SUMMARY CMI

Vesanoid

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Vesanoid?

Vesanoid contains the active ingredient tretinoin or retinoic acid. Vesanoid is used to treat acute promyelocytic leukemia (APL).
For more information, see Section 1. Why am I using Vesanoid? in the full CMI.

2. What should I know before I use Vesanoid?

Do not use if you have ever had an allergic reaction to tretinoin or any of the ingredients listed at the end of the CMI.
Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.
For more information, see Section 2. What should I know before I use Vesanoid? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Vesanoid and affect how it works.
A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Vesanoid?

• 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.
• Capsules should be swallowed whole with a glass of water.
• Do not open the capsules and do not take any capsules that are damaged.

More instructions can be found in Section 4. How do I use Vesanoid? in the full CMI.

5. What should I know while using Vesanoid?

For more information, see Section 5. What should I know while using Vesanoid? in the full CMI.

6. Are there any side effects?

Serious side effects: 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. Less serious side effects: dryness of the lips, mouth, nose, eyes and 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. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

Vesanoid

Active ingredient(s): tretinoin or retinoic acid

Consumer Medicine Information (CMI)

This leaflet provides important information about using Vesanoid. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Vesanoid.

Where to find information in this leaflet:

1. Why am I using Vesanoid?
2. What should I know before I use Vesanoid?
3. What if I am taking other medicines?
4. How do I use Vesanoid?
5. What should I know while using Vesanoid?
6. Are there any side effects?
7. Product details

1. Why am I using Vesanoid?

Vesanoid contains the active ingredient 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 used to treat acute promyelocytic leukemia (APL).

2. What should I know before I use Vesanoid?

Warnings

Do not use Vesanoid if:

• you are allergic to tretinoin or retinoic acid, or any of the ingredients listed at the end of this leaflet.
• Always check the ingredients to make sure you can use this medicine.
• you are allergic to vitamin A or other retinoids
• 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 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.

Check with your doctor if you:

• have ever had any mental health problems including depression, aggressive tendencies or mood changes. This is because taking Vesanoid may affect your mood.
• have high fat levels in your blood.
• have liver or kidney disease.
• have other illnesses.
• develop fever or shortness of breath or difficulties in breathing, as these can be signs of “Retinoic Acid Syndrome” in APL.
• take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

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

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Breastfeeding must stop before treatment begins. Do not breastfeed while taking Vesanoid.

Mental health problem

• 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.

Use in children

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

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Vesanoid.

• 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 immunosuppressants (such as cyclosporine)
• some medicines used for stomach ulcers (such as cimetidine).

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Vesanoid.

4. How do I use Vesanoid?

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.

When to take Vesanoid

• Follow the instructions provided and use Vesanoid until your doctor tells you to stop.
• 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 to take Vesanoid

• Capsules should be swallowed whole with a glass of water.
• Do not open the capsules and do not take any capsules that are damaged.

If you forget to use Vesanoid

Vesanoid should be used regularly at the same time each day.

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

Do not take a double dose to make up for the dose you missed.

If you use too much Vesanoid

If you think that you have used too much Vesanoid, you may need urgent medical attention.

You should immediately:

• phone the Poisons Information Centre
  (Australia: by calling 13 11 26; New Zealand: telephone 0800 POISON or 0800 764 766), or
• contact your doctor, or
• go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Vesanoid?

Things you should do

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

Call your doctor straight away if you:

• do become pregnant while you are taking Vesanoid
• have not taken your medicine exactly as prescribed

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Remind any doctor, dentist or pharmacist you visit that you are using Vesanoid.

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

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Vesanoid affects you.

Your ability to drive or operate machinery might be impaired while you are taking Vesanoid, especially if you are feeling dizzy or have a severe headache.

Looking after your medicine

• Keep your capsules in the bottle until it is time to take them.
• Keep Vesanoid in a cool dry place where the temperature stays below 30°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

• in the bathroom or near a sink, or
• in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

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.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Serious side effects

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems (Australia) or refer to the Medsafe website www.medsafe.govt.nz/safety/report-a-problem.asp (New Zealand). By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Vesanoid contains

Do not take this medicine if you are allergic to any of these ingredients.

What Vesanoid looks like

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

(Aust R 53160).

Who distributes Vesanoid

Distributed in Australia by:
Pharmaco (Australia) Ltd,
Level 13, 465 Victoria Avenue
Chatswood NSW 2067
Australia
Phone: 1800 210 564

Distributed in New Zealand by:
Pharmaco (NZ) Ltd
4 Fisher Crescent
Mt Wellington
Auckland 1060
Phone: 0800 804 079

Under license of CHEPLAPHARM Arzneimittel GmbH, Germany

This leaflet was prepared in January 2024

Published by MIMS February 2024

1 Name of Medicine

Tretinoin.

2 Qualitative and Quantitative Composition

Each Vesanoid capsule contains 10 mg of tretinoin.

Excipients of known effect.

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.

Use in hepatic impairment.

Use in renal impairment.

Use in the elderly.

Paediatric use.

Effects on laboratory tests.

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.

Tetracyclines.

Vitamin A.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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.

Gastrointestinal effects.

Cardiovascular effects.

Respiratory effects.

Central nervous system effects.

Neurosensory effects.

Other effects.

Postmarketing experience.

Dermatological effects.

Musculoskeletal system.

Haematologic.

Reproductive system and breast disorders.

Others.

Reporting suspected adverse effects.

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.

Clinical trials.

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 (C_max 5.3 ± 0.93 nanomol/L [1.6 ± 0.28 nanogram/mL], C_min 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 C_max 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 AUC_0-∞ 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 C_max 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.

5.3 Preclinical Safety Data

Genotoxicity.

Carcinogenicity.

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.

7 Medicine Schedule (Poisons Standard)

Schedule S4.

Summary Table of Changes