isotretinoin (Roaccutane)

see also:

• retinoids
• dermatology

• isotretinoin (13-cis-retinoic acid) is an oral retinoid that has dramatically changed the Rx of a number of conditions, particularly acne vulgaris
• it regulates growth and differentiation of epithelial cells by inhibiting epithelial proliferation
• it induces apoptosis (cell death) in various cells in the body such as sebaceous glands, meibomian glands, hypothalamus, and hippocampus
• may be converted intracellularly to metabolites that act as agonists of RAR and RXR nuclear receptors
• significantly changes the expression of hundreds of genes in skin after eight weeks of therapy
• decreases the size and sebum output of the sebaceous glands
• inhibits the action of the metalloprotease MMP-9 (gelatinase) in sebum
• its effects are long lasting and as it is highly teratogenic, patients must take contraception and avoid getting pregnant while taking it or even for months after ceasing it.
• it has many adverse effects, although most are dose-related and thus starting on lowest dose possible is often best for most patients
• in Australia, it can only be prescribed by a dermatologist

• efficacy appears to be related to total cumulative dose and most achieve excellent results after a cumulative dose of 120-150mg/kg
• dose should be taken with food as it is best abdorbed with a high fat meal
• courses are generally for 3-10 months

• much higher incidence of adverse effects but more effective and lower relapse rates
• oral dose: 0.5-2mg/kg/day

• higher relapse rates which may require repeat Rx but much more tolerable
• oral dose: 10-20mg/day

• children aged 12 years or younger
• pregnancy
• lactation
• impaired liver function
• hyperlipidaemia
• hypervitaminosis A
• allergy to peanuts, soya, or the sugar sorbitol: isotretinoin contains these ingredients
• exposure to excessive sunlight (patients should use sunscreens if going out in the sun)
• blood donations
• should be used with caution in people with:
  • a history of depression
  • diabetes
  • dry-eye syndrome
  • impaired kidney function
  • smokers
• should not be used concurrently with:
  • vitamin A (risk of hypervitaminosis A)
  • keratolytic agents
    • avoid waxing, surgical dermabrasion, or laser surgery of the skin during treatment and for at least 6 months after stopping isotretinoin. This will help prevent any stripping, scarring, or pigmentation of the skin
  • tetracycline antibiotics (increased risk of benign intracranial hypertension)

• teratogenic
• cheilitis
• chapped lips
• dry skin +/- localised exfoliation
• pruritus
• erythema
• skin fragility
• epistaxes
• conjunctivitis / dry eyes / blepharitis
• prolongation of nasal mucociliary clearance time ¹⁾
  • systemic isotretinoin alters the mucociliary transport, decreases the squamous cell ratio, increases the reactive changes in the respiratory epithelium significantly, and increases neutrophils in the nasal surface mucosa in the third month of treatment ²⁾
• anaemia
• raised erythrocyte sedimentation rate (ESR)
• thrombocytopenia
• thrombocytosis
• less commonly, neutropenia
• raised LFTs
• arthralgia / myalgia / back pain
• raised triglycerides
• decreased HDL
• headache
• persistent impaired night vision, esp. if low vitamin A levels prior to starting (eg. cystic fibrosis patients who have impaired fat absorption)
• keratoconjunctivitis sicca
• keloid scarring
• reduced growth hormone (GH) levels and insulin-like growth factor-1 (IGF-1) levels
• impaired chondrogenesis
• premature epiphyseal closure (rare)
• alopecia (rare)
• bronchospasm (rare) ³⁾
• eosinophilic pleural effusion (rare)
• acquired hearing impairment (rare) ⁴⁾
• exacerbation of depression although there is no evidence that it actually causes depression or increased suicidality
• increased lung cancer and cardiovascular disease risk in smokers
  • smokers have a higher mortality if on isotretinoin from both cardiovascular disease and lung cancer, but this effect was not evident in non-smokers or ex-smokers ⁵⁾
    • retinoids are necessary for the maintenance of respiratory epithelial cell differentiation in vivo and can induce terminal differentiation or apoptosis of initiated epithelial cells.
    • retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal models of emphysema⁶⁾
    • conversely, some studies have shown that 1-2mg/kg/d of isotretinoin may help prevent some aerodigestive cancers, but side effects are too great at these doses ⁷⁾
      • isotretinoin makes dramatic improvement in a patient with extensive respiratory papillomatosis ⁸⁾, but seems there is a highly variable response rate.
• there is little evidence to support a causal relationship with inflammatory bowel disease (IBD) ⁹⁾
• many other rare adverse effects