Extemporaneous dispensing used to be the foundation of pharmaceutical products, dating back to Ancient Greece, Rome and Egypt. Throughout history, pharmacopoeias have been developed to explain the strategies of preparing a variety of extemporaneously dispensed products. Whilst many of these preparations were based on anecdotal evidence, they were the main source of pharmaceutical products for pharmacies. It was during 1851, and the final edition of the London Pharmacopoeia, that chloroform was added as an anaesthetic. Over 100 years later Concentrated Chloroform Water BPC was developed, which could be diluted to produce single strength or double strength chloroform water (Marriott, 2010).
Over time, particularly with the development of the MHRA and GMP guidance, it became apparent that extemporaneous dispensing was one of the most high-risk activities that a pharmacy could conduct. This was particularly important due to many of the products being indicated for use in children, as safety of such products had not been established for that age range. This is still the case today, with many manufacturers advising avoidance of use in children due to lack of safety data. Chloroform water posed a particular danger, with its high toxicity and notable risk of causing cardiac arrhythmia in excessive doses. A combination of all of the above, as well as greater production of pharmaceuticals by licensed manufacturers, meant that the incidence of extemporaneous dispensing gradually declined (General Pharmaceutical Council, 2014).
The turning point for extemporaneous dispensing happened with the peppermint water case in 1998. A miscalculation concerning the preparation of double strength chloroform (DSCW) water led to the death of a three week-old baby. The pre-registration pharmacist should have diluted 3.75mL up to 75mL with water to prepare the DSCW. 75mL of concentrated chloroform water was added instead of this, 20 times stronger than the intended product and leading to cardiac arrhythmia (The Pharmaceutical Journal, 2000). Following this case it was clear that the preparation of chloroform water was not ideal in a community pharmacy, particularly if quality assurance guidance was not adhered to as strictly as in industrial settings. This has led to a rapid decline of the extemporaneous dispensing of chloroform water, with many of these items being ordered from specials manufacturers. With the need for regular audits and quality assurance checks, many community pharmacies simply do not have the time to prepare such products under current pressures. The peppermint water case also raised awareness of how dangerous the practice can be.
With this fact in mind, and also the dynamic of the role of the pharmacist, it appears much safer and less time consuming to obtain chloroform water from an industrialised process with elaborate QA/QC procedures. Whilst extemporaneous products are still prepared in the hospital setting, general guidance suggests that extemporaneous dispensing should only be performed where safety can be assured. The stigma created by the peppermint water case means that the extemporaneous preparation of chloroform water is rarely, if at all, performed.
References: General Pharmaceutical Council. (2014). Guidance for Registered Pharmacies Preparing Unlicensed Medicines. Online Resource. Available from: https://www.pharmacyregulation.org/sites/default/files/guidance_for_registered_pharmacies_preparing_unlicensed_medicines_23_05_14.pdf (Accessed on 7 February 2017).
Marriott, J. (2010). Pharmaceutical Compounding and Dispensing, 2nd edition. Pharmaceutical Press, London. pp. 3-34.
The Pharmaceutical Journal. (2000). Boots pharmacist and trainee cleared of baby’s manslaughter, but fined for dispensing a defective medicine. Online reference. Available from: http://www.pharmaceutical-journal.com/boots-pharmacist-and-trainee-cleared-of-babys-manslaughter-but-fined-for-dispensing-a-defective-medicine/20000781.article (Accessed on 7 February 2017).
In modern society, extemporaneous dispensing is the process of compounding ingredients to prepare an unlicensed medicine for a patient in accordance with a prescription. It is used where no licensed product is available or where the formulation of the licensed product is not suitable (McCague, 2012). Chloroform, or trichloromethane, is an organic compound with formula CHCl3. It is a colourless, sweet-smelling, dense liquid that is produced on a large scale as a precursor to PTFE (Rossberg. et al. (2005) however the use and application of this compound is declining and is no longer a suitable vehicle used in extemporaneous dispensing of suspensions and solutions. The ability to dispense medicines extemporaneously was and is still currently regarded as a skill unique to the pharmacy profession. However, the peppermint case in 1998 was a turning point for the use of extemporaneous products and especially the use of chloroform, as this case formed the basis for the re-evaluation of chloroform as suitable vehicle for the formulation of solutions and suspensions. The miscalculation and inaccuracy of double-strength chloroform water was the cause for the death of a baby due to a cardiac arrhythmia (Pharmaceutical Journal, 