Aftermath of a drug ban

September 14, 2018 0 By CH Unnikrishnan

Manjit Babu

The Drug Controller General of India (DCGI) banned the production of the painkiller injectable diclofenac sodium 75 mg/ml sold under the brand name Voveran on July 4, 2018. The regulator ordered therecall of the product based on concerns raised by an expert panel constituted by the health ministry for the purpose.

In its recommendation, the committee said 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.

“No evidence has been presented before the Committee that it can be used in parenteral formulations even including Indian Pharmacopoeia, especially on parenteral preparation for human use,” it says.

“Likewise, the data in a cumulative form is indicative of its toxicity, which entails a detailed study on its toxicity and safety profile in line with the observations given above. Whether the same could be permitted for use especially in the parenteral formulation has to be decided by drug regulatory authority as per provisions of drug regulations on excipients to be used in the parenteral form particularly those which are reportedly not inert, as in the present case,” it said.

Subsequent to the report, the regulator issued  an order to the drug licensing authorities in Dehradun, Uttarakhand, and Daman and Diu to cancel the manufacturing licence granted to Themis Medicare for diclofenac sodium injection 75 mg/ml using theexcipient Transcutol-P.

Voveran 1ml, which was sold in India at a price of around Rs 129 a pack (according to Apollo Pharmacy website), comprises non-steroidal anti-inflammatory drug (NSAID) diclofenac sodium, to reduce pain and inflammation. The intramuscular injection has been useful in treating a number of painful conditions, including attacks of gout, flare-ups, joint pain and back pain, pain from kidney stone and pain from injuries, making it an important part of the arsenal across specialties dealing with painful conditions.

Troikaa, one of the rival companies producing diclofenac injection, has, in a lawsuit, alleged that the excipient Transcutol P could affect the health of the patient, and thus do not benefit the treatment per se.

As per a court directive, the allegation on the safety and tolerability of diethylene glycol monoethyl ether (Transcutol-P) in diclofenac injection has been considered by various expert committees. The third and the latest was by the expert committee which submitted the recommendations in December, 2017, and was headed by Girish Sahni, who was then secretary of Department of Scientific and Industrial Research, Ministry of Science and Technology.

Novartis sells the drug under the brand Voveran, while Themis Medicare, which does contract manufacturing for Novartis, sells it under Aquadol.Troikaa’s diclofenac injection is branded Dynapar AQ in the market.

The dispute of Gujarat-based Troikaa Pharmaceuticals Ltd against the painkiller injectable has entered a new phase with the Indian drug regulator ordering the withdrawal of the medicine from the market.

For Novartis, the drug reportedly contributed around Rs 250 crore of revenue.

“Diclofenac 1 ml injection forms a small part of the larger Novartis portfolio,” says a Novartis spokesperson.

While the dispute, which dates back to 2015 when Troikaa approached the authorities, may continue in the courts in the future, the reaction from the medical fraternity to the ban has been mixed.

Doctors are of diverse views about the non-availability of the drug, which was one of the less painful options in the low-dose category.

For several years now, the drug has been used to manage moderate pain in rheumatoid arthritis and orthopaedic treatments. Many physicians consider it as the best option for treating moderate pain regardless of the side effects which any other painkiller drug might also have.

Will the ban have any significant impact on pain management now? Many say no, with good reason.

“The ban on Voveran is not going to affect pain management at all, because there are plenty of other options,” says Dr Charu Singh, Professor & Head, Anaesthesiology and Palliative Medicine, AIMS, Kochi. “We don’t use diclofenac injection for pain relief in our clinic. NSAIDS, as a class of drugs, can cause severe gastric side effects, besides renal toxicity. So when we want to use an NSAID, we prefer the ones having lesser side-effects, such as ibuprofen or paracetamol.”

If one needs an NSAID, the rule is to have it at the lowest possible dose at the lowest number of times. Smaller doses and shorter durations, that is the thumb rule when it comes to NSAIDS, she added.

Five years back, Voveran was one of the most frequently used pain management medicine in its segment and a ban would have meant a serious challenge to the doctors. However, in the past three to four years, several alternatives emerged. They also have certain advantages, like less pain to the patients and the ability to be used intravenously, said an orthopedist from Thiruvananthapuram, Kerala.

“Now, there are alternatives such as tramadol injection, paracetamol injection and others, which are more effective and can be provided as an infusion,” he said.

“We have not been using Voveran for at least five years. We have alternatives from the same non-steroidal anti-inflammatory drug class to treat pain,” said the chief medical officer of a hospital in Chennai.

Novartis says Transcutol P
well within the limit

Aspokesperson for Novartis India, which sells diclofenac 1 ml injection under the brand name Voveran, gave the following statement:

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 75 mg is recommended twice daily and should not be given for more than 2 days. Permissible Daily Exposure (PDE) in animal studies for intramuscular/intravenous routes ranges from 434 mg/day to 784 mg/day. Each 1 ml of diclofenac injection contains 200 mg of Transcutol P, keeping it well within the safety parameters.

Novel data provides evidence that the toxicity previously associated with high levels of impurities in Transcutol in non-clinical studies is no longer valid.

It is specifically designed for use by the parenteral route. Current pharmaceutical grade Transcutol P is >99.8% pure. Gattefosse, the global supplier of Transcutol P, has all the required safety/toxicology data for this. Transcutol P is also used in the parenteral route in the CIS countries and Korea.

Transcutol P is listed in the Indian Pharmacopeia (IP) 2018, which does not restrict its parenteral use. Also, the British Pharmacopeia and the European Pharmacopeia do not restrict the 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. No global regulator anywhere in the world has called for the withdrawal of any parenteral formulation containing Transcutol P.