Off-label drug use

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Off-label & Substitution of medicines–essentials for South African Anaesthetists (2025)

Definitions

Term Meaning Regulatory note
Off-label use (OLU) Prescribing a registered medicine or device outside its SAHPRA-approved indications, dose, age-group or route. Permitted when peer-reviewed evidence supports benefit.
Unlicensed use Use of a product not registered by any regulatory authority in the country. Requires Section 21 authorisation from SAHPRA.
Generic substitution Pharmacist dispenses an identical molecule (bio-equivalent) instead of the originator. Allowed under Medicines Act §22F unless “no substitution” written.
Therapeutic substitution Replacing with a different molecule judged therapeutically equivalent. Needs a new prescription; pharmacist may not change on own.

SASA Guidance on Off-label Prescribing (2022)

  1. Evidence first–ensure robust peer-reviewed data or overseas licence.
  2. Written informed consent–explain purpose, benefits, specific risks, lack of registration and alternatives; attach to anaesthetic record.
  3. Document rationale in notes and AIMS.
  4. Notify manufacturer of intended OLU and check known safety issues.
  5. Shared liability–prescriber, dispenser and institution all accountable.
  6. Prefer products registered elsewhere by a stringent authority (e.g. FDA/EMA).
  • (SASA Practice Guidelines 2022, Section 10)
Domain Requirement Practical tip
Clinical Balance risk–benefit; use lowest effective dose; monitor. Start propofol infusion for ICU sedation (off-label) with target monitoring & daily plan review.
Informed consent HPCSA Booklet 3: full disclosure when deviating from licence. Use pre-printed OLU consent form; patient keeps copy.
Advertising ban Pharma may not promote off-label indications in SA. Rely on independent literature, not reps.
Malpractice cover Insurer may request evidence of consent & guideline support. MPS/SASA advise documenting literature citation in file.

Narrow Therapeutic-Index (NTI) drugs–avoid Generic Swapping unless clinically justified

NTI examples Why risky FDA 2023 recommendation
Warfarin, levothyroxine, digoxin, ciclosporin, phenytoin < 2-fold margin between effective & toxic levels; variable bioavailability Prescriber review, INR/levels after any brand change; same manufacturer each refill.

Generic substitution–pharmacist & Prescriber Duties (Medicines Act §22F)

  1. Pharmacist informs patient of cheaper bio-equivalent.
  2. Must notify prescriber (reasonable steps).
  3. Cannot substitute if:
    • “No substitution” noted;
    • Patient refuses;
    • Generic price higher;
    • MCC/SAHPRA lists as non-substitutable (e.g. modified-release theophylline).
  4. Therapeutic substitution requires new script–e.g. pantoprazole for omeprazole.

Decision Algorithm for the Anaesthetist

  1. Need identified → licensed drug suitable? Yes → prescribe. No → Step 2.
  2. Evidence search (guideline/RCT/meta-analysis) supports OLU? Yes → Step 3.
  3. Discuss & obtain written consent → document → monitor.
  4. If NTI or paediatric/obstetric setting, consider Section 21 import of licensed formulation instead.

Links

Past Exam Questions

Scheduling and Regulation of Ketamine in South Africa

a) According to the Medicines Control Council of South Africa, how is ketamine scheduled? (1)
b) What does this scheduling imply according to the Medicines and Related Substances Act? (6)
c) In your opinion, would changing the scheduling of ketamine to increase control be of benefit or not? Motivate your answer briefly. (3)

References:

  1. Generic Substitution and Off Label Drug Use Prof C. Lundgren Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand. 2012
  2. Johnston, A., Asmar, R., Dahlöf, B., hill, k., Jones, D. F., Jordan, J., … & Zamorano, J. L. (2011). Generic and therapeutic substitution: a viewpoint on achieving best practice in europe. British Journal of Clinical Pharmacology, 72(5), 727-730. https://doi.org/10.1111/j.1365-2125.2011.03987.x
  3. South African Society of Anaesthesiologists. Practice Guidelines 2022–Off-label Use & Prescribing. sasaweb.com
  4. Health Professions Council of South Africa. Ethical Guidelines for Good Practice–Booklet 3 (Informed Consent). 2020. headroom.co.za
  5. Medicines & Related Substances Act 101 of 1965–Section 22F (Generic substitution). sahpra.org.za
  6. U.S. FDA. Understanding Generic Narrow Therapeutic Index Drugs (Fact Sheet, 2023). fda.gov
  7. CDER Conversation. Setting and Implementing Standards for NTI Drugs. FDA, 2023. fda.gov

Summaries:

Copyright

© 2025 Francois Uys. All Rights Reserved.

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