Off-label and unlicensed prescribing

In the UK, licensed medicines are those products that have received a ‘marketing authorisation’ previously referred to as a ‘product licence’.

A marketing authorisation (MA) is required in order for a manufacturer to sell, advertise and promote a medicine for a defined population. Licensing arrangements are determined by the Human Medicines Regulations 2012 (a consolidation of legislation including the Medicines Act 1968) and implemented through the MHRA (Medicines and Healthcare products Regulatory Agency).

A summary of product characteristics (SPC) is a description of a medicinal product’s properties and the conditions attached to its use.

Off-label and unlicensed prescribing are often used interchangeably, however, for the purpose of this guidance, the definitions are;

• Off-label prescribing occurs when medication use falls outside the terms of the Marketing Authorisation.
• Unlicensed prescribing is where a medicine has no Marketing Authorisation in the UK or the Marketing Authorisation has been withdrawn.

Off-label prescribing occurs when medication use falls outside the scope of the marketing authorisation with respect to one of five key domains¹:

1. Demographic. The age of the patient may lie outwith the recommended range e.g. the use of sertraline for depression in a 16 year old
2. Disorder. Prescribing for a condition which is outwith the marketing authorisation e.g. the use of hyoscine hydrobromide for clozapine-related hypersalivation
3. Dosage. Prescribing at a dose that is higher than recommended e.g. olanzapine prescribed at 30mg daily
4. Duration. Prescribing for a longer period of time than is recommended e.g. a benzodiazepine prescribed for longer than 4 weeks
5. Domain. Where a drug is licensed for a particular indication in one country and not another e.g. in some EU member states, valproate salts have a licence for prevention of migraine

In addition, the following situations would also constitute off-label prescribing:

1. Prescribing a medicine in a circumstance that is specified as contraindicated e.g. the use of haloperidol in combination with another mediation known to prolong the QTc interval
2. Where the form of a preparation is changed before administration e.g. crushing tablets and mixing with yoghurt as part of a covert medication pathway
3. Administering medication via a route not specified within the SPC e.g. down a nasogastric tube

Within mental health services, the vast majority of unlicensed prescribing occurs when:

1. The UK marketing authorisation has been suspended (usually for commercial reasons) with the product now imported from abroad e.g. pirenzepine for clozapine-related hypersalivation
2. The UK marketing authorisation has been suspended but where the company continues to make product available for named individuals e.g. sertindole
3. There has never been a UK marketing authorisation and the product needs imported from abroad e.g. ziprasidone

It is helpful to consider off-label and unlicensed prescribing on a spectrum with some prescribing ‘near-label’ lower risk and others ‘very far off-label’ or unlicensed and potentially higher risk.

Medications whose off-label use is supported by evidence-based texts (e.g. BNF, BNF for Children, SIGN, NICE or BAP Guidelines) are generally considered lower risk provided the prescribing information in that text is followed.

The risks associated with some off-label medicine use may be due to poor evidence base or to the risk of adverse effects associated with the off-label treatment.

Examples of off-label medicine use:

Examples of unlicensed medicine use:

Independent prescribers can prescribe any medication (licensed, off-label or unlicensed) so long as prescribing would be supported by a reasonable body of medical opinion.²

In general, off-label prescribing would not be deemed a breach of duty of care provided that the treatment was supported by a respected body of medical opinion (Bolam v Friern Hospital Management Committee, 1957). In addition, that medical opinion needs to withstand logical analysis (Bolitho v City and Hackney health Authority, 1997). It is therefore essential to consider risks and benefits of various treatment options with regard to the evidence that is available and the nature of the clinical case.³

There is no legal requirement to disclose the off-label use of a drug to a patient but such disclosure is advocated strongly¹ and the GMC advice on prescribing states that sufficient information must be given to enable informed consent to be made to any treatment, including explaining the off-label nature of prescribing to the patient (or carer as appropriate) and the reasons for doing so.^2,4

Prescribers must now ensure that patients (or their carers if the patient lacks legal capacity) are aware of any ‘material risks’ involved in a proposed treatment, and of reasonable alternatives, following the judgment in the Montgomery case (Montgomery v Lanarkshire Health Board 2015). ‘The test of materiality is whether, in the circumstances of the particular case, a reasonable person in the patient’s position would be likely to attach significance to the risk, or the doctor is or should reasonably be aware that the particular patient would be likely to attach significance to it.’

