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’.).

THE REALITY IS PRODUCT PROMOTIONAL MESSAGES

Ground level product promotional activity

Ref. for above image: https://www.imd.org/research-knowledge/articles/digital-business-transformation/

Product promotional messaging is the life breath of every business, and finance is the life blood of every business.  Both feed each other. Promotional messages are transmitted through messengers – both animate and non-animate.  From the inception of pharmaceutical industry in India, the medical representatives (MRs) have played a hallmark role of being messengers of product promotional messages to target doctors and pharmacists.  Alongside, they have performed the role of relationship managers too, providing persuasion tools like samples and other knickknacks or sponsorships. 

Marketing myopia is another truism of marketing domain - it happens because marketers like to remain in the comfort zone.  Instead of viewing the product messages as being the pull creator of product sales, companies began to view medical representatives as the product sales pullers.  Yes, the MRs are certainly product sales pullers, but is so only when they push product promotional messages.  Otherwise, they are just mendicant or postman medical representatives.  Hence, the prima donna force providing sales pull is the array of product promotional messages (through MRs or through other means).

There are some pharmaceutical companies who learnt this home truth early on; that the medical representatives are relationship managers, people who handle collaterals in a value added manner, and are product promotional message transmitters.  This is what makes the MRs’ masters of persuasion practice.  The MR based product messaging activity is through the classic modes of visual aid and collateral detailing, extempore detailing and dialogue detailing with yes momentum.  Earlier on the printed visual aid and literatures were main tools for collateral based detailing, today, electronic aids like ipad, smartphone and tablet pc based collateral detailing are being done by MRs to engage the doctors and get them engrossed in the message.  Videos, digital images, gif images, and audio recordings used on these electronic devices have gripped the attention and engaged doctors during in-clinic activity, in-CME product promotion and in-stall or in-booth activity.  So the nub of the matter is that delivery of PRODUCT PROMOTIONAL MESSAGES produces the business outcomes, while other ‘give and take’ transactions, provides a higher level to the business outcome.  For example negotiated sponsorships along with product messaging activity have provided rocket growth to pharmaceutical companies in India.

The digital dimension of product promotional messaging activity

Covid-19 coronaviral infection has upset the apple cart of routine product promotional messaging activity in the pharmaceutical sector.  Doctors have been used to medical representative visits, who provide positive strokes, appreciation, ego massage, informational product points (these are very important to help recapitulate, after all knowledge is volatile) and other inputs that are valued by them (samples, gifts etc).  The virulent pandemic Covid-19 has made people go in for social and physical distancing.  Doctors have seen the horrid of morbidity and mortality with Covid-19 infection from close quarters; hence, they are hesitant to meet up with medical representatives.  This has changed the way pharmaceutical companies transfer product promotional messages and do the relationship management.

Pharmaceutical companies adapt to the market change

There is a saying - IF IT IS IMPORTANT, YOU WILL FIND A WAY - OR YOU WILL FIND AN EXCUSE.  Thus, savvy pharmaceutical marketers have immediately redrawn the blue print of product promotional message transfer, from relying solely on medical representatives to laying focus on the digital route of messaging to target audiences. 

Abbott has found its solution through international Key Opinion Leader (KOL) webinars and focus group discussions involving core doctors.  Micro Labs has started influencing and messaging doctors through zoom based advisory board discussions, and phone talking with core doctors.  Whatsapp has proved a great help to push messages to core doctors and core pharmacies.  So the focus is to find the 20% of doctors, pharmacies and territories (or areas or pincodes) that provide the 80% of the business - and ring-fencing them to protect businesses.

Group Pharmaceuticals, Bangalore is a very innovative and dynamic pharmaceutical company with research based oral care products - this company has focused on digital means of reaching target patients, doctors and pharmacies, through the website route, webinars (for pharmacists and doctors), social cause marketing like Dental Reach and ensuring push messaging of useful nuggets of wisdom to engage doctors and end consumers.  Group Pharmaceuticals has a committed field force with a high morale for ground level activation too.  

The nature of patient-centric reality of the pharmaceutical business especially for OTX (over-the –counter plus prescription products) portfolio has come to the fore due to the Covid-19 disruption.  Many companies are also facilitating or drawing up plans to help doctors provide telemedicine connects to patients.