2000). Due to this catastrophic case, there had been ongoing debates over the safety of extemporaneous prepared medicines led to the protocols and guidelines changing due to the lack of information over safety. The GPhC/RPS has an underlying principle promote safety and well-being of the public and after the peppermint case, the use of extemporaneous products needed re-evaluating. The 'Royal Pharmaceutical Society published a document laying down brief standards of good professional practice for the dispensing of extemporaneous preparations' (Pharmaceutical Journal, 2000), and so this case has been a declining factor for the use of chloroform water that was once a commonly used vehicle in extemporaneous dispensing. Moreover there have been many incidences of death regarding the use of chloroform with the peppermint case being the escalating factor, there were also cases before this, in which there were two fatal deaths resulting from chloroform poisoning. In this case, the cause of death was chloroform poisoning by forced inhalation in addition to oronasal obstruction (Kim, et al, 1996). Overall, these cases concluded the fact that the re-evaluation of chloroform was important for the safety and health for the public, with regards to its use in medicine and also in its abuse. Even though chloroform is no longer used as a vehicle in extemporaneous preparations, it is still a useful chemical for industrial and biological purposes. Whilst extemporaneous dispensing is still a skill used mostly in secondary setting (i.e. In hospitals), the guidance from the RPS recommends that the manufacture of extemporaneous products must be made whilst assuring safety to the community (Pharmaceutical Journal, 2000). To conclude, there was a lack of safety and fear of making repeated ‘accidents’ with the use of chloroform which is the reason why it is not currently being used today. References Kim, N., Park, S. and Suh, J. (1996). Two Fatal Cases of Dichloromethane or Chloroform Poisoning. Journal of Forensic Sciences, 41(3), p.13951J. McCague, P. (2012). What are your views on specials and extemporaneous medicines preparation?. [online] Pharmaceutical Journal. Available at: http://www.pharmaceutical-journal.com/news-and-analysis/news/what-are-your-views-on-specials-and-extemporaneous-medicines-preparation/11102745.article [Accessed 9 Feb. 2017]. Pharmaceutical Journal. (2000). Council sets standards for extemporaneous dispensing. [online] Available at: http://www.pharmaceutical-journal.com/council-sets-standards-for-extemporaneous-dispensing/20002542.article [Accessed 9 Feb. 2017]. Rossberg, M.; et al. (2005), "Chlorinated Hydrocarbons", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a06_233.pub2 (used for the chemistry of chloroform).
With your blog Lauren you have made good points with why chloroform is a commonly used vehicle for extemporaneous products, but they are still regarded important with the use in industry settings. The use of chloroform is reduced in medicines and is replaced with a less-toxic and more appropriate solutions such as water and diluted ethanol which prove to be more safe and seen more acceptable as a vehicle for medicine formulations.
Chloroform water still has a place in industry, but even so the numbers of requests for chloroform water has declined over the years. In terms of community pharmacies, sourcing medicines containing chloroform water relies heavily on the use of specials manufacturers. However, chloroform is also still being used in OTC products such as Collis Browne’s Mixture for coughs, diarrhoea and upset stomach. Products are now limited to contain no more than 0.5% chloroform, and it’s classification as a class 3 carcinogen means that it is more suitable to prepare in an environment equipped to handle such substances i.e. in industry (Lowey, 2008). Despite this in many cases it is recommended that prescribers should seek a ready-made, licensed product before considering extemporaneous preparations.
References: Lowey, A., Jackson, M. (2008). How to ensure the quality and safety of unlicensed oral medicines. Online reference. Available from: http://www.pharmaceutical-journal.com/opinion/comment/how-to-ensure-the-quality-and-safety-of-unlicensed-oral-medicines/10028707.article (Accessed on 16 February 2017). (This reference described the classification of chloroform, and the impact on its prescribing).
I did not know about chloroform water's modern day use in OTC preparations Lauren, very interesting. It makes me wonder whether it is just the stigma around the 1998 case that stops chloroform water being used more. Maybe if extemporaneous dispensing was emphasised more in Pharmacy Schools it could be a viable option.
Interesting about the other case you have included Noore, I suppose the safety of chloroform generally needs to be considered, regardless of the risk of extemporaneous dispensing.
After reading through your comments, i am also surprised that chloroform is still being used OTC after the some regulations being put forward about the negative uses of it in extemporaneous dispensing. I also agree with you Jennifer that the the whole aspect of Chloroform safety has to be judged and not based on extemporaneous dispensing.