In emergencies or where there is no realistic alternative treatment to an off-label treatment and such information is likely to cause distress, it may not be practical or necessary to draw attention to the licence. In other cases, where prescribing unlicensed medicines is supported by published clinical guidance, it may be sufficient to describe in general terms why the medicine is not licensed for the proposed use or patient population.⁴ However, in circumstances where the evidence base is less clear cut then it would be sensible to seek a second opinion to support the prescribing decision.²

Prescribing unlicensed medicines or medicines outside the recommendations of their marketing authorisation alters (and probably increases) the prescriber’s professional responsibility and potential liability.²

The prescriber is always responsible for the use of a medicine and the patient’s welfare and in the event of adverse reactions may be called upon to justify the decisions that they have made.⁵

Good record-keeping and documentation is fundamental to all prescribing practice.

Remember to RECoRD......

Rationale

Evidence-base

Consent

Review

Document

When prescribing is off-label or unlicensed, it is even more important to document the rationale for treatment, the evidence-base where appropriate, record the key elements of discussion with the patient and/or carer and consider ongoing review of the treatment.

Patients should be provided with sufficient information about the proposed treatment to allow them to make an informed decision.

General advice about the off-label use of licensed medicines or use of unlicensed medicines from the Choice and Medication may be useful in aiding discussions with patients. 

Choice and Medication also has some specific medicine information leaflets on off-label medicine use e.g. metformin for weight gain and for some unlicensed medicines e.g. pirenzepine, ziprasidone, sertindole.

In addition, the use of off-label or unlicensed medicines in children is discussed in the following resource; Medicines for children unlicensed medicine advice

In general, T3 treatment plans should record the class of drug and route of administration and state that dose and frequency are within BNF guidelines; however, it is best practice for T2 certificates to specify the actual medication(s) rather than a class of medicines.⁷

It may be appropriate for the treatment plan to refer to guidelines or local protocols for off-label medication use e.g. dosing of lorazepam up to 8mg/24 hours in line with GGC guidance for acutely disturbed behaviour.⁸

High dose antipsychotic therapy should state a requirement for monitoring in accordance with guidance from RCPsych or local GGC high dose antipsychotic monitoring policy.⁹

Where a proposed treatment plan contains novel treatments (including some higher risk off-label or unlicensed medicine use), it is the responsibility of the referring RMO to ensure that any relevant literature or references are available for the DMP to refer to and a clear rationale for the use of the medication is recorded in the casenotes.

For full unlicensed medication, the specific medication and the fact that it is unlicensed should be included in the treatment plan (referring to the BNF in this case would be irrelevant).

The legal responsibility for prescribing falls to the clinician who signs the prescription.

Clear communication between a recommending specialist and the patient’s GP about the rationale for use of an off-label or unlicensed medication over a licensed alternative is essential.

Offering information to GP colleagues on indication, evidence-base, safety, patient need etc with the prescribing request is important in order for the patient’s GP to be adequately satisfied with the clinical decision.

Note: as a rule, the majority of full unlicensed medicines (i.e. with no UK marketing authorisation) used in mental health services, e.g. pirenzepine for clozapine-related hypersalivation, named-patient sertindole, ziprasidone will be supplied by MHS for patients in primary care.

1. Royal College of Psychiatrists. Use of licensed medicines for unlicensed applications in psychiatric practice. Dec 2017. College Report 2nd edition. CR210

2. Sharma AN, Arango C, Coghill D, Gingas P, Nutt DJ, Pratt P, Young AH, Hillis V. BAP Position Statement: Off-label prescribing of psychotropic medication to children and adolescents. J Psychopharm 2016;30(5):416-421

3. Baldwin Ds, Kosky N. Off-label prescribing in psychiatric practice. Adv Psych Treat 2007; 13:414-422

4. General Medical Council. Good practice in prescribing and managing medicines and devices. 2013

5. NHS GG&C Unlicensed medicine policy. Dec 2010

6. Mental Welfare Commission for Scotland. Medical Treatment under part 16 of the Mental Health (Care and Treatment) (Scotland) Act 2003. March 2014.

7. Mental Welfare Commission for Scotland. Consent to Treatment. December 2010

8. GG&C MHS. Intramuscular Medication for Acutely Disturbed Behaviour, Mental Health and Associated Service. MHS 40. March 2018

9. GG&C MHS High Dose Antipsychotic Monitoring Policy. MHS 34. August 2018.