(10p) Codeine as example how product information of medicines continue to change

This article is a follow-up of my previous article to illustrate how the product information of medication is never final but pharmaceutical companies continue to update the information to be sure healthcare professionals and patients can trust that the information is up-to-date and medications are safe to use. 

When companies want to make changes or government medicine agencies tell them to do so, companies must submit dossiers to these agencies and pay for the assessment of the suggested changes and after their approval, the updated product information will be published on the website of medicine agencies but also printed in the leaflet that is enclosed in the packaging of the medication. And yes, civil servants working at those agencies declare each year that they have no conflicts of interest and thus are independent from the companies to work in the interest of society.  


Codeine can be taken as example of what happens after medications receive their authorisation as the public knows this molecule and to illustrate how the scientific knowledge, not only before commercialisation but also afterwards when a medicine is on the market, can result in changes in the product information, i.e. the scientific and patient leaflets.


Codeine and why it is used

  • Codeine used for pain relief

Codeine is an opioid that is approved to treat mild to moderate pain. It is a pro-drug that will be metabolised by the liver into morphine that is the real active substance. Although codeine can be taken on its own, often it is in combination with other active substances such as paracetamol and ibuprofen to increase their pain-reducing actions. 

Paracetamol and ibuprofen can be used to reduce pain and fever via their own specific mechanisms, the reason why one or the other is preferred in case of certain illnesses (such as paracetamol is preferable in case of Covid-19 - Dutch - French) and they have their own specific side-effects (such as paracetamol is toxic for the liver). 

Their use and abuse can to some extend be controlled as smaller pack sizes and lower strengths can be free from prescription (thus pharmacists can give them to patients who didn't go to the doctor and more details about correct use is present on the packaging). 

In contrast, larger pack sizes and/or higher strengths are often on prescription for which patients need to visit a doctor who will prescribe how to use the medicine. These differences are intended to reduce the risk of (deliberate) overdosing. Indeed, these drugs can have serious side-effects that can even result in death and thus they should be taken as explained in the leaflet or by the doctor.  

However, when paracetamol or ibuprofen on their own are insufficient to reduce pain, medication that contain both paracetamol and codeine or ibuprofen and codeine can be used. But, as codeine is metabolised in our body to form morphine that can have serious side-effects such as the risk of respiratory depression and low blood pressure and as it is addictive, it is normal that the combination drugs are on prescription to prevent abuse as much as possible. Later more limitations were introduced to increase safe use - see below. 


These are examples of good practice: products are available for acute and mild to moderate pain with or workout fever. When pain is more intense, people need to contact their doctor who may prescribe a pain reliever for a longer period or a higher strength or one that contains also codeine. That doesn't exclude that the doctor may refer the patient to a specialist to be sure nothing more serious such as cancer causes the more severe pain. 


  • Codeine used for cough relieve 

In addition, codeine can also be used in cough and cold medicines because it has a cough suppressing action (although this is no longer accepted by everyone) as it acts on the respiratory centre. Codeine was thus in many cough and cold products and originally doctors could prescribe it to any person although with caution to avoid dependency (remember, it becomes morphine in our body). Later more limitations were introduced to increase safe use - see below. 


Genetic differences to convert codeine into morphine

In the liver, the enzyme Cytochrome P45 2D6 or in short CYP2D6 converts codeine into morphine. Due to genetic polymorphism, differences exist between people as small differences in the CYP2D6 gene translate in differences in the CYP2D6 enzyme and thus in differences in the activity of this CYP2D6 enzyme, ie normal, decreased or no activity while also the number of copies of the gene can differ between individuals (see figure).

Figure: The conversion of codeine into morphine happens in the liver by the CYP2D6 enzyme

Most people have two normal copies of this gene that are translated into the CYP2D6 enzyme with normal activity and thus at the correct doses of codeine the enzyme changes codeine into morphine at a normal rate, the extensive metabolisers. 

However, as differences in the CYP2D6 gene result in differences in the enzyme with different enzyme activity, some people have one or two genes that translate in CYP2D6 enzymes with decreased or no activity so these people convert little to no codeine into morphine, the so-called intermediate or poor metabolisers. Here the effect of codeine is decreased.

Other persons have more than two copies of the active CYP2D6 gene so they produce more than normal of the active CYP2D6 enzyme and thus metabolize codeine much faster into morphine, resulting in an early much higher peak of morphine after intake of normal doses of codeine; these people are known as ultra-rapid metabolisers that can be dangerous for the person when they use codeine. 


History - important changes in the product information of codeine containing medicines

Although codeine was discovered in 1832, thus close to 200 years ago, its product information is still updated according new information. Below I discuss three procedures in the 21th century that resulted in major changes in the product information and in the use of codeine. However, these were not the only changes and more will follow to further improve the safety of the product when e.g. a new medicine is authorised that may interfere with codeine. 


  • Changes in product information when codeine is used as painkiller

Before 2013, codeine was authorised as a painkiller in adults and children. However, in a press release in 2013, the European Medicine Agency EMA informed about the outcome of a referral that investigated the use of codeine for pain relief in children after reports of serious and even fatal respiratory depression in children after taking codeine for pain relief. To understand, some knowledge of the metabolism of codeine into its metabolite morphine is needed as I explained higher. Further, the CYP2D6 enzyme may not be completely functional until the age of 12 years.

The outcome of the referral resulted in changes in a number of sections of the scientific leaflet, including the indication in section 4.1 (i.e. for who is the product intended) that now informs that only children above 12 years may use it if needed, in section 4.2 how much and how to use it, addition in section 4.3 of contraindications (i.e. that list who must not use the product) such as do not use below the age of 18 years in certain situations, do not take when you are known as an ultra-rapid metabolisers and do not breastfeed as codeine can be found in breast milk. In the warning section 4.4, information about the genetic differences was included while in section 4.6, the information about breastfeeding was updated. In addition, changes in the patient leaflet that reflect those in the scientific leaflet were also approved. 