A key feature in the decline of chloroform use in pharmacy is the change in the role of the pharmacist. Extemporaneous dispensing used to be the bread and butter of pharmacists everywhere, however due to the standardisation process of pharmacy preparations and a change in work pressure has led to many community pharmacists preferring to not prepare mixtures on site. Not only is it more responsibility but it is more time consuming and the high workload of a community pharmacy no-longer allows the time required for accurate and moreover safe preparation of extemporaneous formulation. Chloroform water was a standard diluent/vehicle as when taken by mouth, it had a ‘pleasant taste and a sensation of warmth’ (Marriot et Al., 2012) It also has the use as a preservative and a flavouring agent, seemingly the wonder excipient doing the role of several additives for a fraction of the price. It was used in the form of Chloroform Water BP, Double Strength Chloroform Water BP or as Chloroform Spirit BP. (BP 1988) Over the years, pharmacy became more regulated and safety conscious and it became evident that the irregularity/accidents/miscalculations involved in extemporaneous dispensing were a key area for improvement. (Lowey, Jackson, 2008) So more guidance was established and extemporaneous dispensing was still used widely. As highlighted by my peers, the turning point was the peppermint water case in 1998, where the pre-reg did not know of the double strength chloroform water and instead used the concentrated form of chloroform, resulting in handing a baby a preparation with 75mL of conc chloroform as opposed to 3.75mL, obviously a much too strong preparation, sadly resulting in fatality. (The Pharmaceutical Journal, 2000) This explicitly highlighted the associated risks with extemporaneous dispensing and how easily the mistake could be made and furthermore how extemporaneous dispensing needed to take a back seat in modern day community pharmacy. The incident was not taken lightly and has ultimately led to the decline in use, there’s nothing to say that this wouldn’t have happened anyways but this was the catalyst to the event. Now preparations are commonly outsourced to specials manufacturers just to remove the risk and allow professionals with surplus time to formulate them. Extemporaneous dispensing still has a role in hospital pharmacy, however even in this setting, chloroform water is rarely used as a diluent due to the social taboo around the excipient since the 1998 incident. Lowey, Jackson. (2008). How to ensure the quality and safety of unlicensed oral medicines. Available: http://www.pharmaceutical-journal.com/opinion/comment/how-to-ensure-the-quality-and-safety-of-unlicensed-oral-medicines/10028707.article. Last accessed 19/02/17. Marriot, Wilson, Langley and Belcher (2012). Pharmaceutical Compounding and Dispensing. 2nd ed. London: Pharmaceutical Press. 32-33. MHRA. (1988). BP 1988. Available: https://www.pharmacopoeia.com/. Last accessed 19/02/17. The Pharmaceutical Journal. (2000). Boots pharmacist and trainee cleared of baby's manslaughter, but fined for dispensing a defective medicine. Available: http://www.pharmaceutical-journal.com/boots-pharmacist-and-trainee-cleared-of-babys-manslaughter-but-fined-for-dispensing-a-defective-medicine/20000781.article. Last accessed 19/02/17.
Chloroform water has been a staple in the formulation of extemporaneous products. Historically it has been the solvent of choice in liquid preparations and has been widely used until the last few decades. But if it was so commonly used, why has the recent trend been to move away from its use? The main factor for this is safety. Dedicated manufacturers can produce much larger quantities in more sterile environments, enabling much safer products to be made. Manufacturers produce consistently safe products whereas, depending of technique and training a product made extemporaneously in a pharmacy may vary from products made by other pharmacists. Pharmacists are simply not able to test products in the way that large scale manufacturers can to ensure the medicine is safe to use. In 1998 a pharmacist and a pre-registration pharmacist supplied a extemporaneously prepared peppermint solution to a four day old baby, little did they know that the solution contained concentrated chloroform water that was 20 times stronger than the intended ingredient double-strength chloroform water. The baby died 18 days later (Carter, H. 2000). This case shows you how easy it is for extemporaneous dispensing to turn deadly. Today we are seeing the industry move away from extemporaneous dispensing in general and chloroform water is being replaced with other less toxic solvents. On top of this, the ability of pharmacies to order in manufactured products quickly and easily only hastened the decline in the use of chloroform water. This is likely a good thing as these products are subject to QC and QA analysis resulting in the likelihood of harm coming to patients being reduced. Reference: Carter, H. (2000). Chemists fined over deadly medicine. Available: https://www.theguardian.com/uk/2000/mar/02/helencarter. Last accessed 21/02/2017.
