Consumer medicine information

Zetin

Acitretin

BRAND INFORMATION

Brand name

Zetin

Active ingredient

Acitretin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zetin.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about ZETIN. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

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

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is ZETIN. It contains the active ingredient acitretin.

It is used to treat:

  • psoriasis
  • keratinisation disorders

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

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

How it works

Acitretin, the active ingredient of ZETIN, belongs to a group of medicines called retinoids.

It is very similar to Vitamin A which is obtained from our diet and is vital for the normal growth and development of the body, especially the skin.

Psoriasis is a skin disease with thickened patches of red skin, often with silvery scales. ZETIN is used to treat severe psoriasis and other severe skin disorders.

ZETIN works to return skin to normal when problems with the normal development of the skin are present, as in the case of severe psoriasis and some other skin disorders.

There is no evidence that this medicine is addictive.

Use in children

ZETIN capsules should only be taken by children where alternative therapy cannot be used.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You have or have had any of the following:
    - severe kidney disease
    - severe liver disease
    - abnormally high levels of fat in your blood
    - an allergic reaction to retinoids or Vitamin A
  • You are pregnant or you intend to become pregnant in the next 36 months.
    Any possibility that you may be pregnant must be ruled out by both yourself and your doctor before you start taking ZETIN capsules. The result of a pregnancy test must be negative when performed within two weeks before beginning of ZETIN treatment. ZETIN is highly teratogenic, i.e. there is an extremely high risk of having a baby that is severely deformed.
    This means you must use effective contraception (preferably 2 complementary methods) for one month before, during and 3 years after treatment with ZETIN.
    You must also tell your doctor immediately if you become pregnant in the 3 years following the end of treatment.
  • You are breastfeeding.
    Breastfeeding must stop before ZETIN treatment can start. Do not breastfeed while taking ZETIN capsules.
  • You are taking tetracycline antibiotics. These include doxycycline HCl, Doxine®, Doxy®, Achromycin® and Minomycin®.
  • You are taking vitamin A, or preparations that contain vitamin A.
  • You are taking methotrexate.
  • You are hypersensitive to, or have had an allergic reaction to, acitretin or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Donation of blood by a patient being treated with ZETIN is prohibited during and for three years after completion of treatment with ZETIN.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • diabetes, or family members with diabetes
  • liver disease
  • high triglycerides or cholesterol levels in the blood, or family members with a history of high blood triglycerides or cholesterol levels
  1. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant.
  2. You are currently breastfeeding or you plan to breast-feed. Do not take this medicine whilst breastfeeding.
  3. You are planning to have surgery.
  4. You are currently receiving or are planning to receive dental treatment.
  5. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with ZETIN. These include:

  • tetracycline antibiotics (such as Vibramycin®, Doxine®, Doxy®, Achromycin® and Minomycin®)
  • phenytoin
  • methotrexate
  • alcohol containing medicines
  • the "mini-pill", a low-dose progestogen oral contraceptive
  • vitamin A, or formulations that contain vitamin A

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with ZETIN.

How to take this medicine

Carefully follow all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines. This may also consider your bodyweight and whether you develop any side effects.

The starting dose is usually either 25 mg (1 x 25 mg capsule) or 30 mg (3 x 10 mg capsules) per day for 2 to 4 weeks.

Your dose will probably then be adjusted by your doctor when it is known how you respond to ZETIN capsules.

The initial signs of improvement may be seen in the first week but, more often, after 2 or 3 weeks. It may take 2 to 3 months until the full effect is seen.

Do not change your dosage without first checking with your doctor.

Affected skin areas will either peel off or steadily clear. Sometimes more redness or itching may be present at first, but this will normally improve as treatment continues.

How to take it

ZETIN capsules should be swallowed whole with a glass of water or milk.

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

Female patients should wait until the 2nd or 3rd day of their menstrual period before starting ZETIN capsules. This helps to ensure that you are not pregnant before you start to take ZETIN therapy.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

A temporary increase in psoriasis is sometimes seen when first starting treatment.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

It is critical to keep all of your appointments with your doctor so your progress with ZETIN therapy can be monitored regularly. Your doctor may ask you to do some blood, liver function and other tests from time to time in order to check your progress and pick up any unwanted side effects.

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

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Decreased night vision has been reported with acitretin therapy. Be careful when driving or operating any vehicle at night.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking ZETIN or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Common side effects can include:

  • dryness of the lips, mouth, nose, eyes and skin.
    Either a moisturiser or petroleum jelly can be used to soften the lining of the nose, lips and the skin
  • drying and inflammation of mucous membranes
  • thirst
  • flushing
  • difficulty producing tears
  • intolerant of contact lenses
  • itchiness, redness or rashes
  • thinning or peeling of the skin that was not previously affected
  • nail fragility or conditions
  • eye infections
  • abnormal liver tests
  • increase in blood cholesterol
  • muscle, joint or bone pain

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

  • headache
  • tiredness
  • heartburn
  • strange hair texture or loss
  • more prone to sun burn
  • impaired night vision
  • noises or ringing in ears
  • changes in taste
  • hay fever-like symptoms
  • nose bleeds
  • swelling in limbs

Tell your doctor as soon as possible if you notice any of the following.

