The ranitidine conundrum

 

Ranitidine is a unique pharma drug story!  In a way it depicts the age old adage: what goes up must come down!  The ranitidine story is a ride on the giant Ferris wheel, starting in the summer of 1977 at one of the laboratories in UK as AH19065 to becoming the largest prescribed drugs in terms of units in India and the world-over, it seems now ranitidine is seeing a dead end.  Is it control + alt + delete for ranitidine? 

Ranitidine hit national headlines when the NLEM 2022 (National List of Essential Medicines 2022) was released by Dr. Mansukh Mandaviya, Union Health Minister of Govt. of India in September 2022.  Compared to NLEM 2015, the NLEM 2022 that has a total of 384 listed medicines - has dropped 26 drugs, of which one is ranitidine.  And many were wondering why ranitidine was dropped, since ranitidine is traditionally one of the largest prescribed drugs in India in terms of units.  In India, the ranitidine market is about Rs. 700 crores sales per annum. 

Launched first in 1981 in UK, ranitidine had become one of the world’s most prescribed medicines by 1987.  Sales of ranitidine started becoming muted only when omeprazole proton pump inhibitor was launched in 1989.  In 2020, Zinetac was 9% of GSK India’s revenues at about Rs. 200 crores. 

Ranitidine - the cancer connection?

Valisure is an independent laboratory and till 2021 they had a pharmacy in New Haven, Connecticut, USA.  Valisure pharmacy would check the chemicals in a medicine before sending to patients.  Before founding Valisure - one of the founders of Valisure, Clark Joseph used to take generic medicines for his health problem, but continued to feel sick.  He tested the medicine and was shocked to see the generic medicine was not of quality.  When he escalated this problem to his pharmacist, the pharmacist brushed it off saying that it must have been a problem batch.  This stimulated Clark and his colleagues to start Valisure, the pharmacy that tests medicines in its lab before shipping to patients.  It was during one of these testing practices (because Clark’s daughter was taking ranitidine syrup) that Valisure discovered enormous abnormal amounts of NDMA (N-nitrosodimethylamine) in ranitidine tablets/syrup.  Valisure detected 3 million nanograms of NDMA per tablet of ranitidine (due to higher temperature used in their testing procedure).   US FDA states the safe limit of NDMA for human consumption is 96 nanograms per day.  Valisure escalated the problem to US FDA in June 2019.  Thereby, in 2019 after investigation, US FDA also found NDMA (N-nitrosodimethylamine) in ranitidine tablets however it was in much lower levels much less than Valisure.

Similarly, Valisure in the past has shown that certain extended release tablets did not behave as claimed and they even proved that rapid release Tylenol (paracetamol) was dissolving slower than regular paracetamol! 

NDMA is a compound of nitrosamine chemical class, and above 96 ng/day consumption, NDMA is a probable (unproven) human carcinogen and is observed to be a carcinogen in animal studies.  NDMA is described as a genotoxic material.  NDMA is found in nature, plants and food too – in these very tiny amounts, NDMA is not a problem.  NDMA is a problem in larger quantity - if more than 96 ng/day is consumed.    NDMA impurity problem has been seen in various formulations from 2018, due to improper API manufacturing (impurity through solvents) - as in cases of antihypertensive angiotensin 2 receptor blockers (valsartan, irbesartan and losartan) and metformin sustained release products. The problems of excess NDMA are ill effects on liver and abdominal organs, and brain. 

Valisure has a thesis that ranitidine reacts with stomach acid to produce NDMA, however, this view is not accepted by US FDA.  Another theory is that NDMA is produced inside the body by reacting with a specific enzyme in the body’s kidney, brain and prostate. 

Storage of ranitidine tablets at higher temperatures such as 40 degree celsius for 8 weeks and more - causes formation of NDMA inside the ranitidine tablet.  Also, if the active ingredient ranitidine is not properly manufactured, NDMA impurity is created when the ranitidine bulk drug used for manufacturing tablets.  

Consequence of Valisure's findings and US FDA's independent investigation

US FDA pulled out all ranitidine brands including Zantac and ranitidine generics, from USA in April 2020.  Zantac disappeared from pharmacy shelves of UK in October 2019 and ranitidine is not available in UK.  Ranitidine is not allowed to be sold as per EMA (European Medicines Agency).    

Law suits in line!

In USA, normally law suits are filed by aggrieved parties when such problems of medicinal ill effects spring up.  For instance Merck Vioxx (rofecoxib) caused stroke problem, Merck settled its law suits by paying 4.85 billion USD.  Similarly, many law firms in USA are urging Zantac consumers to contact them for filing law suits.  Court proceedings are going on, lawyers are citing a Taiwanese study that ranitidine increases vulnerability to gastric, liver and other cancers. 

Ranitidine in India

Ranitidine is not banned in India nor taken off the shelf by manufacturers.  However, ranitidine is no more in the NLEM 2022.  This is because there is no conclusive and firm evidence that ranitidine tablet loads up dangerous levels of NDMA, which is a probable (not proven) human carcinogen.  Since, the picture is unclear; and court proceedings are still going on in USA, there is no Indian regulatory action on ranitidine.

Zantac – an iconic marketing success brand

The most popular brand of ranitidine across the world is Zantac, from Glaxo Smith Kline, a British company.  In India GSK launched ranitidine as Zinetac.  Zantac global launch was in early 1980s - a sensational market vibration was created since ranitidine had the advantage of lesser side effects compared to earlier H₂ receptor blocker cimetidine.  International speaker experts were flown in to have educational symposia at glitzy hotels.  Glaxo appointed - a daredevil move in India - a separate field force to promote Zinetac, so each of this division medical representative had just one product to promote: Zinetac!  Doctors were pulled to the symposia and drawn by the superiority of ranitidine.  Zinetac was also promoted to primary care physicians giving GSK a large prescriber base.  Abroad, where direct-to-consumer product promotion is allowed, bulletins were distributed on the new novel drug ranitidine, causing patients to ask doctors for prescriptions.  Thereby, a new era in H₂ receptor drug marketing started.

In 1990, Zantac was 50% of GSK’s annual revenues.  The global sales in 1990 fiscal year was 2.40 billion USD.  Zinetac was approved by US FDA in 1983, and Zantac clocked 1 billion USD global sales in 1988.  In India, Zinetac was launched in mid 1980s and again a runaway success in India.

The NDMA ranitidine problem has hit GSK so badly that it sold its Vemegal, Karnataka manufacturing plant to Hetero Drugs as there was a slump in global demand for Zantac.  

Zantac 360

Zantac 360 is a new launch in USA, from GSK, however, this brand contains famotidine and not ranitidine. 

In India, Rantac (J B Chemicals) is a very popular brand of ranitidine.  Interestingly, marketers at J B Chemicals have put on their creative cap and launched RANRAFT antacid suspension in which sodium alginate floats as a raft and the antacid ingredients are on the raft to neutralize excess stomach acid.  The other popular brand of ranitidine is Aciloc (Cadila).

The story is far from over ...

The ranitidine conundrum is far from being solved.  It is in the courts, various theories and assumptions are circulating.  Data from different sources are being compared and debated.  Picture abhi baaki hain!  (the ‘ranitidine movie is not yet ended’.).