Tretinoin

Tretinoin is all-trans-retinoic acid, a natural metabolite of retinol (vitamin A) and a member of the retinoid class. The cream acts locally in the skin, while the capsules act on leukaemic cells, so the two forms are described separately where they differ.

Mechanism of Action

• Receptor binding: tretinoin is believed to bind to and activate the nuclear retinoic acid receptors (RAR-α, -β and -γ) and the retinoid X receptors (RXR). These receptors regulate genes that control cell differentiation and proliferation. The exact mechanism in skin disease and in leukaemia has not been fully established.
• Acne (cream): tretinoin appears to increase mitosis and turnover of epidermal cells, giving a less cohesive horny layer that sheds more easily. This helps clear existing comedones and may stop new ones forming; faster renewal of the follicular epithelium is thought to prevent keratin plugs. It has also been described as suppressing keratin synthesis.
• Acute promyelocytic leukaemia (capsules): in APL the RAR-α gene is fused with the PML gene, and the resulting PML/RARα protein blocks the maturation of promyelocytes. At pharmacological doses tretinoin induces proteolytic degradation of this fusion protein; transcriptomic analyses suggest it may also remove PML/RARα from gene promoters, restoring normal RAR-α function and lifting the block on differentiation.
• Cell effects: in vitro, tretinoin induces differentiation and inhibits proliferation in transformed haematopoietic cell lines, including human myeloid leukaemia lines. In patients, together with cytotoxic chemotherapy or arsenic trioxide, it inhibits proliferation and induces differentiation of promyelocytic blasts, giving high complete remission rates and low relapse rates.
• Clinical evidence in APL: in the APL0406 study, 276 adults aged 18 to 71 with newly diagnosed APL that was not high risk received tretinoin with arsenic trioxide or tretinoin with chemotherapy. Complete remission was reached in 100% and 97% respectively. At 50 months, event-free survival was 97.3% versus 80%, cumulative incidence of relapse 1.9% versus 13.9% and overall survival 99.2% versus 92.6%.

Pharmacokinetics

• Absorption (cream): percutaneous absorption of tretinoin from an emollient cream was below 2% in healthy men after a single application and after daily applications, and physiological levels of tretinoin and its main metabolites were unchanged. The cream penetrates both the epidermis and the dermis.
• Absorption (capsules): tretinoin is absorbed from the gut and peaks in plasma within about 3 hours in healthy volunteers. Levels vary widely between patients and within the same patient. Absolute oral bioavailability is about 50%, and food increases the absorption of retinoids.
• Distribution: very highly bound to plasma proteins (above 95%, mainly albumin). Tretinoin is an endogenous metabolite of vitamin A and is normally present in plasma. The mean elimination half-life is 0.7 hours; after a single 40 mg dose, plasma levels return to endogenous values within 7 to 12 hours. There is no tissue accumulation with repeated doses.
• Metabolism: tretinoin is metabolised by CYP26A1 as well as CYP3A4, so CYP26A1 inhibitors such as ketoconazole could raise exposure. It is isomerised to 13-cis-retinoic acid and oxidised to 4-oxo metabolites, which have longer half-lives and may accumulate somewhat. With repeated oral dosing, plasma concentrations can fall markedly, possibly because induction of cytochrome P450 raises clearance and lowers bioavailability.
• Elimination: metabolites formed by oxidation and glucuronidation are excreted mainly by the kidneys (about 60%); about 30% is excreted in the faeces.
• Renal and hepatic impairment: the need for dose adjustment has not been studied. As a precaution, the oral dose is reduced to 25 mg/m² a day.

• Acne vulgaris (Neocare 4 mg/g cream): topical treatment of non-inflammatory lesions (comedones) and inflammatory lesions (pustules and papules) in mild to moderate acne vulgaris.
• Acute promyelocytic leukaemia (Vesanoid 10 mg capsules): in combination with arsenic trioxide or chemotherapy, for patients with newly diagnosed APL, or APL that has relapsed or is refractory to chemotherapy.
• Genetic confirmation: the SmPC makes genetic confirmation of APL mandatory, shown by the t(15;17) translocation in the blasts (karyotype or FISH) or by the PML/RARα fusion (PCR).
• Early start: because APL carries a high risk of early death from a haemorrhagic syndrome, current guidance calls for starting tretinoin as soon as possible on morphological suspicion alone.
• Choice of strategy: tretinoin with arsenic trioxide is an effective option in newly diagnosed patients with low or intermediate risk. The relapse risk is classified before treatment from the white cell and platelet counts (Sanz score): high risk is white cells above 10 × 10⁹/L; intermediate risk is white cells of 10 × 10⁹/L or below with platelets of 40 × 10⁹/L or below; low risk is white cells of 10 × 10⁹/L or below with platelets above 40 × 10⁹/L.