These may be serious side effects and you may need medical attention:

  • changes in mood including depression or aggression
  • male breast enlargement
  • changes in hearing

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation:

  • headache, nausea and vomiting, and visual disturbances can be signs of papilloedema and needs medical investigation
  • itchy, yellowing skin, lighter coloured stool or darker urine can be signs of jaundice.

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to ZETIN, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it. If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where 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 this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What ZETIN capsules looks like

10 mg Capsule*:
Hard gelatin capsule containing a yellow powder with a white to off-white body and a brown cap printed in black with "A10" on the capsule body.

25 mg Capsule*:
Hard gelatin capsule containing a yellow powder with a yellow to light yellow body and a brown cap printed in black with "A25" on the capsule body.

Available in blister packs of 60 and 100 capsules

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each ZETIN capsule contains 10 or 25 mg of acitretin as the active ingredient.

It also contains the following inactive ingredients:

  • maltodextrin
  • sodium ascorbate
  • microcrystalline cellulose
  • gelatin
  • sodium lauryl sulphate
  • purified water
  • black printing ink (shellac glaze, iron oxide black (E172), propylene glycol (E1520))
  • iron oxide red (E172) (colourant)
  • iron oxide yellow (E172) (colourant) (25mg only)
  • titanium dioxide

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

May contain trace amounts of phenylalanine and sulfites.

Australian Registration Numbers

ZETIN 10 mg capsule (blister): AUST R 196005

ZETIN 25 mg capsule (blister): AUST R 196004

Sponsor

Douglas Pharmaceuticals Australia Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

Distributed by Arrow Pharmaceuticals Pty Ltd on behalf of

Oraderm Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

This leaflet was last updated in September 2021.

Published by MIMS October 2021

BRAND INFORMATION

Brand name

Zetin

Active ingredient

Acitretin

Schedule

S4

 

Notes

(Sponsor Douglas Pharmaceuticals Australia Pty Ltd)

1 Name of Medicine

Acitretin.

6.7 Physicochemical Properties

Acitretin is a metabolite of etretinate and is related to both retinoic acid and retinol (Vitamin A). Acitretin is a green-yellow crystalline powder. It is virtually insoluble in water (< 0.1 mg/100 mL). The pKa is approximately 5. It is present in the capsules as a spray-dried powder.
Molecular Formula: C21H26O3. Molecular Weight: 326.44.

Chemical structure.


CAS number.

CAS Registry Number: 55079-83-9.

2 Qualitative and Quantitative Composition

Zetin (acitretin) is a retinoid for the oral treatment of severe cases of psoriasis and disorders of keratinisation. It is available in 10 and 25 mg capsules.
For full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zetin hard gelatin capsule is intended for oral administration.

Zetin 10 mg capsule.

Hard gelatin capsule containing a yellow powder with a white to off-white body and a brown cap printed in black with "A10" on the capsule body.

Zetin 25 mg capsule.

Hard gelatin capsule containing a yellow powder with a yellow to light yellow body and a brown cap printed in black with "A25" on the capsule body.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Zetin (acitretin) reverses the epidermal proliferation and increased keratinisation seen both in chemically induced epithelial tumours in animals and in hyperkeratotic disorders in man.
Vitamin A (retinol and its esters) can beneficially influence hyperkeratotic changes in the skin or metaplasias of the mucous membranes.

Clinical trials.

Use of acitretin in psoriatic patients results in improvement manifested by a decrease in scale, erythema and thickness of lesions, and decreased inflammation in the epidermis.

5.2 Pharmacokinetic Properties

Absorption.

Acitretin reaches peak plasma concentration 1 - 5 hours after ingestion of the medicine. Bioavailability of orally administered acitretin is best when the medicine is taken together with food. Bioavailability of a single dose is approximately 60%, but this may vary considerably from one patient to another (36 - 95%).
After administration of a single 50 mg oral dose of acitretin to 18 healthy subjects, maximum plasma concentrations ranged from 196 to 728 nanogram/mL (mean 416 nanogram/mL) and were achieved in 2 to 5 hours (mean 3.5 hours). The oral absorption of acitretin is linear and proportional with increasing doses from 25 to 100 mg. Following multiple doses, acitretin plasma concentrations reached steady-state conditions within two weeks and accumulation was 0.5 to 2.6-fold higher than after a single dose. In patients with psoriasis, mean steady-state trough concentrations of acitretin increased in a proportional manner and ranged between 6 and 7 nanogram/mL, 11 and 14 nanogram/mL, and 19 and 25 nanogram/mL over an eight week period at daily oral doses of 10 mg, 25 mg and 50 mg, respectively. In this same study, acitretin plasma concentrations were non-measurable (< 4-6 nanogram/mL) in all patients where blood samples were drawn three weeks after cessation of therapy.

