Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2022 Publisher: Douglas Pharmaceuticals Ltd, PO Box 45 027, Auckland 0651, New Zealand, Phone: (09) 835 0660
Isotretinoin is highly TERATOGENIC.
It is, therefore, contraindicated not only in women who are pregnant or who may become pregnant while undergoing treatment but also in all women of childbearing potential. There is an extremely high risk that a deformed infant will result if pregnancy occurs while taking ORATANE in any amount even for short periods. Potentially all exposed foetuses can be affected.
Prescribers should inform the individual patient of the risks associated with the use of isotretinoin.
Isotretinoin should only be prescribed by doctors who are experienced in the use of systemic retinoids and understand the risk of teratogenicity associated with isotretinoin therapy.
Isotretinoin is contraindicated in women of childbearing potential unless the female patient meets all of the following conditions:
Even female patients, who normally do not employ contraception because of a history of infertility, should be advised to do so while taking isotretinoin, following the above guidelines.
Should pregnancy occur in spite of these precautions during treatment with isotretinoin or in the month following, there is a great risk of very severe malformation of the foetus (involving in particular the central nervous system, the heart and the large blood vessels). If pregnancy does occur, the doctor and patient should discuss the advisability of continuing the pregnancy.
Major human foetal abnormalities related to isotretinoin administration have been documented, including hydrocephalus, microcephalus, abnormalities of the external ear (micropinna, small or absent external auditory canals), microphthalmia, cardiovascular abnormalities, facial dysmorphia, thymus gland abnormalities, parathyroid hormone deficiency and cerebellar malformation.
There is also an increased risk of spontaneous abortion.
The available data suggest that the level of maternal exposure from the semen of patients receiving isotretinoin, is not of sufficient magnitude to be associated with the teratogenic effect of isotretinoin.
Male patients should be reminded that they must not share their medication with anyone, particularly not females.
Hypersensitivity reactions may occur in susceptible individuals.
Several cases of clinical hepatitis have been noted which are considered to be possibly or probably isotretinoin therapy. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalised with dosage reduction or continued administration of the drug. If normalisation does not readily occur or if hepatitis is suspected during treatment with isotretinoin, discontinue treatment with isotretinoin and the etiology further investigated.
Depression psychotic symptoms and rarely suicide attempts and suicide have been reported in patients treated with isotretinoin (refer to section 4.8). Although a causal relationship has not been established particular care needs to be taken in patients with a history of depression and all patients should be monitored for signs of depression and referred for appropriate treatment if necessary.
Blood donation to women of childbearing age by patients being treated or recently treated (one month) with isotretinoin is contraindicated.
Acute exacerbation of acne is generally seen during the initial period of treatment; but this subsides with continued treatment, usually within 7-10 days, and usually does not require dose adjustments.
Aggressive dermabrasion and cutaneous laser should be avoided in patients on isotretinoin and for a period of 5-6 months after treatment because of the risk of hypertrophic scarring in atypical areas and more rarely hyper- or hypopigmentation in treated areas.
Wax epilation should be avoided during therapy and at least for a period of 6 months thereafter due to the possibility of scarring or dermatitis.
Exposure to intense sunlight or UV rays should be avoided. Where necessary, a sun protection product with a high protection factor of at least SPF 15 should be used.
Patients should be advised to use a skin-moisturising ointment or cream and a lip balm from the start of treatment as isotretinoin is likely to cause dryness of the skin and lips.
There have been post-marketing reports of severe skin reactions (e.g., erythema multiforme, Stevens Johnson syndrome, and toxic epidermal necrolysis) associated with isotretinoin use. These events may be serious and result in death, life-threatening events, hospitalisation, or disability. Patients should be monitored closely for severe skin reactions and discontinuation of isotretinoin should be considered if warranted.
Isotretinoin use has been associated with a number of cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved the concomitant use of tetracyclines, See Section 4.8. Supplementary treatment with tetracyclines is, therefore, contraindicated. Early signs and symptoms of benign intracranial hypertension include papilloedema, headache, nausea and vomiting, and visual disturbances.
Patients who develop benign intracranial hypertension should discontinue isotretinoin immediately.
Dry eyes, corneal opacities, conjunctivitis, blepharitis, decreased night vision and keratitis usually resolve after discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Patients, particularly those with dry eyes, should be monitored for the development of keratitis.
Patients experiencing visual difficulties should be referred for an expert ophthalmological examination and withdrawal of isotretinoin considered. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment.
Corneal opacities have occurred in patients receiving isotretinoin for acne and more frequently when higher drug dosages were used in patients with disorders of keratinisation. All isotretinoin patients experiencing visual difficulties should discontinue the drug and have an ophthalmological examination.
Impaired hearing has been reported in patients taking isotretinoin. Hearing impairment can be unilateral or bilateral, and symptoms include tinnitus, impaired hearing at certain frequencies and deafness. In some cases, hearing impairment has been reported to persist after therapy has been discontinued. Anyone who experiences these symptoms should immediately seek medical advice; the drug should be ceased, and the patient should undergo urgent formal audiology assessment.