The use and feature of chloroform has changed remarkably since its first uses in medical practice, dating back to the 1840's where the primary function was for sedation in surgery. Prior to this, the uses included treatment for scurvy and pulmonary inflammation (History.com Staff, 2010). Chloroform had a sweet taste and smell and was the medicine of choice. Following on from this use, chloroform began to be more widely used in a variety of other preparations, such as cough syrups, sedatives and pain relievers (Anon, 2017). In more recent times, chloroform has been classed as a carcinogen and is limited to smaller concentrations in products, and alternatives are used where need be. Research has proven that prolonged use of chloroform can cause hepatic toxicity and respiratory failure. Acutely, dizziness and irritation in the mouth and throat can occur (Foxhall, 2007). Chloroform became a standard ingredient in the British Pharmacopeia, and was used regularly in the preparation of single/double strength chloroform water. Used for many years in preparations made in community and hospital pharmacies, chloroform water was used widely in a number of preparations. However, following the peppermint water case, in 1998, whist resulted in the death of a weeks old baby, extemporaneous dispensing is rarely, if ever, done in community pharmacies now. The peppermint water case, which was done incorrectly, played a key role in the discontinuation of this practice. The preparation contained 75mL of chloroform water when in fact it should have contained merely 3.75mL. The dispensing error cost a child's life (Pharmaceutical Journal, 2000). All medicines that are dispensed in community pharmacies are now ordered in from manufacturers, and if there is no availability, patients are told to come back to collect their items once an order has been placed; nothing is made. Extemporaneous dispensing is now usually limited to hospital environments, where thorough protocols are in place to minimise chances of mistakes occurring. Chloroform is not listed in the BNF anymore, and alternative solvents should be used for any extemporaneous product that may need to be prepared, such as morphine oral solutions or potassium citrate mixture (BNF 72, 2017). In manufactured products, chloroform is rarely used, other than in limited medicines, such as J. Collins Browne's syrup and Kaolin and Morphine for diarrhoea relief References: Anon (2017) Chloroform Available at: http://www.discoveriesinmedicine.com/Bar-Cod/Chloroform.html Last accessed 02/03/2017
BNF. (2017) Kaolin with Morphine Available: https://www.medicinescomplete.com/mc/bnf/current/DMD3238211000001102.htm?q=chloroform&t=advanced&ss=pr&tot=3&p=1#DMD3238211000001102. Last accessed 02/03/2017
Foxhall, K (2007) Chloroform, Toxicological Review Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/338535/Chloroform_Toxicological_Overview.pdf Last accessed 02/03/2017
History.com Staff, (2010), Ether and Chloroform Available at: http://www.history.com/topics/ether-and-chloroform Last accessed 02/03/2017
The Pharmaceutical Journal (2000) Boots pharmacist and trainee cleared of baby's manslaughter, but fined for dispensing a defective medicine. Available at: http://www.pharmaceutical-journal.com/boots-pharmacist-and-trainee-cleared-of-babys-manslaughter-but-fined-for-dispensing-a-defective-medicine/20000781.article Last accessed 02/03/2017
The point you made about chloroform water being carcinogenic is interesting Meera, I was not aware of this. It is also interesting how it has been known to cause health problems such as hepatic toxicity, I also read about this. It makes me wonder if people already knew about the dangers of chloroform water before the peppermint case but did not decrease its use until after this or if more research was done on the solvent after this incident took place in order to truly understand its nature.
Chloroform water played a vital role in the preparations of extemporaneously prepared medicines. It was introduced in the 1840s where it was used for sedation for hospital surgeries and from there progressed to becoming the vehicle of choice for solvent based medications. Single and double strength chloroform water was versatile and became widely popular in the preparation of various medicines such as cough syrups and pain relievers. It was an ingredient that was listed in the British Pharmacopeia and was also included within the BNF. However, the safety of chloroform water was highly questioned after the peppermint water incident of 1998 which led to the death of a baby. The preparation given to the child contained 75mL of the solvent instead of 3.75mL. This calculation error caused an uproar in the health industry and inevitably played a significant role in the declined use of chloroform water and the profession of extemporaneous dispensing. In addition to this case it was also proven that chloroform water was not as safe as first anticipated and was known to cause hepatic toxicity and respiratory failure. It was also seen to cause adverse effects such as dizziness and irritation to mouth and throat. Thus it was decided that this product could be replaced with less toxic alternatives which were much safer for use. In the past extemporaneous dispensing was seen as a common pharmacy profession whereby unlicensed medicines would be prepared for patients according to the requirements on their prescription. This profession requires high skill and accuracy and is time consuming. This made it very impractical to prepare medications efficiently and safely. Over the years this practice has become increasingly rare due to this, pharmacies are not able to prepare products at the same rate as large scale manufactures and with the same level of safety. Extemporaneous dispensing is known as one of the highest risk activities to be carried out in pharmacies. There is a positive correlation between the extemporaneous services declining and the use of chloroform water decreasing. It is not seen as a suitable option anymore as in the current day and age there are many alternatives to products that are safer and more appropriate.
References:
General Pharmaceutical Council. (2014). Guidance for Registered Pharmacies Preparing Unlicensed Medicines. Online Resource. Available from: https://www.pharmacyregulation.org/sites/default/files/guidance_for_registered_pharmacies_preparing_unlicensed_medicines_23_05_14.pdf (Last accessed: 20 February 2017).
The Pharmaceutical Journal. (2000). Boots pharmacist and trainee cleared of baby's manslaughter, but fined for dispensing a defective medicine. Available: http://www.pharmaceutical-journal.com/boots-pharmacist-and-trainee-cleared-of-babys-manslaughter-but-fined-for-dispensing-a-defective-medicine/20000781.article. Last accessed: 20th February 2017)
Foxhall, K (2007) Chloroform, Toxicological Review Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/338535/Chloroform_Toxicological_Overview.pdf Last accessed: 20th February 2017
Keele university . (2012). Extemporaneous preparation. Available: http://www.dysphagia-medicine.com/extemporaneous-preparation.html. Last accessed: 21st February 2017.
