DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

Overview of Products

Isotretinoin, chemically known as 13-cis retinoic acid, is a retinoid derivative of vitamin A.^1-2 In Malaysia, there are a total of eight registered isotretinoin-containing products, all available as oral formulations.³ Isotretinoin is approved for the treatment of severe acne forms, such as nodular or conglobate acne, or acne at risk of permanent scarring, as well as acne that has failed to respond to standard therapies with systemic antibacterials and topical treatments.^1-2

Isotretinoin exerts its effects through multiple mechanisms, primarily by reducing the size and function of sebaceous glands, which leads to decreased sebum production.¹ It also alters keratinocyte differentiation, reduces cell proliferation, and promotes apoptosis in sebocytes, making it highly effective in treating acne. Additionally, isotretinoin indirectly decreases the population of Propionibacterium acnes by altering the follicular microclimate.

 

Overview of Safety Concerns

Sacroiliitis is an inflammation of the sacroiliac joint (SIJ), presenting clinically with deep-rooted pain that typically begins in the posterior thigh and may extend to the knee or the entire lower extremity.^4-5 This pain is often felt on one side, just below the lower back, near the top of the buttock, and may worsen with activities such as sitting, walking for long periods, climbing stairs, or lying on the affected side.⁵ Due to its clinical presentation, which resembles other disorders like facet joint arthritis and piriformis syndrome, accurate diagnosis and treatment of sacroiliitis are crucial, with magnetic resonance imaging (MRI) being one of the key diagnostic tools.^5-6

Urethritis is a common genitourinary condition in men, typically presenting with urethral discharge, penile itching or tingling, and dysuria.^7-8 It is often associated with bacterial infections, particularly Neisseria gonorrhoeae and Chlamydia trachomatis. Other pathogens such as Mycoplasma genitalium, Trichomonas vaginalis, Ureaplasma urealyticum, herpes simplex virus, and adenovirus have also been implicated.

 

Source of the Safety Issue

Based on information provided by the product registration holder of isotretinoin, the National Pharmaceutical Regulatory Agency (NPRA) became aware of the regulatory action taken by the Therapeutic Goods Administration (TGA) in Australia, which requested marketing authorisation holders of isotretinoin-containing products to update their product information to include the risks of sacroiliitis and urethritis.⁹

The TGA's decision followed a review that found sufficient safety grounds to support updating the Australian product information with these risks. This review was prompted by an assessment conducted by the European Medicines Agency (EMA) as part of the Periodic Safety Update Report (PSUR) evaluation in June 2022.¹⁰ The EMA concluded that there is a reasonable possibility that isotretinoin may be associated with both risks, basing their conclusion on data from the literature and spontaneous reports. In some cases, there was a close temporal relationship, a positive de-challenge and re-challenge, and a plausible mechanism of action linking isotretinoin to these risks.

 

Background of the Safety Issue

Risk of Sacroiliitis

Several theories have been proposed to explain how isotretinoin may induce sacroiliitis. One possibility suggests that isotretinoin's detergent-like properties alter lysosomal membranes, causing cytopathic destruction of synovial cells and increasing joint susceptibility to mechanical irritation.^6,11 Another hypothesis involves the potential for isotretinoin, as a derivative of retinoic acid, to stimulate matrix metalloproteinase-2 (MMP-2) activity. MMP-2 is an enzyme that degrades type IV collagen in the basement membrane and is more abundant in arthritic joints.¹¹ Furthermore, isotretinoin may interact with Cutibacterium (Propionibacterium) acnes antigens to provoke hypersensitivity reactions that exacerbates synovial damage and joint inflammation.^6,12 Genetic predispositions, such as polymorphisms in the retinoic acid receptor alpha genes, may also increase individual susceptibility to these rheumatologic side effects.⁶

Based on literature review and case reports, the time-to-onset of isotretinoin-induced sacroiliitis ranged from a few days to several months, and in rare instances, up to 2 years.^6,11-19 Notably, some cases developed sacroiliitis 2 months after completing isotretinoin treatment.^6,14 Most cases demonstrated a positive dechallenge, with patients showing improvement or full recovery following isotretinoin discontinuation and appropriate treatment. ^6,11-19 Additionally, positive rechallenge cases have been reported, with recurrence of sacroiliitis after reinitiating isotretinoin.^11,15

Isotretinoin‐induced sacroiliitis is typically self‐limited, with most patients responding to nonsteroidal anti‐inflammatory drugs (NSAIDs) and steroid treatment. In some cases, disease‐modifying antirheumatic drugs (DMARDS) such as sulfasalazine and methotrexate were required. A few cases also received concomitant physical therapy or underwent a rehabilitation programme.^11,14,16 In addition, one case unresponsive to both NSAID and DMARD reported complete recovery following short-term biologic therapy with adalimumab.¹⁹

