Off-label Use

Introduction

Off-label use is the use of pharmaceutical drugs

• For an unapproved indication or
• In an unapproved age group, dosage or route of administration

In clinical practice, unlicensed or off-label drug use occurs across all medical specialties and is more prevalent in areas where patient populations are less likely to be included in clinical trials (e.g. paediatric, pregnant, or psychiatric) due to ethical reasons.

• Indeed, off-label drug uses can become standard practices and even predominate as treatments for specific conditions.

Nevertheless, pharmaceutical companies may be reluctant to invest in additional regulatory approvals due to the associated costs, especially if the anticipated financial return is insufficient.

• This is particularly true for low-cost drugs, those with generic or biosimilar alternatives, or medications prescribed to a small patient population.
• Even without updated product information, off-label prescribing will still occur in hospitals when supported by robust evidence and guidelines.

Off-label use should always be based on adequate evidence and experience.

• A study published in JAMA Internal Medicine revealed a higher adverse drug event rate associated with off-label use lacking strong scientific evidence compared to on-label use. Conversely, off-label use supported by robust evidence carried a similar risk of adverse drug events as on-label use.

There is an increased risk of prescriber liability and patient complaints if adverse events occur from off-label drug use.

• Therefore, patients must be fully informed about the potential benefits and risks of any prescribed medication and given the opportunity to provide informed consent before starting treatment.
• This process can be more complex for off-label use, especially when evidence is limited for a specific indication.

Reference

As a practicing pharmacist, much of my knowledge on off-label use of medications are learned from working experiences.

To verify the dosage and off-label use, you may check-up these drug references:

• Lexicomp - personal preference
• British National Formulary and BNF for Children
• Micromedex
• Medscape
• Epocrates
  

Yup, technically, you should not look up product leaflet for off-label use (and its dosage).

NOTE: NICE has produced Evidence Summaries for some unlicensed and off-label use medicines.

Examples

Examples of off-label indication

• Acetazolamide - Idiopathic intracranial hypertension
• Amantadine - Traumatic brain injury
• Aspirin - Prevention of preeclampsia in pregnant woman with risk factors
• Amitriptyline - Neuropathic pain
• Atropine 1% ophthalmic suspension (sublingual) - Terminal respiratory secretions
• Azathioprine - Psoriasis, uveitis
• Bleomycin - Pleurodesis
• Cabergoline - Acromegaly, Cushing's syndrome, Ovarian hyperstimulation syndrome
• Caffeine citrate - Postdural puncture headache
• Cyclopentolate 1% eye drops - Anterior uveitis
• Danazol - Refractory immune thrombocytopenia
• Domperidone - Induce lactation
• Erythromycin - Prokinetic
• Ketoconazole - Cushing's syndrome
• Letrozole - Infertility/ovulation stimulation in anovulatory females with PCOS
• Lorazepam - Prevention and treatment of anticipatory emesis associated with chemotherapy and radiotherapy
• Magnesium sulphate - Acute exacerbation of bronchial asthma
• Metformin - Gestational diabetes
• Methotrexate - Uveitis
• Metoclopramide - Induce lactation
• Prednisolone - Bell palsy
• Rituximab - Immune thrombocytopenia
• Sildenafil - Severe Raynaud Phenomenon
• Terazosin - Ureteral calculi expulsion
• Timolol 0.5% ophthalmic gel forming solution - Infantile haemangioma, superficial
• Vancomycin injection (for oral use) - Treatment of Clostridium Difficile associated diarrhoea

Examples of off-label dose

• Antihistamine - Updosing up to fourfold.
• Baclofen - Although 80 mg per day is a commonly accepted maximum, dosing up to 200 mg per day has been used safely and effectively.
• Betahistine - Range: 24 to 48 mg daily in divided doses. Doses slowly titrated up to 480 mg daily have been reported in a small number of cases with severe, resistant disease.
• Cyclosporine 0.05% eye drop - 3-4 times daily in patients with severe dry eye disease who had inadequate responses to twice-daily use.
• Desvenlafaxine - Doses up to 400 mg once daily have been studied and have shown to be effective.
• Felodipine - 10 mg twice daily.
• Mirtazapine - Maximum dose: 45 mg/day (product labelling); however, doses up to 60 mg/day have been used in clinical trials.

Examples of off-label route of administration

• Atropine 1% eye drop - sublingual
• Chloramphenicol eye ointment - skin
• Lorazepam 1 mg tablet -sublingual
• Normal saline eye drop - nasal
• Timolol 0.5% ophthalmic gel forming solution - skin

NOTE: Crushing tablets and opening capsules for administration through enteral feeding tubes is unlicensed but common practice.

Malaysia

In Malaysia government health care facilities, when a drug is used off-label, a consent form for treatment using unregistered medication/indication (off label) must be completed by a consultant/specialist/medical officers who want to use medicine/indication not registered with any regulatory body worldwide.

• The patient must be explained thoroughly on the medicine and give consent by signing the attached form.
• Copy of the consent form must be kept in the patients' record.
• This document is vital for medicolegal purposes.

NOTE:

• There is a list of off-label use of medications are exempted from completing the consent form above. You may ask your facility pharmacy drug information department for more information.
• When a medicine is used off-labelled, on top of the consent form, physician may still need to submit Medicines Special Authorization Form.

Summary

In everyday practice, there are many patients whose clinical needs are not well managed by legally approved drugs, especially paediatric and pregnant patients who are often not included in clinical trials.

• The decision to use these drugs by health care professionals for off-label use should be made with sound clinical judgment after carefully considering the potential risks.
• Remember, the off-label use is not an absolute contraindication, but just lacking of safety data.

External Links

• Understanding Unapproved Use of Approved Drugs "Off Label"
• Medicines for Children - Unlicensed Medicines
  
• NICE Evidence Summaries
  
• Ten Common Questions (and Their Answers) About Off-label Drug Use, 2012
  
• Off-label medicine use: Ethics, practice and future directions, 2021
  
• Ongoing challenges of off-label prescribing, 2023