Extemporaneous dispensing used to be the foundation of pharmaceutical products, dating back to Ancient Greece, Rome and Egypt. Throughout history, pharmacopoeias have been developed to explain the strategies of preparing a variety of extemporaneously dispensed products. Whilst many of these preparations were based on anecdotal evidence, they were the main source of pharmaceutical products for pharmacies. It was during 1851, and the final edition of the London Pharmacopoeia, that chloroform was added as an anaesthetic. Over 100 years later Concentrated Chloroform Water BPC was developed, which could be diluted to produce single strength or double strength chloroform water (Marriott, 2010).
ReplyDeleteOver time, particularly with the development of the MHRA and GMP guidance, it became apparent that extemporaneous dispensing was one of the most high-risk activities that a pharmacy could conduct. This was particularly important due to many of the products being indicated for use in children, as safety of such products had not been established for that age range. This is still the case today, with many manufacturers advising avoidance of use in children due to lack of safety data. Chloroform water posed a particular danger, with its high toxicity and notable risk of causing cardiac arrhythmia in excessive doses. A combination of all of the above, as well as greater production of pharmaceuticals by licensed manufacturers, meant that the incidence of extemporaneous dispensing gradually declined (General Pharmaceutical Council, 2014).
The turning point for extemporaneous dispensing happened with the peppermint water case in 1998. A miscalculation concerning the preparation of double strength chloroform (DSCW) water led to the death of a three week-old baby. The pre-registration pharmacist should have diluted 3.75mL up to 75mL with water to prepare the DSCW. 75mL of concentrated chloroform water was added instead of this, 20 times stronger than the intended product and leading to cardiac arrhythmia (The Pharmaceutical Journal, 2000). Following this case it was clear that the preparation of chloroform water was not ideal in a community pharmacy, particularly if quality assurance guidance was not adhered to as strictly as in industrial settings. This has led to a rapid decline of the extemporaneous dispensing of chloroform water, with many of these items being ordered from specials manufacturers. With the need for regular audits and quality assurance checks, many community pharmacies simply do not have the time to prepare such products under current pressures. The peppermint water case also raised awareness of how dangerous the practice can be.
With this fact in mind, and also the dynamic of the role of the pharmacist, it appears much safer and less time consuming to obtain chloroform water from an industrialised process with elaborate QA/QC procedures. Whilst extemporaneous products are still prepared in the hospital setting, general guidance suggests that extemporaneous dispensing should only be performed where safety can be assured. The stigma created by the peppermint water case means that the extemporaneous preparation of chloroform water is rarely, if at all, performed.
References:
General Pharmaceutical Council. (2014). Guidance for Registered Pharmacies Preparing Unlicensed Medicines. Online Resource. Available from: https://www.pharmacyregulation.org/sites/default/files/guidance_for_registered_pharmacies_preparing_unlicensed_medicines_23_05_14.pdf (Accessed on 7 February 2017).
Marriott, J. (2010). Pharmaceutical Compounding and Dispensing, 2nd edition. Pharmaceutical Press, London. pp. 3-34.
The Pharmaceutical Journal. (2000). Boots pharmacist and trainee cleared of baby’s manslaughter, but fined for dispensing a defective medicine. Online reference. Available from: http://www.pharmaceutical-journal.com/boots-pharmacist-and-trainee-cleared-of-babys-manslaughter-but-fined-for-dispensing-a-defective-medicine/20000781.article (Accessed on 7 February 2017).
In modern society, extemporaneous dispensing is the process of compounding ingredients to prepare an unlicensed medicine for a patient in accordance with a prescription. It is used where no licensed product is available or where the formulation of the licensed product is not suitable (McCague, 2012).
ReplyDeleteChloroform, or trichloromethane, is an organic compound with formula CHCl3. It is a colourless, sweet-smelling, dense liquid that is produced on a large scale as a precursor to PTFE (Rossberg. et al. (2005) however the use and application of this compound is declining and is no longer a suitable vehicle used in extemporaneous dispensing of suspensions and solutions.
The ability to dispense medicines extemporaneously was and is still currently regarded as a skill unique to the pharmacy profession. However, the peppermint case in 1998 was a turning point for the use of extemporaneous products and especially the use of chloroform, as this case formed the basis for the re-evaluation of chloroform as suitable vehicle for the formulation of solutions and suspensions. The miscalculation and inaccuracy of double-strength chloroform water was the cause for the death of a baby due to a cardiac arrhythmia (Pharmaceutical Journal, 2000). Due to this catastrophic case, there had been ongoing debates over the safety of extemporaneous prepared medicines led to the protocols and guidelines changing due to the lack of information over safety. The GPhC/RPS has an underlying principle promote safety and well-being of the public and after the peppermint case, the use of extemporaneous products needed re-evaluating. The 'Royal Pharmaceutical Society published a document laying down brief standards of good professional practice for the dispensing of extemporaneous preparations' (Pharmaceutical Journal, 2000), and so this case has been a declining factor for the use of chloroform water that was once a commonly used vehicle in extemporaneous dispensing.