The above numbers refer to the different sections in the scientific product information that are standard for all medications so doctors can find quickly the information they need to know; something similar exist for the patient leaflet (see table for more information). 

Table showing the different sections with their specific information in the scientific and public leaflets. In brackets what is only present for certain products. Section 4.8 of the scientific product information and section 4 of the public product information mention where possible side-effects can be reported.

These changes to the product information had to be made by all companies that sell products that contain codeine to relieve pain. Because of openness, the whole procedure is available on the EMA website - see restrictions of use of codeine as painkiller for children, in every European language whereby the changes to be made in the leaflets are present in Annex III. It is also possible that newspapers published about these changes. 


  • Changes in product information when codeine is used to treat cough and cold

Later, in a press release in 2015, EMA informed about the outcome of a referral that investigated the use of codeine in cough and cold relieve by children. This investigation was started as a consequence of the earlier investigation for the use of codeine to relieve pain by children and resulted in almost similar restrictions. 

This new outcome included contraindications in section 4.3 that codeine must not be used for children below 12 year as the conversion of codeine into morphine is still unpredictable, anyone known as ultra-rapid metabolisers must not use it and as codeine can be found in breast milk, breastfeeding women must not use codeine. Here too more information was added in the warning section 4.4 about the genetic differences and a recommendation against the use for children and adolescents between 12 and 18 years who have breathing problems. Also the section about breastfeeding was updated in section 4.6. Although this seems similar with the outcome of the referral to restrict codeine in the use as a painkiller in children, there are some differences. 

These changes to the product information had to be made by all companies that sell products that contain codeine for treatment of cough and cold; because of openness, the whole procedure is available on the EMA website - see prohibiting of use of codeine as cough and cold medicine for children below 12 years, in every European language whereby the changes to be made in the leaflets are present in Annex III. It is also possible that newspapers published about these changes. 

Further, not only the product information needed to change, Annex II informs that to reduce the risk of accidental overdose, bottles that contain liquid codeine should be child-resistant; quite a cost for pharmaceutical companies when bottles and caps need to change, but worth it to prevent accidental deaths by children. 


  • Changes in product information when codeine is used together with benzodiazepines and benzodiazepine-like products

It didn't end here. In 2016, the American Food and Drug Administration (FDA) issued a warning about the use of opioid drugs (that include codeine) to relieve pain or cough together with benzodiazepines. 

In 2018, after the EMA looked into the issue, a CMDh advice was published that confirmed that information should be added in the warning section 4.4 and the interaction with other drugs section 4.5 of the scientific product information and in corresponding sections of the public leaflet of opioids when they are used together with benzodiazepines because of the serious risk of respiratory depression, coma and death. 

In addition, also wording was proposed to add in the product information of benzodiazepines that are used together with opioids. This shows that changes in the product information in one country may result in similar changes in the rest of the world, while changes in the product information for one kind of drugs such as opioids can also result in changes for another kind of drugs such as benzodiazepines. 


In  summary

The above illustrates that the originally approved product information during the authorisation of a certain medicine is not written in stone but very likely will change over the course of the lifetime of the drugs when more information becomes available when it is used in humans. These changes in the product information can result from the characteristics of an active substance itself (such as codeine is metabolised differently by different persons because of differences in the CYP2D6 gene) or because of interactions when the drug is used together with other drugs (such as the combined use of codeine and benzodiazepines is dangerous). Also differences in gender and ethnicity should be considered as differences in how people respond to certain drugs are possible between Caucasian, Asian and African people, even more locally, due to genetic variations as the example codeine showed; still, today's mixed societies warrant such information is present in leaflets throughout the world.

Pharmaceutical companies, health professionals, scientists and even patients can report any possible side-effects they notice and are even encouraged to do so because then the safety of the product can be assessed and if needed the product information updated. Ones certain information is known, it may help to increase the safety of other similar medicines with the same or related active substance (such as the product information of all opioids changed as a result of above decisions) or of other drugs that interfere. To make these changes, companies need to pay medicine agencies such as the FDA, EMA and national agencies and thus part of the profits from the sale of medicines is used to keep the product information up-to-date. Sometimes proposed changes are refused when the relation between a side-effect and the drug is not proven; still, even then companies and agencies will follow-up this and consider changes when more evidence emerges. Remember, too early approval of changes may reduce the product for certain groups of patients who may have no alternative. 

Another example are influenza (flu) vaccines that need yearly updates, each time to be approved by agencies. And now companies submit files at agencies for the approval of vaccines against Covid-19; it is sure their product information will change over the next months when missing information will become available during their use. 

To improve the quality of the product information, companies, national agencies, EMA, FDA and other agencies exchange information when they notice new data is available such as the reporting of side-effects or scientific publications by scientists or doctors. 

As mentioned higher, this is not secret knowledge. Instead, the EMA investigated reported problems by codeine and published the outcome of their investigation on their website. Further, the EMA demanded that all companies that sell medicines that contain codeine change their product information so doctors and nurses but also patients know they have to be careful when they use the product. Indeed, this is important information that reduced the numbers of people who can use the product and thus reduces profits for companies so they will try to find other medicines that are safer for more people. However, certain illnesses are limited to small numbers of people and thus either sales of certain widely used drugs finance the research into rare diseases, or treatments will be expensive. 


Note: In case I made mistakes, please leave a comment to point to that mistake so I can improve this text.

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