RETINOIC ACID
(Isotretinoin )
A yellow or light orange, crystalline powder or yellow crys-
tals. Practically Insoluble in water: sparingly soluble to
slightly soluble in alcohol: sparingly soluble in ether, in iso-
propyl alcohol, and in macrogol 400: soluble in chloroform
and in dichloromethane. Store in airtight containers at a tem-
perature not exceeding 25Β°. Protect from light. The Ph. Eur.
recommends that the contents of an opened container be used
as soon as possible and that any unused part be protected by
an atmosphere of an inert gas. The USP specifies that all the
contents should be stored under an atmosphere of an inert gas.
Adverse Effects
The adverse effects of isotretinoin and other oral
retinoids are similar to those of vitamin A and are generally
reversible and dose-relat-
ed. The most common are dryness of the mucous
membranes and of the skin with scaling, fragility,
and erythema, especially of the face, cheilitis, pruri-
tus, epistaxis, conjunctivitis, dry sore mouth, and
palmo-plantar exfoliation. Corneal opacities, dry
eyes. visual disturbance & skeletal hyperostosis. and
musculoskeletal symptoms may also occur. Eleva-
tion of serum triglyceride, hepatic enzymes, eryth-
rocyte sedimentation rate and blood glucose have
been reported. Other effects have included hair thin-
ning, photosensitivity, changes in skin pigmenta-
tion, paronychia, gastro-intestinal symptoms,
headache, drowsiness, sweating, mood changes.
psychotic symptoms, depression, suicidal behav-
iour, benign intracranial hypertension, seizures, vas-
culitis. and an association with skin infections and
an inflammatory bowel syndrome.
Isotretinoin and other retinoids are teratogenic.
When isotretinoin is applied topically the adverse
effects are similar to those of tretinoin.
EffectS on the blood. Thrombocytopenia has been reported
in 2 patients receiving etretinate and in one patient treated
with isotretinoin. There has also been a report of agranulocy -
tosis associated with isotretinoin therapy in a 16-year-old
boy. Leucocytosis and multiple thrombosis have been re-
ported in patients who received tretinoin by mouth for treat-
ment of acute promyelocytic leukaemia.
Effects on the liver. Transient slight elevations of serum
concentrations of liver enzymes are common with etretinate.
but there have been few reports of acute hepatitis or chole-
static jaundice. In one patient, acute hepatitis progressed
to chronic active hepatitis, despite cessation of etretinate
therapy but studies examining serial liver biopsies from pa-
tients receiving long-term etretinate have failed to show any
significant chronic liver damage. The manufacturers have
reported instances of hepatic fibrosis, necrosis, and/or
cirrhosis.
In a recent overview it was considered that some form of
hepatotoxicity may be seen in up to 20% of patients treated
with etretinate and significant liver disease is thought to
occur in l%.
Isotretinoin may also cause mild elevations of liver enzymes
and the manufacturers state that jaundice and hepatitis have
occurred rarely. There is also a report of fatty liver.
Effects on the musculoskeletal system. An ossification
disorder resembling diffuse skeletal hyperostosis. with myal-
gia, arthralgia, and stiffness was first reported by Pittsley
in patients who had taken large doses of isotretinoin for pro-
longed periods. Premature closure of the epiphyses in a
child treated with isotretinoin has also been described.
Digiovanna later found radiographic evidence of extra spinal
tendon and ligament calcification in patients who had
received long term therapy with etretinate and there were
reports of spinal
hyperostosis from other workers and one of spinal cord com-
pression. Gilbert el al. were unable to find radiographic
skeletal changes after 6 to 18 months of treatment with etret-
inate but Wilson et a1. found that hyperostosis was fairly
common in patients taking moderately prolonged therapy and
they recommended that radiological examinations should be
carried out every 12 months in patients taking etretinate.
However, they were unable tor find any clear association be-
tween these effects and the total dose or duration of
treatment.
Others have found evidence of changes after 4 months in pa-
tients who had taken isotretinoin I mg per kg body-weight
daily and recommended that radiological examinations
should be made every 6 months in patients receiving isotretin-
oin for more than a year. However, another study found that
although 12% of patients receiving isotretinoin 0.5 mg per kg
had evidence of hyperostoses this was not clinically signifi-
cant in any patient. Tangrea et al. suggested that monitoring
beyond the treatment period might be unnecessary as calcifi-
cations and hyperostosis in patients who had received
isotretinoin for 3 years had neither progressed nor improved
10 lo 24 months after the end of treatment; additionally no
new hyperostoses had developed during that period.