Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Alliance Pharmaceuticals Limited, Avonbridge House, Bath Road, Chippenham, Wiltshire, SN15 2BB, UK
Isotretinoin is contraindicated in women who are pregnant or breastfeeding. (see section 4.6 “Fertility, pregnancy and lactation”).
Isotretinoin is contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met (see section 4.4 “Special warnings and special precautions for use”).
Isotretinoin is also contraindicated in patients with hypersensitivity to isotretinoin or to any of the excipients listed in section 6.1. This medicine contains hydrogenated soya-bean oil and refined soya-bean oil. Therefore, this product is contraindicated in patients who are allergic to peanuts or soya.
Isotretinoin is also contraindicated in patients:
Isotretinoin is a powerful human teratogen inducing a high frequency of severe and life threatening birth defects.
Isotretinoin is strictly contraindicated in:
This medicinal product is TERATOGENIC.
Isotretinoin is contraindicated in women of childbearing potential unless all of the following conditions of the Pregnancy Prevention Programme are met:
These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.
The prescriber must ensure that:
If pregnancy occurs in a woman treated with isotretinoin, treatment must be stopped and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice.
If pregnancy occurs after stopping treatment there remains a risk of severe and serious malformation of the foetus. This risk persists until the product has been completely eliminated, which is within one month following the end of treatment.
Female patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. If the prescribing physician is not in a position to provide such information the patient should be referred to the relevant healthcare professional.
As a minimum requirement, female patients of childbearing potential pregnancy must use at least one highly effective method of contraception (i.e. a user-independent form), or two complementary user-dependent forms of contraception. Contraception should be used for at least 1 month prior to starting treatment throughout treatment and continue for at least 1 month after stopping treatment with isotretinoin, even in patients with amenorrhea.
Individual circumstances should be evaluated in each case, when choosing the contraception method involving the patient in the discussion, to guarantee her engagement and compliance with the chosen measures.
According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25mIU/mL are recommended to be performed, as follows.
At least one month after the patient has started using contraception, and shortly (preferably a few days) prior to the first prescription, the patient should undergo a medically supervised pregnancy test. This test should ensure the patient is not pregnant when she starts treatment with isotretinoin.
Follow-up visits should be arranged at regular intervals, ideally monthly. The need for repeated medically supervised pregnancy tests every month should be determined according to local practice including consideration of the patient’s sexual activity and recent menstrual history (abnormal menses, missed periods or amenorrhea) and method of contraception. Where indicated, follow-up pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.
1 month after stopping treatment, women should undergo a final pregnancy test to exclude pregnancy.
For women of childbearing potential, the prescription duration of Isotretinoin capsules should ideally be limited to 30 days in order to support regular follow up, including pregnancy testing and monitoring. Ideally, pregnancy testing, issuing a prescription and dispensing of Isotretinoin capsules should occur on the same day. Dispensing of isotretinoin should occur within a maximum of 7 days of the prescription.
This monthly follow-up will allow ensuring that regular pregnancy testing and monitoring is performed and that the patient is not pregnant before receiving the next cycle of medication.
The available data suggests that the level of maternal exposure from the semen of the patients receiving isotretinoin is not of a sufficient magnitude to be associated with the teratogenic effects of isotretinoin.
Male patients should be reminded that they must not share their medication with anyone, particularly not females.
Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment.
Patients should not donate blood during therapy and for 1 month following discontinuation of isotretinoin because of the potential risk to the foetus of a pregnant transfusion recipient.
In order to assist prescribers, pharmacists and patients in avoiding foetal exposure to isotretinoin the Marketing Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of isotretinoin, to provide advice on contraception before therapy is started and to provide guidance on the need for pregnancy testing.
Full patient information about the teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme should be given by the physician to all patients, both male and female.
Depression, depression aggravated, anxiety, aggressive tendencies, mood alterations, psychotic symptoms and, very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with isotretinoin (see section 4.8 “Undesirable effects”). 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.
However, discontinuation of isotretinoin may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary.
Awareness by family or friends may be useful to detect mental health deterioration.
Acute exacerbation of acne is occasionally seen during the initial period but this subsides with continued treatment, usually within 7-10 days, and usually does not require dose adjustment.
Exposure to intense sunlight or to UV rays should be avoided. Where necessary a sun-protection product with a high protection factor of at least SPF 15 should be used.