Risk of Urethritis

Isotretinoin-induced urethritis may be attributed to its interaction with skin-specific receptors, such as RAR_γ and RXR_α, which leads to thinning of the stratum corneum and increased transepithelial water loss.²⁰ Along with keratolysis resulting from desmosomal loss, these mechanisms increase skin fragility and dehydrate the urogenital mucosa. The resultant loss of epithelial integrity makes mucosal surfaces more vulnerable to bacterial invasion, allowing pathogens to penetrate the skin barrier and access subcutaneous tissues.^20,21 These changes may contribute to the inflammation and symptoms of urethritis observed in patients receiving isotretinoin.²⁰

The onset of isotretinoin-induced urethritis has been reported to range from 2 weeks to 3 months in published case reports.^20,22,23 Both positive dechallenge and positive rechallenge have been observed in these cases, with symptoms emerging at high doses of isotretinoin, resolving upon dose reduction, and recurring after dose re-escalation, suggesting a dose-dependent relationship.^20,22,23 In one case, antibiotics were prescribed to avoid stopping isotretinoin, but symptoms persisted until dose reduction.²⁰ In the absence of an immunocompromised state, a positive sexually transmitted disease workup, or a positive urine culture, the use of antibiotics or antivirals should be avoided in patients with isotretinoin-induced urethritis.

 

Local Adverse Drug Reaction Reports²⁴

To date, the NPRA has received 56 reports involving 115 adverse events suspected to be associated with isotretinoin. The most frequently reported adverse events include pruritus (6 cases), maculopapular rash (6), and hyperlipidaemia (5). Among the reported cases, no cases of sacroiliitis or urethritis have been identified. However, there was one case each of back pain and lower back pain reported following the administration of isotretinoin. 

 

Advice for Healthcare Professionals

• Be aware that sacroiliitis and urethritis are rare but potential adverse events associated with isotretinoin treatment.

Sacroiliitis

• • Educate patients to inform their doctors if they experience persistent pain in lower back or buttocks during or even months after isotretinoin treatment.
  • Confirming the diagnosis of sacroiliitis is crucial. Further evaluation, including using imaging modalities such as MRI, may be needed to differentiate sacroiliitis from other causes of back pain.
  • If sacroiliitis is suspected or confirmed, consider discontinuing isotretinoin treatment, initiating appropriate treatment, and referring the patient to a rheumatologist.

Urethritis

• • Educate male patients to inform their doctors if they experience unusual urinary symptoms such as burning sensation, discomfort, or unusual discharge while receiving isotretinoin treatment.
  • When urethritis is suspected, consider isotretinoin as a potential aetiological factor. Confirming the root cause of urethritis may help avoid unnecessary use of antibiotics or antivirals.
  • If isotretinoin is suspected to be the cause, consider dose reduction or cessation of the medication.
    
    
• Report all suspected adverse effects associated with isotretinoin-containing products to the NPRA.

 

Regulatory Action

NPRA completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13(54) Jld.1] had been issued for all registration holders of products containing isotretinoin to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

 

References:

