Consumer medicine information

Neotigason

Acitretin

BRAND INFORMATION

Brand name

Neotigason

Active ingredient

Acitretin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Neotigason.

What is in this leaflet

This leaflet answers some common questions about NEOTIGASON 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 NEOTIGASON Capsules 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 is Neotigason used for

NEOTIGASON contains the active ingredient acitretin.

NEOTIGASON is used to treat severe psoriasis (skin disease with thickened patches of red skin, often with silvery scales) and other severe disorders of the skin.

NEOTIGASON belongs to a group of medicines called retinoids, which are very similar to Vitamin A. Vitamin A, which we obtain from food, is important for the normal growth and development of the body, especially the skin.

In severe psoriasis and some other skin disorders, where there is problem with the normal development of the skin, NEOTIGASON helps return the skin to normal.

There are many different types of medicines used to treat skin conditions.

Your doctor may have prescribed NEOTIGASON for another purpose.

Ask your doctor if you have any questions why NEOTIGASON has been prescribed for you.

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

Before you take Neotigason

Do not take NEOTIGASON if:

  • you are pregnant, or intend to become pregnant during treatment or in the 3 years after stopping treatment.

The possibility that you may be pregnant must be ruled out by you and your doctor before you start taking Neotigason.

A pregnancy test must be negative when performed within one week before beginning of treatment.

NEOTIGASON is highly teratogenic and there is an extremely high risk that a severely deformed baby will result if taken before or during pregnancy, no matter for how long or at what dose.

You must use effective contraception (preferably two complementary forms), without interruption for one month before, during and 3 years after treatment.

A combination hormonal contraceptive product or an intrauterine device should be used. It is recommended that a diaphragm is also used. Low dose minipills (progesterone only) are not recommended.

  • you are breastfeeding. Breastfeeding must be stopped before treatment begins. Do not breastfeed while taking NEOTIGASON.
  • you have had an allergic reaction to NEOTIGASON, Vitamin A, other retinoids or any ingredients listed in the Ingredients section of this leaflet.
  • you are taking tetracycline antibiotics (such as doxycycline HCl: In Australia, Doryx®, Vibramycin®; in New Zealand Doxine®, Doxy 50®, or Minocycline HCl, Minomycin®)
  • you are taking vitamin A, or preparations containing vitamin A.
  • You have severe liver or kidney disease or abnormally high fat levels in your blood
  • You are also taking methotrexate

Do not take NEOTIGASON after the expiry date (EXP) printed on the pack. It may have no effect or, worse, an entirely unexpected effect if you take it after the expiry date.

Do not take NEOTIGASON if the package is torn or shows signs of tampering.

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

You must tell your doctor if:

  1. you are allergic to any other medicines, foods, dyes or preservatives.
  2. you have any other health problems including:
  • diabetes, or a history of diabetes in your family
  • liver disease
  • high triglycerides or cholesterol levels in the blood, or a history of high blood triglycerides or cholesterol levels in your family

Taking other medicines

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

Other medicines may interfere with NEOTIGASON. These medicines include:

  • tetracycline antibiotics (such as minomycin, or in Australia, Vibramycin®; in New Zealand, Doxine®)
  • phenytoin (such as Dilantin®)
  • methotrexate
  • alcohol containing medicines
  • you are taking a low-dose progestogen oral contraceptive (also called the "mini-pill")
  • vitamin A supplements, or preparations containing vitamin A.

Your doctor or pharmacist has a complete list of medicines to avoid while taking NEOTIGASON.

If you have not told your doctor about any of the above, tell them before you start taking NEOTIGASON.

Use NEOTIGASON exactly as your doctor has prescribed.

Use in Children

NEOTIGASON should only be used in children where alternative therapy cannot be used.

How to take Neotigason

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

Take NEOTIGASON exactly as your doctor has prescribed.

Your doctor will tell you how many NEOTIGASON Capsules to take each day.

This quantity will be especially matched to your needs and whether you develop any side effects.

The initial dose is usually 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.

You may notice the first signs of improvement during the first week but, more often, after 2 or 3 weeks. It may take 2 to 3 months before the full effect is seen.

The affected skin will either peel off or gradually clear. Sometimes there will be more redness or itching at first, but this will normally improve as treatment continues.

How to take it

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

When to take it

NEOTIGASON is usually taken once daily with meals or with a glass of milk.

If you are female, you should wait until the 2nd or 3rd day of your next normal menstrual period before you start NEOTIGASON therapy.

How long to take NEOTIGASON

Continue taking NEOTIGASON until your doctor tells you to stop.

If you forget to take NEOTIGASON

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 double a dose to make up for one you have missed.

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

If you have trouble remembering your dose, ask your pharmacist for some hints.

In case of an overdose

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) in Australia or New Zealand National Poisons Centre (0800764766) 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 NEOTIGASON. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

There is no information currently available on the effects of overdose with NEOTIGASON. However, based on experience with excessive vitamin A and other drugs similar to NEOTIGASON, signs of overdosage may include transient headache, vomiting, flushed face, dry skin and lips, pain in the stomach, dizziness and unco-ordination. You should recover without any after effects. You may need some tests to see if your liver has been affected.