Neocare cream

• Hypersensitivity to tretinoin or to any of the excipients.
• Pregnancy.
• Women planning to become pregnant.
• Personal or family history of cutaneous epithelioma.
• Application to skin with eczema, abrasions or wounds. Use on eczema or sunburn can cause severe local erythema, inflammation, itching, burning, blisters, crusts and peeling, and severe irritation of eczematous skin has been reported with tretinoin.

Vesanoid capsules

• Hypersensitivity to tretinoin, to other retinoids, to soya or peanuts, or to any of the excipients.
• Breastfeeding. The SmPC also states that tretinoin is teratogenic; see the pregnancy conditions in Special Instructions.
• Combination with vitamin A, tetracyclines or other retinoids.

Neocare cream: the most frequently reported reactions are local: dry or scaling skin, burning, itching, stinging, severe local erythema, oedema, blisters, scabs and transient hypo- or hyperpigmentation. They were generally mild to moderate, well tolerated and settled when applications were reduced or temporarily stopped. Most appeared early in treatment, except dryness and peeling, which persisted but generally eased as treatment went on. Increased sensitivity to sunlight and other UVB sources has been observed. The SmPC gives no frequency categories.

Vesanoid capsules: at the recommended daily doses, the most frequent reactions match the signs and symptoms of hypervitaminosis A, as with other retinoids. The SmPC table, drawn from pivotal studies and post-marketing reports, lists the following.

Very common (≥1/10): decreased appetite, confusional state, anxiety, depression, insomnia, headache, raised intracranial pressure, pseudotumour cerebri, dizziness, paraesthesia, visual disturbances, conjunctival disorders, hearing impairment, arrhythmia, flushing, respiratory insufficiency, nasal dryness, asthma, dry mouth, nausea, vomiting, abdominal pain, diarrhoea, constipation, pancreatitis, cheilitis, erythema, rash, pruritus, alopecia, hyperhidrosis, bone pain, chest pain, chills, malaise, raised triglycerides, raised creatinine, raised cholesterol, raised transaminases.

Not known: necrotising fasciitis, thrombocytosis, leucocytosis, basophilia (with or without symptomatic hyperhistaminaemia), hypercalcaemia, stroke, myocardial infarction, myocarditis, pericarditis, arterial thrombosis, venous thrombosis at various sites (for example stroke, myocardial infarction, renal infarction), vasculitis, erythema nodosum, acute febrile neutrophilic dermatosis (Sweet’s syndrome), myositis, renal infarction, genital ulceration, increased histamine.

Differentiation syndrome (formerly the retinoic acid syndrome) can be fatal: fever, dyspnoea, acute respiratory distress, pulmonary infiltrates, pleural and pericardial effusions, hypotension, oedema, weight gain, and renal, hepatic and multi-organ failure, often with hyperleucocytosis. Leucocytosis and hyperleucocytosis are common in tretinoin-treated APL but mostly occur without differentiation syndrome. In clinical studies, hyperleucocytosis, QTc prolongation and liver toxicity were more frequent with tretinoin plus arsenic trioxide than with tretinoin plus chemotherapy. Safety data in children are limited; some cases of increased toxicity, especially pseudotumour cerebri, have been reported. Continuing or stopping treatment is decided by weighing its benefit against the severity of the reaction.

Neocare cream

• Photosensitising medicines (such as thiazides, tetracyclines, fluoroquinolones, phenothiazines and sulfonamides): the cream must not be used with them, because toxicity may increase.
• Other skin products: use with caution alongside other topical medicines, other anti-acne or exfoliating preparations, and anything containing alcohol; also with abrasive, drying or peeling products such as soaps, shampoos, cleansers, cosmetics and astringents (especially those containing alcohol), medicated shampoos or soaps, permanent-wave liquids, electrolysis, and depilatory creams or waxes, unless done under medical supervision.
• Cosmetics: they may be used during treatment but not applied to the skin at the same time as the cream.

