Consumer medicine information

Vesanoid

Tretinoin

BRAND INFORMATION

Brand name

Vesanoid

Active ingredient

Tretinoin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Vesanoid.

What is in this leaflet

This leaflet answers some common questions about VESANOID capsules.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking VESANOID against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What VESANOID is used for

VESANOID contains the active ingredient called tretinoin or retinoic acid.

VESANOID belongs to a group of medicines called chemotherapeutic agents which works by stopping or slowing the growth of cancer-causing cells.

It is specially developed to target cancer cells rather than normal, healthy cells.

VESANOID belongs to a class of drugs known as retinoids, which are very similar to Vitamin A.

VESANOID is given to people who have acute promyelocytic leukaemia (APL). This is a disease which affects the way the myelocytes grow. Myelocytes are large cells in your bone marrow from which leucocytes (white blood cells) develop. VESANOID is thought to work by stopping the growth of APL cells. VESANOID may be used whether or not you have had chemotherapy before.

Your doctor may have prescribed VESANOID for another purpose.

Ask your doctor if you have any questions about why VESANOID has been prescribed for you. This medicine is available only with a doctor’s prescription.

Before you take VESANOID

When you must not take it

Do not take VESANOID if:

• you are pregnant, or within one month before you intend to become pregnant. If you fall pregnant while taking VESANOID there is an extremely high risk of having a baby that is severely deformed. You must use effective contraception for one month before, during and one month after treatment.
• you are breastfeeding.
Breastfeeding must stop before treatment begins. Do not breastfeed while taking VESANOID.
  • you have an allergy to VESANOID, Vitamin A, other retinoids or any ingredients listed at the end of this leaflet.
  • you are taking tetracycline antibiotics (such as Doryx®, Vibramycin®, Achromycin®, Tetrex®, Minomycin®).
  • you are taking a low-dose progestogen oral contraceptive (also called the “mini-pill”).
  • you are taking vitamin A, or preparations containing vitamin A.
  • the packaging is torn or shows signs of tampering.
  • the expiry date (EXP) printed on the pack has passed. If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure if you should be taking VESANOID, talk to your doctor.

Use in Children

There is limited information available on the use of VESANOID in children.

Before you start to take it

You must tell your doctor if:

  1. you are pregnant or intend to become pregnant
  2. you are breastfeeding
  3. you are allergic to any other medicines, foods, dyes or preservatives
  4. you have ever had any mental health problems including depression, aggressive tendencies or mood changes. This is because taking VESANOID may affect your mood.
  5. you have any other health problems including:
  • high fat levels in your blood
  • liver or kidney disease
  • other illnesses
  • you develop fever or shortness of breath or difficulties in breathing, as these can be signs of “Retinoic Acid Syndrome” in APL.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you have bought from a pharmacy, supermarket or health food shop.

Some medicines may interfere with VESANOID. These include:

  • some medicines used to treat acne
  • progestogen oral contraceptive
  • vitamin A or any other vitamin preparations
  • some antibiotics (such as doxycycline, erythromycin, minocycline, rifampicin, tetracycline)
  • medicines that help to reduce or prevent bleeding (antifibrinolytic agents)
  • some antifungals (such as fluconazole, ketoconazole)
  • some medicines used to treat heart disease (such as diltiazem, verapamil)
  • some anticonvulsants (such as phenobarbitone)
  • glucocorticoids
  • some immunosuppresants (such as cyclosporine)
  • some medicines used for stomach ulcers (such as cimetidine).

These medicines may be affected by VESANOID, or may affect how well it works. You may need to take different amounts of your medicine or you may need to take different medicines. Your doctor will advise you.

Your doctor or pharmacist may have more information on medicines to avoid or to be careful with while taking VESANOID.

Ask your doctor or pharmacist if you are not sure about this list of medicines.

How to take VESANOID

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

How much to take

Your doctor will tell you how many VESANOID capsules to take each day.

The dose is usually 8 capsules per day split into two equal doses. This depends on your condition and your weight and whether or not you are taking any other medicines.

How to take it

Capsules should be swallowed whole with a glass of water.

Do not open the capsules and do not take any capsules that are damaged.

