Novartis' Diclofenac injection 75 mg/1 ml was recently banned at the behest of Indian drug regulator after complaints by a little known Ahmedabad-based company, which had a competing product
A product with an annual market of Rs 250 crore may not be worth the time for most companies. But over the last five years, an intense battle has broken over a painkiller with sales of Rs 250 crore. It involves a multinational giant, challenged by a homegrown Indian company few would have heard of.
The painkiller is diclofenac, and the two companies are the Swiss giant, Novartis, and a small closely held Ahmedabad-based drug maker Troikaa.
The first inkling of the feud emerged when the Indian unit Novartis on July 12 told stock exchanges that its manufacturing partner Themis Medicare had received a notice from Drugs Licensing Authority (DLA) of union territory Daman and Diu, directing it to stop manufacturing of painkiller Diclofenac 75 mg/1 ml injection with immediate effect.
The action came at the behest of Indian drug regulator, the Drug Controller General of India (DCGI) who early in July directed the state drug controllers of Uttarakhand, and Daman and Diu to cancel the manufacturing license granted to Themis for Diclofenac injection 75 mg/1 ml for using an excipient called Transcutol-P, on grounds that the substance is nephrotoxic leading to slow damage of kidneys.
Themis manufacturers the drug, sells it on its own brand, in addition to supplying it exclusively to Novartis, for latter’s sale and distribution of the drug in India under its popular pain management brand Voveran.
The stocks of both Novartis and Themis reacted negatively to the news of the ban. While Themis' stock fell 14 percent in next two trading sessions, Novartis shares dipped 3 percent.
“Themis has been manufacturing Diclofenac 1 ml injection under Voveran brand since 2015 and has been marketed by the Company in India based on regulatory approvals granted to them earlier,” Novartis said in a statement.
Novartis said it has sold over 110 million ampoules of this drug with no serious adverse events reported.
Themis said it has been “aggrieved by the developments” and has filed a writ petition in the Delhi high court challenging the ban.
Moneycontrol has put together a story after pouring through reports of various committees, court filings and talking to people with the knowledge of the matter all pointing towards regulatory flip-flops, messy approval system, and business rivalry.
Novartis vs Troikaa
It all started in 2008 when Troikaa cracked a way to enter into highly crowded pain and inflammation segment dominated by entrenched rivals.
Rather than going with the flow, Troikaa saw a gap in the Diclofenac pain management portfolio.
Until then the most popular low dose Diclofenac injection with doctors was Voveran 75 mg/3ml. The injection was painful for the patient given the high viscosity and had to be administered in the buttocks.
In January 2008, Troikaa launched its own diclofenac called Dynapar AQ - a 75 mg/1 ml injection - a unique high concentration, low viscosity injection of diclofenac sodium delivering the full therapeutic dose of diclofenac in just one millilitre injection volume.
Interestingly, it can be administered in the arm muscles as well, a less painful option.
It didn’t take long - Troikaa’s diclofenac injection not just won awards from the government for the novelty of drug delivery system but started gaining market share eating into sales of the established brand like Voveran.
Novartis saw the gaping hole in its portfolio and by 2013 the drug behemoth tied up with Indian drugmaker Themis to bridge the gap with the launch of Voveran 75 mg/ 1 ml injection.
Themis developed the 1 ml formulation in-house and got manufacturing licenses from state drug regulators of Uttarakhand and Daman and Diu.
It's not known whether state drug regulators of Uttarakhand and Daman and Diu while approving the drug have considered the presence of Transcutol-P in the formulation.
Soon, Troikaa began to feel the heat, as Novartis slowly recovered its lost market share.
Market sources say both the competitors now have 30 percent market share each in the Rs 250 crore market.
For a company that derived one-fifth of its Rs 400-crore annual revenue from diclofenac, the product was crucial for Troikaa.
In its search for a way out, Troikaa found a loose brick, a solvent-cum-excipient called Transcutol-P, to breach Novartis' Voveran wall.
Solvents aid solubility of poorly soluble active pharmaceutical ingredients like diclofenac in this case. Excipients are inactive substances that serve as the vehicle or medium for a drug, for example, a pain relief balm can have a regular petroleum jelly as a base for application.
Themis has been using Transcutol-P, chemically called Diethylene Glycol Monoethyl Ether (DEGEE) in the production of its Diclofenac injection.But there is a problem. Transcutol isn't widely used in the parenteral formulation, owing to its alleged side effect of slowly poisoning one's kidney. Parenteral formulations are basically intravenous drugs such as injections.
Some experts argue it could be double-whammy if used with Diclofenac - given the fact the painkiller is also toxic to kidneys.
Four years and three committees…
In 2015, Troikaa and some clinicians filed complaints before the DCGI, alleging the use of Transcutol-P as excipient is not safe for injections and may lead to nephrotoxicity (prove toxic to the kidneys).
The DCGI took cognisance of the complaints and constituted a nine-member expert committee headed by Dr Sudhir K Gupta, Professor and Head of the Department of Forensic Medicine and Toxicology at All India Institute of Medical Sciences (AIIMS), to examine the safety and tolerability of Transcutol P in injectable formulations
The committee had members like Arvind K Bansal, Department of Pharmaceutics, NIPER, Chandigarh, Dr SK Rath, Principal Scientist, Toxicology Division, CDRI, Lucknow, Dr Sheelendra Pratap Singh, Analytical Toxicologist, CSIR-IITR; Dr DS Arya, Dept of Pharmacology, AIIMS, New Delhi; Dr Bikash Medhi, Prof; and additional medical superintendent, Pharmacology, PGIMER, Chandigarh.
