VESANOID^®10 mg soft capsules

Active substance:

1 capsule contains 10 mg of tretinoin

Excipients:

1 capsule contains 107.92 mg of soya-bean oil.

The capsule-shell contains between 0.96 – 1.46 mg of sorbitol (E420).

For the full list of excipients, see section 6.1

Capsule, soft

Bi-coloured orange-yellow / reddish-brown capsules.

VESANOID (tretinoin) is indicated for induction of remission in acute promyelocytic leukaemia(APL; FAB classification AML-M3).

This treatment is intended for previously untreated patients as well as patients who relapse after a standard chemotherapy (anthracycline and cytosine arabinoside or equivalent therapies) or patients who are refractory to chemotherapy.

The association of tretinoin with chemotherapy increases the duration of survival and reduces the risk of relapse compared to chemotherapy alone.

A total daily dose of 45 mg/m² body surface divided in two equal doses is recommended for oral administration. This is approximately 8 capsules per adult dose.

Capsules should be swallowed together with water. Capsules should not be chewed. It is recommended to take the capsules with a meal or shortly thereafter.

There is limited safety and efficacy information on the use of tretinoin in children.

Paediatric patients can be treated with 45 mg/m² unless severe toxicity becomes apparent. Dose reduction should be particularly considered for children with intractable headache.

Treatment should be continued until complete remission has been achieved or up to a maximum of 90 days.

Due to limited information on patients with hepatic and/or renal insufficiency, the dose will be decreased to 25 mg/m² as a precautionary measure.

Full-dose anthracycline-based chemotherapy should be added to the tretinoin regimen as follows (see section 4.4):

• When the leucocyte count at start of therapy is greater than 5 x 10 ⁹/L, chemotherapy should be started together with tretinoin on day one.

• When the leucocyte count at start of therapy is less than 5 x 10 ⁹/L but rapidly increases during tretinoin therapy, chemotherapy should be immediately added to the tretinoin regimen if the leucocyte count reaches greater than 6 x 10 ⁹/L by day five, or greater than 10 x 10⁹/L by day ten, or greater than 15 x 10⁹/L by day 28.

• All other patients should receive chemotherapy immediately after complete remission is attained.

If chemotherapy is added to tretinoin because of hyperleucocytosis, it is not necessary to modify the dose of tretinoin.

After completion of tretinoin therapy and the first chemotherapy course, consolidation anthracycline-based chemotherapy should be given, for example, a further two courses at 4 to 6 week intervals.

In some patients the plasma levels of tretinoin may fall significantly in spite of continued administration.

Known allergy to tretinoin, retinoids or to any of the excipients.

Pregnancy (see section 4.6).

Lactation (see section 4.6 ).

Tetracyclines (see section 4.5).

Vitamin A (see section 4.5).

Vesanoid contains soya-bean oil, therefore Vesanoid is contraindicated in patients allergic to soya or peanut.

Tretinoin should be administered to patients with acute promyelocytic leukaemia only under the strict supervision of a physician who is experienced in the treatment of haematological / oncological diseases.

Supportive care appropriate for patients with acute promyelocytic leukaemia, for example prophylaxis for bleeding and prompt therapy for infection, should be maintained during therapy with tretinoin. The patient's haematologic profile, coagulation profile, liver function test results, and triglyceride and cholesterol levels should be monitored frequently.

During clinical trials hyperleucocytosis has been frequently observed (in 75% of the cases), sometimes associated with the “Retinoic Acid Syndrome”. Retinoic acid syndrome has been reported in many acute promyelocytic leukaemia patients (up to 25% in some centers) treated with tretinoin.

Retinoic acid syndrome is characterised by fever, dyspnoea, acute respiratory distress, pulmonary infiltrates, pleural and pericardial effusions, hypotension, oedema, weight gain, hepatic, renal and multi-organ failure.

Retinoic acid syndrome is frequently associated with hyperleucocytosis and may be fatal.

