18 CHEMIST+DRUGGIST 03.08.2013

CPD Zone Update

This module covers:

● The meaning of the terms off-label, off-licence and unlicensed

● Common examples of off-label or unlicensed usage

● Implications for pharmacists

● Sources of information about off-label, off-licence and unlicensed medicines

UPDATEModule 1666

AUGUST» Therapy choices

● Unlicensed medicines August 3

● Appraising evidence August 10

● Literature reviews August 24

● Interactions August 31*

*Online-only module for Update and Update Plus subscribers.

Use of unlicensed medicines

chemistanddruggist.co.uk/update

Hayley Johnson

The use of unlicensed medicines a�ects a wide range of patients such as pregnant women, children, patients with swallowing diculties and those prescribed antidepressants for neuropathic pain. Community pharmacists are therefore well placed to answer any queries patients might have, and to provide reassurance when necessary.

The terms o�-licence and o�-label are used interchangeably for the use of a medicinal product that is outside the terms of its UK marketing authorisation (MA), previously known as a product licence.

An MA is granted to a medicinal product in light of clinical studies and trials demonstrating quality, safety and ecacy for specific patient groups and indications. Only under these circumstances has the MHRA (Medicines and Healthcare products Regulatory Agency) or the EMA (European Medicines Agency) determined that the benefits of the drug outweigh its risks. If used outside these terms, the positive risk versus benefit balance cannot be guaranteed.

O�-label usage, however, is commonplace in daily medical practice. A drug may need to be used at a higher than recommended dose, may be useful for an illness that is not a licensed indication or may need to be given via a di�erent route.

Unlicensed medicines do not hold a UK MA and may include specials, extemporaneously prepared and imported products. Specials have to be made in a licensed facility in response to an order for a patient whose needs are not catered for by a licensed preparation, such as swallowing diculties where no licensed liquid preparation exists.

O�-label and unlicensed prescribing should be done only in the patient’s best interests and after considering the available evidence. Where a patient su�ers harm due to an unlicensed use, the prescriber assumes responsibility. There is also the possibility that another

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healthcare professional (such as the dispensing pharmacist) might also be considered liable. This has not yet been tested in the courts, but may apply if the pharmacist is judged to have been aware of the o�-label or unlicensed nature of the supply, the potential harms and could have acted to reduce them.

Considerations for useWhere possible, a licensed medicine should always be used in preference to unlicensed or o�-label products. Pharmacists should ensure they are fully aware of the potential benefits and risks, including adverse e�ect profile, quality assurance issues, labelling and the availability of appropriate patient information. They should also ensure they are working in accordance with local policies and guidelines.

Manufacturers cannot promote o�-label usage and, therefore, there will be no guidance about it in information sources produced by them, namely the patient information leaflet (PIL) and summary of product characteristics (SPC). The BNF may contain some information

on unlicensed uses of drugs, but mainly focuses on licensed indications. More in-depth information on o�-licence or unlicensed uses may be dicult to find; some sources are listed on p20, overleaf.

Serious adverse drug reactions to unlicensed or o�-label medicines should be reported via the Yellow Card scheme. For medicines being used in children, herbal products and black triangle drugs, all adverse reactions should be reported.

Specific prescription endorsements will be required where a specials medicine has been prescribed. PSNC and the NPA provide advice for community pharmacists on ensuring appropriate endorsing.

Common examples of usageSpecial populationsCertain populations are commonly under-represented in clinical trials, leading to a lack of medical products licensed for them. The MHRA estimates that more than half of the medicines used in children have not been studied in that age group. Conducting clinical trials in

Where a patient su�ers harm due to an unlicensed use, the prescriber assumes responsibility. It is also

possible another healthcare professional (such as the dispensing pharmacist) might also be considered liable

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CPD Zone Update

children is not only complicated by ethical considerations, but also by the diversity of the paediatric population, commercial interests and practical considerations such as dosing and the requirement for flexible formulations. Clinical trials in pregnancy and breast-feeding are also rarely conducted, again due to ethical considerations.

