ISSN 0362 1197, Human Physiology, 2012, Vol. 38, No. 5, pp. 541–544. © Pleiades Publishing, Inc., 2012. Original Russian Text © V.M. Pokrovskii, O.G. Kompaniets, 2012, published in Fiziologiya Cheloveka, 2012, Vol. 38, No. 5, pp. 102–107. Influence of the Level of Blood Pressure on the Regulatory–Adaptive State V. M. Pokrovskii and O. G. Kompaniets Kuban State Medical Universi
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How stable are medicines moved fromoriginal packs into compliance aids? In this article, Claire Church and Jane Smith have compiled a table based on information received from manufacturers about the possible
stability of their medicines after removal from their packaging and placement in compliance aids The use of compliance aids has increased in longer than eight weeks” and that “certain original packs to compliance aids as it may be
medications should not be placed in moni- outside the terms of their product licence. For cent years. Compliance aids aim to act as tored dosage systems. These include efferves- the majority of manufacturers any informa- a reminder for patients to take their medi- cent tablets, dispersible tablets, buccal tion they provide is based on anecdotal evi- tablets, sublingual tablets, significantly hygro- dence or in-house studies as no formal studies often complex and confusing drug regimens.
scopic preparations and solid dose cytotoxic They also act as a visual prompt for carers, in- Wyeth Laboratories requested its own dis- dicating that patients have taken their medi- A general article by Roger Walker in The claimer to be used as well, since it believed Pharmaceutical Journal in 19922 contained in- this would be a more accurate reflection of its products and is as follows: “The product in- The use of these aids involves the transfer pharmaceutical manufacturers. The leading formation provided in this article has been of medicines from the manufacturer’s original article in the same journal discussed the lack packaging to the compliance aid. The origi- of data and concluded: “Manufacturers and holders for these products.The marketing au- nal packaging is designed to protect the con- regulatory authorities urgently need to catch up with current practice.”3 In response to their products are stored in accordance with quality standards for a variety of criteria, eg, these articles a series of letters appeared a few the summary of product characteristics for water vapour transmission, as required in the each product and that storage of products in any other way is entirely at the pharmacist’s health care professionals in East Lancashire own risk.” These products are highlighted in published data on approximately 30 products the Table by an asterix (*) in the additional frequently reused without cleaning. The haz- ards associated with physical, chemical and Pinderfields General Hospital has collated Data presentation
microbiological cross-contamination could data that are largely derived from pharmaceu- The Table now contains a list of 392 products be a major risk factor. All other dispensing tical manufacturers and not in-house stability in alphabetical order by generic name.
containers are designed for single use.
data. This was last updated in January 2004 Defined against each name is the brand name and contains information on 176 products.
(if applicable), company, stability code and space for each dose, are not airtight and offer any other additional information relating to less moisture and light protection than origi- available to other medicines information de- stability.The stability data have been classified nal packs. Doubts are raised as to the stability partments and may be available in the future into six groups according to the data re- of medicines that have been transferred to ceived. Each group was allocated a code for compliance aids: is there a deterioration in ease of numbering in the Table linked to the quality and can this result in a reduction of extent of suitability for use in a compliance guidance on potential stability problems, we aid. Stability codes were allocated as follows: Despite the increased dispensing of medi- cines in this way, guidance on their stability in for their opinion on the stability of their 1. Do not put into a compliance aid.
these systems is limited and little new infor- 2. No stability data available, therefore com- mation has been published in recent years.
Certain products are particularly unsuitable Data collection
for transferring into compliance aids, but even this information is often not readily 3. No stability data available, therefore com- and December 2002 and asked whether their “Medicines, ethics and practice” guide (sec- solid oral dosage forms could be transferred stated, eg, light-sensitive. Individual phar- tion 3.4.7) says that “medicines should not be to a compliance aid. No specific brand of aid macists must accept responsibility for put- left in sealed monitored dosage systems for minimised by additional safeguards, eg, use Claire Church, BPharm, MRPharmS, is
all the pharmaceutical companies contacted and these data covered 243 products. A fur- 4. No stability data available, but it is proba- ther exercise to confirm data was carried out bly suitable to put in a compliance aid.
Jane Smith, MSc,MRPharmS, is acting
5. Stability data available in an alternative principal pharmacist, service development, container, but not necessarily in a compli- at North Bristol NHS Trust (formerly senior pharmacist, patient services at Southmead to be used in this article provided the follow- 6. Stability data available which state that it is ing disclaimer is included and strongly em- suitable to put in a compliance aid.
phasised: “It is important to note that the Correspondence to: Mrs Church (e-mail
individual manufacturers do not endorse this The additional information that relates to practice of transferring medicines from the stability is based on that received from the 21 January 2006 The Pharmaceutical Journal (Vol 276) 75
manufacturers and is the best available from are unstable.This information could be made the resources at the time of compilation.