Distribution.

Acitretin is highly lipophilic and penetrates readily into body tissues. Protein binding of acitretin exceeds 99%. In animal studies, acitretin passed the placental barrier in quantities sufficient to produce foetal malformations. Due to its lipophilic nature, it can be assumed that acitretin passes into breast milk in considerable quantities.

Metabolism.

Acitretin is metabolised by isomerisation into its 13-cis isomer (cis acitretin), by glucuronidation and cleavage of the side chain. Both acitretin and its 13-cis isomer are eliminated from the body primarily by metabolism to chain-shortened breakdown products and conjugates that are ultimately excreted in the faeces (35 - 45%) and urine (48 - 61%). The formation of the 13-cis isomer relative to parent compound is not altered by dose or fed/fasted conditions of oral administration of acitretin. The elimination of the 13-cis isomer is essentially parallel to that of acitretin after multiple doses.
There was no detectable formation of etretinate when a single 100 mg oral dose of acitretin was administered without concurrent ethanol ingestion. Although the formation of etretinate without concurrent ethanol ingestion cannot be excluded, only 7.5% of 240 evaluated psoriatic patients on acitretin therapy (5 - 60 mg/day) in controlled and uncontrolled clinical trials were found to have measurable etretinate concentrations (5 nanogram/mL). Of these patients, the last measurable etretinate concentration was observed at two months after cessation of acitretin therapy.
Animal studies confirm the possibility that, in the rat at least, metabolism of acitretin to etretinate in the absence of alcohol can occur.

Excretion.

Multiple-dose studies in patients aged 21-70 years showed an elimination half-life of approximately 50 hours for acitretin and 60 hours for its main metabolite in plasma, cis acitretin, which is also a teratogen. From the longest elimination half-life observed in these patients for acitretin (96 hours) and cis acitretin (123 hours), and assuming linear kinetics, it can be predicted that more than 99% of the drug is eliminated within 36 days after cessation of long-term therapy. Furthermore, plasma concentrations of acitretin and cis acitretin dropped below the sensitivity limit of the assay (< 6 nanogram/mL) within 36 days following cessation of treatment. Acitretin is excreted entirely in the form of its metabolites, in approximately equal parts via the kidneys and the bile.

Special populations.

Plasma concentrations of acitretin were significantly lower in end stage renal failure subjects (n = 6) when compared to age-matched controls following single 50 mg oral doses. However, acitretin was not removed by haemodialysis in these subjects.
In a multiple-dose study in healthy young (n = 6) and elderly (n = 8) subjects, increased acitretin plasma concentrations were seen in elderly subjects although the elimination half-life did not change.

5.3 Preclinical Safety Data

Genotoxicity.

Acitretin has been shown to be embryotoxic and/or teratogenic in mice, rats and rabbits at doses approximately 3, 15 and 0.5 times the maximum recommended therapeutic dose, respectively.

Carcinogenicity.

Carcinogenicity studies carried out with acitretin showed an increase in the frequency of blood vessel tumours (haemangiomas and haemangiosarcomas) in male mice.

4 Clinical Particulars

4.1 Therapeutic Indications

Zetin (acitretin) may be used for the treatment of:
Severe intractable psoriasis in all its forms.
Severe forms of disorders of keratinisation such as: hyperkeratosis palmaris et plantaris; pustulosis palmaris et plantaris; ichthyosis; keratosis follicularis (Darier's disease); lichen planus affecting the skin or the mucosae; pityriasis rubra pilaris.

4.3 Contraindications

Zetin (acitretin) is strictly contraindicated in:
pregnant women;
women of childbearing potential unless all of the other conditions of the Pregnancy Prevention Program are met.
Zetin (acitretin) is highly teratogenic and must not be used by patients who are pregnant or who intend to become pregnant during therapy or for 3 years after cessation of therapy.
Zetin is also contraindicated in people who are hypersensitive to acitretin or other ingredients in Zetin or to other retinoids.
Women of childbearing potential must not receive blood from patients being treated with acitretin. Donation of blood by a patient being treated with acitretin is prohibited during and for three years after completion of treatment with acitretin.
Zetin (acitretin) is contraindicated while breast feeding.
Zetin (acitretin) is contraindicated in patients with severely impaired liver or kidney function and in patients with chronic abnormally elevated blood lipid values.
Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated.
An increased risk of hepatitis has been reported to result from combined use of methotrexate and Tigason (active ingredient: etretinate). Consequently, the combination of methotrexate with acitretin is also contraindicated.
Concomitant administration of acitretin and vitamin A or other retinoids is contraindicated due to the risk of hypervitaminosis A.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Pregnancy Prevention Program.