Consequently there are few products licensed for use during childhood, pregnancy or lactation. In these populations, a lack of a licence may not be indicative of a drug being dangerous, but merely of a scarcity of information from clinical trial data. Where a medication is required in children, pregnancy or breast-feeding and there is no licensed product, an individual benefit versus risk decision will need to be taken by the prescriber.

Storage of medicinesWhere a medicine is stored outside the manufacturer’s recommendations, its use is rendered o�-label. This is particularly common when medicines that need to be stored between 2°C to 8°C are exposed to higher or lower temperatures, due to a fridge malfunction for example. The decision to use the medicine will become a clinical one, and the prescriber will assume liability for any harm caused by products used.

Pharmacists who experience fridge temperature variations should consult the manufacturer or their local medicines information centre, who will be able to advise on the stability of medicines stored outside the cold chain.

Most medicinal products, especially those packaged in blisterpacks or in special containers, will become unlicensed if stored in an alternative container to the original pack. Pharmacists involved in repackaging products into compliance aids or monitored dosage systems should be aware of the legal implications of repackaging medicines. They should also consider the safety implications and stability of drugs stored in compliance aids and monitored dosage systems.

Melatonin in childrenMelatonin is a naturally occurring hormone involved in sleep regulation. It is widely available in the US and other countries as a dietary supplement. In the UK, melatonin is a prescription-only medicine licensed for the treatment of short-term primary insomnia in patients over 55 years old. It is available as prolonged release 2mg tablets (Circadin). Other strengths and presentations of melatonin may be imported or obtained as specials.

Melatonin may be prescribed by specialists for use in children with attention deficit hyperactivity disorder (ADHD) to treat sleep disorders. Use of the licensed product should, where clinically appropriate, be the preferred option, but its use will remain o�-label.

There is no high quality evidence assessing the e�ectiveness of Circadin in children. However, two small randomised controlled trials and one long-term follow-up study indicate limited usefulness for melatonin in children, whether they are being treated with stimulant drugs or not.

Metformin in PCOSMetformin, licensed in the UK for treatment of type 2 diabetes mellitus, may also be helpful in treating polycystic ovary syndrome (PCOS), although it is not licensed for this purpose. Other commonly used medicines for PCOS are co-cyprindiol and the combined oral contraceptive pill, which are also unlicensed for this purpose.

There is some evidence to suggest that metformin is as e�ective as co-cyprindiol at treating the hirsutism and acne, but not the menstrual irregularity associated with PCOS. Metformin was found to cause more severe gastrointestinal side e�ects than co-cyprindiol, but had less association with other severe adverse e�ects such as weight gain, hypertension, depression, chest pain and headache.

Neuropathic painPossibly the most common use of o�-label medicines in primary care is in the treatment of neuropathic pain. Centrally acting drugs, such as antidepressants and antiepileptics, may be used as adjunctive or atypical painkillers.

Amitriptyline is recommended by Nice as a first-line pharmacological option for neuropathic pain, although its licence extends only to treatment of depression or nocturnal enuresis. This use is based on moderate to low quality clinical evidence paired with expert consensus. Imipramine or nortriptyline are

other tricyclic antidepressants that may be options where the patient su�ers intolerable adverse e�ects due to amitriptyline.

Enteral feeding or swallowing di�cultiesAltering the formulation of a medication (including crushing tablets, opening capsules, or diluting liquids) usually renders its use o�-label. This is most commonly done when administering medicines down an enteral feeding tube, or if a patient has swallowing diculties.

In addition, administering a medicine via a feeding tube is almost always unlicensed, even when using a licensed liquid preparation, and may lead to a variable (or inadequate) clinical response.

Choosing an appropriate administration method should follow a stepwise approach, considering licensed liquid preparations, other routes of administration, switching to another medicine, special liquids or crushing tablets/opening capsules and will depend on the clinical situation of the patient.