Moreover there have been many incidences of death regarding the use of chloroform with the peppermint case being the escalating factor, there were also cases before this, in which there were two fatal deaths resulting from chloroform poisoning. In this case, the cause of death was chloroform poisoning by forced inhalation in addition to oronasal obstruction (Kim, et al, 1996). Overall, these cases concluded the fact that the re-evaluation of chloroform was important for the safety and health for the public, with regards to its use in medicine and also in its abuse.
Even though chloroform is no longer used as a vehicle in extemporaneous preparations, it is still a useful chemical for industrial and biological purposes. Whilst extemporaneous dispensing is still a skill used mostly in secondary setting (i.e. In hospitals), the guidance from the RPS recommends that the manufacture of extemporaneous products must be made whilst assuring safety to the community (Pharmaceutical Journal, 2000). To conclude, there was a lack of safety and fear of making repeated ‘accidents’ with the use of chloroform which is the reason why it is not currently being used today.
References
Kim, N., Park, S. and Suh, J. (1996). Two Fatal Cases of Dichloromethane or Chloroform Poisoning. Journal of Forensic Sciences, 41(3), p.13951J.
McCague, P. (2012). What are your views on specials and extemporaneous medicines preparation?. [online] Pharmaceutical Journal. Available at: http://www.pharmaceutical-journal.com/news-and-analysis/news/what-are-your-views-on-specials-and-extemporaneous-medicines-preparation/11102745.article [Accessed 9 Feb. 2017].
Pharmaceutical Journal. (2000). Council sets standards for extemporaneous dispensing. [online] Available at: http://www.pharmaceutical-journal.com/council-sets-standards-for-extemporaneous-dispensing/20002542.article [Accessed 9 Feb. 2017].
Rossberg, M.; et al. (2005), "Chlorinated Hydrocarbons", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a06_233.pub2 (used for the chemistry of chloroform).
With your blog Lauren you have made good points with why chloroform is a commonly used vehicle for extemporaneous products, but they are still regarded important with the use in industry settings. The use of chloroform is reduced in medicines and is replaced with a less-toxic and more appropriate solutions such as water and diluted ethanol which prove to be more safe and seen more acceptable as a vehicle for medicine formulations.
ReplyDeleteChloroform water still has a place in industry, but even so the numbers of requests for chloroform water has declined over the years. In terms of community pharmacies, sourcing medicines containing chloroform water relies heavily on the use of specials manufacturers. However, chloroform is also still being used in OTC products such as Collis Browne’s Mixture for coughs, diarrhoea and upset stomach. Products are now limited to contain no more than 0.5% chloroform, and it’s classification as a class 3 carcinogen means that it is more suitable to prepare in an environment equipped to handle such substances i.e. in industry (Lowey, 2008). Despite this in many cases it is recommended that prescribers should seek a ready-made, licensed product before considering extemporaneous preparations.
DeleteReferences:
Lowey, A., Jackson, M. (2008). How to ensure the quality and safety of unlicensed oral medicines. Online reference. Available from: http://www.pharmaceutical-journal.com/opinion/comment/how-to-ensure-the-quality-and-safety-of-unlicensed-oral-medicines/10028707.article (Accessed on 16 February 2017). (This reference described the classification of chloroform, and the impact on its prescribing).
I did not know about chloroform water's modern day use in OTC preparations Lauren, very interesting. It makes me wonder whether it is just the stigma around the 1998 case that stops chloroform water being used more. Maybe if extemporaneous dispensing was emphasised more in Pharmacy Schools it could be a viable option.
DeleteInteresting about the other case you have included Noore, I suppose the safety of chloroform generally needs to be considered, regardless of the risk of extemporaneous dispensing.
After reading through your comments, i am also surprised that chloroform is still being used OTC after the some regulations being put forward about the negative uses of it in extemporaneous dispensing. I also agree with you Jennifer that the the whole aspect of Chloroform safety has to be judged and not based on extemporaneous dispensing.
DeleteA key feature in the decline of chloroform use in pharmacy is the change in the role of the pharmacist. Extemporaneous dispensing used to be the bread and butter of pharmacists everywhere, however due to the standardisation process of pharmacy preparations and a change in work pressure has led to many community pharmacists preferring to not prepare mixtures on site. Not only is it more responsibility but it is more time consuming and the high workload of a community pharmacy no-longer allows the time required for accurate and moreover safe preparation of extemporaneous formulation.