Vesanoid capsules

• Other retinoids (contraindicated): risk of symptoms of hypervitaminosis A.
• Vitamin A (contraindicated): risk of hypervitaminosis A symptoms at daily doses above 10,000 IU.
• Tetracyclines (contraindicated): risk of raised intracranial pressure (pseudotumour cerebri).
• Cytochrome P450 inducers and inhibitors: tretinoin is metabolised in the liver by cytochrome P450, so its pharmacokinetics may change. Typical inducers include rifampicin, glucocorticoids, phenobarbital and pentobarbital; typical inhibitors include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and ciclosporin.
• Azole antifungals and other strong CYP3A4 inhibitors: increased tretinoin toxicity (for example pseudotumour cerebri and hypercalcaemia) has been reported with fluconazole, voriconazole and posaconazole, apparently through CYP3A4. Protease inhibitors and macrolides such as clarithromycin may do the same. Consider reducing the tretinoin dose if needed.
• Antifibrinolytics (tranexamic acid, aminocaproic acid, aprotinin): fatal thrombotic complications have rarely been reported with tretinoin, so take particular care.
• Chemotherapy: there are no data on a pharmacokinetic interaction with daunorubicin, idarubicin or cytarabine.
• Food: take the capsules during or just after a meal, because food increases the bioavailability of retinoids.

The two forms are used differently. Neocare cream is applied to the skin by the patient as prescribed. Tretinoin capsules are given to patients with APL only under the close supervision of a physician experienced in haematological or oncological disease; in France the capsules are subject to hospital prescription (see Pharmacy Dispensing Conditions).

Neocare 4 mg/g Cream

• Strength: the dose is prescribed according to skin type and the severity of the acne. The SmPC recommends starting with the lowest strength (0.1 mg/g) and, according to the patient’s response, increasing gradually to 0.25 and 0.5 mg/g, finishing with 4 mg/g.
• Application: wash the skin with water and a mild soap and let it dry without rubbing for at least 20 to 30 minutes. Spread enough cream to cover only the affected area, twice a day; the amount and number of applications are adjusted to the individual.
• Avoid: contact with the eyes, eyelids, corners of the nose and mouth, and other mucous membranes.
• Expected effects: transient itching and a feeling of warmth may occur. More frequent application or large amounts do not improve the result and can cause marked irritation, such as erythema, itching and peeling.
• Cosmetics: they may be used during treatment but not applied to the skin at the same time.

Vesanoid 10 mg Capsules

• How to take: swallow the capsules whole with water; do not chew them. Take them during a meal or shortly after.
• Dose: for all phases of treatment, 45 mg/m² of body surface area a day, divided into two equal oral doses, in adult and elderly patients. This is about 8 capsules a day (each capsule contains 10 mg).
• Induction: continued until complete remission, or for 90 days at most.
• Consolidation: after induction, tretinoin is combined with arsenic trioxide or with an anthracycline-based chemotherapy protocol, at the same dose of 45 mg/m² a day in two equal doses. Several consolidation cycles are given, and current guidance recommends tretinoin-free windows after remission and between consolidation cycles.
• Maintenance: if used, the same dose, in a schedule with drug-free windows (pulsed treatment) as for consolidation.
• High relapse risk (Sanz score): one option is tretinoin, arsenic trioxide and anthracycline chemotherapy together for induction, followed by consolidation with tretinoin and arsenic trioxide.
• Hyperleucocytosis: patients may receive additional chemotherapy from the start of induction.
• Local practice: clinical practice varies within the EU and between national centres, so national and local guidelines and protocols should be taken into account.

Dose Adjustments (Capsules)

• Severe differentiation syndrome: consider interrupting tretinoin temporarily. It may need to be suspended during the initial acute symptomatic period and can be resumed when the symptoms disappear.
• Raised intracranial pressure or pseudotumour cerebri: reduce the tretinoin dose.

Special Populations

• Cream, elderly and children: safety and efficacy have not been established.
• Capsules, elderly: the same dose as for adults, 45 mg/m² a day.
• Capsules, hepatic or renal impairment: data are limited, so as a precaution the dose is reduced to 25 mg/m² a day.
• Capsules, children: data on safety and efficacy are limited. The schedule is the same as for adults and the optimal paediatric dose has not been established. To limit toxicity the daily dose may be reduced to 25 mg/m², and a reduction should be considered in particular if the child has symptoms of toxicity such as refractory headache.