Aggressive chemical dermabrasion and cutaneous laser treatment should be avoided in patients on isotretinoin for a period of 5-6 months after the end of the treatment because of the risk of hypertrophic scarring in atypical areas and more rarely post inflammatory hyper or hypopigmentation in treated areas. Wax depilation should be avoided in patients on isotretinoin for at least a period of 6 months after treatment because of the risk of epidermal stripping.
Concurrent administration of isotretinoin with topical keratolytic or exfoliative anti-acne agents should be avoided as local irritation may increase (see section 4.5 Interaction with other medicinal products and other forms of interaction).
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 (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) associated with isotretinoin use. As these events may be difficult to distinguish from other skin reactions that may occur (see section 4.8), patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If a severe skin reaction is suspected, isotretinoin treatment should be discontinued.
Anaphylactic reactions have been rarely reported, in some cases 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.
Dry eyes, corneal opacities, 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.
Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment.
Decreased night vision has also been reported and the onset in some patients was sudden (see section 4.7 “Effects on ability to drive and to use machines”). Patients experiencing visual difficulties should be referred for an expert ophthalmological opinion. Withdrawal of isotretinoin may be necessary.
Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in patients receiving isotretinoin, particularly in those undertaking vigorous physical activity (see section 4.8 “Undesirable effects”). In some cases, this may progress to potentially life threatening rhabdomyolysis.
Bone changes including premature epiphyseal closure, hyperostosis, and calcification of tendons and ligaments have occurred after several years of administration at very high doses 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.
Cases of benign intracranial hypertension have been reported, some of which involved concomitant use of tetracyclines (see sections 4.3 “Contraindications” and 4.5 “Interactions with other medicinal products and other forms of interaction”). Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop benign intracranial hypertension should discontinue isotretinoin immediately.
Liver enzymes should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Transient and reversible increases in liver transaminases have been reported. In many cases these changes have been within the normal range and values have returned to baseline levels during treatment. However, in the event of persistent clinically relevant elevation of transaminase levels, reduction of the dose or discontinuation of treatment should be considered.
Renal insufficiency and renal failure do not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin can be given to patients with renal insufficiency. However, it is recommended that patients are started on a low dose and titrated up to the maximum tolerated dose (see section 4.2 “Posology and Method of Administration”).
Serum lipids (fasting values) should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Elevated serum lipid values usually return to normal on reduction of the dose or discontinuation of treatment and may also respond to dietary measures.
Isotretinoin has been associated with an increase in plasma triglyceride levels. Isotretinoin should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur (see section 4.8 “Undesirable effects”). Levels in excess of 800mg/dL or 9mmol/L are sometimes associated with acute pancreatitis, which may be fatal.
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.
Isotretinoin capsules contain sorbitol and maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
In patients with diabetes, obesity, alcoholism or a lipid metabolism disorder undergoing treatment with isotretinoin, more frequent checks of serum values for lipids and/or blood glucose may be necessary. Elevated fasting blood sugars have been reported, and new cases of diabetes have been diagnosed during isotretinoin therapy.
Patients should not take vitamin A as concurrent medication due to the risk of developing hypervitaminosis A.
Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported with concomitant use of isotretinoin and tetracyclines. Therefore, concomitant treatment with tetracyclines must be avoided (see section 4.3 “Contraindications” and section 4.4 “Special warnings and special precautions for use”).
Concurrent administration of isotretinoin with topical keratolytic or exfoliative anti-acne agents should be avoided as local irritation may increase (see section 4.4 Special warnings and special precautions for use).
Pregnancy is an absolute contraindication to treatment with isotretinoin (see section 4.3 “Contraindications”). Women of childbearing potential have to use effective contraception one month before, during and up to one month after treatment. If pregnancy does occur in spite of these precautions during treatment with isotretinoin or in the month following, there is a great risk of very severe and serious malformation of the foetus.
The foetal malformations associated with exposure to isotretinoin include central nervous system abnormalities (hydrocephalus, cerebellar malformation/abnormalities, microcephaly), facial dysmorphia, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canals), eye abnormalities (microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of great vessels, septal defects), thymus gland abnormality and parathyroid gland abnormalities. There is also an increased incidence of spontaneous abortion.
If pregnancy occurs in a woman treated with isotretinoin, treatment must be stopped and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice.
Isotretinoin is highly lipophilic, therefore the passage of isotretinoin into human milk is very likely. Due to the potential for adverse effects in the child exposed via mothers' milk, the use of isotretinoin is contraindicated in nursing mothers.
Isotretinoin, in therapeutic dosages, does not affect the number, motility and morphology of sperm and does not jeopardise the formation and development of the embryo on the part of the men taking isotretinoin.
Isotretinoin could potentially have an influence on the ability to drive and use machines. A number of cases of decreased night vision have occurred during isotretinoin therapy and in rare instances have persisted after therapy (see section 4.4 “Special warnings and special precautions for use” and section 4.8 “Undesirable effects”). Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating machines.
Drowsiness, dizziness and visual disturbances have been reported very rarely. Patients should be warned that if they experience these effects, they should not drive, operate machinery or take part in any other activities where the symptoms could put either themselves or others at risk.
Some of the side effects associated with the use of isotretinoin are dose-related. The side effects are generally reversible after altering the dose or discontinuation of treatment, however some may persist after treatment has stopped. The following symptoms are the most commonly reported undesirable effects with isotretinoin: dryness of the skin, dryness of the mucosae e.g. of the lips (cheilitis), the nasal mucosa (epistaxis) and the eyes (conjunctivitis).
Very Rare (≤1/10 000): Gram positive (mucocutaneous) bacterial infection
Very common (≥1/10): Anaemia, Red blood cell sedimentation rate increased, Thrombocytopenia, Thrombocytosis
Common (≥1/100, <1/10): Neutropenia
Very Rare (≤1/10000): Lymphadenopathy
Rare(≥1/10000, <1/1000): Allergic skin reaction, Anaphylactic reactions, Hypersensitivity
Very Rare (≤1/10000): Diabetes mellitus, Hyperuricaemia
Rare (≥1/10000, <1/1000): Depression, Depression aggravated, Aggressive tendencies, Anxiety, Mood alterations
Very Rare (≤1/10000): Abnormal behaviour, Psychotic disorder, Suicidal ideation, Suicide attempt, Suicide
Common (≥1/100, <1/10): Headache
Very Rare (≤1/10 000): Benign intracranial hypertension, Convulsions, Drowsiness, Dizziness
Very common (≥1/10): Blepharitis, Conjunctivitis, Dry eye, Eye irritation
Very Rare (≤1/10000): Blurred vision, Cataract, Colour blindness (colour vision deficiencies), Contact lens intolerance, Corneal opacity, Decreased night vision, Keratitis, Papilloedema (as sign of benign intracranial hypertension), Photophobia, Visual disturbances
Very Rare (≤1/10 000): Hearing impaired
Very Rare (≤1/10000): Vasculitis (for example Wegener’s granulomatosis, allergic vasculitis)
Common (≥1/100, <1/10): Epistaxis, Nasal dryness, Nasopharyngitis
Very Rare (≤1/10000): Bronchospasm (particularly in patients with asthma), Hoarseness
Very Rare (≤1/10000): Colitis, Ileitis, Dry throat, Gastrointestinal haemorrhage, haemorrhagic diarrhoea and inflammatory bowel disease, Nausea, Pancreatitis (see section 4.4 “Special warnings and special precautions for use”)
Very common (≥1/10): Transaminase increased (see section 4.4 “Special warnings and special precautions for use”)
Very Rare (≤1/10000): Hepatitis
Very common (≥1/10): Cheilitis, Dermatitis, Dry skin, Localised exfoliation, Pruritus, Rash erythematous, Skin fragility (risk of frictional trauma)
Rare (≥l/10000,<l/1000): Alopecia
Very Rare (≤1/10 000): Acne fulminans. Acne aggravated (acne flare), Erythema (facial), Exanthema, Hair disorders, Hirsutism, Nail dystrophy, Paronychia, Photosensitivity reaction, Pyogenic granuloma, Skin hyperpigmentation, Sweating increased
Frequency unknown*: Erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis.
Very common (≥1/10): Arthralgia, myalgia, back pain (particularly in children and adolescent patients)
Very Rare (≤1/10 000): Arthritis, Calcinosis (calcification of ligaments and tendons), Epiphyses premature fusion, Exostosis, (hyperostosis), Reduced bone density, Tendonitis
Frequency unknown*: Rhabdomyolysis
Very Rare (≤1/10 000): Glomerulonephritis
Frequency unknown*: Sexual dysfunction including erectile dysfunction and decreased libido, Gynaecomastia
Very Rare (≤1/10 000): Granulation tissue (increased formation of), Malaise
Very common (≥1/10): Blood triglycerides increased, High density lipoprotein decreased
Common (≥1/100, <1/10): Blood cholesterol increased, Blood glucose increased, Haematuria, Proteinuria
Very Rare (≤1/10000): Blood creatine phosphokinase increased
* cannot be estimated from the available data
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Not applicable.
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