ReplyDeleteChloroform water was a standard diluent/vehicle as when taken by mouth, it had a ‘pleasant taste and a sensation of warmth’ (Marriot et Al., 2012) It also has the use as a preservative and a flavouring agent, seemingly the wonder excipient doing the role of several additives for a fraction of the price. It was used in the form of Chloroform Water BP, Double Strength Chloroform Water BP or as Chloroform Spirit BP. (BP 1988)
Over the years, pharmacy became more regulated and safety conscious and it became evident that the irregularity/accidents/miscalculations involved in extemporaneous dispensing were a key area for improvement. (Lowey, Jackson, 2008) So more guidance was established and extemporaneous dispensing was still used widely. As highlighted by my peers, the turning point was the peppermint water case in 1998, where the pre-reg did not know of the double strength chloroform water and instead used the concentrated form of chloroform, resulting in handing a baby a preparation with 75mL of conc chloroform as opposed to 3.75mL, obviously a much too strong preparation, sadly resulting in fatality. (The Pharmaceutical Journal, 2000) This explicitly highlighted the associated risks with extemporaneous dispensing and how easily the mistake could be made and furthermore how extemporaneous dispensing needed to take a back seat in modern day community pharmacy. The incident was not taken lightly and has ultimately led to the decline in use, there’s nothing to say that this wouldn’t have happened anyways but this was the catalyst to the event. Now preparations are commonly outsourced to specials manufacturers just to remove the risk and allow professionals with surplus time to formulate them.
Extemporaneous dispensing still has a role in hospital pharmacy, however even in this setting, chloroform water is rarely used as a diluent due to the social taboo around the excipient since the 1998 incident.
Lowey, Jackson. (2008). How to ensure the quality and safety of unlicensed oral medicines. Available: http://www.pharmaceutical-journal.com/opinion/comment/how-to-ensure-the-quality-and-safety-of-unlicensed-oral-medicines/10028707.article. Last accessed 19/02/17.
Marriot, Wilson, Langley and Belcher (2012). Pharmaceutical Compounding and Dispensing. 2nd ed. London: Pharmaceutical Press. 32-33.
MHRA. (1988). BP 1988. Available: https://www.pharmacopoeia.com/. Last accessed 19/02/17.
The Pharmaceutical Journal. (2000). Boots pharmacist and trainee cleared of baby's manslaughter, but fined for dispensing a defective medicine. Available: http://www.pharmaceutical-journal.com/boots-pharmacist-and-trainee-cleared-of-babys-manslaughter-but-fined-for-dispensing-a-defective-medicine/20000781.article. Last accessed 19/02/17.
Chloroform water has been a staple in the formulation of extemporaneous products. Historically it has been the solvent of choice in liquid preparations and has been widely used until the last few decades. But if it was so commonly used, why has the recent trend been to move away from its use?
ReplyDeleteThe main factor for this is safety. Dedicated manufacturers can produce much larger quantities in more sterile environments, enabling much safer products to be made. Manufacturers produce consistently safe products whereas, depending of technique and training a product made extemporaneously in a pharmacy may vary from products made by other pharmacists. Pharmacists are simply not able to test products in the way that large scale manufacturers can to ensure the medicine is safe to use.
In 1998 a pharmacist and a pre-registration pharmacist supplied a extemporaneously prepared peppermint solution to a four day old baby, little did they know that the solution contained concentrated chloroform water that was 20 times stronger than the intended ingredient double-strength chloroform water. The baby died 18 days later (Carter, H. 2000). This case shows you how easy it is for extemporaneous dispensing to turn deadly.
Today we are seeing the industry move away from extemporaneous dispensing in general and chloroform water is being replaced with other less toxic solvents. On top of this, the ability of pharmacies to order in manufactured products quickly and easily only hastened the decline in the use of chloroform water. This is likely a good thing as these products are subject to QC and QA analysis resulting in the likelihood of harm coming to patients being reduced.
Reference:
Carter, H. (2000). Chemists fined over deadly medicine. Available: https://www.theguardian.com/uk/2000/mar/02/helencarter. Last accessed 21/02/2017.
The use and feature of chloroform has changed remarkably since its first uses in medical practice, dating back to the 1840's where the primary function was for sedation in surgery. Prior to this, the uses included treatment for scurvy and pulmonary inflammation (History.com Staff, 2010). Chloroform had a sweet taste and smell and was the medicine of choice. Following on from this use, chloroform began to be more widely used in a variety of other preparations, such as cough syrups, sedatives and pain relievers (Anon, 2017). In more recent times, chloroform has been classed as a carcinogen and is limited to smaller concentrations in products, and alternatives are used where need be. Research has proven that prolonged use of chloroform can cause hepatic toxicity and respiratory failure. Acutely, dizziness and irritation in the mouth and throat can occur (Foxhall, 2007).