This medicinal product is teratogenic.
Acitretin is contraindicated in women of childbearing potential unless all of the following conditions of the Pregnancy Prevention Program are met:
She has severe forms of psoriasis (erythrodermic psoriasis, local or generalized pustular psoriasis) or severe keratinization disorders (congenital ichthyosis, pityriasis rubra pilaris, Darier's disease, other disorders of keratinization which may be resistant to other therapies) (see Section 4.1 Therapeutic Indications).
The potential for pregnancy must be assessed for all female patients.
She understands the teratogenic risk.
She understands the need for rigorous follow-up on a monthly basis.
She understands and accepts the need for effective contraception, without interruption, 1 month before starting treatment, throughout the entire duration of treatment and for 3 years after the end of treatment. At least one highly effective method of contraception (i.e. a user-independent form) or two complementary user-dependent forms of contraception should be used.
Individual circumstances should be evaluated in each case, when choosing the contraception method, involving the patient in the discussion, to guarantee her engagement and compliance with the chosen measures.
Even if she has amenorrhea she must follow all the advice on effective contraception.
She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy or if she might be pregnant.
She understands the need and accepts to undergo regular pregnancy testing before, ideally monthly during treatment and periodically with 1-3 monthly intervals for a period of 3 years after stopping treatment (see Section 4.6 Fertility, Pregnancy and Lactation).
She has acknowledged that she has understood the hazards and necessary precautions associated with the use of acitretin.
These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.
The prescriber must ensure that:
The patient complies with the conditions for pregnancy prevention as listed above, including confirmation that she has an adequate level of understanding.
The patient has acknowledged the aforementioned conditions.
The patient understands that she must consistently and correctly use one highly effective method of contraception (i.e. a user-independent form) or two complementary user-dependent forms of contraception, for at least 1 month prior to starting treatment and is continuing to use effective contraception throughout the treatment period and for at least 3 years after cessation of treatment.
Negative pregnancy test results have been obtained before, during and periodically with 1-3 monthly intervals for a period of 3 years after stopping treatment. The dates and results of pregnancy tests should be documented.
If pregnancy occurs in a woman treated with acitretin, treatment must be stopped and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice.
If pregnancy occurs after stopping treatment there remains a risk of severe and serious malformation of the foetus. This risk persists until the product has been completely eliminated, which is within 3 years following the end of treatment.

Contraception.

Female patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. If the prescribing physician is not in a position to provide such information the patient should be referred to the relevant healthcare professional.
As a minimum requirement, female patients of childbearing potential must use at least one highly effective method of contraception (i.e. a user-independent form), or two complementary user dependent forms of contraception. Contraception should be used for at least 1 month prior to starting treatment, throughout treatment and continue for at least 3 years after stopping treatment with acitretin, even in patients with amenorrhea.
Individual circumstances should be evaluated in each case, when choosing the contraception method involving the patient in the discussion, to guarantee her engagement and compliance with the chosen measures.

Pregnancy testing.

According to local practice, medically supervised pregnancy tests are recommended to be performed, as follows:

Prior to starting therapy.

At least one month after the patient has started using contraception, and shortly (preferably a few days) prior to the first prescription, the patient should undergo a medically supervised pregnancy test. This test should ensure the patient is not pregnant when she starts treatment with acitretin.

Follow-up visits.

Follow-up visits should be arranged at regular intervals, ideally monthly. The need for repeated medically supervised pregnancy tests every month should be determined according to local practice including consideration of the patient's sexual activity, recent menstrual history (abnormal menses, missed periods or amenorrhea) and method of contraception. Where indicated, follow-up pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.

End of treatment.

Women should undergo pregnancy test periodically with 1-3 monthly intervals for a period of 3 years after stopping treatment.

Prescribing and dispensing restrictions.

For women of childbearing potential, the prescription duration of acitretin should ideally be limited to 30 days in order to support regular follow up, including pregnancy testing and monitoring. Ideally, pregnancy testing, issuing a prescription and dispensing of acitretin should occur on the same day.
This monthly follow-up will allow ensuring that regular pregnancy testing and monitoring is performed and that the patient is not pregnant before receiving the next cycle of medication.

Male patients.

For male patients treated with acitretin, available data, based on the level of maternal exposure from the semen and seminal fluid indicate a minimal, if any, risk of teratogenic effects.
Male patients should be reminded that they must not share their medication with anyone, particularly not females.

Additional precautions.

Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment.
Patients should not donate blood during therapy and for 3 years following discontinuation of acitretin because of the potential risk to the foetus of a pregnant transfusion recipient.

Educational material.

In order to assist prescribers, pharmacists and patients in avoiding foetal exposure to acitretin the Marketing Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of acitretin, to provide advice on contraception before therapy is started and to provide guidance on the need for pregnancy testing.

Psychiatric disorders.

Depression, depression aggravated, anxiety, and mood alterations have been reported in patients treated with systemic retinoids, including acitretin. 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.

Use in diabetes.

In diabetics, retinoids can either improve or worsen glucose tolerance. Blood sugar levels must therefore be checked more frequently than usual in the early stages of treatment.

Pseudotumour cerebri.