available in the SPC. It is essential that action General exclusions
The Table does not represent an exhaustive is taken now to fill this information gap and list and many companies were keen to remind Using the information obtained, more general so benefit patients and practice in the future.
professionals that the most suitable and cur- guidelines for the transfer of solid oral dosage rent source of information regarding the sta- forms from original packs to compliance aids have Conclusion
bility of a medicinal product can be obtained been written. They assume that all compliance This survey has revealed that although some direct from the medicine information depart- aids will be stored at ambient temperature, in a information can be obtained from the phar- dry environment and away from direct sunlight.
maceutical companies there is still a shortage of short-term stability data for the transfer of SPCs may be a reference source for deter- publication of the leading article in The the original packaging.These can be accessed Pharmaceutical Journal in 19923 little appears to ■ Medicinal products which are likely to be have changed in the availability of this stabil- endium website at www.medicines.org.uk.
ity information. It is impracticable to prevent the use of compliance aids until such data be- does not mean that the medicine is suitable — Effervescent, dispersible, and soluble comes available. It is hoped that this collec- products, which are unsuitable for packing in tion of data in a compact format will provide compliance aids owing to their hygroscopic Discussion
Out of 392 products investigated, none had had stability tests carried out on them within dissolution properties of the product, or chemical drug degradation of the product may various pharmaceutical companies and also the following pharmacists for their help in (MHRA), which issues product licences, re- — Buccal and mucosal products, which may compiling this article: Hazel Arnold, senior quires companies to provide evidence of sta- be unsuitable since they are formulated to pharmacist, quality assurance; Alison Yeo, for- bility of the medicine in its original pack dissolve and so are sensitive to moisture.
merly senior pharmacist, medicines informa- until its stated expiry date, if stored as recom- — Significantly hygroscopic products, which tion; Eve Wood, formerly patient services mended. The licence only covers storage in the original packaging and transfer to any other container cannot be advocated without Bristol); and Richard Cattell, director, South extensive stability testing being carried out.
■ Medicinal products that are susceptible to the West Medicines Information and Training.
transferring medicines from original packs to ■ Medicinal products that are required to be kept compliance aids due to the absence of stabil- References
■ Medicinal products the handling of which is 1. Royal Pharmaceutical Society of Great Britain. Medicines,
bioavailability, efficacy or palatability of any ethics and practice: a guide for pharmacists (number 27).
formulation that is stored outside its original 2. Walker R. Stability of medicinal products in compliance
devices. Pharmaceutical Journal 1992;248:124–6.
they do not have any stability data to support compliance aid. However, this practice is 3. Dealing with dosage aids (leading article). Pharmaceutical
the storage in compliance aids, and therefore avoided in our dispensary since the publica- cannot recommend the practice. Some stated tion of a warning in The Pharmaceutical Journal 4. Stability of medicines dispensed in compliance devices
that storage in such devices would be an un- which concerned two incidents, one fatal, (letters). Pharmaceutical Journal 1992;248:174–5.
licensed use of their product and as such 5. Stability of medicines in compliance aids and monitored
would remain the responsibility of the phar- whole blister resulting in intestinal perfora- dose systems. Interface 2000; no 45.
tion.6 It is also more difficult to remove the 6. Blister-strip warning. Pharmaceutical Journal 1996;256:85.
dose from a small area of packaging.
pharmacists’ position and appreciate the fact It was interesting that different companies Future research
that the use of compliance aids is becoming sometimes offered conflicting advice for the increasingly popular or indeed necessary and same product, eg, omeprazole. This may be ■ We have initiated joint research with our that it is obviously impractical to prevent the due to different production processes, differ- regional quality assurance officer to carry out ent stability testing or one manufacturer in-house stability testing of specific drugs in more useful comments that included:“We do compliance aids that we routinely use. At the not have any relevant stability studies, but The survey carried out suggests that most time of writing, the stability of dispersible and these tablets are generally stable and we are solid oral dosage forms can be safely trans- enteric coated aspirin has been investigated.
not aware of any specific reason why they ferred to a compliance aid for a short period.
This was carried out in various compliance should not be stored in a compliance aid for There are, however, both general and specific aids at normal (35–50%) and high (up to exceptions to this and it is important that 85%) humidity. We hope to extend this to other pharmacists, patients and carers are aware of companies that provided information on the ■ We have liaised with the other two Bristol chemical and physical properties of their hospitals and the local primary care trusts drug, eg, hygroscopicity, light sensitivity. This continues to grow, with an ageing population with the aim of developing a common policy.
at least enables a pharmacist to make a judge- and greater care in patient’s homes, there is a This will reduce the problems that arise when necessity for short-term stability data for all patients using compliance aids are transferred drug from a compliance aid in the absence of ■ We plan to work with medicines information when applying for a new product licence, to pharmacists to ensure that the resources we avoid removal from their packaging by sug- provide data on the stability of the product and Pinderfields have developed are presented gesting cutting around the blister and putting when redispensed into a compliance aid.This in a suitable format for web presentation.