Pregnancy Test and Contraception Condition (Capsules)

Tretinoin is a retinoid and is teratogenic. Teratogenic effects have been seen in humans with this class of medicine. Data on tretinoin in pregnant women are limited, but there is a high risk of severe foetal malformations, especially when it is given in the first trimester. According to the SmPC, treatment of a woman of childbearing potential can be considered only if all of the following conditions are met:

• the prescriber has told her of the risks if she becomes pregnant during treatment or in the month after stopping;
• she accepts the mandatory contraception: an effective method used without interruption throughout treatment and for one month after it ends;
• a pregnancy test is done before treatment and repeated every month during treatment.

Micro-dosed progestogens (mini-pills) may be an unsuitable method of contraception during tretinoin treatment. Vesanoid must not be used in pregnancy, particularly in the first trimester, nor in a woman of childbearing potential who is not using contraception, unless her clinical situation (the severity of her condition and the urgency of starting treatment) justifies tretinoin. If it is given in early pregnancy, the patient must be warned of the risk of teratogenic effects and severe foetal malformations. These measures are weighed against the severity of the disease and the urgency of treatment.

Pregnancy, Breastfeeding and Fertility

• Cream, pregnancy: Neocare is contraindicated in pregnancy and in women planning a pregnancy. If it is used during pregnancy, or the patient becomes pregnant while using it, treatment must be stopped. Oral retinoids are linked to congenital anomalies; topical retinoids are generally assumed to give low systemic exposure when used as the SmPC directs, but individual factors such as a damaged skin barrier or excessive use can raise it.
• Cream, breastfeeding: it is not known whether tretinoin passes into breast milk, although no problems have been described in humans. It is given to breastfeeding women only if the therapeutic benefit justifies the possible risks.
• Capsules, breastfeeding: breastfeeding must be stopped if tretinoin treatment is started, and the capsules are contraindicated in breastfeeding women.
• Capsules, fertility: no human data are available.

Skin Reactions and Sun Protection (Cream)

• Irritation: it is linked to the effect of the medicine and eases when applications are spaced out. Acne may seem to worsen in the first weeks; this is normal and reflects accelerated clearing of microcysts forming deep in the skin. If irritation is persistent or severe, the patient should stop completely and consult a doctor if needed.
• Where not to apply: eyes, eyelids, corners of the nose and mouth and other mucous membranes; skin with eczema, abrasions, wounds or sunburn; and infected areas. Do not let cream collect in skin folds. Irritation is more likely on sensitive areas such as the neck and forearms, where applications should be less frequent. If the skin is irritated, wait until it has recovered fully before starting.
• Other irritants: take care with other medicines that may cause local irritation, especially abrasive, drying or peeling ones. Wind, cold and low humidity can also irritate treated skin and dry it further.
• Sun: treated areas must not be exposed to the sun (even when cloudy) or to UVA lamps; sunscreens, moisturisers and suitable clothing should be used. Patients with sunburn should not use the cream until fully recovered. People who are exposed to a lot of sun at work, or who are inherently sun-sensitive, need special precautions.
• Not established: efficacy in elderly people and in people with moderately to heavily pigmented skin.

Supervision and Supportive Care (Capsules)

Tretinoin is given to APL patients only under the close supervision of a physician experienced in treating haematological or oncological disease. Supportive care for APL, such as bleeding prevention and prompt control of infection, continues throughout treatment. Blood counts, coagulation parameters, liver function tests, triglycerides and cholesterol are checked frequently. The coagulopathy of APL is treated with platelet transfusions to keep platelets above 30 to 50 × 10⁹/L, and with fresh frozen plasma or fibrinogen to keep fibrinogen above 100 to 150 mg/dL. These values are checked daily, and symptomatic treatment continues through the whole induction phase until the clinical and laboratory signs of coagulopathy have gone.