When to take it

Take VESANOID during or immediately after a meal, at about the same time each day.

Taking your capsules at the same time each day will have the best effect. It will also help you remember when to take the capsules.

How long to take it

Continue taking VESANOID until your doctor tells you to stop. This is usually 30 to 120 days, until the APL completely disappears. After this, you will receive a different course of chemotherapy.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking it as you would normally.

Do not take a double dose to make up for one you have missed. This may increase the chance of you getting an unwanted side effect.

If you have forgotten to take a dose of VESANOID, contact your doctor.

If you are not sure what to do, ask your doctor or pharmacist.

In case of an overdose

Immediately telephone your doctor or pharmacist or Poisons Information Centre (Australia: telephone 13 11 26, New Zealand: telephone 0800 POISON or 0800 764 766) for advice or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much VESANOID. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers for these places handy.

While you are taking VESANOID

Things you must do

Tell all doctors, dentists and pharmacists who are treating you that you are taking VESANOID.

You must use strict birth control for at least 1 month before you start VESANOID and for the whole time you are taking VESANOID and for at least 1 month after you finish taking VESANOID.

Stop taking VESANOID immediately and tell your doctor if you do become pregnant while you are taking VESANOID.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Be sure to keep all of your appointments with your doctor so that your progress can be checked. Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and detect any unwanted side effects.

Mental health problems You may not notice some changes in your mood and behaviour and so it is very important that you tell your friends and family that this medicine could affect your mood and behaviour. They may notice these changes and help you identify any problems that you need to talk to your doctor about.

Things you must not do

Do not stop taking VESANOID or lower the dose without first checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays.

Do not give VESANOID to anyone else even if their symptoms seem similar to yours.

Do not use VESANOID to treat any other complaints unless your doctor says to.

Do not take any other medicines whether they require a prescription or not without first telling your doctor.

Things to be careful of

Your ability to drive cars or operate machinery may be impaired particularly if you experience dizziness or severe headache. Disturbed night vision and other visual disturbances may occur. Patients should be sure they do not have these conditions before they drive a car or operate machinery.

Wearing contact lenses during treatment with VESANOID may cause discomfort and you may temporarily need to wear glasses instead.

Your skin may be more prone to sunburn while on VESANOID. Avoid excessive sun exposure and apply a sunscreen while taking VESANOID.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking VESANOID. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you.

  • dryness of the lips, mouth, nose, eyes and skin. A moisturiser or petroleum jelly can be used to soften the lining of the nose, lips and the skin
  • swelling of hands, ankles, feet
  • nausea, vomiting, stomach pain
  • tenderness or stiffness in your bones or muscles
  • headache, dizziness
  • rash
  • raised painful plaques on face, limbs or neck
  • hair loss
  • depression
  • numbness or tingling feeling
  • diarrhoea, constipation
  • vision or hearing problems
  • loss of libido, male sexual dysfunction
  • breast enlargement in men.

Stop taking VESANOID and see your doctor immediately, or go to Accident and Emergency at your nearest hospital if you experience any of the following:

  • severe headache
  • sudden fever
  • sudden difficulty in breathing or shortness of breath
  • sudden weight gain
  • sudden tiredness or listlessness
  • fast or irregular heartbeats, flushing, swelling of ankles, hands and feet, sudden chest pain or pain in the neck, back or arm, appearing during the first month of therapy.

These are very serious side effects. You may need urgent medical attention or hospitalisation.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don't understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking VESANOID

Storage

Keep your capsules in the bottle until it is time to take them. If you take the capsules out of the bottle they may not keep well.

Keep VESANOID in a cool dry place where the temperature stays below 30°C.

Do not store it, or any other medicine, in a bathroom or near a sink.

Do not leave it in the car or on window sills.

Protect VESANOID from light. Heat and dampness can destroy some medicines.

Keep VESANOID where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking VESANOID, or the capsules have passed their expiry date, you should return any capsules remaining at the end of treatment to your specialist, GP or pharmacist.

Product description

What it looks like

VESANOID capsules are soft, oval and have an orange-yellow top and a reddish-brown bottom.