1. Ganceviciene R, Zouboulis CC. Isotretinoin: state of the art treatment for acne vulgaris. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2010 Mar 16;8:S47–59.. Available from: https://doi.org/1111/j.1610-0387.2009.07238.x
2. National Pharmaceutical Regulatory Agency (NPRA). ROACCUTANE (isotretinoin) [Package Insert]. QUEST3+ Product Search. 2024 Jun [cited 2025 Jan 28].Available from: http://www.npra.gov.my
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2025 Jan 28]. Available from: https://www.npra.gov.my
4. Slobodin G, Rimar D, Boulman N, Kaly L, Rozenbaum M, Rosner I, et al. Acute sacroiliitis. Clinical Rheumatology [Internet]. 2016 Apr 1 [cited 2020 Aug 16];35(4):851–6. Available from: https://doi.org/10.1007/s10067-016-3200-6
5. Lee A, Gupta M, Boyinepally K, Stokey PJ, Ebraheim NA. Sacroiliitis: A Review on Anatomy, Diagnosis, and Treatment. Korovessis P, editor. Advances in Orthopedics. 2022 Dec 28;2022:1–8. Available from: https://doi.org/10.1155/2022/3283296
6. Kocak O, Kocak AY, Sanal B, Kulan G. Bilateral Sacroiliitis Confirmed with Magnetic Resonance Imaging during Isotretinoin Treatment: Assessment of 11 Patients and a Review of the Literature. Acta Dermatovenerologica Croatica [Internet]. 2017 Mar 18 [cited 2024 Aug 20];25(3):228–33. Available from: https://core.ac.uk/download/pdf/141543571.pdf
7. Bachmann LH, Manhart LE, Martin DH, Seña AC, Dimitrakoff J, Jensen JS, et al. Advances in the Understanding and Treatment of Male Urethritis. Clinical Infectious Diseases. 2015 Nov 24;61(suppl 8):S763–9. Available from: https://doi.org/DOI:10.1093/cid/civ755
8. John RB. Diagnosis and Treatment of Urethritis in Men. American Family Physician [Internet]. 2010 Apr 1 [cited 2024 Aug 20];81(7):873–8. Available from: https://www.aafp.org/pubs/afp/issues/2010/0401/p873.html
9. Australian Therapeutic Goods Administration (TGA). Product Information safety updates - May 2024.2024 May 23 [cited 2024 Aug 20]. Available from: https://www.tga.gov.au/news/safety-updates/product-information-safety-updates-may-2024
10. European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s): Isotretinoin [Internet]. 2021 Dec [cited 2024 Aug 20]. Available from: https://www.ema.europa.eu/en/documents/psusa/isotretinoin-oral-formulations-cmdh-scientific-conclusions-and-grounds-variation-amendments-product-information-and-timetable-implementation-psusa00010488202105_en.pdf
11. Levinson M, Gibson A, Stephenson G. Sacroiliitis secondary to isotretinoin. Australasian Journal of Dermatology. 2011 Dec 29;53(4):298–300. Available from: https://doi.org/10.1111/j.1440-0960.2011.00841.x
12. Karadağ ŞG, Sönmez HE, Tanatar A, Çakan M, Aktay Ayaz N. Isotretinoin‐induced sacroiliitis: Case series of four patients and a systematic review of the literature. Pediatric Dermatology. 2019 Nov 25;37(1):171–5. Available from: https://doi.org/10.1111/pde.14035
13. Yasar Bilge NS, Kasifoglu T, Korkmaz T. A rare adverse effect of isotretinoin treatment: sacroiliitis. Ann Rheum Dis 2014;73:1030-1. https://doi.org/10.1136/annrheumdis-2014-eular.4705
14. Aydog E, Ozturk G, Comert A, Tasdelen N, Akin O, Kulcu DG. Sacroiliitis during isotretinoin treatment: Causal association or coincidence? North Clin Istanb. 2018 Aug 7;6(1):75-80. Available from: https://doi.org/10.14744/nci.2018.93798
15. Bachmeyer C, Charoud A, Turc Y, Callot V, Blum L, Aractingi S. Isotretinoin-Induced Bilateral Sacroiliitis. Dermatology [Internet]. 2003 Apr 17 [cited 2024 Jul 25];206(3):285–6. Available from: https://doi.org/10.1159/000069849
16. Barbareschi M, Paresce E, Chiaratti A, Ferla Lodigiani A, Clerici G, Greppi F. Unilateral sacroiliitis associated with systemic isotretinoin treatment. International Journal of Dermatology. 2010 Mar;49(3):331–3. Available from: https://doi.org/10.1111/j.1365-4632.2009.04334.x
17. Eksioglu E, Oztekin F, Unlu E, Cakci A, Keyik B, Karadavut IK. Sacroiliitis and polyneuropathy during isotretinoin treatment. Clinical and Experimental Dermatology. 2008 Mar 1;33(2):122–4. Available from: https://doi.org/10.1111/j.1365-2230.2007.02532.x
18. Rozin AP, Kagna O, Shiller Y. Sacroiliitis and severe disability due to isotretinoin therapy. Rheumatology International. 2009 Jun 17;30(7):985–6. Available from: https://doi.org/10.1007/s00296-009-1014-4
19. Dawoud NM, Elnady BM, Elkhouly T, Yosef A. Adalimumab as a successful treatment for acne fulminans and bilateral acute sacroiliitis with hip synovitis complicating isotretinoin therapy. Indian J Dermatol Venereol Leprol. 2018 Jan-Feb;84(1):104-107. Available from: https://doi.org/10.4103/ijdvl.ijdvl_834_16
20. Paredes-Bhushan V, Rezaee ME, Chavez DR. Isotretinoin induced urethritis: A case report & review of the literature. Urology Case Reports. 2019 Dec 23;29:101109–9. Available from: https://doi.org/10.1016/j.eucr.2019.101109 ‌
21. Alli N, Ahu Yorulmaz. An unusual side effect of isotretinoin: retinoid dermatitis affecting external urethral meatus. Cutaneous and Ocular Toxicology. 2014 Jun 25;34(2):176–7. Available from: https://doi.org/10.3109/15569527.2014.918140
22. Kellock DJ, R Parslew, Mendelsohn SS, O’Mahony CP. Non-specific urethritis- possible association with isotretinoin therapy. International Journal of STD & AIDS. 1996 Apr 1;7(2):135–6. Available from: https://doi.org/10.1258/0956462961917357
23. Ballout RA, Maatouk I. Isotretinoin-induced urethritis versus non-gonococcal urethritis in a man who has sex with men: an open debate. International Journal of STD & AIDS. 2018 Mar 7;29(10):1024–6. Available from: https://doi.org/10.1177/0956462418761261
24. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2024 [Cited on 2025 Jan 22]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Noor'ain Shamsuddin
Reviewed/Edited by: Choo Sim Mei, Dr. Rema Panickar, Norleen Mohamed Ali