The incidence of the retinoic acid syndrome is diminished when full dose chemotherapy is added to the tretinoin regimen based on the white blood cell count. The current therapeutic treatment recommendations and method of administration are detailed in section 4.2.

Immediate treatment with dexamethasone (10 mg every 12 hours for up to maximum 3 days or until resolution of the symptoms) should be given, if the patient presents any symptom(s) or sign(s) of this syndrome.

In cases of moderate and severe retinoic acid syndrome, temporary interruption of Vesanoid therapy should be considered.

Vesanoid may cause pseudotumor cerebri. This condition should be treated according to standard medical practice. Temporary discontinuation of Vesanoid should be considered in patients not responding to treatment.

Sweet's syndrome or acute febrile neutrophilic dermatitis responded dramatically to corticosteroid treatment.

There is a risk of thrombosis (both venous and arterial) which may involve any organ system, during the first month of treatment (see section 4.8). Therefore, caution should be exercised when treating patients with the combination of Vesanoid and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin (see section 4.5).

Because hypercalcaemia may occur during therapy, serum calcium levels should be monitored.

Micro-dosed progesterone preparations (”minipill”) are an inadequate method of contraception during treatment with tretinoin (see section 4.6).

Vesanoid contains sorbitol, therefore patients with rare hereditary problems of fructose intolerance should not take Vesanoid.

Tetracyclines: systemic treatment with retinoids may cause elevation of the intracranial pressure. As tetracyclines may also cause elevation of the intracranial pressure, patients must not be treated with tretinoin and tetracyclines at the same time (see section 4.3).

Vitamin A: As with other retinoids, tretinoin must not be administered in combination with vitamin A because symptoms of hypervitaminosis A could be aggravated (see section 4.3).

The effect of food on the bioavailability of tretinoin has not been characterised. Since the bioavailability of retinoids, as a class, is known to increase in the presence of food, it is recommended that tretinoin be administered with a meal or shortly thereafter.

As tretinoin is metabolised by the hepatic P450 system, there is the potential for alteration of pharmacokinetics parameters in patients administered concomitant medications that are also inducers or inhibitors of this system. Medications that generally induce hepatic P450 enzymes include rifampicin, glucocorticoids, phenobarbital and pentobarbital. Medications that generally inhibit hepatic P450 enzymes include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and ciclosporin. There are no data to suggest that co-use with these medications increases or decreases either efficacy or toxicity of tretinoin.

Cases of fatal thrombotic complications have been reported rarely in patients concomitantly treated with all-trans retinoic acid and anti-fibrinolytic agents such as tranexamic acid, aminocaproic acid and aprotinin (see section 4.4). Therefore, caution should be exercised when administering all-trans retinoic acid concomitantly with these agents.

There are no data on a possible pharmacokinetic interaction between tretinoin and daunorubicin or AraC.

All the measures listed below should be considered in relationship to the severity of the disease and the urgency of the treatment.

Pregnancy: Vesanoid contains a retinoid similar to vitamin A. Therefore Vesanoid should not be used by women who are pregnant or likely to become pregnant. Tretinoin causes serious birth defects when administered during pregnancy. Its use is contraindicated in pregnant women and women who might become pregnant during the treatment with tretinoin and within one month after cessation of treatment, unless the benefit of tretinoin treatment outweighs the risk of foetal abnormalities due to the severity of the patient's condition and the urgency of treatment.

There is a very high risk for any exposed foetus that a deformed infant will result if pregnancy occurs while taking tretinoin, irrespective of the dose or duration of the treatment.

Therapy with tretinoin should only be started in female patients of child-bearing age if each of the following conditions is met:

• She is informed by her physician of the hazards of becoming pregnant during and one month after treatment with tretinoin.

• She is willing to comply with the mandatory effective contraception measures: to use a reliable contraception method without interruption during therapy and for one month after discontinuation of treatment with tretinoin (see section 4.4).

• Pregnancy tests must be performed at monthly intervals during therapy.