Acitretin and other retinoids administered orally have been associated with cases of pseudotumour cerebri (benign intracranial hypertension). Early signs and symptoms include papilloedema, headache, nausea and vomiting, and visual disturbances. Patients with these signs and symptoms should be examined for papilloedema and, if present, should discontinue acitretin immediately and be referred for neurologic evaluation and care.

Hyperostosis.

In clinical trials with acitretin, patients were prospectively evaluated for evidence of development or change in bony abnormalities of the vertebral column. Of 262 patients treated with acitretin, 7% had pre-existing abnormalities of the spine, which showed new changes or progression of pre-existing findings. Changes included degenerative spurs, anterior bridging of spinal vertebrae, diffuse idiopathic skeletal hyperostosis, and narrowing and destruction of a cervical disc space. These existing abnormalities may be in some part attributable to the underlying psoriasis and/or the patient's age. No bone changes were seen in patients who had normal pre-treatment X-rays. A substantially higher incidence of hyperostosis has been observed with oral administration of other retinoids also involving patients without pre-existing abnormalities of the spine. Maintenance treatment may result in progression of existing spinal hyperostosis, in appearance of new hyperostotic lesions and in extraskeletal calcification, as has been observed in long-term systemic treatment with retinoids.
In adults receiving long-term treatment with acitretin, appropriate examinations should be periodically performed in view of possible ossification abnormalities (see Section 4.8 Adverse Effects (Undesirable Effects)). If such disorders arise, the continuation of therapy should be discussed with the patient on the basis of a careful risk/benefit analysis.

General.

Patients should be advised that a transient increase in psoriasis is sometimes seen during the initial treatment period.
Patients with severe headache, nausea, vomiting, and visual disturbances should discontinue acitretin immediately and be referred for neurologic evaluation and care.
Patients should be advised that they may experience decreased tolerance to contact lenses during the initial treatment period.
Donation of blood by a patient being treated with acitretin is prohibited during and for three years after completion of treatment with acitretin.
It should be emphasized that, at the present time, not all the consequences of life-long administration of acitretin are known.
For male patients treated with acitretin, available data, based on the level of maternal exposure from the semen and seminal fluid indicate a minimal, if any, risk of teratogenic effects.

Use in hepatic impairment.

Elevated transaminase and alkaline phosphatase levels have been noted in a number of patients receiving acitretin. Several cases of hepatitis have been noted in association with etretinate.
Hepatic function should be monitored before and every one to two weeks for the first two months after starting treatment with acitretin and then every three months during treatment. If pathological values for hepatic function are found, monitoring should be repeated at weekly intervals. If hepatotoxicity is suspected during acitretin treatment, the drug must be discontinued and the aetiology further investigated. In such cases it is advisable to continue monitoring hepatic function for at least 3 months.

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Paediatric use.

Skeletal changes in premature epiphysial ossification are seen in young animals treated with etretinate. These effects have not been observed in man but only a limited number of children have been studied. Because of the uncertain effects of acitretin on growth and skeletal development, the drug should only be used in those under 18 in the following situations: life-threatening circumstances where other therapy cannot be used or is not effective; and in severe forms of the disorder for which there is no alternative therapy. Growth parameters and bone development must be closely monitored in all patients on long-term therapy, by regular measurement and X-ray.
In view of possible severe adverse effects associated with long-term treatment, the risk should be carefully weighed against the therapeutic benefit. Acitretin should be used only when alternative therapies have been exhausted.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Effects on laboratory tests.

Lipids.

