Since RAR are found in many organs of the body, isotretinoin can cause numerous side effects (Table 9). This profile of adverse effects closely mimics those of hypervitaminosis A (96). Mucocutaneous side effects are the most common and are dose dependent. The most frequently encountered mucocutaneous side effects are: cheilitis, generalized xerosis, and dry mucosa. Cheilitis is so common that its absence would indicate a suboptimal dose or cause suspicion of the patient’s compliance. Dry nasal mucosa frequently results in epistaxis (97). Xerophthalmia is common with subsequent contact lens intolerance, and possible conjunctivitis. Photophobia, decreased night vision, keratitis, and optic neuritis are less common, while cataracts, and corneal opacities rarely develop. Hair thinning, and hair loss occurs in less than 10% of patients on isotretinoin (98,99).
Neuromuscular complaints are relatively common in patients taking isotretinoin. About 14% of patients will experience myalgias, and a higher percentage will experience arthralgias and back pain. These neuromuscular complaints may coexist with a transient rise in creatinine phosphokinase, and are more common in physically active patients (100,101).
Nausea, vomiting, diarrhea, and abdominal pain have occurred in patients on isotretinoin but are rare. Transient mild increases in liver transaminases occur in about 15% of patients. Frank hepatitis is very rare, and has been reported in adults but not in children on isotretinoin (102).
Pseudotumor cerebri, or benign intracranial hypertension, is a rare side effect of isotretinoin. Patients who develop this increase in intracranial pressure will complain of headache, blurred vision, double vision, and/or vomiting. If recognized by history, and the finding of papilledema, a lumbar puncture can confirm the diagnosis, and be therapeutic. The likelihood of developing pseudotumor cerebri is increased with concomitant tetracycline use (103).
The impact of isotretinoin on a patient’s psychological well-being has incited much attention. From 1982 to May 2000, 37 cases of suicide, 110 cases of hospitalized depression, suicidal ideation, or suicide attempt, and 284 cases of nonhospitalized depression were reported to the FDA’s Adverse Event Reporting System (104). In one population-based cohort study comparing isotretinoin users with oral antibiotic users, the relative risk for development of depression or psychosis was approximately 1.0, indicating
Table 9 Isotretinoin Side Effects
Teratogenicity Hydrocephalus Micorcephaly External ear abnormalities Microphthalmia Craniofacial dysmorphia Cardiac septal defects Thymus gland abnormalities
Mucocutaneous Chelitisa Xerosisa Skin fragilitya Palmoplantar peelinga Dry nosea Epistaxsisa Pruritusa
Facial erythema/ rasha
Desquamation
Atrophy
Granulation tissue Alopecia Brittle nails Acne fulminans
Pyogenic granuloma-like lesions
Ophthalmologic Xerophthalmiaa Blepharitis Papilledema Blurred vision Night blindness Corneal opacities
Gastrointestinal Nausea Anorexia Abdominal pain Cirrhosis
Neuromuscular/Psychiatric Headachea Fatigue Lethargy Myalgias Stillness Irritiablility Depression Suicidal ideation Psychosis Papilledema Pseudotumor cerebri
Rheumatologic
Arthralgias
DISH-like vertebral hyperostoses
Table 9 Isotretinoin Side Effects (Continued)
Altered bone remodeling Extraspinal tendon and ligament calcification Premature epiphyseal closure Demineralization/ osteoporosis Periosteal thickening Laboratory
Elevated triglyceridesa Elevated cholesterol Elevated liver function tests Elevated creatine phosphokinase
a Denotes most common side effects. Source: Adapted from Refs. 100, 129, 130.
no increased risk (105). A recent study demonstrated a decrease in depressive symptoms in patients undergoing treatment with isotretinoin (106). Further studies are needed to resolve this issue of causality.
Isotretinoin is a potent teratogen, and is rated pregnancy category X. The exact mechanism of embryopathy is unknown, but exposed infants have characteristic craniofacial defects as well as cardiac, thymus, and central nervous system abnormalities (107). Approximately 3-4 per 1000 women on isotretinoin become pregnant. In an effort to eliminate pregnancy while on isotretinoin, the manufacturer has implemented several regulations. There are additional consent forms for women regarding the potential teratogenicity. Appropriate contraception must be used one month prior to and one month following a course of isotretinoin. Two negative pregnancy tests must be obtained before starting isotretinoin, and a negative test must be obtained each month while on therapy.