Rises in alanine and aspartate aminotransferase enzymes (ALT and AST) have been reported. Liver function tests, especially AST and blood lipids should be checked before and one month after the start of treatment and subsequently at monthly intervals during therapy and at the end of treatment. When transaminase levels exceed the normal levels, reduction of the dose or discontinuation of treatment may be necessary.
Isotretinoin causes elevation of serum triglycerides and cholesterol as well as a decrease in H.D.L., which appear to be related to duration of treatment and are reversible on cessation of treatment. The degree of elevation may also be dose dependent although this has not been conclusively established.
At doses of greater than 1 mg/kg/day, approximately one in four patients have been found to develop elevated triglycerides while taking isotretinoin. At lower doses triglyceride levels elevated above the normal range are uncommon.
Some patients have been able to reverse triglyceride elevations by weight reduction and restriction of dietary fat and alcohol while continuing to take Roaccutane. Serum lipid values usually return to normal on reduction of the dose or discontinuation of treatment. Acute pancreatitis, which is potentially fatal, sometimes associated with serum triglycerides levels >8g/L, has been reported. Hence, Roaccutane should be discontinued if uncontrolled hypertriglyceridemia or symptoms of pancreatitis occur.
Serum lipids (fasting value) should be determined one month prior to therapy and again after about 4 weeks of therapy and subsequently at three-month intervals unless more frequent monitoring is clinically indicated.
Predisposing factors such as a family history of lipid metabolism disorders, obesity, alcoholism, diabetes and smoking should be assessed. In high risk patients (with diabetes, obesity, alcoholism or lipid metabolism disorder) undergoing treatment with isotretinoin, more frequent checks of serum values for lipids and/or blood glucose may be necessary.
Myalgia and arthralgia may occur and may be associated with reduced tolerance to vigorous exercise (refer to section 4.8). Isolated instances of raised serum CPK values have been reported in patients receiving isotretinoin, particularly those undertaking vigorous physical activity. In clinical trials of disorders of keratinisation with a mean dose of 2.24 mg/kg/day a high prevalence of skeletal hyperostosis was noted. Bone changes including premature epiphyseal closure and calcifications of tendons and ligaments have occurred after administration of high doses for long periods for treating disorders of keratinisation. The dose levels, duration of treatment and total cumulative dose in these patients generally far exceeded those recommended for the treatment of acne.
Minimal skeletal hyperostosis has also been observed by X-rays in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses.
Isotretinoin may be associated with growth retardation in prepubertal children.
Due to the possible occurrence of bone changes, a careful evaluation of the risk/benefit ratio should be carried out in every patient and isotretinoin administration should be restricted to severe cases.
Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing severe (haemorrhagic) diarrhoea should discontinue isotretinoin immediately.
Anaphylactic reactions have been rarely reported and only after previous topical exposure to retinoids. Allergic cutaneous reactions are reported infrequently. Serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement have been reported. Severe allergic reactions necessitate interruption of therapy and careful monitoring.
Elevation of lipid (triglycerides and cholesterol) levels occurs with isotretinoin therapy. These are usually mild in doses less than 1 mg/kg/day and elevations above the normal range are unusual at 0.5 mg/kg/day. At doses above 1 mg/kg/day, elevation (above the normal range) occurs in 25% of patients.
These changes are seen more frequently in patients where a family history of lipid disorders, or obesity, alcohol abuse, diabetes mellitus or smoking is present. The changes are dose related and may be controlled by dietary means (including alcohol restriction) or dosage reduction.
Elevated ESR values occur in about 40% of patients treated with isotretinoin.
A rise in aspartate aminotransferase (AST) levels may occur, especially with the higher dosages of isotretinoin. Although the changes have usually been within the normal range, and may return to baseline levels despite continued treatment, significant increases have occurred in a few cases, necessitating dosage reduction or discontinuation of isotretinoin.
Certain patients receiving isotretinoin have experienced problems in the control of their blood sugar. Therefore, known or suspected diabetics should have frequent blood sugar determinations performed during isotretinoin therapy. New cases of diabetes have been diagnosed.
A small number of patients have shown proteinuria, microscopic or gross haematuria and elevated CPK.
Concurrent therapy with ORATANE and vitamin A must be avoided, as symptoms of hypervitaminosis A may be intensified (refer to section 4.3 and 4.8).
Cases of pseudotumour cerebri and/or papilloedema have been reported in association with the use of isotretinoin. Four out of ten of these patients had retinal hemorrhages. Symptoms appeared after 21 days to 6 months therapy with 40 to 120 mg daily. As tetracyclines or minocycline was administered in 5 out of 10 cases – both of these drugs can also an increase in intracranial pressure, their combination with isotretinoin is contraindicated, see Section 4.4.
No further interactions between isotretinoin and other medicines including combined oral contraceptives as recommended for pregnancy prevention have been observed to date.
Concurrent administration of other topical keratolytic or exfoliative antiacne agents is not indicated, nor is concurrent radiation therapy with ultraviolet light indicated.
