KOLKATA - The hype generated around the world's first oral antiviral treatment for Covid-19 has been cut short in India, with worried authorities cautioning against its indiscriminate use amid an ongoing wave propelled by the highly infectious Omicron variant.

The Indian Council of Medical Research (ICMR) has flagged "major" concerns around the safety and effectiveness of molnupiravir, developed by Merck and Ridgeback Biotherapeutics in the United States.

It even excluded the drug from India's Covid-19 treatment protocol less than a fortnight after it secured an emergency authorisation for restricted use on Dec 28 from the Central Drugs Standard Control Organisation. The drug regulator has allowed 13 companies to market generic versions of molnupiravir.

The drug works by introducing errors in the virus' genetic code, thus preventing it from replicating.

"Molnupiravir has certain risks that warrant caution in its use... Efforts should be made to restrict its use as harms far outweigh its claimed benefit," Dr Balram Bhargava, the director-general of ICMR, said on Jan 5.

"It can cause teratogenicity (foetal defects), mutagenicity (genetic damage), cartilage damage and can also damage muscles... We still have concerns about pregnancy, lactation, children, soft tissue injuries," he added, citing international findings. This warning was repeated by the ICMR last week as well.

The United States Food and Drug Administration (FDA) cleared the drug on Dec 23 for the treatment of mild to moderate coronavirus disease in adults who are at high risk for progression to severe Covid-19 and for whom alternative treatment options are not accessible or clinically appropriate.

The FDA has not authorised molnupiravir for patients below 18 because it can affect bone and cartilage growth. Citing findings from animal studies, the agency has also stated that the drug may cause foetal harm and recommended against its use during pregnancy.

However, in India, which has a lax drug regulatory set-up and where prescription drug abuse is rampant, molnupiravir has quickly emerged as a manna of sorts, with the drug even being prescribed to those beyond the intended group of patients.

"This is negligence!! Please stop this madness!!" tweeted genomic scientist Vinod Scaria on Jan 6 to express his concern after receiving three calls seeking advice on the use of molnupriavir.

The three individuals who had been prescribed the drug were young and double-vaccinated - one was asymptomatic and two had mild symptoms. None of them had any comorbidities, nor had they received explanation detailing molnupiravir's risks.

Dr Ameet Dravid, an infectious disease specialist, told The Straits Times that many doctors are prescribing the drug widely without adequate information about who it should be administered to. Besides potential harm from its unauthorised use, Dr Dravid said he is worried that such widespread abuse can cause the virus to become resistant to this drug.

"This is why I keep telling people it is not a drug for young people without comorbidities," he added. "This is a drug reserved for a certain section of people with certain comorbidities."

Dr Dravid has used molnupiravir on patients who are either more than 60 years old, making them vulnerable; or above 40, with a high risk of progression to severe disease because of factors such as hypertension and cancer. All were fully vaccinated but had not received their booster shot.

He has avoided its use on diabetic patients because details of a key trial funded by Merck, which is known as MSD outside the US and Canada, and published in the New England Journal of Medicine (NEJM) last month showed that the drug fared worse than the placebo in reducing hospitalisation or death among diabetic participants.

However, data generated from all trial participants showed that incidents of hospitalisation or death throughout the 29-day trial period were lower in the molnupiravir group than in the placebo group. Of the 709 people who received molnupiravir, 6.8 per cent were hospitalised or died compared with 9.7 per cent of the 699 who received a placebo.

Dr S.P. Kalantri, professor of medicine at the Mahatma Gandhi Institute of Medical Sciences, said that statistically, this represents a "small benefit" that is outweighed by the drug's potential risks.

Given the absolute risk reduction of around 3 percentage points compared with the placebo, he said one would need to treat 33 individuals to prevent one additional hospitalisation or death. "This is a big number and you don't know who that one person could be out of this 33," he added. "Is this the game changer or magic bullet that it is made out to be?"

The drug was also less effective than the placebo on certain population groups such as Asians and blacks, as well as those who had a low viral load and past coronavirus infections.

There was no specific mention of South Asians in the trial, which also did not evaluate the drug's potential benefit in treating vaccine breakthrough infections as all trial participants were unvaccinated.

"This means that doctors have to be very, very selective despite their busy schedule to figure out who the real beneficiary could be, something that is not always possible," Dr Kalantri told ST.

He added that this drug needs to be followed up longer to ascertain its full impact, referring to past instances when several drugs were recalled years after their launch because of serious adverse effects.

These include cisapride from Janssen Pharmaceuticals, which was recalled in 2000, seven years after its approval, due to the risk of serious cardiac arrhythmia and death.

"My concern is that a large proportion of people will end up taking molnupiravir and risk themselves for potential harms that significantly outweigh its proven benefits. The drug should not be part of routine practice," he said.

Several Indian pharma companies have launched their versions of molnupiravir, promoting it through their well-oiled sales and publicity network.

One of them has even branded the drug as "the profound game changer", suggesting it could be used for asymptomatic patients and claiming that it reduces post-Covid-19 symptoms such as weakness, fatigue and even depression. These are unverified claims that Dr Kalantri termed as "unethical and disgusting".

Molnupiravir has caught the attention of others in the region too. In Bangladesh, Beximco Pharmaceuticals began selling a generic version of the drug in November, days after Britain's Medicines and Healthcare products Regulatory Agency cleared it for use. Thailand and Indonesia have also unveiled plans this month to develop the pills.

Developing an effective oral antiviral against Covid-19 remains a high priority to widen treatment access in rural and resource-poor settings. The cost of a 40-tablet five-day course of molnupiravir in India starts at around 1,400 rupees (S$25). In comparison, monoclonal antibody treatments, while more effective, are far more costly and need to be administered intravenously.

Despite its limited benefits and the warning from federal Indian authorities, the drug remains an option for treatment of Covid-19 patients.

The NEJM study's authors said molnupiravir yielded "a substantial mortality benefit" and added that oral agents such as this drug are a "more practical and patient-friendly" intervention for non-hospitalised cases, allowing them to become important new tools for Covid-19 treatment and reduce patient load on healthcare set-ups.

In Maharashtra, the state Covid-19 task force has recommended it for restricted use on those with persistent high fever for more than three days, who are above 50 and who have more than two comorbidities.

"The drug is a valid and reasonable option for such people who are at high risk (of deteriorating)," Dr Shashank Joshi, a member of the task force, told ST. "But it has to be used with caution in the most appropriately selected cases, and definitely not on those below 50 without comorbidities and without (Covid-19) symptoms."

Dr A.K. Singh, a senior consultant endocrinologist, said he has used the drug "only sparingly" on elderly, high-risk and partially vaccinated individuals.

"Molnupiravir has only been studied in mild to moderate unvaccinated Covid-19 adult patients with at least one risk factor for progression to severe Covid-19. Therefore, one must limit its use only for these groups of patients," he said.

"Since it has not been studied in vaccinated individuals and its effectiveness is questionable in people who had past history of Covid-19, we need to assess risk versus benefit while prescribing this drug, if at all," he told ST.