Conclusion – ‘phygital’ is the way forward

Phygital (physical + digital) is the way forward for ensuring product promotional messages are delivered at the right time, in the right amount of the right quality to the targeted audience, because it is the product promotional messages that actually bring in the business rather than the messenger, -this is the home truth.  The other home truth that has once again hit investors is that cash is king, and businesses survive only when marketing is sharp enough to ensure smooth cash flow into the organization.  And if the business outcomes have to be further improved, then relationship management concepts become important, and here too, ‘phygital ’ is the way forward.

What next?

What next?

Question: What next?

Answer: Stay relevant - through digital!

What next? Perhaps this is the top of mind question of all marketers and others.  

The situation got changed

We are all used to a way of life.  Getting up at 6.00 am, getting ready and being out of home at 8.15 am, reaching office or work place or work spot (for field workers) at about 9.15 am and following the pattern till evening.  As evening falls, going home via a friend’s place or favourite café or after a walk in the park is what one does.  This pattern repeated day after day.  Every pharma company marketer has a pattern of ensuring that its foot soldiers performed in-clinic (may be 11 calls/day), in-stall, in-CME, in-pharmacy (approx. 6 chemist calls/day), and campaigning activities for demand creation and fulfillment. And suddenly, one fine day, it is curtains for this pattern.

Virus break

The SARS-CoV-2 virus that goes by the name Covid-19 originated from a bat or pangolin or from a bat to pangolin and then to the butcher at the Wuhan wet non-veg wildlife food market of Wuhan, Hubei province, China and finally to rest of world - has disrupted the pattern of normal existence of every citizen in the world.  In any case this is a highly mutated virulent contagious coronavirus of which Bill Gates warned and many movies like Contagion signaled – this virus is causing immobilization.  This pandemic has ensured economic cycles are broken.  Everyone is wondering - what next?

We are aware marketing is an important organ of business development.  Marketing is an organizational process (not just departmental) to create, communicate and deliver value to target audiences, stimulate and facilitate exchange processes.  Marketing generates customer satisfaction and delight (the latter happens when we do something extra unexpected to the customer and he gets delighted).  When marketing is effective there is ever increasing market penetration and spontaneous word-of-mouth - and in modern times it means marketing makes messages go viral.  Marketing is accountable for customer acquisition and retention.  Just like measurement is critical, training is a game changer and all other aspects of a business are vital; marketing is the life breath of business development.

The current socio-economic scenario is certainly not going to the normal we know any soon, is my viewpoint.  The future scenario will have several new normals’, this will include hefty digitalization of marketing - digital messaging with lesser face-to-face interactions.  The Covid-19 pandemic induced lifestyle change is a trend and we need to change our marketing activities accordingly.  Digital marketing and e-messaging is the only way out.  Jo dikta hain woh bikta hain is the only truth of marketing and business development.

Already online medicine companies have got the green signal from government - https://timesofindia.indiatimes.com/india/centre-permits-doorstep-delivery-of-medicines-during-covid-19-lockdown/articleshow/74829942.cms 

We are seeing a sea change of attitude towards digital activity by govt. of India and all other business organizations:

Big Bazaar has revved up the home delivery activity.  Ref.: https://www.bigbazaar.com/door-step-delivery/ also second reference: https://economictimes.indiatimes.com/industry/cons-products/fmcg/big-bazaar-expands-home-delivery-footprint-as-india-gets-stuck-in-lockdown/articleshow/74807089.cms

Big Basket is now a seen as a life saviour service – they have innovated with times to handle huge volumes, they are working with fervor and a missionary zeal similar to a coronawarrior.  Big Basket offers contact-less service too, now, where the delivery man places the items at the doorstep of buyer or at security ,and does not meet the person who is ordering.  Big Basket is taking pooled orders from a single apartment complex that makes fulfillment faster and easier.  That is how market responsive firms respond; they rise to the occasion, at Mahindra, a few innovator employees locked themselves up to finally come up with the prototype of a ventilator. 

THE MOST IMPORTANT THING FOR AN ORGANIZATION IS NOT TO GET OVERWHELMED AND IMMOBILIZED. 

A challenging crisis time is the opportunity to recast marketing procedures and get relevant to stay in business! 