Differentiation Syndrome (Capsules)

Differentiation syndrome has been reported in many APL patients treated with tretinoin (about 26% in some trials) or with tretinoin plus arsenic trioxide, and it can be fatal. It is characterised by fever, dyspnoea, acute respiratory distress, pulmonary infiltrates, hypotension, pleural and pericardial effusions, peripheral oedema and weight gain, and can progress to respiratory, hepatic, renal and multi-organ failure. It is often linked to hyperleucocytosis. A high body mass index predicts the syndrome, so these patients need close monitoring of respiratory function, urine output and creatinine. At the first clinical signs, dexamethasone 10 mg intravenously every 12 hours is started at once and given for at least 3 days or until the symptoms resolve. In severe cases, a temporary interruption of tretinoin should be considered.

Hyperleucocytosis, Intracranial Pressure and Children (Capsules)

• Hyperleucocytosis: patients are treated with full-dose anthracycline-based chemotherapy; immediate treatment is recommended when the white cell count is ≥ 5 × 10⁹/L at diagnosis or at any time during treatment. In patients on tretinoin with arsenic trioxide, hydroxycarbamide should be considered to keep the white cell count below 10,000/µL.
• Pseudotumour cerebri: tretinoin can cause raised intracranial pressure or pseudotumour cerebri (headache, papilloedema, diplopia and possibly altered consciousness). Other medicines known to cause it can add to the risk. The tretinoin dose is reduced, and diuretics (acetazolamide), corticosteroids and/or analgesics are given.
• Children: pseudotumour cerebri is more frequent in children than in adults, and trial data showed a lower incidence with a reduced tretinoin dose without loss of results.

Other Warnings (Capsules)

• QTc prolongation: seen when tretinoin is combined with arsenic trioxide, with a risk of life-threatening torsades de pointes. ECG monitoring before and during treatment is recommended, especially in patients with risk factors.
• Hepatotoxicity: increased with tretinoin plus arsenic trioxide, mainly during induction, as raised transaminases. The liver injury is reversible when arsenic trioxide and/or tretinoin is stopped.
• Mental health: depression, worsened depression, anxiety and mood changes have been reported with systemic retinoids, including tretinoin. Take particular care in patients with a history of depression and watch for signs; telling family and friends can help to spot deterioration.
• Thrombosis and calcium: there is a risk of venous and arterial thrombosis, in any organ, during the first month of treatment, so take particular care with antifibrinolytic medicines. Hypercalcaemia can occur, so serum calcium is monitored.
• Sweet’s syndrome: cases of acute febrile neutrophilic dermatosis have responded particularly well to corticosteroids.

Excipients

• Cream: cetyl alcohol (20 mg/g) can cause local skin reactions such as contact dermatitis; propylene glycol (50 mg/g, 5%) can irritate the skin; butylhydroxytoluene (E321) can cause local skin reactions or irritate the eyes and mucous membranes; the sodium salts of methyl and propyl parahydroxybenzoate may cause allergic reactions, possibly delayed.
• Capsules: each capsule contains 107.92 mg soya oil, 1.93 to 2.94 mg sorbitol and less than 1 mmol (23 mg) sodium, so it is essentially sodium-free. The capsules are contraindicated in people allergic to soya or peanuts.

Effect on Driving

• Cream: the influence on the ability to drive and use machines is not known.
• Capsules: minor to moderate influence, especially in patients who are prone to dizziness or severe headache.

• Neocare cream: no special storage conditions. Close the container tightly after use. It is supplied in an aluminium tube holding 20 g of cream.
• Vesanoid capsules: store at a temperature not above 30 °C. Keep the bottle tightly closed and protected from moisture, and keep it in the outer carton to protect it from light.

Neither form needs refrigeration, so no cold chain is required.

• Neocare cream: 5 years.
• Vesanoid capsules: 3 years.

Do not use after the expiry date on the pack.

Prescription only (Rx).

• Neocare cream: applied by the patient, so it is supplied to the patient on prescription.
• Vesanoid capsules: in France a medicinal product subject to hospital prescription, with prescription restricted to specialists in oncology or haematology or to doctors competent in cancer care. The SmPC describes it as a medicine requiring special monitoring during treatment and allows tretinoin to be given to APL patients only under the close supervision of a physician experienced in haematological or oncological disease. The capsules are swallowed by the patient, so they are supplied to the patient or to the treating hospital or clinic on prescription.
• Pregnancy-test condition for the capsules: in a woman of childbearing potential, treatment is possible only if the prescriber has told her of the risks of pregnancy during treatment and in the month after it, she accepts mandatory effective contraception without interruption during treatment and for one month after it, and a pregnancy test is done before treatment and repeated every month during treatment.