Blood lipid determinations should be performed before acitretin is administered and again at intervals of one to two weeks until the lipid response to the drug is established, which is usually within four to eight weeks. Approximately 65% of patients receiving acitretin during clinical trials experienced an elevation in triglycerides. Approximately 30% developed a decrease in high density lipoproteins (HDL). The mean cholesterol level of the study population rose slightly with time but never exceeded the normal range, although some individual patients did exceed the normal range. These effects of acitretin were reversible upon cessation of therapy.
Patients with an increased tendency to develop hypertriglyceridaemia include those with diabetes mellitus, obesity, increased alcohol intake or a familial history of these conditions.
Hypertriglyceridaemia and lowered HDL may increase a patient's cardiovascular risk status. Therefore, every attempt should be made to control significant elevations of triglycerides or HDL decreases by reduction of weight or restriction of dietary fat and alcohol intake while continuing acitretin therapy. Acitretin treatment should be discontinued in case of uncontrolled levels of hypertriglyceridemia or if symptoms of pancreatitis occur.
Serum cholesterol and serum triglycerides (fasting values) must be monitored, before starting treatment, one month after the commencement and then every 3 months during treatment, especially in high-risk patients (disturbances of lipid metabolism, diabetes mellitus, obesity, alcoholism) and during long-term treatment. During treatment with high doses of acitretin, reversible elevation of serum triglycerides and serum cholesterol has occurred, especially in high-risk patients (disturbances of lipid metabolism, diabetes mellitus, obesity, alcoholism). An associated risk of atherogenesis cannot be ruled out if these conditions persist.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Preliminary studies indicated that acitretin does not interfere with the actions of oestrogen-progesterone oral contraceptives. In a study of ten healthy male volunteers, acitretin did not interfere with the hypoprothrombinemic effect of the coumarin-type anticoagulant, phenprocoumon. Progestogen-only oral contraceptives ("Minipills") should be avoided as a contraceptive measure because their efficacy may be reduced by retinoid treatment.
Concomitant administration of vitamin A and other retinoids must be avoided because of the risk of hypervitaminosis A (see Section 4.3 Contraindications).
Investigations into the effect of acitretin on the protein binding of anticoagulants of the coumarin type (warfarin) revealed no interaction.
Methotrexate, tetracyclines (see Section 4.3 Contraindications).
In a study of twelve healthy male subjects, the concomitant administration of digoxin and acitretin did not alter the pharmacokinetics of either drug. In a study of ten healthy men, the concomitant administration of cimetidine and acitretin did not alter the pharmacokinetics of either drug.
Further interactions between acitretin and other substances (e.g. digoxin, cimetidine, combined estrogen/progestogen oral contraceptives) have not been observed so far.
In concurrent treatment with phenytoin, it must be remembered that acitretin partially reduces the protein binding of phenytoin.
Concomitant administration of alcohol may cause increased levels of etretinate, which is much slower than acitretin to be eliminated from the body. Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol. In a 2-way crossover study, all 10 subjects formed etretinate with concurrent ingestion of a single 100 mg oral dose of acitretin during a 3 hour period of ethanol ingestion (total ethanol ~1.4 g/kg body weight). A mean peak etretinate concentration of 59 nanogram/mL (range: 22 - 105 nanogram/mL) was observed and extrapolation of AUC values indicated that the formation of etretinate in this study was comparable to a single 5 mg oral dose of etretinate. Ethanol must not be ingested during treatment with acitretin by women of childbearing age, as clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol. This result was also observed in vitro. The mechanism of this metabolic process has not been defined, so it is not clear whether other interacting agents are also possible. Ethanol should be avoided for two months after cessation of acitretin therapy.

Note.

In a study with healthy volunteers, concurrent intake of a single dose of acitretin together with ethanol led to the formation of etretinate. This was already observed in vitro. In recent investigations, the formation of etretinate has also been observed in certain patients treated with acitretin. Until this phenomenon has been fully explained, the pharmacokinetic behaviour of etretinate must be taken into account. Therefore, since the elimination half-life of etretinate is approximately 120 days, contraceptive measures must be taken for 3 years after completion of acitretin treatment.
There appears to be no pharmacokinetic interaction between acitretin and cimetidine, digoxin, phenprocoumon, oral contraceptives or glyburide.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Full patient information as specified in the Pregnancy Prevention Program about the tetratogenic risk and the strict pregnancy prevention measures should be given by the physician to all patients, both male and female.
Acitretin should only be prescribed by physicians who are experienced in the use of systemic retinoids and understand the risk of teratogenicity associated with acitretin therapy.
See Section 4.6, Use in pregnancy for further information.
(Category X)
Acitretin must not be used by females who are pregnant or who may become pregnant while undergoing treatment. Acitretin is highly teratogenic. Its use is contraindicated in pregnant women and women who might become pregnant during or within 3 years of the cessation of treatment. The risk of giving birth to a deformed child is exceptionally high if acitretin is taken before or during pregnancy, no matter for how long or at what dosage. Foetal exposure to acitretin always involves a risk of congenital malformation.
Acitretin is contraindicated in women of childbearing potential unless the patient meets all of the following conditions:
has severe psoriasis or disorder of keratinisation;
is unresponsive to or intolerant of standard non-teratogenic therapies;
is reliable in understanding and carrying out instructions;
is capable of complying with the mandatory contraceptive measures;
it is absolutely essential that every woman of childbearing potential who is to undergo treatment with acitretin uses effective contraception (preferably 2 complementary methods) without interruption for four weeks before, during and for 3 years after the discontinuation of treatment with acitretin. Primary contraceptive method is a combination hormonal contraceptive product or an intrauterine device and it is recommended that a condom or diaphragm (cap) is also used. Low dose progesterone-only products (minipills) are not recommended due to indications of possible interference with their contraceptive effect;
has received both oral and written warnings of the hazards of foetal exposure to acitretin and the risk of possible contraception failure and the possible consequences if pregnancy occurs during the course of treatment with acitretin or within 3 years of discontinuing therapy and has acknowledged her understanding of these warnings;
has had a negative serum or urine pregnancy test (minimum sensitivity of 25 mlU/mL) must be obtained up to three days before the first dose is given. During therapy, pregnancy tests should be arranged at 28-day intervals. A negative pregnancy test not older than 3 days is mandatory before prescription is made at these visits. After stopping therapy, pregnancy tests should be performed at 1-3 monthly intervals for a period of 3 years after the last dose is given;
will begin therapy only on the second or third day of the next normal menstrual period;
must avoid alcohol consumption (in food, drinks and medicine) during treatment and for 2 months after stopping treatment.
It is recommended that a prescription should not be issued until a report of a negative pregnancy test has been obtained and the patient has begun her menstrual period. It is also recommended that additional pregnancy tests are performed at monthly intervals during therapy and at 1-3 monthly intervals after stopping therapy. Acitretin is a metabolite of etretinate. Major human foetal abnormalities related to etretinate administration have been reported, including meningomyelocele, meningoencephalocele, multiple synostoses, facial dysmorphia, syndactylies, absence of terminal phalanges, malformations of hip, ankle and forearm, low set ears, high palate, decreased cranial volume, and alterations of the skull and cervical vertebrae on x-ray. Fatalities related to some of these malformations have been reported.
It is absolutely essential that every woman of childbearing potential who is to undergo treatment with acitretin uses effective contraception (preferably 2 complementary methods) must be used for at least one month before beginning acitretin therapy, throughout therapy and for three years following discontinuation of therapy. The same effective and uninterrupted contraceptive measures must be taken every time therapy is repeated, however long the intervening period may have been, and must be continued for 3 years afterwards.
The formation of etretinate has been observed in certain patients treated with acitretin. Until this phenomenon has been fully explained, the pharmacokinetic behaviour of etretinate must be taken into account. Since the elimination half-life of etretinate is approximately 120 days, contraceptive measures must be taken for three years following discontinuation of therapy even where there has been a history of infertility, unless due to hysterectomy.
Women who have taken Tigason (etretinate) must continue to follow the contraceptive recommendations for Tigason.
Should pregnancy occur, in spite of these precautions, there is a high risk of severe malformation of the foetus (e.g. craniofacial defects, cardiac and vascular or CNS malformations, skeletal and thymic defects) and the incidence of spontaneous abortion is increased. The risk applies especially during treatment with acitretin and 2 months after treatment. For up to 3 years after acitretin discontinuation, the risk is lower (particularly in women who have not consumed alcohol) but cannot be entirely excluded (due to possible formation of etretinate).
 Acitretin must not be given to nursing mothers.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects are seen in most patients receiving acitretin. However, they usually disappear when the dosage is reduced or the drug withdrawn. An initial worsening of the disease symptoms is sometimes seen.
Most of the adverse effects occurring in association with systemic retinoids, including acitretin, resemble those of excessive vitamin A intake.
During treatment with high doses of acitretin, reversible elevation of serum triglycerides and serum cholesterol has occurred, especially in high risk patients (disturbances of lipid metabolism, diabetes mellitus, obesity, alcoholism). An associated risk of atherogenesis cannot be ruled out if these conditions persist.

