What is a product licence?
A product licence is a marketing authorisation issued by the Medicines and Healthcare products Regulatory Agency (MHRA) for a drug to be marketed in the United Kingdom (UK). A product licence is granted following an application by the pharmaceutical company which must be supported by data on safety and efficacy relevant to a particular clinical indication and a particular age group. MHRA gives special consideration to the safety, efficacy and quality of the product before granting a license. When a drug is approved, the licence as such is not published but the summary of product characteristics (SPC) acts as a summary of the product licence and contains the indications, contraindications, adverse reactions and dosages for which risk- benefit ratio has been reviewed and accepted by the regulatory authority.
What is Off label use?
‘Off label’ and unlicensed prescribing refer to the use of medicines outside of the indications for which they are licensed by national regulatory bodies or is disclaimed in the product information1. Examples include the use of the drug for different indications, age groups, dosage or routes to that which has been evaluated or approved by the drug regulatory bodies in that country.
Extent of problem
Off-label prescribing is common in children both in hospital practice and in the community. There are many publications relating to the extent and problems of off-label use of medicines in the paediatric population2-10, 14. This is because many drugs in paediatrics are used on the basis of trials that have been performed in adults. It has been reported that the off-label use of medicines varies from 7.5% to 40% in adults2-5 to as high as 90% in some hospital paediatric patients6-10. The drugs used for off-label indications in pregnancy are often prescribed for obstetric rather than for medical conditions16. In a prospective study15, 22.6% of 731 pregnant women took one or more drugs for off-label indications and nearly all drugs were taken short term during third trimester. Indications for such off-label use during pregnancy include prevention of repetitive abortion, inhibition of premature labour, reduction of fetal or neonatal infection, reduction in development of pre-eclampsia and cervical ripening or induction of labour16.
It is impossible to be certain if any drug is truly ‘safe’ in pregnancy because it is unethical to conduct the randomised placebo-controlled trials that would be necessary to prove the point. It would involve not treating the medical condition in the women in a placebo arm and intentionally exposing fetuses to a potential teratogen in an active treatment arm. Hence the data available to support prescribing decisions in pregnancy are usually of limited quantity and quality.
Many drugs in used off-label in obstetric practice were originally studied in non-pregnant adults or pregnant animals and therefore the safety and efficacy of these studies cannot be extrapolated directly to pregnant humans. The summary of the product characteristics in such drugs are therefore ambiguous in their statements, especially for the use in pregnancy and lactation due to lack of safety data.
During pregnancy there are occasions when maternal health is the priority and the obstetrician will have no alternative other than to use these drugs off-label. In most other situations, fetal safety has to be addressed. Many obstetricians therefore fear of litigation if adverse events occur to mother and the foetus.
Legal situation in the UK
Unlicensed or off label prescribing is not illegal because of the exemptions in the Medicines Act 1968 to meet the special needs of a patient. Medical practitioners are allowed to prescribe off-label and in the UK, this is covered by the Medicines Act 1968 and the EC Pharmaceutical Directive 89/341/EEC which outlines requirements of the EEC pharmaceutical legislation relating to medicinal products for human use11.
A physician therefore has a legal right to prescribe for off-label indications despite regulatory, manufacturer, and cost constraints. Such prescribing habits would not be considered experimental if based on sound scientific evidence16. Adequate and well-controlled studies are difficult to perform during pregnancy and evidence of widespread use and support from another qualified clinicians would be sufficient to justify off-label prescribing16.
What should we do?
In contrast to the considerable literature about the extent and consequences of off-label prescribing, there has been no specific guidance to help clinicians trying to make decisions about the appropriateness of such prescribing in pregnancy12.
Each patient is entitled to know why she and her fetus would benefit from the treatment and whether any unnecessary risk is anticipated. Even when there is high quality evidence supporting off label use of medicine, routine off label use is not justified but the usual process of obtaining consent for treatment should be followed12. The consent procedure should include discussing with the patient the reasons for using the medicine, possible alternative therapy and potential side effects. As the medicine is being used off-label, additional information about any uncertainties associated with such use should be given to the patient. Legible documentation of these discussions in the medical records is important and an unlicensed form for the drug needs to be completed as per hospital protocol.
It is becoming increasingly recognised that as new products come to market, regulatory agencies internationally are requiring pharmaceutical companies to obtain rigorous and comprehensive data as part of their submission.
For the present, off-label and off-licence prescribing in obstetric practice is acceptable and indeed necessary when no suitable alternative to the required treatment is available1. Although ultimately legal responsibility lies with the prescriber, the prescribing of these treatments does not constitute a breach of duty as long as the prescriber can rely on information and guidance from a respected body of medical opinion.
In general, the use of medications in pregnancy should be avoided where possible, in the first trimester. The use of all medications in pregnancy should follow a careful risk versus benefit assessment. Drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus and medication with the best safety record over time should be chosen over a new medication, unless the safety of a new medication has been clearly established.