the dosage form (still in the blister) into the would be particularly useful for products that The Pharmaceutical Journal (Vol 276) 21 January 2006 Additional information
Effervescent tablet is moisture sensitive Can cause contact dermatitis when handled (wear Ethanol vaporises out of the capsule when out of the May absorb a small amount of water over time; light Should only be dispensed in glass bottles Brand name
aging and congeal with other tablets in the Additional information
Stable for 3 months at 40C and 75% relative Moisture sensitive; can become sticky out of original Disintegrates in the presence of small amounts of water Probably ok for short term storage in a compliance aid Not suitable as sensitive to atmospheric moisture Probably not suitable as sensitive to moisture Brand name
The stability of drugs in compliance aids, based on information provided by manufacturers (acarbose to co
21 January 2006 The Pharmaceutical Journal (Vol 276) 77
they are or potentially may be pregnant (if the dispenser and/or carer is male or not pregnant the stability code Additional information
Stable for 6 months at 25C and relative humidity of 60% Probably stable for maximum of 14 days (could taint other Brand name
-careldopa to hydro
will cause levodopa to turn black on prolonged exposure SPC states “must be stored in the original pack moisture; 10% loss of potency occurred when exposed to Additional information
Blue dye can fade on light exposure; also moisture Misoprostol is extremely moisture sensitive and may degrade Moisture sensitive; stable for 30 days out of the original Stable for 30 days out of the original container Not recommended for inclusion in compliance aid; May hydrolyse at high temperature and in the presence of Brand name
The stability of drugs in compliance aids, based on information provided by manufacturers (co
The Pharmaceutical Journal (Vol 276) 21 January 2006 aged in high density polyethylene bottles quickly; moisture can affect release mechanism Additional information
Hygroscopic; as an alternative, can write days of the week Stable for at least 7 days in a dry environment Very light sensitive and will significantly degrade very Probably stable for up to 4 weeks; sensitive to light; wear gloves if breaking or dividing the tablets due to potential Particularly fragile/brittle — may disintegrate due to Stable for 14 days at room temperature (25–30C) and Stable for 3 months at 25C and relative humidity of 60% Brand name
Probably stable for up to 4 weeks in a compliance aid which Moisture sensitive and could change colour Tablet coating is moisture and light sensitive Brand name
The stability of drugs in compliance aids, based on information provided by manufacturers (ibuprofen to paracetamol/codeine)
21 January 2006 The Pharmaceutical Journal (Vol 276) 79
Stable for 3 months at 30C and 75% humidity Very sensitive to moisture and becomes “sticky Hygroscopic; hydroxylates and becomes unstable with water Brand name
Unstable — light sensitive and extremely hygroscopic May absorb water; probably stable in an airtight compliance Hygroscopic and degrades in the presence of water Not known to be hygroscopic or need a drying agent during Refrigeration by patient not required if used within 30 days Stable for up to 28 days below 25C and at 60% relative Probably stable for 3 months out of the refrigerato; store in Brand name
The stability of drugs in compliance aids, based on information provided by manufacturers (paracetamol/metoclopramide to valsar
The Pharmaceutical Journal (Vol 276) 21 January 2006 , but not necessarily in a
sensitive. Individual pharmacists must accept
eting authorisation holders for these products. The mark , use of a black bag
: BI, Boehringer Ingelheim; BSM, Bristol-Myers Squibb; GSK efer to SPC for additional stability information.)
eason for concern is stated, eg
Do not put into a compliance aid.
No stability data available, therefore company does not recommend putting in a compliance
No stability data available, therefore company does not recommend putting in a compliance
responsibility for putting in a compliance aid. Risks can be minimised by additional
No stability data available, but it is probably suitable to put in a compliance aid.
Stability data available in an alternative container
Stability data available which state that it is suitable to put in a compliance aid.
Key to stability codes
information provided in this article has been provided by the mark t and that storage of products in any other way is entirely at the pharmacist om the original packs to compliance aids as it may be outside the terms of their product licences. For the majority of manufact Additional information
Stable for 30 days at 60-80% relative humidity 2mg stable for 14 days; other strengths stable for 4 weeks Brand name
: It is important to note that the individual manufacturers do not endorse the practice of transferring medicines fr Generic name
The stability of drugs in compliance aids, based on information provided by manufacturers (vancomycin to zuclopenthix
they provide is based on anecdotal evidence or in-house studies as no formal studies would have been carried out. *The product holders only recommend that their products are stored in accordance with the summary of product characteristics for each produc 21 January 2006 The Pharmaceutical Journal (Vol 276) 81
Randomized-block and randomized complete-block designs (Chapters 21 and 25)Randomized block designs. In a randomized block (RB) design, experimental units are grouped into \blocks" thatare thought to be similar. The random assignment of units to treatments is done separately within each block. Therationale for doing this is that, in the resulting dataset, the proportion of units receiving e