In spite of these precautions, should pregnancy occur during treatment with tretinoin or up to one month after its discontinuation, there is a high risk of severe malformation of the foetus, particularly when tretinoin is given during the first trimester of pregnancy.

Lactation: Nursing must be discontinued if therapy with tretinoin is initiated.

Vesanoid has minor or moderate influence on the ability to drive and use machines, particularly if patients are experiencing dizziness or severe headache.

In patients treated with the recommended daily doses of tretinoin the most frequent undesirable effects are consistent with the signs and symptoms of the hypervitaminosis A syndrome (as for other retinoids).

Retinoic acid syndrome has been reported in many acute promyelocytic leukaemia patients (up to 25% in some centres) treated with tretinoin. Retinoic acid syndrome is characterized by fever, dyspnoea, acute respiratory distress, pulmonary infiltrates, pleural and pericardial effusions, hypotension, oedema, weight gain, hepatic, renal and multi-organ failure. Retinoic acid syndrome is frequently associated with hyperleucocytosis and may be fatal. For prevention and treatment of retinoic acid syndrome see section 4.4.

In addition, the following adverse reactions have been reported in clinical studies and during the post-marketing period.

(“Frequency not known” corresponds to post marketing experience)

Infections and infestations:

Frequency not known: Necrotising fasciitis.

Blood and lymphatic system disorders:

Frequency not known: Thrombocythaemia, basophilia.

Metabolism and nutrition disorders:

Very common ( 1/10): Decreased appetite.

Frequency not known: Hypercalcaemia.

Psychiatric disorders:

Very common ( 1/10): Confusional state, anxiety, depression, insomnia.

Nervous system disorders:

Very common ( 1/10): Headache, intracranial pressure increased, benign intracranial hypertension, dizziness, paraesthesia.

Frequency not known: Cerebrovascular accident.

Eye disorders:

Very common ( 1/10): Visual disturbances, conjunctival disorders.

Ear and labyrinth disorders:

Very common ( 1/10): Hearing impaired.

Cardiac disorders:

Very common ( 1/10): Arrhythmia.

Frequency not known: Myocardial infarction.

Vascular disorders:

Very common ( 1/10):Flushing.

Frequency not known: Thrombosis, vasculitis.

Respiratory, thoracic and mediastinal disorders:

Very common ( 1/10): Respiratory failure, nasal dryness, asthma.

Gastrointestinal disorders:

Very common ( 1/10): Dry mouth, nausea, vomiting, abdominal pain, diarrhoea, constipation, pancreatitis, cheilitis.

Skin and subcutaneous tissue disorders:

Very common ( 1/10): Erythema, rash, pruritus, alopecia, hyperhidrosis.

Frequency not known: Erythema nodosum, acute febrile neutrophilic dermatosis.

Musculoskeletal and connective tissue disorders:

Very common ( 1/10): Bone pain.

Frequency not known: Myositis.

Renal and urinary disorders:

Frequency not known: Renal infarct.

Reproductive system and breast disorders:

Frequency not known: Genital ulceration.

General disorders and administration site conditions:

Very common ( 1/10): Chest pain, chills, malaise.

Investigations:

Very common ( 1/10): Blood triglyceride increased, blood creatinine increased, blood cholesterol increased, transaminases increased.

Frequency not known: Histamine level increased.

The decision to interrupt or continue therapy should be based on an eva luation of the benefit of the treatment versus the severity of the side-effects.

Teratogenicity: See section 4.6.

There is limited safety information on the use of tretinoin in children. There have been some reports of increased toxicity in children treated with tretinoin, particularly increased pseudotumor cerebri.

In case of overdose with all-trans retinoic acid, reversible signs of hyper-vitaminosis A (headache, nausea, vomiting, mucocutaneous symptoms) can appear.

The recommended dose in acute promyelocytic leukaemia is one-quarter of the maximum tolerated dose in solid tumor patients and below the maximum tolerated dose in children.