That is what Cipla is doing with Cofsil.  Many in the market never knew that this respiratory health brand had a mouthwash gargle.  Suddenly Cofsil Experdine Gargle https://www.cofsils.com/experdine-gargle is making its presence felt in you tube advertisements and other digital media.  Cofsil Experdine Gargle is a mouthwash.  Positioned as a gargle and mouthwash, Cofsil is useful for oral health.  The beauty is that mouthwashes can be used to gargle in the mouth and cleanse the throat.

Betadine has put its mouthwash and gargle on a high exposure mode digitally.

Many sore throats are caused by viruses and some types of bacteria.  And this is the time of Covid-19 virus - ideally we should be using more of mouthwash for oral and throat gargling along with hand hygiene.

Two vital trends for good health in the background of Covid-19 pandemic that pharma marketers can use:

a)     Hand hygiene

b)     Mouthwash based oral hygiene (for oral cavity hygiene and throat gargling)

We have a habit of touching the face, studies say we do it up to 16 times a hour, unknowingly by force of habit.  Contaminated hands transfer bacteria and virus to the nose, mouth, eyes and lips.  Thus, absence of hand hygiene can be dangerous - may lead to Covid-19 infection.  Hence, along with hand hygiene, oral hygiene through mouthwash (for oral cavity cleaning and throat gargling) is essential.

The era of digital marketing in pharma has arrived firmly thanks to disruptive pandemic Covid-19.  Pharma companies are racing to engage doctors, pharmacies and patients on health and products.

Freshchlor is a mouthwash for oral hygiene (mouthwash and throat gargle with proven use against viruses and bacteria)

There are many possible digital marketing approaches:

a)  Right time to offer online CME programs to doctors, dentists and other medical professionals who are having free time to participate in them, and gain CME points  (many private medical practitioners are having reduced patient flow and dentists are not practicing chair procedures)

b)     Engage with campaigns through whatsapp to targeted doctors and pharmacies

c) Make product websites interactive so that patients engage with them eg., https://www.cofsils.com/experdine-gargle and https://www.dettol.co.in/en/ the latter have created a web link on Covid-19 information

d) Offer a helpline manned by doctors offering information on Covid-19, respiratory disease and Cofsil mouthwash eg., Cipla Covid-19 helpline Ph. XXXXXXXXXX

e)     Offer a dentist hotline to answer quiz questions and gain points that can be redeemed later for gift hampers, eg., Group Pharma dentist quiz hotline Ph. XXXXXXXXXX

f)     Offer a doctor-only website that hosts medically relevant information on Covid-19

g)    Brand based messaging on various aspects of Covid-19 and other things to do through social media (it requires a social media team)

What next?  It is to stay relevant, that is what marketing is all about!  Best of luck pharma and healthcare marketers, stay safe in the times of Covid-19!

Clove oil and headache

Oral cancer and dentists

Does mouth health affect success in life? Dental nugget

The INOSEPT story

Background:

The Covid-19 coronavirus is highly contagious…

The virus that causes COVID-19 remains for several hours to days on surfaces and in aerosols, a new study published in the New England Journal of Medicine found.

The study suggests that people may acquire the coronavirus through the air and after touching contaminated objects. Scientists discovered the virus is detectable for up to three hours in aerosols, up to four hours on copper, up to 24 hours on cardboard and up to two to three days on plastic and stainless steel.

https://www.sciencedaily.com/releases/2020/03/200320192755.htm

There is a new challenge on the professional, personal, social and family front.  This challenge originated from the wet non-veg wildlife food market of Wuhan, Hubei province, China and is sparing none across the world.  Even Prince Charles is tested Covid-19 positive.  Such is the nature of this contagion called Covid-19 coronavirus.

In the third para of this link: https://www.who.int/docs/default-source/coronaviruse/getting-workplace-ready-for-covid-19.pdf WHO document states that when a Covid-19 infected person coughs or exhales, droplets of infected fluid are released.

Story:

Sharon is a widow – mother of three children.  A single mother balancing her home duties with a job was straining every nerve and muscle in her body.  Her husband a brave warrior of the Indian army was martyred at the border.   The Indian army facilities for war widows were good - so it took a lot of load from Sharon’s frail shoulders.

The contagious Covid-19 viral infection affected Sharon’s family life deeply.  The three kids were a handful at home.  A ray of hope was elderly Peter, her brother, who lived in their large home.  Peter would come over to the hall, and tell stories to the three kids and keep them occupied while Sharon would do the home chores.

Today, Peter was looking grim.  Peter was a successful medical representative during his heyday and he now led a quiet retired life.  He retired 8 years back, and Peter with his bed-ridden wife Elda lived with Sharon, his only sister. 