Malaria prophylaxis in childrenThe Advisory Committee on Malaria Prevention in UK Travellers (ACMP) guidelines advise doses of antimalarial products for prophylaxis in children that may be higher than those licensed (and therefore higher than those stated in their SPC).

Pharmacists should not advise such doses where a product is being sold over the counter and the licensed dosing guidelines should be followed. Only where a product is provided in response to a prescription does the ACMP advise these doses be given.

Providing information to patientsThe use of medicines in an o�-label or

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Examples of o�-licence/o�-label uses of medicines in the UK

Disease Medicine

Neuropathic pain Antidepressants/antieplieptics, eg amitriptyline

Polycystic ovary syndrome Antidiabetic – metformin

Attention deficit hyperactivity disorder

Hypnotic – melatonin

Malaria prophylaxis In children Antimalarials – higher than licensed dosages

Other situations where the use of a medicine would probably be considered to be o�-licence or unlicensed:

● Storage – outside the manufacturer’s recommended temperature range, for example, particularly for medicines that require refrigeration

● Repackaging – in blisterpacks or special containers, for example

● Enteral feeding – administering a licensed liquid medicine via a feeding tube is almost always unlicensed

● Altering the formulation – crushing tablets, opening capsules or diluting liquids to help people with swallowing di�culties

20 CHEMIST+DRUGGIST 03.08.2013

CPD Zone Update

unlicensed fashion can be a common source of confusion for patients, as the written information supplied with the medicine does not reflect the way they have been advised to use it.

Patients may be concerned that they have been given the wrong medication, that it will do them harm, or even that their doctor has diagnosed them with another illness without telling them.

General Medical Council (GMC) guidance advises that prescribers give patients or their representatives enough information about a proposed treatment in order to make an informed decision. Where o�-label use is common and supported by clinical practice, it may not always be necessary to draw attention to it when seeking consent, but prescribers are advised to “explain in broad terms the reasons why medicines are not licensed for their proposed use”.

Community pharmacists are well-placed to reinforce this advice, and answer any queries patients may have about o�-licence/o�-label or unlicensed medicines. Any information should be given in terms appropriate to the patient’s level of understanding and should be reassuring where possible. Where a specials or imported product is prescribed, patients should also be advised that the ordering process may take longer than usual.

Further information● Information for parents about unlicensed medicines in children may be found on the Medicines for Children website at http://tinyurl.com/children-unlicensed.● General information about the licensing process, and o�-label and unlicensed prescribing for patients, is on the NHS Choices website at http://tinyurl.com/nhs-licensing

References● Medicines and Healthcare Products Regulatory Agency: O�-label or unlicensed use of medicines: prescribers’ responsibilities. Drug Safety Update 2009: 2 (9). http://tinyurl.com/mhra-prescriber-responsibility ● Medicines and Healthcare Products Regulatory Agency: Review of unlicensed medicines.

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ASK THE EXPERTAugust is therapy choices month and our expert is on hand to answer your queries. From unlicensed medications to appraising evidence, submit your questions by email: steve.titmarsh@ubm.com

Box 1. Sources of information about o�-licence and unlicensed medicines

● Nice has a series of evidence summaries, but these are lengthy and currently limited in number: http://tinyurl.com/niceevidence● The MHRA provides information on the legal status of drugs that do not require a licence, and guidance for prescribers in a 2009 drug safety update: http://tinyurl.com/mhraunlicensed ● The NPA and PSNC have guidance on ordering specials and endorsing

prescriptions: http://tinyurl.com/unlicensed-responsibilities● Martindale (requiring a subscription) often includes information on unlicensed uses● Local medicines information services may be able to provide evidence and help with practical aspects● The UK Teratology Information Service provides expert advice on the use of drugs in pregnancy: www.uktis.org

