipla made an application seeking registration of the pellets in February 2016. But the Central Drugs Standard Control Organisation’s subject technical group insisted on a further clinical trial as a prerequisite to the registration of the pellets.
Not the first stock out
On March 3 this year, Delhi resident Rakesh Mohan, a young adult who contracted HIV at birth, wrote a letter to Prime Minister Narendra Modi, Finance Minister Arun Jaitley, and Health minister JP Nadda to look into the issue of shortage of paediatric medicines immediately.
Mohan claimed that bureaucratic delays were leading to stockouts of these essential medicines. “Procurement and supply chain reforms for pharmaceuticals led by the Health Ministry are taking a long time,” he wrote. The letter was endorsed by 637 people living with HIV across the country.
This is not the first time that NACO’s programme has had a stockout of these paediatric drugs. In 2013-’14, Cipla, which was then the sole supplier of paediatric anti-HIV drugs for the country did not participate in government tenders. BB Rewari,who was then a senior NACO official, wrote to Cipla asking for supply of three months worth of syrup bottles under its corporate social responsibility programme.
Broun said that all buyers, including NACO, had been told about the company discontinuing syrup manufacture. “If the AIDS control programmes still wanted to use syrup, they could get it from Abbvie, a subsidiary of Abbott Laboratories, at affordable prices,” he said.
Firoz Khan, national co-ordinator of the National Coalition of People Living with HIV in India, in a letter to NACO this month said that it is difficult to import the medicine from Abbvie since the medicine has never been registered or marketed in India. Khan further wrote, “There are no other quality assured suppliers of the formulation in the country.”
How do you cut a tablet?
With the stockout of these syrups, antiretroviral therapy centres are giving adult or paediatric drugs containing the same drug formulation and asking parents of HIV-infected children to divide and administer them.
Dr SK Binjhwar, additional project director of the Chhattisgarh State Aids Control Programme, said, “Ma baap itna to kar hi sakte hai.” Parents can surely cut the drugs while we handle this stockout.
But Paul Lhungdim from the Delhi Network of Positive People asked whether these parents are really counseled on the correct way to cut tablets. “Are the parents able to understand? Are they able to break into the required dose?” he asked.
In Raipur, when a toddler’s mother tried breaking the available tablet by hand, it crumbled. “The medicine does not dissolve in water,” she said. “I tried warm water too.” She had not been told how she should cut the tablet.
Lack of counselling, especially regarding dosage, can have dire consequences. In December 2015, after an acute stockout of paediatric antiretroviral drugs, government doctors asked the mother of a 10-year old boy from Bhilai city to cut the adult dose and give him. The child died within a month, possibly of an overdose. The doctors later told his mother that she got the dosage wrong, which she denied vehemently. Activists then alleged that the mother was not counseled properly.
This time, NACO has asked some parents of toddlers to cut adult tablets into eight parts. “You can ask parents to cut a tablet into two parts, or maximum four. How do they manage eight?” asked Khan. NACO guidelines say that a tablet can be divided into four parts with a knife. These parts should be further carefully divided into two equal portions so that one portion of the table is one-eighth of the tablet.
Dr Mamta Manglani, retired head of the Paediatric Centre of Excellence in HIV care in Mumbai, said that the hospital dealt with stock outs of paediatric drugs often by asking the hospital pharmacy to divide the tablets into portions using its fine electronic scale. “This is the procedure to be followed by the pharmacy only,” said Manglani.
When the parents do try divide the tablet themselves, it can result in an overdose that could lead to toxicity or an underdose that can lead to drug resistance, said Manglani.
Programme not alert enough?
In the last week of February, NACO ordered 3,000 bottles of the lopinavir and ritonavir syrup from MacNeil Argus Pharmaceuticals, which will last about three months. Under normal circumstances NACO would have placed an order for about 25,000 bottles, which would last approximately two years. NACO now plans to change the specification of the medicine required under the programme from the syrup to pellets that have already been approved by the US Food and Drug Administration and the World Health Organisation. Gupta was confident that it will not take long for Indian regulators to approve the pellets.
Why did NACO not change the specification earlier? “We could not change the specification while we were using the syrup,” said Gupta. He added that they cannot have two specifications for the same drug in the programme.
But the bigger question is whether a pharmaceutical company can stop manufacturing an essential drug.
Under US law, drug manufacturers are required to notify the government of the discontinuance or interruption in the production of life-saving drugs six months in advance. There are also extensive provisions on how an errant company can be dealt with, if they do not comply with the law. There is no such provision in India.
A 2016 paper in the Journal of Pharmaceutical Policy and Practice demonstrated how a the actions of a company that acquired a drug to treat multi-drug resistant tuberculosis but gave it back to its previous owner led to a massive rise in its price. The authors of the paper observed that, “Indeed, the decision to stop manufacturing a crucial drug, even one serving only a small market, should itself be carefully considered. It is certainly not unreasonable to expect that corporate good citizenry should encompass continuing to ensure access to vital legacy drugs serving a critical market.”
Khan, in his letter, said that NACO needs to play an important role in supporting Cipla to get registration of the drug pellets, and ensure waiver of the clinical trial to immediately procure the drug. Gupta said that NACO is ready to convince the Drugs Controller General of India of the importance of the drug that India is already importing to South Africa. “Before that we have to change the specification under the NACO programme,” he said.