Ingredients

Active ingredient - tretinoin

  • each 10 mg capsule contains 10 mg tretinoin

Inactive ingredients -

  • yellow beeswax, hydrogenated soya oil, partially hydrogenated soya oil, soya oil, gelatin, glycerol, Karion 83, titanium dioxide, iron oxide yellow and iron oxide red.

VESANOID Capsules are gluten free.

VESANOID Capsules are lactose free.

VESANOID Capsules come in bottles of 100.

Manufacturer

Distributed in Australia by:

Pharmaco (Australia) Ltd,
Gordon NSW 2072

Distributed in New Zealand by:

Pharmaco (NZ) Ltd,
Auckland

Australian Registration Number:


  • AUST R 53160

This leaflet was prepared in July 2019.

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Vesanoid

Active ingredient

Tretinoin

Schedule

S4

 

1 Name of Medicine

Tretinoin.

2 Qualitative and Quantitative Composition

Each Vesanoid capsule contains 10 mg of tretinoin.

Excipients of known effect.

Soya bean products.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Vesanoid is available as oval, soft gelatin capsules containing 10 mg of tretinoin; one half of each capsule is opaque orange-yellow and the other half opaque reddish brown.

4 Clinical Particulars

4.1 Therapeutic Indications

Vesanoid should be used for induction of remission in acute promyelocytic leukaemia (APL; FAB classification AML-M3). Previously untreated patients as well as patients who relapse after or are refractory to standard chemotherapy (daunorubicin and cytosine arabinoside (ARA-C) or equivalent therapies) may be treated with Vesanoid. Following complete remission, consolidation full dose chemotherapy should be employed. A loss of responsiveness to Vesanoid has been reported among patients maintained on Vesanoid. The median time to relapse for patients maintained on Vesanoid is 4 to 6 months.

4.2 Dose and Method of Administration

A total daily dose of 45 mg/m2 body surface area, divided in two equal doses, is recommended for oral administration to APL patients. This is approximately 8 capsules per patient per day. Data on the correct dose for paediatric, geriatric, renally and hepatically impaired patients are limited. A dose of 45 mg/m2 may be given, and a dose reduction should be considered if severe toxicity occurs. Dose reduction should be particularly considered for children with intractable headache. Treatment should be continued for 30 to 120 days except when the disease progresses; 84% of responding patients achieve CR by 90 days. After complete remission, a standard course of consolidation chemotherapy should be initiated immediately; for example, three 7-day courses of daunorubicin and cytosine arabinoside, in 5 to 6 week intervals. This treatment is subject to change with improvements in medical practice.

4.3 Contraindications

Tretinoin is highly teratogenic; it is strictly contraindicated in pregnancy. Vesanoid must not be used by women of childbearing potential unless effective contraception is practiced for at least one month before beginning therapy, during therapy and at least one month following discontinuation of therapy. Breastfeeding should be discontinued if therapy with Vesanoid is initiated.
Vesanoid is contraindicated for use in patients with known hypersensitivity to Vesanoid or any of its components.
The use of Vesanoid in combination with vitamin A is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

During clinical trials hyperleukocytosis has been frequently observed (75%), sometimes associated with the "Retinoic Acid Syndrome" (RAS). RAS has been reported in many APL patients (up to 25% in some clinical trials) treated with Vesanoid (RA-APL syndrome). This syndrome is characterised by fever, dyspnoea, shortness of breath, acute respiratory distress, pulmonary infiltrates, hyperleukocytosis, hypotension, pleural and pericardial effusions, oedema, weight gain, hepatic, renal and multiorgan failure. Untreated, this syndrome can be fatal. The RA-APL syndrome may occur with and without leukocytosis. Prevention of RAS may be achieved by administration of full dose chemotherapy in combination with Vesanoid, if significant elevation of leukocyte count is observed. The role of corticosteroids in preventing RAS is not established.
The current recommendations for treating hyperleukocytosis with or without RAS are as follows:
immediate treatment with a combination of Vesanoid and full dose chemotherapy for patients presenting with a WBC count of > 5 x 109/L at any time;
addition of full dose chemotherapy to Vesanoid therapy in the case of rapidly evolving leukocytosis in a leukopenic patient (WBC < 5 x 109/L) at diagnosis/ initiation of treatment. Rapidly evolving leukocytosis is defined as a WBC count of ≥ 6 x 109/L at any time from day 1 to day 6 and/or ≥ 10 x 109/L at any time from day 7 to day 10 of treatment and/or ≥ 15 x 109/L at any time from day 11 to day 28 of treatment;
treatment with dexamethasone (10 mg every 12 hours for up to 3 days or until resolution of the symptoms) if the patient presents early clinical signs of the syndrome.
There is a risk of thrombosis (both venous and arterial), which may involve any organ system, during the first month of treatment. Therefore, caution should be exercised when treating patients with antifibrinolytic agents (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Vesanoid should be administered only to patients with APL under the strict supervision of a physician who is experienced in the treatment of haematological/ oncological diseases. Current treatment guidelines for APL should be consulted before use of Vesanoid.
Supportive care appropriate for patients with acute promyelocytic leukaemia (e.g. prophylaxis for bleeding and prompt therapy for infection) should be maintained during therapy with Vesanoid. The patient's haematologic profile, coagulation profile, liver function, triglyceride and cholesterol levels should be monitored frequently.