Off label-prescribing still remains a widespread practice in Obstetrics and such type of prescribing is not illegal because of the exemptions in the Medicines Act 1968 to meet the special needs of a patient. Off-label prescribing could be considered as acceptable if there is no suitable alternative and obstetricians are confident that they are using agents in accordance with the body of respected medical opinion.
Examples of off label/unlicensed drug use in Obstetric practice
|Drug||Licensed indication (17)||Contraindication as per summary of product license (SPC) (17)||Unlicensed Use in Obstetrics|
|Nifedipine capsules 5 mg and 10 mg||Prophylaxis of chronic stable angina pectoris, the treatment of Raynaud’s phenomenon and hypertension.||Treatment of acute hypertensionAs a tocolytic in preterm labour|
|Betamethasone 12mg Inj||Suppression of inflammatory and allergic disorders; congenital adrenal hyperplasia||Two doses of 12mg given 24 hours apart antenatally to women at risk of preterm delivery to prevent neonatal respiratory distress syndrome|
|Misoprostol 200mcg tablets (Cytotec)||Cytotec is indicated for the healing of duodenal ulcer and gastric ulcer including those induced by non-steroidal anti-inflammatory drugs (NSAID) in arthritic patients at risk, whilst continuing their NSAID therapy. In addition, Cytotec can be used for the prophylaxis of NSAID-induced ulcers.||Cytotec is contraindicated in pregnant women and in women planning a pregnancy as it increases uterine tone and contractions in pregnancy which may cause partial or complete expulsion of the products of conception. Use in pregnancy has been associated with birth defects.||800 mcg p/r for PPH400 mcg p/v for termination of pregnancy, cervical ripening before termination of pregnancy (TOP)|
|Terbutaline sulphate 0.5 mg/ml injection||Recommended for the relief of bronchospasm in bronchial asthma and other bronchopulmonary disorders in which bronchospasm is a complicating factorFor the management of uncomplicated premature labourTo arrest labour between 24 and 33 weeks of gestation in patients with no medical or obstetric contraindication to tocolytic therapy. The main effect of tocolytic therapy is a delay in delivery of up to 48 hours||0.25 mg s/c used in uterine hyper-stimulation caused by prostaglandins and Oxytocin induction of labour|
|Aspirin BP 75 mg tablets||Secondary prevention of thrombotic cerebrovascular or cardiovascular disease and following by-pass surgery. The advice of a doctor should be sought before commencing therapy for the first time.||75mg po once daily for recurrent miscarriage.Thrombophilia,Prevention of post partum venous thromboembolism|
|Carboprost 250 micrograms/mL injection (Hemabate)||An initial dose of 250 micrograms (1.0 ml) of Hemabate should be administered as a deep intramuscular injection. If necessary, further doses of 250 micrograms may be administered at intervals of approximately 1.5 hours. In severe cases the interval between doses may be reduced at the discretion of the attending physician, but it should not be less than 15 minutes. The total dose of Hemabate should not exceed 2 mg (8 doses).||Intramyometrial injection for post partum haemorrhage (PPH)|
|Dinoprostone 1 mg or 2 mg vaginal gel||In primigravida patients with unfavourable induction features (Bishop score of 4 or less), an initial dose of 2 mg should be administered vaginally. In other patients an initial dose of 1 mg should be administered vaginally. In both groups of patients, a second dose of 1 mg or 2 mg may be administered after 6 hours as follows:Maximum dose 4 mg in unfavourable primigravida patients or 3 mg in other patients||Dose more than recommended used in induction of labour when the initial dose fails|
|Dalteparin sodium 2500-5000iu injection (Fragmin)||Peri- and post-operative surgical thromboprophylaxis.Unstable angina and non-Q wave myocardial infarction||Thrombophilia, recurrent miscarriage|
- Turner S. Unregistered and off-label drug use in paediatric inpatients. Aust J Hosp Pharm 1999; 29: 265-268.
- Rayburn W, Farmer K. Off-label prescribing during pregnancy. Obstet Gynecol Clin North Am 1997; 24: 471-479.
- Laetz T, Silberman G. Reimbursement policies constrain the practice of oncology. JAMA 1991; 266: 2996-2999.
- Brosgart C, Mitchell T, Charlebois E, et al. Off-label drug use in human immunodeficiency virus disease. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 12: 56-62.
- Douglas-Hall P, Fuller A, Gill-Banham S. An analysis of off-licence prescribing in psychiatric medicine. Pharm J 2001; 267: 890-891.
- McIntyre J, Conroy S, Avery A, et al. Unlicensed and off label prescribing of drugs in general practice. Arch Dis Child 2000; 83: 498-501.
- Pandolfini C, Impicciatore P, Provasi D, et al. Off-label use of drugs in Italy: a prospective, observational and multicentre study. Acta Paediatr 2002; 91: 339-347.
- Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off-label drug use in paediatric wards in European countries. BMJ 2000; 320: 79-82.
- Cuzzolin L, Zaccaron A, Fanos V. Unlicensed and off-label uses of drugs in paediatrics: a review of the literature. Fundam Clin Pharmacol 2003; 17: 125-131.
- Stephenson T. Medicines for children