Patients should avoid exposure to the sun. Adjuvant therapy with mild topical medicines may be given, as required.
Since acne is an androgen-dependent disease, contraceptives containing an androgen progestational substance, such as one derived from 19-nortestosterone (norsteroid), particularly in the presence of gynaecoendocrinological problems, should be avoided.
Pregnancy (Category X).
Isotretinoin is highly teratogenic and must not be given to women who are pregnant (refer to section 4.3). Isotretinoin crosses the placental barrier in amounts that lead to congenital deformities. There is an extremely high risk that a deformed infant will result if pregnancy occurs while taking isotretinoin in any amount even for short periods. Potentially all exposed foetuses can be affected.
Owing to its lipophilicity, there is a high probability that isotretinoin is secreted into the breast milk. Isotretinoin must not be given to nursing mothers.
In studies in 66 human males, 30 of who were patients with cystic acne, no significant changes were noted in the count or motility of spermatozoa in the ejaculate (refer to section 5.3).
Changes in vision, including decreased night vision, have been reported during isotretinoin therapy (refer to section4.4 and 4.8). Patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night.
Most of the adverse effects of isotretinoin are dose related with more pronounced effects occurring at doses above 1 mg/kg/day. The adverse effects may recede during continued therapy and the mucocutaneous effects were reversible with dosage reduction or discontinuation of therapy. Exacerbation of the cystic acne may occur during the initial stages of therapy.
The most frequently observed symptoms are those associated with hypervitaminosis A, dryness of the skin, in particular peeling of the palms and soles, dryness of the mucosa e.g. of the lips (cheilitis, which occurs in over 90% of patients) can be relieved by the application of a fatty ointment, dryness of the nasal mucosa which can lead to epistaxis (which is seen in up to 30% of patients), dryness of the pharyngeal mucosa (hoarseness)dryness of the eyes (conjunctivitis, reversible corneal opacities and intolerance to contact lenses).
Exanthema, pruritus, facial erythema/dermatitis, sweating, pyogenic granuloma, paronychia, nail dystrophy and increased formation of granulation tissue, persistent hair thinning, reversible alopecia, hirsutism, acne fulminans, hyperpigmentation photosensitivity, photoallergic reactions, skin fragility. Acne flare occurs at the start of treatment and persists for several weeks.
During the post-marketing period, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported with isotretinoin (refer to section 4.4).
Myalgia (muscle pain) with or without elevated serum CPK values (refer to section 4.4), arthralgia (joint pain), hyperostosis, arthritis, calcification of ligaments and tendons and other bone changes, reduced bone density, back pain, epiphyses, premature fusion, tendinitis.
Serious cases of rhabdomyolysis, often leading to hospitalization and some with fatal outcome have been reported, particularly in those undertaking vigorous physical activity. Minimal hyperostosis has been observed in cystic acne patients treated with a single course of isotretinoin. Due to the possible occurrence of these bone changes, a careful evaluation of the risk/benefit ratio should be carried out in every patient and isotretinoin administration should be restricted to severe cases.
Behavioural disorders, depression, suicide attempt, suicide (refer to section 4.4), headache, increased intracranial pressure (pseudotumor cerebri) and seizures.
Visual disturbances, photophobia, dark adaptation disturbances (decreased night vision), colour vision disturbances (reversible upon discontinuation), lenticular cataracts, keratitis, blurred vision, blepharitis, conjunctivitis, eye irritation, papilledema as a sign of intracranial hypertension, impaired hearing at certain frequencies.
Nausea, severe diarrhoea, inflammatory bowel disease such as colitis, ileitis, and hemorrhage have been reported to occur. Patients treated with isotretinoin, especially those with high triglyceride levels are at risk of developing pancreatitis. Fatal pancreatitis has been rarely reported (refer to section 4.4).
Transient and reversible increases in liver transaminases, some cases of hepatitis.
Bronchospasm has been rarely reported; sometimes in patients with a pre-history of asthma.
Sexual dysfunction including erectile dysfunction and decreased libido has been reported with an unknown frequency, i.e. cannot be estimated from the available data.
Decrease in white blood cell count, neutropenia, disorders of red blood cell parameters (such as decrease in red blood cell count and hematocrit), elevation of sedimentation rate increase or decrease in platelet count (thrombocytopenia), anaemia, lymphadenopathy.
Increases in serum triglyceride and cholesterol levels as well as a decrease of HDL have also been observed, particularly at high dosages and in predisposed patients (with a family history of lipid metabolism disorders, diabetes, obesity or alcoholism), which appear to be related to duration of treatment and are reversible on cessation of treatment. The degree of elevation may also be dose dependent although this has not been conclusively established. Haematuria and proteinurea occur rarely.
Local or systemic infections due to Gram-positive microorganisms (Staphylococcus aureus).
Vasculitis (for example Wegener’s granulomatosis, allergic vasculitis).
Glomerulonephritis, haematuria, proteinuria.
Allergic responses and systemic hypersensitivity.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected reactions https://nzphvc.otago.ac.nz/reporting/
Not applicable.
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