ReplyDeleteChloroform became a standard ingredient in the British Pharmacopeia, and was used regularly in the preparation of single/double strength chloroform water. Used for many years in preparations made in community and hospital pharmacies, chloroform water was used widely in a number of preparations. However, following the peppermint water case, in 1998, whist resulted in the death of a weeks old baby, extemporaneous dispensing is rarely, if ever, done in community pharmacies now. The peppermint water case, which was done incorrectly, played a key role in the discontinuation of this practice. The preparation contained 75mL of chloroform water when in fact it should have contained merely 3.75mL. The dispensing error cost a child's life (Pharmaceutical Journal, 2000). All medicines that are dispensed in community pharmacies are now ordered in from manufacturers, and if there is no availability, patients are told to come back to collect their items once an order has been placed; nothing is made. Extemporaneous dispensing is now usually limited to hospital environments, where thorough protocols are in place to minimise chances of mistakes occurring. Chloroform is not listed in the BNF anymore, and alternative solvents should be used for any extemporaneous product that may need to be prepared, such as morphine oral solutions or potassium citrate mixture (BNF 72, 2017). In manufactured products, chloroform is rarely used, other than in limited medicines, such as J. Collins Browne's syrup and Kaolin and Morphine for diarrhoea relief
References:
Anon (2017) Chloroform Available at: http://www.discoveriesinmedicine.com/Bar-Cod/Chloroform.html Last accessed 02/03/2017
BNF. (2017) Kaolin with Morphine Available: https://www.medicinescomplete.com/mc/bnf/current/DMD3238211000001102.htm?q=chloroform&t=advanced&ss=pr&tot=3&p=1#DMD3238211000001102. Last accessed 02/03/2017
Foxhall, K (2007) Chloroform, Toxicological Review Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/338535/Chloroform_Toxicological_Overview.pdf Last accessed 02/03/2017
History.com Staff, (2010), Ether and Chloroform Available at: http://www.history.com/topics/ether-and-chloroform Last accessed 02/03/2017
The Pharmaceutical Journal (2000) Boots pharmacist and trainee cleared of baby's manslaughter, but fined for dispensing a defective medicine. Available at: http://www.pharmaceutical-journal.com/boots-pharmacist-and-trainee-cleared-of-babys-manslaughter-but-fined-for-dispensing-a-defective-medicine/20000781.article Last accessed 02/03/2017
The point you made about chloroform water being carcinogenic is interesting Meera, I was not aware of this. It is also interesting how it has been known to cause health problems such as hepatic toxicity, I also read about this. It makes me wonder if people already knew about the dangers of chloroform water before the peppermint case but did not decrease its use until after this or if more research was done on the solvent after this incident took place in order to truly understand its nature.
DeleteChloroform water played a vital role in the preparations of extemporaneously prepared medicines. It was introduced in the 1840s where it was used for sedation for hospital surgeries and from there progressed to becoming the vehicle of choice for solvent based medications. Single and double strength chloroform water was versatile and became widely popular in the preparation of various medicines such as cough syrups and pain relievers. It was an ingredient that was listed in the British Pharmacopeia and was also included within the BNF. However, the safety of chloroform water was highly questioned after the peppermint water incident of 1998 which led to the death of a baby. The preparation given to the child contained 75mL of the solvent instead of 3.75mL. This calculation error caused an uproar in the health industry and inevitably played a significant role in the declined use of chloroform water and the profession of extemporaneous dispensing. In addition to this case it was also proven that chloroform water was not as safe as first anticipated and was known to cause hepatic toxicity and respiratory failure. It was also seen to cause adverse effects such as dizziness and irritation to mouth and throat. Thus it was decided that this product could be replaced with less toxic alternatives which were much safer for use. In the past extemporaneous dispensing was seen as a common pharmacy profession whereby unlicensed medicines would be prepared for patients according to the requirements on their prescription. This profession requires high skill and accuracy and is time consuming. This made it very impractical to prepare medications efficiently and safely. Over the years this practice has become increasingly rare due to this, pharmacies are not able to prepare products at the same rate as large scale manufactures and with the same level of safety. Extemporaneous dispensing is known as one of the highest risk activities to be carried out in pharmacies. There is a positive correlation between the extemporaneous services declining and the use of chloroform water decreasing. It is not seen as a suitable option anymore as in the current day and age there are many alternatives to products that are safer and more appropriate.
ReplyDeleteReferences:
General Pharmaceutical Council. (2014). Guidance for Registered Pharmacies Preparing Unlicensed Medicines. Online Resource. Available from: https://www.pharmacyregulation.org/sites/default/files/guidance_for_registered_pharmacies_preparing_unlicensed_medicines_23_05_14.pdf (Last accessed: 20 February 2017).
The Pharmaceutical Journal. (2000). Boots pharmacist and trainee cleared of baby's manslaughter, but fined for dispensing a defective medicine. Available: http://www.pharmaceutical-journal.com/boots-pharmacist-and-trainee-cleared-of-babys-manslaughter-but-fined-for-dispensing-a-defective-medicine/20000781.article. Last accessed: 20th February 2017)
Foxhall, K (2007) Chloroform, Toxicological Review Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/338535/Chloroform_Toxicological_Overview.pdf Last accessed: 20th February 2017
Keele university . (2012). Extemporaneous preparation. Available: http://www.dysphagia-medicine.com/extemporaneous-preparation.html. Last accessed: 21st February 2017.