Nowadays, Peter spoke slowly with a gummy and toothy smile.  Elderly Peter was known to be a dedicated and systematic person.  He would seriously insist: ‘PLAN YOUR WORK, AND WORK YOUR PLAN.  This will make you successful’.

A grim looking Peter started: ‘Children, do you know what is a virus?’  Peter sat on the single sofa while the kids gathered on the carpet, seated and listening to him.

The eldest kid of Sharon, Arun - all of 15 years said: “Yeah, it is a small invisible living thing that causes diseases like mumps and common cold!”

Peter was astonished, and realised the power of internet, Arun was a great fan of Natgeo kids and Discovery kids websites.  The smallest child of all, Kristella giggled seeing Peter looking surprised.  Peter started slowly: “Good, do you know how to kill viruses?”  All were quiet and listening.

Peter continued: “Children, there is a dangerous virus on the prowl, it enters mainly through the nose or mouth”.  Immediately, Kristella touched her nose and mouth proudly, showing she knew where the organs were located.  Peter smiled at her innocence and charming smile. 

Peter exclaimed: “Exactly, Kristella, that is what even grownups do, they keep touching the face, nose, eyes or mouth and lips by habit!  Now, if the hands are contaminated with the virus, it gets into the body either through the nose or mouth.”

Arun: “Oh!  Viruses are dangerous!!  I read that some bacteria too have viruses attached to them!”

Peter: “Yes, you are right, now tell me, what happens when you cough or sneeze?”

Mira the middle one who was the quiet and the mature type, raised her hand: “Millions of invisible drops come out!”

Arun, feeling the competition: “Yes, and viruses come out with these invisible drops”.

Peter: “Exactly, now imagine what if viruses come out even when a person breathes out or exhales!  Well that happens with this new dangerous virus, which comes out of certain people due to coughing, sneezing and even exhaling!  And this virus lives on surfaces for several hours!”

Kristella: “Oh! How scary!!”

Peter: “Indeed it is scary!  So that is why we are all staying indoors and not going out of the home.”

Peter slowly took out a bottle of INOSEPT from a large brown bag.  He smiled and said: “Inosept contains safe chemicals that protects us but kills the virus!”

Arun, the intrepid child scientist: “How does INOSPET … sorry INOSEPT work?”

Peter (smiled thinking of his bygone days of detailing): “Viruses have a coat called virion.  This outer covering of the virus has both proteins and fats”.    Peter added: “Now after having breakfast, when you have had bread and butter, you have to wash hands with soap, to remove the fatty butter from your fingers.  Same way, if there are viruses contaminating the hand, you have to wash with soap, and the soap washes off the viruses since these microbes have both proteins and fats in their outer coating.  Soap is essential to remove fat matter.  Washing only with water does not wash out fat.  But remember - to ensure complete removal of viruses including Covid-19 from the hands and fingers, soap has to be in contact with the fingers and hands for minimum 20 seconds”.

Kristella immediately asked: “What are seconds?”

Mira the middle child said: “Quiet!  You will learn when you grow big!”

Arun added: “What if there is no water?  It often happens in Bangalore in our flat!”

Peter smiled: “Yes, that is why INOSEPT is useful.  INOSEPT can also be carried!  Also this is trusted by doctors and used by them too!”

Arun: “Peter uncle, how does this act, what is it?”

Peter: “INOSEPT is an antiseptic broad spectrum hand sanitizer, it means it can kill almost all types of bacteria, viruses and other micro-organisms.  Macetronium ethyl sulphate is the important ingredient in INOSEPT.  This is an antiseptic, it means the compound kills bacteria and viruses and other microbes or invisible small organisms.  Inosept also has two forms of propanol which provides antisepsis and helps give a good feel and good odour!”. 

“Thank you Peter uncle” said all the three.

Peter kept a pack of INOSEPT near the door.  He said that whenever anyone comes into the house or goes out, he or she has to apply the INOSEPT to the front and back of the hands and in between fingers.  “This is called hand hygiene” – Peter added.

Hand hygiene is a saviour.  It helps reduce microbial load from hands, which are the chief sources of contamination.

Lockdown, social distancing, wearing the mouth mask and hand hygiene is clearly the way forward in our battle against the deadly highly contagious Covid-19 viral infection.