Psychiatric disorders.

Depression, depression aggravated, anxiety, and mood alterations have been reported in patients treated with systemic retinoids, including tretinoin. Particular care should be taken in patients with a history of depression. Patients should be monitored for signs of depression and referred for appropriate treatment if necessary. Awareness by family or friends may be useful to detect mental health deterioration.
Vesanoid may cause intracranial hypertension/pseudotumour cerebri. The concomitant use of other agents known to cause intracranial hypertension/pseudotumour cerebri such as tetracyclines might increase the risk of this condition (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Micro-dosed progesterone preparations ("minipill") may be an inadequate method of contraception during treatment with Vesanoid (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Use in hepatic impairment.

The requirement for dosage adjustment in patients with liver dysfunction has not been investigated.

Use in renal impairment.

The requirement for dosage adjustment in patients with kidney dysfunction has not been investigated.

Use in the elderly.

There are limited clinical data on the use of Vesanoid in the elderly.

Paediatric use.

There are limited clinical data on the use of Vesanoid in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs affecting the hepatic cytochrome P450 enzyme system function may interact with Vesanoid, leading to a change of blood levels. 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 cyclosporine.
Postmarketing experience shows that co-administration, in particular of orally administered antimycotics of the imidazole and triazole type, can increase the toxicity of tretinoin. Particular care is advised when combining these agents with orally administered tretinoin.
In 13 patients who had received daily doses of tretinoin for 4 consecutive weeks, administration of ketoconazole (400 to 1200 mg oral dose) 1 hour prior to the administration of the tretinoin dose on day 29 led to a 72% increase (218 ± 224 vs 375 ± 285 nanogram.hour/mL) in tretinoin mean plasma AUC. The precise cytochrome P450 enzymes involved in these interactions have not been specified; CYP3A4, 2C8 and 2E have been implicated in various preliminary reports. Similar effects have been demonstrated with the related azole drugs fluconazole and liarozole. In patients receiving Vesanoid therapy, concomitant use of potent inhibitors or inducers of the cytochrome P450 enzyme system should be avoided if possible.

Antifibrinolytic agents such as tranexamic acid, aminocaproic acid and aprotinin.

Cases of fatal thrombotic complications have been reported rarely in patients concomitantly treated with Vesanoid and antifibrinolytic agents. Therefore, caution should be exercised when administering Vesanoid concomitantly with these agents.

Tetracyclines.

Systemic treatment with retinoids may cause elevation of intracranial pressure/ pseudotumour cerebri. Since tetracyclines may also cause elevation of intracranial pressure/ pseudotumour cerebri, patients treated with Vesanoid and tetracyclines at the same time might be at a greater risk of experiencing this condition.

Vitamin A.