There is no specific treatment in the case of an overdose, however it is important that the patient be treated in a special haematological unit.

Pharmacotherapeutic group: Cytostatic-differentiating agent.

ATC code: L01XX14

Tretinoin is a natural metabolite of retinol and belongs to the class of retinoids, comprising natural and synthetic analogs.

In vitro studies with tretinoin have demonstrated induction of differentiation and inhibition of cell proliferation in transformed hemopoietic cell lines, including human myeloid leukaemia cell lines.

The mechanism of action in acute promyelocytic leukaemia is not known but it may be due to a modification in binding of tretinoin to a nuclear retinoic acid receptor (RAR) given that the α-receptor of retinoic acid is altered by fusion with a protein called PML.

Tretinoin is an endogenous metabolite of vitamin A which is normally present in plasma.

After oral administration, tretinoin is absorbed by the digestive tract and maximum plasma concentrations in healthy volunteers are attained after 3 hours.

There is a large inter-patient and intra-patient variation in plasma levels of tretinoin.

Tretinoin is extensively bound to plasma proteins. Following peak levels, plasma concentrations decline with a mean elimination half life of 0.7 hours. Plasma concentrations return to endogenous levels after 7 to 12 hours following a single 40 mg dose. No accumulation is seen after multiple doses and tretinoin is not retained in body tissues.

After an oral dose of radiolabelled tretinoin, about 60% of the radioactivity was excreted in urine and about 30% in faeces. The metabolites found in urine were formed by oxidation and glucuronidation.

During continuous administration a marked decrease in plasma concentration can occur, possibly due to cytochrome P-450 enzyme induction which increases clearance and decreases bioavailability after oral doses.

At present there are no data on a possible interaction between tretinoin and daunorubicin.

The requirement for dosage adjustment in patients with renal or hepatic insufficiency has not been investigated. As a precautionary measure, the dose will be decreased (see section 4.2).

Oral administration of tretinoin to animals indicated that the compound had very low acute toxicity in all species investigated.

In animal experimental tests it was shown that in all investigated species the acute toxicity of tretinoin administered orally is low. After a longer period of administration rats exhibit a dose- and time-dependent bone matrix dissolution, a decrease in erythrocyte count and toxic alterations in kidney and testes.

Dogs mainly exhibited disorders concerning spermatogenesis and hyperplasia of the bone marrow.

The major metabolites of tretinoin (4-oxo-tretinoin, isotretinoin and 4-oxo-isotretinoin) are less effective than tretinoin in inducing differentiation of human leukaemic cells (HL-60)

Subchronic and chronic toxicity studies in rats indicated that the no effect oral dose was at or below 1 mg/kg/day; in dogs, 30 mg/kg/day was associated with toxic effects including weight loss, dermatological and testicular changes.

Reproduction studies in animals have demonstrated the teratogenic activity of tretinoin.

No evidence of mutagenicity has been found.

Capsule contents:

Yellow beeswax

Hydrogenated soya-bean oil

Partially hydrogenated soya-bean oil

Soya-bean oil

Capsule shell:

Gelatin

Glycerol (E 422)

Karion 83: Sorbitol (E 420), Mannitol (E 421), Starch (maize)

Titanium dioxide (E 171)

Iron oxide yellow (E 172)

Iron oxide red (E 172)

Not applicable.

3 years

Bottles:

Do not store above 30°C.

Keep the bottle tightly closed in order to protect from moisture.

Keep the bottle in the outer carton in order to protect from light.

Blister packs:

Do not store above 30°C.

Keep the blisters in the outer carton in order to protect from light.

Amber glass bottles of 100 capsules.

PVC/PE/PVDC/Aluminium blister packs of 100 capsules.

Not all pack sizes may be marketed.

Use and handling: No special requirements.

Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.

Roche Products Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

PA 50/154/1

Date of first authorisation: 3^rd December 1996

Date of last renewal: 16^th August 2006

December 2008