The Gupta-committee found Transcutol-P was also not part of Indian Pharmacopeia, the book that lists drugs along with their usage and effects, and is published by an authority such as a government or pharmaceutical society.
The committee thus immediately looked into the United States Pharmacopeia National Formulary [USP NF-33] that states that Transcutol should be used for topical or transdermal formulations only (external usage) and it can’t be used in parenteral (injections) formulations.
Further, Transcutol is included in an inactive ingredient database of USFDA as excipient for topical and transdermal formulations only.
Drug regulators of Canada, Australia, and France also have confined Transcutol for topical use.
The committee after examining the data submitted by the firms, and other scientific evidence, opined that the available evidence "is not adequate to demonstrate safety and tolerability of DEGEE (Transcutol-P) in parenteral preparation of human use.”
Moneycontrol reviewed a copy of the Sudhir Gupta’s committee report on the matter.
Taking cues from the report, DCGI directed to immediately cancel the manufacturing license, sale, and distribution of diclofenac injection using Transcutol-P.
Troikaa had just pulled off a major victory against a multinational giant.
But Novartis was not done yet.
Voveran was an important product for Novartis. Though a $49 billion giant globally, Novartis has a relatively smaller presence in India. In FY2018, it had revenues of Rs 563 crore, down from Rs 886 crore in 2013.It couldn't dilute Voveran's product portfolio, which includes several diclofenac pain management formulations such as tablets, sprays, gels, and injections.
Thereafter, the government decided to constitute a second committee under the Director General, Directorate General of Health Services to examine the additional data/literature of Themis.
The seven-member committee had none of the earlier members.
Chaired by Jagdish Prasad, head of DGHS – the seven-member committee had Dr YK Gupta, Prof and HOD, Department of Pharmacology, AIIMS, New Delhi; Dr SK Sharma, Prof and HOD, Department of Medicine, AIIMS, New Delhi; AK Dwivedi, Chief Scientist, Division of Pharmaceutics, Central Drug Research Institute (CDRI); PV Diwan, Ex-Deputy. Director, Toxicology, Indian Institute of Chemical Technology (IICT), Hyderabad; CL Kaul, Ex-Director, Niper, Mohali and Shalini Chawala, Professor, Department of Pharmacology, MAMC New Delhi.
The second committee after going through all the information available gave a clean chit to Themis and Novartis.
The committee in its report submitted in July 2016 said the dosage and the duration of use of diclofenac injection having Transcutol-P “does not have safety concerns which warrants its suspension.”
The committee also maintained that out of 308 adverse drug reactions (ADR) none of the causality was due to drugs marketed by Themis or Novartis.
“Although Pharmacovigilance is still not strong in the country, the fact that of the 308 ADR report, in none the causality was certain and in most there were multiple medications and the fact that a large number of dosage have been administered do not raised safety concerns,” the committee said.
The committee further said it is conscious of the potential of nephrotoxicity of diclofenac preparations and therefore, recommended all the diclofenac preparations be placed under focused Pharmacovigilance programme (PVPI) for intense monitoring. The committee sought PMS data on 2,000 patients covering different parts of the country and submit safety data to the regulator for further evaluation and consideration.
The committee also asked Themis and Novartis to submit the product information brochure clearly depicting the precaution, contra-indication and maximum duration of its use.
If it looked like Novartis had pulled one back, Troikaa was equal to the task.
Troikaa knocked the doors of Delhi High Court requesting a stay on sale of diclofenac formulations using Transcutol-P.
Finally on the basis of "principles of natural justice" – the government decided to form a third committee.
The third committee was formed under the chairmanship of Girish Sahni, Secretary, DSIR and Director General, CSIR. The committee had seven members, none of whom were part of the previous two.
The Sahni committee in its report in December 2017, opined that Transcutol-P as an excipient in parenteral formulation needs to be tested for its toxicity independently in order to establish its safety since it is reportedly not an inert excipient.
The committee also said that no evidence has been presented before the Committee that it can be used in parenteral formulations even including India Pharmacopoeia, especially on parenteral preparation for human use.
Troikaa couldn't be happier. Sources in Troikaa said they finally feel the government took the right decision in the interests of patient safety.
But Novartis believes the final word hasn't been said. The Swiss multinational has moved the Delhi High Court, which has accepted the petition.
Novartis defended the use of Transcutol P as solvent for Diclofenac 1 ml injection within safety limits.
"With respect to Transcutol P, based on solubility studies performed by Themis, Transcutol P is an extremely efficient solvent for Diclofenac and present in the Diclofenac 1 ml injection within safety limits. It is important to understand that Diclofenac injection 75mg is recommended twice daily and should not be given for more than 2 days," Novartis spokesperson said in an email statement.
"No global regulator anywhere in the world has called for the withdrawal of any parenteral formulation containing Transcutol P," the company added.
The company says Transcutol P is also used in the parenteral route in the CIS countries and Korea.
Novartis says Transcutol P is listed in the Indian Pharmacopeia (IP) 2018 and does not restrict its parenteral use, and also maintains that that British Pharmacopeia and European Pharmacopeia do not restrict use of Transcutol P in parenteral formulations and Transcutol P is listed in the Handbook of Pharmaceutical Excipients, 7th edition, Washington DC for parenteral use.
The fight for the injection continues.
(The story is updated on August 8 with Novartis response)Get access to India's fastest growing financial subscriptions service Moneycontrol Pro for as little as Rs 599 for first year. Use the code "GETPRO". Moneycontrol Pro offers you all the information you need for wealth creation including actionable investment ideas, independent research and insights & analysis For more information, check out the Moneycontrol website or mobile app.