Skin and appendages.

Very common: Dry skin or lips, pruritus, erythema, rash, scaling particularly on palms and soles, skin fragility, thinning of skin, sticky skin, alopecia, nail fragility, paronychia.
Common: Bullous eruption, abnormal hair texture, dermatitis.
Uncommon: Photosensitivity reactions.
Rare: Retinoid dermatitis (occasionally provoking psoriatic lesions), urticaria.
Frequency not known: Pyogenic granuloma, madarosis, angioedema, exfoliative dermatitis.

Ocular.

Very common: Dry eyes, eye irritation, intolerance of contact lenses, xerophthalmia, conjunctivitis.
Common: Blurred vision, impaired night vision.
Rare: Keratitis, corneal erosions or ulcerations, abrasion and irregularities leading to corneal opacities, papilloedema.

Special senses other.

Common: Tinnitus, taste perversion.
Uncommon: Deafness.

Respiratory.

Very common: Drying of and inflammation of mucous membranes e.g. epistaxis, rhinitis.
Not known: dysphonia.

Thoracic and mediastinal.

Frequency unknown: Dysphonia

Cardiovascular.

Common: Flushing.

Musculoskeletal.

Common: Arthalgia, arthritis, muscle, joint and bone pain. In chronic hypervitaminosis A syndrome, demineralisation and rarefaction of bone, cortical hyperostosis, periosteal calcification, premature epiphyseal closures (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use). In long-term treatment, irreversible hyperostosis and extra-skeletal calcification e.g. spinal hyperostosis and calcification of spinal ligaments resulting in spinal cord compression (see Section 4.4 Special Warnings and Precautions for Use, Hyperostosis), myalgia in the case of marked CK elevation.
Rare: Elevated serum creatine kinase (CK).
Very rare: Exostosis (maintenance treatment may result in progression of existing spinal hyperostosis, in appearance of new hyperostotic lesions and in extraskeletal calcification, as has been observed in long-term systemic treatment with retinoids) (see Section 4.4 Special Warnings and Precautions for Use.)

Neurological and psychiatric.

Common: Headache, fatigue, depression, somnolence.
Uncommon: Lassitude, vertigo, dizziness, disturbance of consciousness, abnormal thinking, emotional lability, aggressive feelings.
Rare: Pseudotumour cerebri (see Section 4.4 Special Warnings and Precautions for Use, Pseudotumour cerebri), peripheral neuropathy.

