Chemical formula: C₂₀H₂₈O₂ Molecular mass: 300.435 g/mol PubChem compound: 449171
Alitretinoin interacts in the following cases:
Alitretinoin may increase the exposure of CYP2C8 substrates; therefore co-administration with amiodarone (a CYP2C8 substrate with a long half-life and narrow therapeutic index) is not recommended. Caution should be used if alitretinoin is co-administered with other medications that are substrates for CYP2C8 (e.g. paclitaxel, rosiglitazone, repaglinide).
A reduction in dose to 10 mg should be considered when alitretinoin is co-administered with potent CYP2C9 inhibitors (e.g. fluconazole, miconazole, oxandrolone) or potent CYP2C8 inhibitors (e.g. gemfibrozil).
Alitretinoin is metabolized by cytochrome P450 (CYP) 2C9, CYP2C8, CYP3A4 and undergoes isomerisation.
Co-administration with CYP3A4 inhibitors such as ketoconazole increases the plasma level of alitretinoin and therefore dose reduction to 10 mg should be considered. The effects of other inhibitors of CYP3A4 have not been studied.
A 16% reduction of simvastatin plasma levels was observed when co-administered with alitretinoin.
Decreases of <25% in simvastatin and simvastatin acid plasma levels was observed when co-administered with alitretinoin.
Simvastatin did not affect the pharmacokinetics of alitretinoin.
Treatment with alitretinoin has been associated with dry eyes. The symptoms 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.
Treatment with other systemic retinoids has been associated with transient and reversible increases in liver transaminases. In the event of persistent clinically relevant elevation of transaminase levels, reduction of the dose or discontinuation of treatment should be considered.
Systemic retinoids, including alitretinoin, have been associated with inflammatory bowel disease (including regional ileitis) in patients without a history of intestinal disorders. If severe diarrhoea is observed diagnosis of IBD should be considered and alitretinoin should be discontinued immediately.
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 systemic retinoids, including alitretinoin. 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. Prior to initiation of alitretinoin and at each visit during therapy, patients should be asked about any psychiatric disorder, depression, or mood disturbance. Patients should stop alitretinoin if they develop depression, mood disturbance, psychosis, or aggression. However, discontinuation of alitretinoin 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.
Anaphylactic reactions have been rarely reported in systemic retinoids, 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.
Treatment with systemic retinoids has been associated with corneal opacities and keratitis. Decreased night vision has been observed in patients treated with alitretinoin. These effects usually resolve after discontinuation of therapy.
Myalgia, arthralgia and increased serum creatinine phosphokinase values have been observed in patients treated with alitretinoin.
Retinoids as a class have been associated with photosensitivity. There were no reports of photosensitivity associated with the use of Panretin gel in the clinical studies. However, patients must be cautioned to minimise exposure of treated areas to sunlight or other ultraviolet (UV) light.
The effects of UV light are enhanced by retinoid therapy. Therefore patients should avoid excessive exposure to sunlight and the unsupervised use of sun lamps. Where necessary a sun-protection product with a high protection factor of at least SPF 15 should be used.
Treatment with systemic retinoids, including alitretinoin, has been associated with the occurrence of benign intracranial hypertension, some of which involved concomitant use of tetracyclines. Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop signs of benign intracranial hypertension should discontinue alitretinoin immediately.
Alitretinoin should be discontinued if symptoms of pancreatitis occur.
Triglyceride levels in excess of 800 mg/dL (9 mmol/L) are sometimes associated with acute pancreatitis, which may be fatal.
Treatment with other systemic retinoids has been associated with bone changes including premature epiphyseal closure, hyperostosis, and calcification of tendons and ligaments.
Pregnancy is an absolute contraindication to treatment with alitretinoin. If pregnancy does occur in spite of the pregnancy prevention precautions during treatment with alitretinoin or in the month following discontinuation of therapy, there is a great risk of very severe and serious malformation of the foetus.
Alitretinoin is a retinoid and therefore is a potent teratogen. The foetal malformations associated with exposure to retinoids 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.
Alitretinoin is highly lipophilic, therefore the passage of alitretinoin into human milk is very likely. Due to the potential risk for the exposed child, the use of alitretinoin is contraindicated in nursing mothers.
It is not known whether alitretinoin gel is excreted in human milk. Based on the plasma concentrations observed in patients, milk concentrations of 9-cis-retinoic acid probably pose a low risk for the infant. However, because of the potential for undesirable effects from alitretinoin gel in infants being breast-fed, mothers must discontinue breast-feeding prior to using the medicinal product and not initiate breast-feeding while using the medicinal product. Care should be taken not to bring the neonate into skin contact with areas to which alitretinoin has been recently applied. It is recommended that HIV-infected mothers do not breast-feed their children to exclude the risk of transmission of the virus.
Women of child-bearing potential must use effective contraception during, and up to one month after cessation of treatment.
Men using alitretinoin should take precautions to ensure that their female partners do not become pregnant.
Small amounts of alitretinoin (above endogenous levels) have been detected in the semen of some healthy volunteers receiving 40 mg of alitretinoin and drug accumulation in semen is not expected. Assuming complete vaginal absorption, these amounts, would have a negligible effect on the endogenous plasma levels of the female partner or a foetus and therefore do not appear to pose a risk to the foetus if the partner is pregnant. Based on non-clinical findings, male fertility may be compromised by treatment with alitretinoin.
Cutaneous use is unlikely to have an effect on the ability to drive and use machines.
Adverse events associated with the use of alitretinoin gel in AIDS-related KS occurred almost exclusively at the site of application. The dermal toxicity typically begins as erythema; with continued application of alitretinoin gel erythema may increase and oedema may develop. Dermal toxicity may become treatment-limiting, with intense erythema, oedema, and vesiculation. When applying alitretinoin gel, 69.1% of patients experienced adverse drug reactions at the application site.
The following list shows the following application-site drug-related adverse reactions were reported during clinical studies in patients with KS. The frequency of adverse events are classified as very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1,000 to <1/100). Adverse events include verbatim terms in parentheses.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse reactions reported in patients in clinical trials:
Uncommon: Lymphadenopathy
Common: Paraesthesia (stinging, tingling)
Common: Haemorrhage (bleeding at or around lesions), Oedema (oedema, swelling, inflammation), Peripheral oedema
Uncommon: Phlebitis, Vascular disorder
Very common: Skin disorder (cracking, scab, crusting, excoriation, drainage, oozing), Rash (erythema, redness, scaling, irritation, dermatitis), Pruritus (itching, pruritus)
Common: Skin ulcer, Serous drainage, Exfoliative dermatitis (flaking, peeling, desquamation, exfoliation), Skin discoloration (brown discoloration, surrounding hyperpigmentation, paler), Dry skin
Uncommon: Cellulitis, Vesiculobullous rash, Maculopapular rash, Allergic reaction
Very common: Pain (burning, pain, soreness)
Uncommon: Infection, including bacterial infection
The safety of alitretinoin gel has been assessed in clinical studies of more than 469 patients with AIDS-related KS, 439 of whom were treated with an alitretinoin concentration of 0.1%.
The incidence of drug-related skin disorder, skin ulcer, pain and rash appeared to be greater in patients applying alitretinoin gel four times daily than in those applying it less frequently. However, the incidence of other equally common drug-related adverse events such as pruritus, oedema, exfoliative dermatitis and dry skin did not appear to increase as a function of the frequency of application.
The incidence of mild/moderate rash (all events regardless of causality) was less in patients treated for less than 16 weeks than in those treated for 16 weeks or more (mild, 33% v 63%; moderate, 29% v 43%). The incidence of severe skin rash was independent of the duration of treatment (10% in both cases).
Local dermal toxicity associated with alitretinoin gel therapy generally resolved with treatment adjustment or discontinuation.
Only two serious adverse reactions were reported (sepsis and cellulitis in the same patient).
The adverse events seen with alitretinoin gel are similar to those seen with other topical retinoids. It is unlikely that the undesirable systemic side effects associated with oral retinoids will be observed with the use of alitretinoin gel because the range and frequency of quantifiable 9-cis-retinoic acid plasma levels concentrations after application of the medicinal product were comparable to the range and frequency of quantifiable plasma concentrations of circulating, naturally occurring 9-cis-retinoic acid in untreated individuals.
The safety and efficacy of alitretinoin in patients with severe chronic hand eczema (CHE) unresponsive to treatment with potent topical corticosteroids has been evaluated in two randomised, double blind, placebo-controlled clinical studies.
The most frequent adverse drug reactions (ADRs) observed under alitretinoin therapy are headache (30 mg: 23.9%; 10 mg: 10.8%), erythema (30 mg: 5.5%; 10 mg: 1.7%), nausea (30 mg: 5.1%; 10 mg: 2.4%), flushing (30 mg: 5.9%, 10 mg: 1.6%), and laboratory changes consisting of increased levels of triglycerides (30 mg: 35.4%; 10 mg: 17.0%), increased cholesterol (30 mg: 27.8%; 10 mg: 16.7%), decreased levels of thyroid stimulating hormone (TSH, 30 mg: 8.4%, 10 mg: 6.0%) and decreased levels of free T4 (30 mg: 10.5%; 10 mg: 2.9%). These reversible ADRs are dose dependent and may therefore be alleviated by dose reduction.
Very common (≥1/10)
Common (≥1/100 <1/10)
Uncommon (≥1/1000, <1/100)
Rare (≥1/10,000 <1/1000)
Very Rare (<1/10000)
Unknown
Common: Anaemia, increased iron binding capacity, monocytes decreased; thrombocytes increased
Unknown: Anaphylactic reactions, hypersensitivity
Common: TSH decreased, free T4 decreased
Rare: Depression, depression aggravated, aggressive tendencies, anxiety, mood alterations
Very Rare: Suicide, suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour
Very common: Headache
Common: Dizziness
Rare: Benign intracranial hypertension
Common: Conjunctivitis, dry eye, eye irritation
Uncommon: Blurred vision, cataract
Unknown: Decreased night vision
Common: Tinnitus
Common: Flushing, hypertension
Rare: Vasculitis
Uncommon: Epistaxis
Common: Nausea, dry mouth, vomiting
Uncommon: Dyspepsia
Unknown: Inflammatory bowel disease
Common: Transaminase increased1
Common: Dry skin, dry lips, cheileitis, eczema1, dermatitis1, erythema, alopecia
Uncommon: Pruritus, rash, skin exfoliation, asteatotic eczema
Rare: Nail disorders, photosensitivity reaction, hair texture changes
Common: Arthralgia1, myalgia1
Uncommon: Exostosis, (hyperostosis), ankylosing spondylitis
Common: Fatigue
Peripheral oedema
Very common: Hypertriglyceridemia, high density lipoprotein decreased, hypercholesterolemia
Common: Blood creatinine phosphokinase increased
1 The overall incidence of adverse events was not higher than those observed in the corresponding placebo group.
The following adverse events have not been observed in clinical trials with alitretinoin, but have been observed with other retinoids: diabetes mellitus, colour blindness (colour vision deficiencies), and contact lens intolerance.
Changes in bone mineralization and extra-osseous calcifications have been associated with systemic retinoid treatment. In clinical studies with alitretinoin, degenerative changes of the spine and ligamentous calcifications were frequent findings in patients with chronic hand eczema before treatment (baseline), with minor progression in a small number of patients during treatment. These observations were consistent with age dependent degenerative changes. Assessments of bone density (DXA) did not indicate a dose dependent effect on bone mineralization.
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