http://tinyurl.com/unlicensed-responsibilities● General Medical Council. Good Practice in Prescribing Medicines 2008. Accessed via http://tinyurl.com/good-practice-prescribing● Bazian Ltd. ESUOM6: Polycystic ovary syndrome: metformin in women not planning pregnancy. Nice Evidence Summaries: Unlicensed or o�-label medicine. February 21, 2013. http://tinyurl.com/nice-pcos-metformin● Bazian Ltd. ESUOM2: Sleep disorders in children and young people with attention deficit hyperactivity disorder: melatonin. Nice Evidence Summaries: Unlicensed or o�-label medicine January 4, 2013.http://tinyurl.com/nice-kids-melatonin● Nice Clinical Knowledge Summaries: Neuropathic pain – drug treatment 2010. Accessed via http://tinyurl.com/nice-cks-neuropathic-pain ● National Pharmacy Association. Malaria Prophylaxis NPA Information Leaflet. March 2013. ● Summary of Product Characteristics, various, Electronic Medicines Compendium. www.medicines.org.uk/emc ● Thomas S, Yates L. Prescribing without evidence – pregnancy. British Journal of Clinical Pharmacology. 2012; 74 (4): 691-697● Smyth J (Ed). The NEWT Guidelines for administration of medication to patients with enteral feeding tubes or swallowing di�culties. www.newtguidelines.com

Hayley Johnson is senior pharmacist (medicines information) at the Regional Drug and Therapeutic Centre, Newcastle upon Tyne

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22 CHEMIST+DRUGGIST 03.08.2013

CPD Zone Update

1. O�-label is used to describe the use of a medicinal product outside the terms of its UK marketing authorisation. True or false?2. Unlicensed medicines do not have a UK marketing authorisation. True or false?3. Specials, extemporaneously prepared and imported products usually have marketing authorisations. True or false?4. Serious adverse drug reactions to unlicensed or o�-label medicines should be reported via the Yellow Card scheme. True or false?5. The MHRA estimates that a quarter of medicines used in children have not been studied in that age group. True or false?6. Medicinal products packaged in blisterpacks or in special containers may become unlicensed if repackaged. True or false?7. Melatonin is licensed only for use

in children with attention deficit hyperactivity disorder. True or false?8. Amitriptyline is recommended by Nice for neuropathic pain, even though this is an o�-licence use. True or false?9. Altering the formulation of a medication such as by crushing tablets or diluting liquids is usually covered by the marketing authorisation. True or false?10. Administering a medicine via a feeding tube is almost always unlicensed, even when using a licensed liquid preparation. True or false?

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Reflect In which patient groups are unlicensed or o�-label medicines most likely to be used? What should pharmacists consider when dispensing an unlicensed medicine?

Plan This article discusses the unlicensed and o�-label use of medicines, including considerations for prescribing and the implications for the dispensing pharmacist. Examples of when these medicines are commonly used, such as in children, pregnancy, enteral feeding and in the treatment of neuropathic pain and polycystic ovary syndrome are also given.

Act Read the Update article and the suggested reading (below), then take the 5 Minute Test (above). Update and Update Plus subscribers can then access their answers and a pre-filled CPD logsheet at www.chemistand druggist.co.uk/mycpd

Read the guidelines for prescribing unlicensed medicines from the GMC http://tinyurl.com/unlicensed1

Find out more about factors to consider when prescribing or purchasing unlicensed medicines from Rosemont’s website http://tinyurl.com/unlicensed2

Revise your knowledge of some conditions that may require o�-licence medicines, for example, polycystic ovary syndrome and neuropathic pain treatment, on the Patient UK website http://tinyurl.com/unlicensed3 http://tinyurl.com/unlicensed4

Read the information for patients about the licensing process from NHS Choices http://tinyurl.com/unlicensed5

Read the advice for parents whose children have been prescribed unlicensed medicines from Medicines for Children http://tinyurl.com/unlicensed6

Evaluate Are you now confident in your knowledge of which medicines are used o�-licence or o�-label? Could you give advice to patients or carers about unlicensed medicines?

Tips for your CPD entry on unlicensed medicines

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