Endocrine.

Rare: Gynaecomastia.

Metabolic and nutritional.

Very common: Elevated serum cholesterol and triglycerides (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
Rare: Oedema, thirst.

Liver and biliary system.

Very common: Elevated serum transaminases and alkaline phosphatase (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests).
Uncommon: Jaundice, hepatitis.

Gastrointestinal.

Very common: Cheilitis, rhagades of corner of mouth, thirst, dry mouth.
Common: Stomatitis, gingivitis, gastro-intestinal disorders (e.g. abdominal pain, diarrhoea, nausea, vomiting).
Uncommon: Gastritis, heartburn, inflammatory bowel disorders.
Rare: Pancreatitis, hepatitis, icterus.
Frequency not known: Dysgeusia, rectal haemorrhage.

Genitourinary.

Rare: Metrorrhagia.

Immunological.

Uncommon: Vulvovaginitis due to Candida albicans.
Not known: Type I hypersensitivity.

Reproductive system and breast disorders.

Frequency not known: Erectile dysfunction.

General disorders and administration site conditions.

Common: Peripheral oedema.

Investigations.

Very Common: Liver function test abnormal (transient, usually reversible elevation of transaminases and alkaline phosphatases). Lipids abnormal (during treatment with high doses of acitretin, reversible elevation of serum triglycerides and serum cholesterol has occurred, especially in high-risk patients and during long-term treatment. An associated risk of atherogenesis cannot be ruled out if these conditions persist).

Children.

There have been occasional reports of bone changes in children, including premature epiphyseal closure, skeletal hyperostosis and extraosseous calcification after long-term treatment with etretinate, these effects may be expected with acitretin. In children, growth parameters and bone development must be closely monitored.

Diabetics.

Retinoids can either improve or worsen glucose tolerance.

Post market.

Very rare cases of capillary leak syndrome/ retinoic acid syndrome have been reported from worldwide post marketing experience.
Very rare cases of exfoliative dermatitis have been reported from world-wide post marketing experience.

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 http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Zetin should only be prescribed by physicians who are experienced in the use of systemic retinoids and understand the risk of teratogenicity associated with acitretin therapy.

Adults.

Because there are differences in the absorption and rate of metabolism of acitretin, the dosage must be individually adjusted. The capsules should be taken preferably once daily with meals, or with milk.
An initial dosage of 25 mg or 30 mg for about two to four weeks may give satisfactory therapeutic results.
The maintenance dose must be based on clinical efficacy and tolerance. In general, a daily dosage of 25 - 50 mg taken for a further six to eight weeks achieves optimal therapeutic results.
Therapy can be terminated in patients with psoriasis whose lesions have resolved sufficiently. Relapses should be treated as described above.
In disorders of keratinisation, a continuous maintenance is mostly needed with the dose at the lowest possible level. This may be less than 20 mg and should not exceed 50 mg daily.

Children.

In view of possible severe side effects associated with long-term treatment, the risk should be carefully weighed against the therapeutic benefit. Acitretin should be used only when all alternative therapies have provided inadequate. The dosage should be established on a weight basis. The daily dosage is about 0.5 mg/kg. Higher doses up to 1 mg/kg or 35 mg daily may be necessary in some cases for limited periods. Maintenance doses should be kept as low as possible in view of possible long term adverse effects.

Combined treatment.

When Zetin is used in combination with other types of therapy, it may be possible, depending on the patient's individual response, to reduce the dosage of Zetin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Standard topical treatments can generally be continued and do not interfere with Zetin.

4.7 Effects on Ability to Drive and Use Machines

Decreased night vision has been reported with acitretin therapy. Patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. Visual problems should be carefully monitored.

4.9 Overdose

Symptoms.

In the event of acute overdosage, Zetin must be withdrawn at once. Symptoms of overdose are identical to an acute hypervitaminosis A, i.e. headache and vertigo. The acute oral toxicity (LD50) of acitretin in both mice and rats was greater than 4000 mg/kg.

Treatment.

Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Zetin capsule contains acitretin as the active ingredient. In addition, each capsule contains the following inactive ingredients: maltodextrin, sodium ascorbate, microcrystalline cellulose, gelatin, sodium lauryl sulfate, purified water, black printing ink (shellac glaze, iron oxide black (E172), propylene glycol (E1520)) and the colourants iron oxide red (E172), iron oxide yellow (E172) and titanium dioxide.

6.2 Incompatibilities

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

6.3 Shelf Life

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

Store below 25°C. Protect from light and moisture.
The product is sensitive to moisture, therefore, store in the original package.

6.5 Nature and Contents of Container

Zetin 10 mg capsule.

Blister pack (PVC/PVDC/Aluminium foil) of 60 and 100 capsules (AUST R 196005).

Zetin 25 mg capsule.

Blister pack (PVC/PVDC/Aluminium foil) of 60 and 100 capsules (AUST R 196004).
Not all strengths and/or pack sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes