Off-label or unlicensed use of medicines: prescribers’ responsibilities

Healthcare professionals may have more responsibility to accurately prescribe an unlicensed medicine or an off-label medicine than when they prescribe a medicine within the terms of its licence.

From:: Medicines and Healthcare products Regulatory Agency
Published: 11 December 2014

Therapeutic area:: Dentistry and Ophthalmology

Article date: April 2009

Post-publication note: September 2019

MHRA has updated its position on the preparation of bevacizumab for intravitreal use. See Review of MHRA published statements on the supply and use of Avastin (bevacizumab) for intravitreal use

The Agency accepts that when prescribed and/or used by a healthcare professional, this does not create an unlicensed medicine and falls under the scope of off-label use. However, if placed on the market, the product would require a new or extended MA, or an exemption from the need for one.

A licensed medicine meets acceptable standards of efficacy, safety, and quality

A marketing authorisation or product licence defines a medicine’s terms of use: its summary of product characteristics outlines, among other things, the indication(s), recommended dose(s), contraindications, and special warnings and precautions for use on which the licence is based, and it is in line with such use that the benefits of the medicine have been judged to outweigh the potential risks. Furthermore, a licensed medicine: has been assessed for efficacy, safety, and quality; has been manufactured to appropriate quality standards; and when placed on the market is accompanied by appropriate product information and labelling.

Prescribing in a patient’s best interests

However, there are clinical situations when the use of unlicensed medicines or use of medicines outside the terms of the licence (ie, ‘off-label’) may be judged by the prescriber to be in the best interest of the patient on the basis of available evidence. Such practice is particularly common in certain areas of medicine: for instance, in paediatrics where difficulties in the development of age-appropriate formulations means that many medicines used in children are used off-label or are unlicensed.

Healthcare professionals may regard it necessary to prescribe or advise on the use of an unlicensed medicine (eg through the so-called ‘specials’ regime when no licensed suitable alternative is available, or when a medicine is prepared in a pharmacy by, or under the supervision of, a pharmacist), or the use of a licensed medicine outside the terms defined by the licence (eg, outside defined indications, doses, routes of administration, or contrary to listed warnings).

In practice

At present, the following healthcare professionals can prescribe an unlicensed medicine: doctors; dentists; independent nurse and pharmacist prescribers and, in some circumstances, supplementary prescribers (who can be a pharmacist, nurse, midwife, community nurse, optometrist, physiotherapist, radiographer, or chiropodist/podiatrist). In addition to these health professional groups, the following can prescribe a licensed medicine off-label: nurse independent prescribers, pharmacist independent prescribers, and optometrist independent prescribers. However, all healthcare professionals who can prescribe as outlined above are subject to: their individual clinical competence; the professional codes and ethics of their statutory bodies; and the prescribing policies of their employers.

The responsibility that falls on healthcare professionals when prescribing an unlicensed medicine or a medicine off-label may be greater than when prescribing a licensed medicine within the terms of its licence. Prescribers should pay particular attention to the risks associated with using unlicensed medicines or using a licensed medicine off-label. These risks may include: adverse reactions; product quality; or discrepant product information or labelling (eg, absence of information for some unlicensed medicines, information in a foreign language for unlicensed imports, and potential confusion for patients or carers when the Patient Information Leaflet is inconsistent with a medicine’s off-label use).

Examples of off-label use of medicines

Off-label intravitreal use of bevacizumab (Avastin, licensed for treatment of various solid cancers) has been associated with reports of severe eye inflammation and sterile endophthalmitis. The production methods, formulation, and doses for bevacizumab were developed for use in oncology. Its use in the ophthalmology setting has not been authorised.

Clarification (updated August 2011): The preparation of bevacizumab for intravitreal use involves manipulation of the authorised medicine to produce multiple aliquots, usually in plastic syringes (so-called compounding). Therefore, it is important to note that this process also results in the creation of an unlicensed medicine.

Methylthioninium chloride (methylene blue) is authorised for management of drug-induced methaemoglobinaemia; however, it is sometimes used off-label as a visualising agent during parathyroid surgery. We are aware of 33 reports of a suspected interaction between methylthioninium chloride and recent treatment with serotonergic drugs, leading to CNS toxicity. In all cases, patients were receiving methylthioninium chloride outside its licensed indication.

Example of use of unlicensed medicines

Since June 2008, a licensed formulation of thalidomide has been available for treatment of multiple myeloma. Prescribers should consider use of this licensed thalidomide product first. Use of the licensed thalidomide product is important because pregnancy-prevention measures are linked to the prescription and dispensing of the authorised formulation, but not to those that are unlicensed.

Advice for prescribers says you should:

be satisfied that an alternative, licensed medicine would not meet the patient’s needs before prescribing an unlicensed medicine
be satisfied that such use would better serve the patient’s needs than an appropriately licensed alternative before prescribing a medicine off-label,
before prescribing an unlicensed medicine or using a medicine off-label you should:
- be satisfied that there is a sufficient evidence base and/or experience of using the medicine to show its safety and efficacy
- take responsibility for prescribing the medicine and for overseeing the patient’s care, including monitoring and follow-up
- record the medicine prescribed and, where common practice is not being followed, the reasons for prescribing this medicine; you may wish to record that you have discussed the issue with the patient

Best practice for communication includes:

you give patients, or those authorising treatment on their behalf, sufficient information about the proposed treatment, including known serious or common adverse reactions, to enable them to make an informed decision
where current practice supports the use of a medicine outside the terms of its licence, it may not be necessary to draw attention to the licence when seeking consent. However, it is good practice to give as much information as patients or carers require or which they may see as relevant
you explain the reasons for prescribing a medicine off-label or prescribing an unlicensed medicine where there is little evidence to support its use, or where the use of a medicine is innovative

Healthcare professionals have a responsibility to help monitor the safety of medicines in clinical use through submission of suspected adverse drug reactions to the MHRA and CHM via the Yellow Card Scheme. Such reporting is equally important for unlicensed medicines or those used off-label as for those that are licensed