Keep telephone numbers for these places handy.

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

While you are taking Neotigason

Things you must do

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

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 do some blood, liver function and other tests from time to time to check on your progress and detect any unwanted side effects.

Your cholesterol and serum triglyceride levels should be monitored when NEOTIGASON is used for a long time.

Tell your doctor if you are taking vitamin supplements that contain greater than 2500 IU of Vitamin A. If you are not sure, check with your doctor or pharmacist.

Avoid alcohol in drinks, food or medicines during treatment. Alcohol should also be avoided for 2 months after stopping treatment with NEOTIGASON.

FOR FEMALE PATIENTS:

You must use two forms of birth control without interruption for at least 1 month before you start NEOTIGASON and for the whole time you are taking NEOTIGASON and for at least 3 years after you finish taking NEOTIGASON.

Therapy should be started on the second or third day of your next normal menstrual period.

Stop taking NEOTIGASON immediately and tell your doctor if you do become pregnant while you are taking NEOTIGASON. You must also tell your doctor if you become pregnant in the three years following the end of treatment.

Your doctor may ask you to have a pregnancy test every month during use and every 1-3 months after stopping until 3 years have passed.

Things you must not do

Do not stop taking NEOTIGASON 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 donate blood during treatment or for at least 3 years after stopping treatment.

Do not use oral contraceptive "Minipills" (progestogen only pills) as contraception during treatment.

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

Do not use NEOTIGASON to treat 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 or consulting a pharmacist.

Things to be careful of

Normally your ability to drive cars or operate machinery is not affected by NEOTIGASON, however decreased night vision has been reported. Patients may need to be cautious before they drive a car or operate machinery at night.

Wearing contact lenses during treatment and for a little while after treatment with NEOTIGASON may cause discomfort. An eye lubricant, or artificial tears, available from your pharmacist (chemist), will assist with this problem. Otherwise, you may temporarily need to wear glasses instead.

Your skin may be more sensitive to sunburn while on NEOTIGASON.

Avoid excessive sun exposure and apply a sunscreen while taking NEOTIGASON.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking NEOTIGASON.

NEOTIGASON helps most people with skin conditions but it may have unwanted side effects in some people.

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.

If side effects do occur, they may be:

  • 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
  • thinning or peeling of the skin that was not previously affected (for example, hands and feet)
  • sticky skin may occur
  • hair loss sometimes occurs (and in rare cases, has persisted)
  • rash, "redness of the skin" or itchiness
  • flushing.

These side effects will probably stop after the dose of NEOTIGASON is lowered or stopped.

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

  • unusually severe or persistent headaches
  • nausea
  • diarrhoea
  • tenderness or stiffness in your joints or muscles or bones
  • fatigue
  • dizziness
  • sleepiness
  • mood changes
  • depression
  • male breast enlargement
  • water retention
  • gastritis
  • heartburn
  • changes in hearing
  • irregular menstrual bleeding
  • sore mouth or inflammation of the gums
  • taste disturbances
  • tingling, numbing or weakness in the hands or feet.

These side effects could mean that the dose of NEOTIGASON needs to be adjusted.

Stop taking NEOTIGASON and see your doctor if you experience any of the following:

  • nausea
  • vomiting
  • headache
  • blurred vision or visual disturbances

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 Neotigason

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

Keep NEOTIGASON in a cool dry place where the temperature stays below 25°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. Heat and dampness can destroy some medicines.

Protect NEOTIGASON from light.

Keep NEOTIGASON 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 NEOTIGASON, or the capsule has passed its expiry date, you should return any capsules remaining at the end of treatment to your dermatologist.

Product description

What NEOTIGASON looks like

NEOTIGASON 10 mg hard gelatin capsules have a white opaque body and a brown opaque cap with a "10" printed on the body.

NEOTIGASON 25 mg hard gelatin capsules have a yellow opaque body and a brown opaque cap with a "25" printed on the body.

Ingredients

Active ingredient - acitretin

  • each 10 mg capsule contain 10 mg acitretin
  • each 25 mg capsule contain 25 mg acitretin

Inactive ingredients -

  • gelatin, glucose liquid spray-dried, sodium ascorbate, microcrystalline cellulose and the colours iron oxide black (CI77499), iron oxide yellow (CI 77492), iron oxide red (CI 77491) and titanium dioxide.

NEOTIGASON Capsules are gluten free.

NEOTIGASON Capsules are lactose free.

NEOTIGASON Capsules come in cartons of 100.

In Australia

Sponsor:

Teva Pharma Australia Pty Ltd
Level 1, 37 Epping Rd
Macquarie Park, NSW, 2113
Telephone: 1800 288 382

In New Zealand

Sponsor and Distributor:

Teva Pharma (New Zealand) Limited
Auckland, New Zealand

Please check with your pharmacist for the latest Consumer Medicine Information.

Australian Registration Numbers:

NEOTIGASON 10 mg has the registration number AUST R 52455

NEOTIGASON 25 mg has the registration number AUST R 52456.