As with other retinoids, Vesanoid must not be administered in combination with vitamin A because the combination may cause or exacerbate symptoms of hypervitaminosis A.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Effects on fertility and reproductive performance have not yet been investigated in adequate nonclinical studies. In a 6 week toxicology study in dogs, minimal to marked testicular degeneration, with increased numbers of immature spermatozoa, were observed at ≥ 2 mg/kg/day (about 3 times the equivalent human dose based on AUC).
(Category X)
Pregnancy: Vesanoid is highly teratogenic. Its use is contraindicated in pregnant women and women who might become pregnant during or within one month of the cessation of treatment. There is an extremely high risk that a deformed infant will result if pregnancy occurs while taking Vesanoid in any amount even for short periods.
Potentially, all exposed foetuses can be affected. Therapy with Vesanoid should only be started in female patients if each of the following conditions is met:
the patient is suffering from life threatening malignancies. She is informed by her physicians of the hazards of becoming pregnant during and one month after treatment with Vesanoid;
she is capable of complying with the mandatory contraception measures;
it is absolutely essential that every woman of child-bearing potential who is to undergo treatment with Vesanoid uses effective contraception for four weeks before, during and for one month after discontinuation of treatment with Vesanoid;
therapy should not begin until the second or third day of the next normal menstrual period;
a negative pregnancy test result must be obtained within the two weeks before commencement of treatment. Pregnancy tests must be performed at monthly intervals during therapy.
Should pregnancy occur, in spite of these precautions, during treatment with Vesanoid or up to one month after its discontinuation, there is a high risk of severe malformation of the foetus particularly if Vesanoid was taken during the first trimester of pregnancy.
All these measures should be considered in relationship to the severity of the disease and the urgency of the treatment.
 Breastfeeding should be discontinued if therapy with Vesanoid is initiated.

4.7 Effects on Ability to Drive and Use Machines

The ability to drive or operate machinery may be impaired in patients treated with Vesanoid, particularly if they experience dizziness or severe headache.

4.8 Adverse Effects (Undesirable Effects)

In patients treated with the recommended daily doses of tretinoin, the following undesirable effects frequently occur: xeroderma, mouth dryness, cheilitis, rash, oedema, nausea, vomiting and bone pain. Also headache, elevation in serum triglycerides, cholesterol, transaminases (ALT, AST) and creatinine may occur. Occasional cases of hypercalcaemia have been reported.
In addition, the following undesirable effects have been reported at a frequency of greater than 5% in APL patients during clinical trials. These effects were judged by clinical investigators to be possibly or probably related to drug treatment.

Dermatological effects.

Erythema, pruritus, increased sweating, cellulitis, alopecia, dry mucosa (e.g. nose, conjunctiva, with or without inflammatory symptoms), skin exfoliation, dermal bleeding, xerophthalmia, dermatitis, hair loss, genital ulceration has been reported infrequently.

Gastrointestinal effects.

Abdominal pain, diarrhoea, constipation, blisters in the mouth, stomach upset, decreased appetite, pancreatitis.

Cardiovascular effects.

Cardiac arrhythmia, flushing, cases of thrombosis (both venous and arterial), involving various sites including cerebrovascular accident, myocardial infarction and renal infarction (uncommon), have also been reported (see Section 4.4 Special Warnings and Precautions for Use), myocarditis, pericarditis.

Respiratory effects.

Coughing, pleural effusion, nasal congestion, dyspnoea, pharyngitis, respiratory insufficiency or distress, rales and wheezing.

Central nervous system effects.

Dizziness, confusion, intracranial hypertension/ pseudotumour cerebri (mainly in children), anxiety, depression, paraesthesias, insomnia.

Neurosensory effects.

Vision and hearing disorders.

Other effects.

Fever, shivering, fatigue, malaise, weight changes, back and musculoskeletal pain, chest pain, bleeding disorders, pneumonia, infection and septicaemia, generalised weakness and lethargy.

Postmarketing experience.

Dermatological effects.

Sweet's syndrome has been reported uncommonly. Erythema nodosum has been reported rarely.

Musculoskeletal system.

Myositis has been reported rarely.

Haematologic.

Thrombocytosis has been reported rarely. Marked basophilia with or without symptomatic hyperhistaminemia has been reported rarely, mainly in patients with the rare APL variant associated with basophilic differentiation.

Reproductive system and breast disorders.

Sexual dysfunction including erectile dysfunction and decreased libido, gynaecomastia.

Others.

Vasculitis, predominantly involving the skin, has been reported rarely.
Based on the information presently available, these undesirable effects do not represent a permanent or irreversible hazard, but it may be advisable to interrupt or discontinue the therapy, depending on the alternative options available to the patient.
The long-term safety of tretinoin has not been established in clinical trials.
Symptoms of the "Retinoic Acid Syndrome" in APL patients have been frequently reported and may be life threatening unless treated (see Section 4.4 Special Warnings and Precautions for Use).
Vesanoid is teratogenic (see Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).
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 an increased incidence of pseudotumour cerebri.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Cases of acute overdosage with tretinoin have not been reported. Cases of overdose would be expected to show largely reversible effects characteristic of hypervitaminosis A. The recommended dose is one-quarter of the maximum tolerated dose in solid tumour 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tretinoin is a natural metabolite of retinol and belongs to the class of compounds known as retinoids, which are structurally related to vitamin A and comprise natural and synthetic analogs. In vitro studies with tretinoin have demonstrated induction of differentiation and inhibition of cell proliferation in transformed haemopoietic cell lines, including human myeloid leukaemia cell lines.
The majority of acute promyelocytic leukaemia (APL) cases are associated with a nonrandom chromosomal abnormality characterised by balanced and reciprocal translocations between the long arms of chromosomes 15 and 17 [t(15;17) (q22;q21)]. The gene encoding the retinoic acid receptor-alpha (RAR-α) is located on chromosome 17. A promyelocytic leukaemia gene (PML), that appears to code for a transcription factor, is located on chromosome 15. The 15;17 translocation fuses the genes for PML and RAR-α, resulting in the synthesis of a chimeric fusion transcript, PML/RAR-α. In rare cases, alternative fusion genes to PML may be found. In addition to the APL causing chromosomal translocation, additional chromosomal abnormalities have been described in approximately 25% of patients with APL. The PML/RAR-α fusion protein appears to inhibit the differentiation of myeloid cells, resulting in leukaemogenesis, an effect which may be overcome by the use of high doses of tretinoin. Orally administered tretinoin induces a high rate of molecular and clinical remission (CR) in patients with t(15;17) APL. Patients who fail to respond to tretinoin therapy may have APL caused by a rare genotype.
Relapse (secondary acquired resistance) to tretinoin may have a pharmacokinetic component (see below) but more recent evidence points to molecular disturbances in APL cells as the predominant factor. The detection of the PML/RAR-α fusion protein by reverse transcriptase polymerase chain reaction (RT-PCR) in the presence of clinical (morphological) remission after treatment is indicative of minimal residual disease and, therefore, the prognosis is one of ultimate clinical relapse.

Clinical trials.

APL is a rare disease thus making clinical trials difficult; which contributes to the lack of clinical data. Vesanoid has been investigated in 140 APL patients entered into four open label uncontrolled studies: three single investigator studies and one compassionate plea study conducted by the US National Cancer Institute (NCI) with 56 physicians participating. The overall frequency of induction into CR (complete remission) ranged from 62% to 90% in single investigator studies whereas response rates were lower in the compassionate trial population (47%). The two main reasons for this lower response rate were a high early death rate in this much sicker patient group and a high proportion of patients resistant to Vesanoid treatment. The median time to CR, as analysed by survival methodology, ranged from 41 to 69 days with the longest time being 109 days, with 84% of the responding patients achieving CR by 90 days.

5.2 Pharmacokinetic Properties

Tretinoin is an endogenous metabolite of vitamin A and is normally present in plasma. The physiological levels of tretinoin appear largely independent of a normal dietary range of intake of vitamin A (in contrast to blood levels of some other retinol metabolites) but exhibit a diurnal pattern, may decrease with fasting, surgical caloric restriction or disease (but not APL) and may increase with excessive intake of liver or vitamin A supplements. The physiological, diurnal levels of tretinoin in one detailed study in female, healthy subjects (Cmax 5.3 ± 0.93 nanomol/L [1.6 ± 0.28 nanogram/mL], Cmin 3.3 ± 0.48 nanomol/L [0.99 ± 0.14 nanogram/mL]; mean ± SD; N = 35 women, 18-40 years) are representative. One study indicates that physiological tretinoin levels in healthy men are significantly lower (about 25%) than in women.
Oral doses of Vesanoid are well absorbed and maximum plasma concentrations in normal volunteers are attained after 3-4 hours but may be earlier (after 1-3 hours) in patients with APL. There is a large interpatient and intrapatient variation in absorption of Vesanoid. In plasma, tretinoin is extensively bound to plasma proteins. Plasma concentrations decline with a mean elimination half-life of about 0.7 hours and return to endogenous levels following a single dose after 7-12 hours. No accumulation is seen after multiple doses and tretinoin is not retained in body tissues. Renal excretion of metabolites formed by oxidation and glucuronidation is a major route (60%) of elimination. Tretinoin is isomerised to 13-cis-retinoic acid (isotretinoin) and 9-cis-retinoic acid and oxidised to 4-oxo-metabolites. These metabolites have longer half-lives than tretinoin.
During multiple doses a marked decrease in plasma concentration can occur, possibly due to cytochrome P450 enzyme induction, which increases clearance and decreases bioavailability after oral doses. A therapeutic dose of 45 mg/m2 per day Vesanoid in equal divided doses given to 13 healthy men and women for 15 days yielded a Cmax of 1693 ± 717 nanomol/L [508 ± 215 nanogram/mL] for the first dose on day 1 and 1253 ± 1,180 nanomol/L [376 ± 354 nanogram/mL] on day 15; the AUC0-∞ decreased by 31.8%. Increasing the dose 2-fold or administration of cytochrome P450 inhibitors, such as ketoconazole, does not persistently overcome the reduced plasma levels accompanying continuous treatment but a break in treatment of 7 days briefly restores first dose conditions. Pharmacokinetic data from several small studies in a variety of cancer patients and with Vesanoid doses ranging from 12.5 mg/m2 to > 300 mg/m2 suggest a weak relationship between dose and Cmax and a dominant effect of interpatient variability. The therapeutic studies which established the efficacy of Vesanoid induction treatment in APL were conducted with continuous treatment and the recommended dose of 45 mg/m2 per day in equal divided doses. When taken with food, the oral absorption of tretinoin is expected to increase, as has been observed with other retinoids. The influence of food on the bioavailability of Vesanoid has not been investigated.

Pharmacokinetics in special populations.

Paediatric patients.

Limited pharmacokinetic data are available for administration of oral Vesanoid to children covering single doses ranging from 7 mg/m2 to 40 mg/m2 in patients with APL or a variety of other tumours. No striking differences from adult pharmacokinetics are apparent.

5.3 Preclinical Safety Data

Genotoxicity.

Tretinoin did not reveal any genotoxic potential in a series of assays for gene mutations (Ames test, Chinese hamster lung cells). A twofold increase in the sister chromatid exchange (SCE) has been demonstrated in human diploid fibroblasts, but other chromosome aberration assays (human lymphocytes in vitro, mouse micronucleus test in vivo) did not show a clastogenic or aneuploidogenic effect.

Carcinogenicity.

No long-term carcinogenicity studies with tretinoin have been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

The capsule contents are yellow beeswax, hydrogenated soya oil, partially hydrogenated soya oil, and soya oil. The capsule shell contains gelatin, glycerol, Karion 83 (ARTG PI: 1854), titanium dioxide, iron oxide yellow and iron oxide red, purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

This medicine should not be used after the expiration date (EXP) shown on the pack.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Keep the bottle tightly closed; protect capsules from heat (store below 30°C) and light.

6.5 Nature and Contents of Container

Bottles of 100.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemically, tretinoin is 3,7-dimethyl-9-(2,6,6-trimethyl cyclohex-1-enyl)nona- 2,4,6,8-all-trans-retinoic acid. The molecular formula is C20H28O2. The molecular weight is 300.4. Tretinoin is a yellow to light orange powder with very low solubility in water. It is very sensitive to light and oxygen. Tretinoin (all-trans retinoic acid; ATRA) is a well known chemical substance described in all international pharmacopoeia.

Chemical structure.


CAS number.

302-79-4.

7 Medicine Schedule (Poisons Standard)

Schedule S4.

Summary Table of Changes