This leaflet was updated in July 2018

Published by MIMS October 2018

BRAND INFORMATION

Brand name

Neotigason

Active ingredient

Acitretin

Schedule

S4

 

1 Name of Medicine

Acitretin.

2 Qualitative and Quantitative Composition

Neotigason (acitretin) is a retinoid for the oral treatment of severe cases of psoriasis and disorders of keratinisation. It is available as 10 and 25 mg capsules.
The chemical name of acitretin is all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl- 2,4,6,8-nonatetranoic acid. Its empirical formula is C21H26O3 with a molecular weight of 326.44.
Each 10 mg Neotigason capsule contains 10 mg of acitretin.
Each 25 mg Neotigason capsule contains 25 mg of acitretin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

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.
The hard gelatin capsules have a white opaque body and a brown opaque cap with the number "10" printed in black ink on the body.
The hard gelatin capsules have a yellow opaque body and a brown opaque cap with the number "25" printed in black ink on the body.

4 Clinical Particulars

4.1 Therapeutic Indications

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.

4.2 Dose and Method of Administration

Neotigason 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.

Dosage considerations.

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 Neotigason 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 Neotigason (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Standard topical treatments can generally be continued and do not interfere with Neotigason.

4.3 Contraindications

Neotigason (acitretin) is strictly contraindicated in:
pregnant women;
women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met.
Neotigason is highly teratogenic, inducing a high frequency of severe and life threatening birth defects. Neotigason 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.
Neotigason is also contraindicated in people who are hypersensitive to acitretin or other ingredients in Neotigason capsules, or to other retinoids.
Women of childbearing potential must not receive blood from patients being treated with Neotigason. Donation of blood by a patient being treated with Neotigason is prohibited during and for three years after completion of treatment with Neotigason.
Neotigason is contraindicated while breastfeeding.
Neotigason is contraindicated in patients with severely impaired liver or kidney function and in patients with chronic abnormally elevated blood lipid values.
Since both Neotigason 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 Neotigason is also contraindicated.
Concomitant administration of Neotigason 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 programme.

This medicinal product is teratogenic.
Acitretin is contraindicated in women of childbearing potential unless all of the following conditions of the Pregnancy Prevention Programme 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 with a minimum sensitivity of 25 mUI/mL 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.

Pseudotumour cerebri.

Neotigason 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 Neotigason immediately and be referred for neurologic evaluation and care.

Hyperostosis.

In clinical trials with Neotigason, patients were prospectively evaluated for evidence of development or change in bony abnormalities of the vertebral column. Of 262 patients treated with Neotigason, 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 Neotigason, 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.

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.

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 Neotigason 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 Neotigason 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.

Use in the elderly.

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.

Effects on laboratory tests.

Lipids.

Blood lipid determinations should be performed before Neotigason 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 Neotigason 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 Neotigason 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 Neotigason 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 hypoprothrombinaemic 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 Neotigason 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 bodyweight). 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 Neotigason 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 Programme about the teratogenic risk and the strict pregnancy prevention measures should be given by the physician to all patients, both male and female.
Neotigason 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 Fertility, Pregnancy and Lactation for further information.
(Category X)
Neotigason 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.
Neotigason 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 Neotigason 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 mIU/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 Neotigason 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 Neotigason. 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).
 Neotigason must not be given to nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

Decreased night vision has been reported with Neotigason 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.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects are seen in most patients receiving Neotigason. 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 Neotigason 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.

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.

Summary of the safety profile.

Undesirable effects reported for acitretin in clinical trials or as post-marketing events are listed in Table 1 by System Organ Class and frequency. The frequencies of adverse events are ranked according to the following: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Post market.

Very rare cases of Capillary Leak Syndrome/ retinoic acid syndrome have been reported from world-wide 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 www.tga.gov.au/reporting-problems.

4.9 Overdose

In the event of acute overdose, Neotigason 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 4,000 mg/kg.
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).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Neotigason 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 Neotigason 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each 10 mg Neotigason capsule contains 10 mg of acitretin.
It also contains Cellulose - microcrystalline, Gelatin, Glucose - spray-dried liquid, Iron oxide black, Iron oxide red, Iron oxide yellow, Opacode monogramming ink S-1-17822 Black (PI), Opacode monogramming ink S-1-17823 Black (PI), Sodium ascorbate and Titanium dioxide.
Each 25 mg Neotigason capsule contains 25 mg of acitretin.
It also contains Cellulose - microcrystalline, Gelatin, Glucose - spray-dried liquid, Iron oxide black, Iron oxide red, Iron oxide yellow, Opacode monogramming ink S-1-17822 Black (PI), Opacode monogramming ink S-1-17823 Black (PI), Sodium ascorbate 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.
The product is sensitive to moisture, therefore, store in the original package.

6.5 Nature and Contents of Container

Capsules 10 mg.

Cartons of 10, 30, 100.

Capsules 25 mg.

Cartons of 10, 30, 100.
Note: Not all sizes may be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


CAS number.

CAS Registry Number: 55079-83-9.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes