Consumer medicine information

Oratane

Isotretinoin

BRAND INFORMATION

Brand name

Oratane

Active ingredient

Isotretinoin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Oratane.

What is in this leaflet

This leaflet answers some of the common questions about ORATANE® 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 ORATANE® capsules against the benefits the medicine is expected to 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 ORATANE® used for

The active ingredient in ORATANE® capsules is isotretinoin, a substance very similar to vitamin A.

ORATANE® belongs to a group of medicines called retinoids.

ORATANE® capsules are used to treat acne. Of the many acne medicines, ORATANE® is used for more severe cases.

ORATANE® capsules work by cutting down the amount of oily substances (sebum) made by glands in your skin. ORATANE® capsules will also help to reduce bacteria, inflammation and open clogged pores.

Your doctor may have prescribed ORATANE® capsules for another purpose.

Ask your doctor if you have any questions about why ORATANE® capsules have been prescribed for you.

ORATANE® capsules are not addictive.

Before you take ORATANE®

When you must not take ORATANE® capsules

Do not take ORATANE® capsules if:

1. you are pregnant or for at least one month before you intend to become pregnant.
If you fall pregnant while taking Oratane® Capsules, there is an extremely high risk of having a baby that is severely deformed. This means that you must use effective contraception for one month before, during and one month after treatment with Oratane® Capsules.
2. you are breastfeeding.
Breastfeeding must stop before Oratane® treatment can start. Do not breastfeed while taking Oratane® Capsules.
  1. you have had an allergic reaction to ORATANE® capsules, vitamin A, other retinoids or any ingredients listed at the end of this leaflet.
  2. you are taking tetracycline antibiotics. These include doxycycline hydrochloride (Doryx®, Doxine, Doxy, Vibra-Tabs 50®, Frakas®), tetracyclin hydrochloride (Achromycin®) , minomycin hydrochloride (Minomycin® 50, Akamin®).
  3. you have severe liver disease.
  4. you have very high levels of fat (triglycerides, cholesterol) in your blood.
  5. you have an excessive amount of vitamin A in your diet (hypervitaminosis A).
  6. the packaging is torn or shows signs of tampering, or if the capsules do not look quite right.
  7. the expiry date (EXP) printed on the pack has passed. If you take this medicine after the expiry has passed, it may not work as well.

If you are not sure if you should start taking ORATANE® capsules, contact your doctor.

Do not give ORATANE® capsules to children. There is very little information available on the effects of ORATANE® in children.

Before you start to take ORATANE® capsules.

You must tell your doctor if:

  1. you have allergies to other substances, such as medicines, foods, preservatives or dyes. Oratane® capsules contain soya oil, which may contain traces of arachidic acid (a component of peanut oil).
  2. you have any other health problems or issues including:
  • diabetes, or family members with diabetes
  • depression, or family members with depression
  • liver disease
  • kidney disease
  • lipid (cholesterol or triglyceride) disorder
  • hormone disorder
  • stomach or bowel disease
  1. you drink large amounts of alcohol.

If you have not told your doctor about any of the above, tell him or her before starting ORATANE® capsules.

Taking other medicines

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

Some medicines interfere with ORATANE® capsules. These include:

  • tetracycline antibiotics, including Doryx®, Doxine, Doxy, Vibra-Tabs 50®, Frakas® Achromycin® Minomycin® 50 and Akamin®.
  • vitamin A or formulations containing vitamin A, including vitamin supplements.
  • other medicines for acne.
  • the mini-pill, a progesterone-only oral contraceptive pill.

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

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

How to take ORATANE® capsules

How much to take

Always take ORATANE® capsules exactly as your doctor or pharmacist tells you to. The directions given may differ from information contained in this leaflet.

Your doctor will determine exactly how much ORATANE® capsules you need for your condition.

This will be matched especially to your needs and your bodyweight and may be adjusted by your doctor when it is known how you respond to ORATANE® capsules.

How to take it

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

Do not open ORATANE® capsules or take damaged ORATANE® capsules.

When to take it

ORATANE® capsules are taken once or twice a day and must be taken with meals.

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

How long to take it

Continue taking ORATANE® capsules for as long as your doctor prescribes.

Your treatment with ORATANE® capsules will usually last 16 weeks. Sometimes a second course of treatment may be necessary. In the first few weeks your acne will probably get worse before it gets better. Don’t worry as this is a sign that ORATANE® capsules are working.

After this treatment period, your skin should have cleared up significantly. Skin condition continues to improve even after ORATANE® treatment has finished.

ORATANE® capsules cannot improve scars or pitting that existed before commencement of treatment, but it will prevent further scarring.

If you forget to take ORATANE® capsules

If you forget to take ORATANE® capsules, do not make up for the missing dose by doubling the next dose. This may increase the chance of getting an unwanted side effect.

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

If you have missed several doses, please inform your doctor and follow the advice given to you.

In case of an overdose

Immediately telephone your doctor, or Poisons Information Centre (Ph: 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too many ORATANE® capsules. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Signs of overdose include transient headache, vomiting, facial flushing, reddened, cracked lips, stomach pain, headache, dizziness and unsteady walking.

Keep telephone numbers for these places handy.

While you are taking ORATANE®

Things you must do

If you become pregnant while taking ORATANE® capsules, stop taking it and inform your doctor immediately. ORATANE® capsules can cause birth defects (damage to unborn babies). This means that you must use strict birth control for at least 1 month before you start ORATANE® capsules and for the whole time you are taking ORATANE® capsules and for at least 1 month after you finish taking ORATANE® capsules.

There is no known risk to males who wish to father children.

Tell all doctors, dentists and pharmacists who are treating you, that you are on ORATANE® capsules.

Tell your doctor if you feel ORATANE® capsules are not helping your condition. But also tell the doctor if, for any reason, you have not taken your medicine exactly as prescribed.

If you are intending to do a lot of heavy lifting or exercise, tell your doctor. ORATANE® capsules can make your muscles and joints prone to stiffness or tenderness.

Be sure to keep all of your appointments with your doctor so he or she can monitor your progress. You may require regular tests to check your liver, blood sugar levels and blood cholesterol levels.

Things you must not do

Do not stop taking ORATANE® capsules or change the dose without first checking with your doctor.

Do not let yourself run out of ORATANE® capsules over the weekend or on holidays.

Do not use ORATANE® capsules to treat other complaints unless told to by your doctor.

Do not give ORATANE® capsules to anyone else, even if their symptoms seem similar to yours.

Do not donate blood while taking ORATANE® capsules or for at least four weeks after stopping treatment.

Do not take any other medicines without first telling your doctor or pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how ORATANE® capsules affect you. Normally ORATANE® capsules would not affect your ability to drive a car or operate machinery. However, altered night vision and other visual disturbances may occur while taking ORATANE® capsules. Make sure you know how you react to ORATANE® Capsules before you drive a car, operate machinery or do anything else that may be dangerous if your vision is affected.

Wearing contact lenses during treatment with ORATANE® Capsules may cause discomfort. ORATANE® capsules cause dry eyes so an artificial lubricant might be necessary. Otherwise you may need to compensate by wearing your glasses.

Avoid waxing or dermatological abrasions while taking ORATANE® Capsules and for six months after ORATANE® treatment has stopped. Your skin may be more sensitive while on ORATANE® Capsules. Waxing may cause dermatitis and dermatological abrasions may cause scarring during and for several months after treatment.

Avoid excessive sun exposure, solariums and always apply sunscreen while taking ORATANE® capsules. Your skin may be more prone to sunburn while on ORATANE® capsules.

Avoid using facial peels, electrolysis and some hair treatments. Your skin and hair will be more delicate while taking ORATANE® capsules.

Side effects

In addition to the beneficial effects of ORATANE® capsules it is possible that unwanted effects will occur during treatment, even when it is used as directed.

Tell your doctor or pharmacist as soon as possible if you do not feel well while taking ORATANE® capsules.

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.

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

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

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

  • dryness of the lips, mouth, nose, eyes and skin. Soften these areas not affected by acne with moisturiser or petroleum jelly to avoid dryness
  • fragile skin
  • change in colour of the skin
  • peeling of skin on palms of hands and soles of feet
  • itchy skin rash
  • an increased susceptibility to sunburn
  • sweating
  • changes to nails
  • eye problems such as dry, sore, swollen or itchy eyes, discharge or trouble seeing at night
  • sexual dysfunction including impaired sexual function in males, decreased libido and gynaecomastia
  • nosebleeds
  • tenderness, stiffness in bones, joints or muscles
  • headache
  • tiredness
  • temporary hair loss (sometimes occurs and is usually temporary but in rare cases has persisted)
  • excessive hairiness
  • hoarseness

These side effects are usually mild, and dose related. After the dose of ORATANE® capsules is reduced or stopped most of these side effects should disappear within a few days or weeks.

Stop taking ORATANE® capsules and contact your doctor immediately if you experience any of the following:

  • vomiting
  • nausea
  • persistent headache
  • blurred vision or visual disturbances
  • changes in your hearing or ringing in your ears
  • severe upper stomach pain
  • unexpected muscle pain, tenderness or weakness
  • blood in stools or severe diarrhoea
  • severe bruising
  • sudden red, often itchy spots, similar to the rash of measles starting on the face, hands or feet. The spots may blister or change to flat round, raised, red, pale centred marks. Also, you may have fever, sore throat, headache and/or diarrhoea.
  • painful red areas that change to large blisters and end with peeling of layers of skin that may occur on the lips, mouth, eyes, nose and genitals. Those affected may have fever and chill, aching muscle and generally feel unwell.
  • thinking, seeing or hearing things that are not real
  • feeling depressed with or without suicidal thoughts

Symptoms of depression may include:

  • start to feel sad or have crying spells
  • lose interest in activities you once enjoyed
  • sleep too much or have trouble sleeping
  • become more irritable, angry or aggressive than usual e.g. temper outbursts, thoughts of violence
  • have a change in your appetite or body weight
  • have trouble concentrating
  • withdraw from your friends or family
  • feel like you have no energy
  • have feelings of worthlessness or inappropriate guilt
  • start having thoughts about hurting yourself or taking your own life (suicidal thoughts).

These may be serious side effects and may require urgent medical attention. Serious side effects are rare.

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

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list. In some cases, your doctor may want to reduce your dose or stop treatment.

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

If you are concerned about these or any other unexpected effects, please talk to your doctor.

After taking ORATANE® capsules

Storage

Keep your capsules in the blister pack and closed carton until it is time to take them. If you take the capsules out of the packaging they will not keep as well.

Keep ORATANE® 5 mg, 10 mg and 40 mg capsules in a cool dry place where the temperature stays below 25°C. Protect from light and moisture.

Keep ORATANE® 20 mg and 30mg capsules in a cool dry place where the temperature stays below 30°C. Protect from light and moisture.

Do not store ORATANE® capsules or any other medicine in the bathroom or near a sink.

Do not leave ORATANE® capsules in the car or on windowsills. Heat and dampness can destroy some medicines.

Keep ORATANE® capsules where children can not reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

Tell your doctor if you stop taking the capsules or the capsules have passed their expiry date. Ask your pharmacist what to do with any capsules that are left over.

Product description

What ORATANE® capsules look like

ORATANE® 5 mg capsules are soft, oval, faint pinkish/cream to cream in colour containing a yellow/orange liquid. Available in blister packs of 60 capsules.

ORATANE® 10 mg capsules are soft, oval, opaque light violet in colour containing a yellow/orange liquid. Available in blister packs of 60 capsules.

ORATANE® 20 mg capsules are soft, oval, opaque maroon red in colour containing a yellow/orange liquid. Available in blister packs of 60 capsules.

ORATANE® 30 mg capsules are pink coloured soft gelatin capsules containing a yellow/ orange liquid. Available in blister pack of 60 capsules.

ORATANE® 40 mg capsules are soft, oval, opaque orange in colour containing a yellow/orange liquid. Available in blister packs of 30 capsules.

Ingredients

Active ingredient:

Isotretinoin

Inactive ingredients:

The capsules also contain Beeswax – yellow, Disodium edetate, Butylated Hydroxyanisole, dl-alpha-tocopherol, Soya oil – partially hydrogenated, Soya oil, Vegetable oil – hydrogenated (5mg, 10mg and 20mg only), Soya oil – hydrogenated (30mg and 40mg only).

The capsule shell contains Sorbitol solution (70% non-crystallising), Glycerol, Gelatin†, Titanium dioxide, Water – purified, Brilliant scarlet 4R CI16255 (10mg and 20mg only), Sunset yellow FCF CI15985 (40mg only), Indigo carmine CI73015 (20mg only), Iron oxide black CI177499 (10mg only), Iron oxide red (30mg only).

†Contains sulfites. May contain trace amounts of phenylalanine.

ORATANE® 5 mg AUST R 127499

ORATANE® 10 mg AUST R 75034

ORATANE® 20 mg AUST R 69868

ORATANE® 30 mg AUST R 303071

ORATANE® 40 mg AUST R 117206

Further information

If you have any questions about ORATANE® capsules, please ask your doctor or pharmacist. Further information may also be obtained from Arrow Pharmaceuticals Pty Ltd (Ph: 1300 927 769). ORATANE® capsules are only available on your dermatologist’s prescription.

Sponsor

Douglas Pharmaceuticals Australia Pty Ltd
15 – 17 Chapel Street
Cremorne Victoria 3121

Distributed by Arrow Pharmaceuticals Pty Ltd on behalf of Oraderm Pharmaceuticals Pty Ltd
15 – 17 Chapel Street
Cremorne Victoria 3121

This leaflet was last updated in February 2022.

*ORATANE is a registered trade mark of Douglas Pharmaceuticals Limited in New Zealand and other countries.

Published by MIMS January 2023

BRAND INFORMATION

Brand name

Oratane

Active ingredient

Isotretinoin

Schedule

S4

 

Notes

Distributed by Arrow Pharmaceuticals Pty Ltd

1 Name of Medicine

Isotretinoin.

2 Qualitative and Quantitative Composition

Oratane capsules contain either 5 mg, 10 mg, 20 mg, 30 mg, or 40 mg of isotretinoin.
Isotretinoin is related to both retinoic acid and retinol (vitamin A). Isotretinoin is a yellow orange to orange crystalline powder that is practically insoluble in water, soluble in methylene chloride, sparingly soluble in ether and slightly soluble in alcohol. It is sensitive to air, heat and light, especially in solution.

Excipients with known effect.

Soy bean oil.
For full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Oratane 5 mg capsules are soft, oval, faint pinkish/cream to cream in colour containing a yellow/orange liquid.
Oratane 10 mg capsules are light violet coloured soft capsules containing a yellow/orange viscous liquid.
Oratane 20 mg capsules are maroon coloured soft capsules containing a yellow/orange viscous liquid.
Oratane 30 mg capsules are pink coloured soft capsules containing a yellow/orange viscous liquid.
Oratane 40 mg capsules are orange coloured soft capsules containing a yellow/orange viscous liquid.

4 Clinical Particulars

4.1 Therapeutic Indications

Oratane is indicated for the treatment of severe cystic acne and a single course of therapy has been shown to result in complete and prolonged remission of disease in many patients. If a second course of therapy is needed, it should not be initiated until at least eight weeks after completion of the first course, since experience has shown that patients may continue to improve while off the drug. Because of significant adverse effects associated with its use, isotretinoin should be reserved for patients with severe cystic acne who are unresponsive to conventional therapy, including systemic antibiotics.

4.2 Dose and Method of Administration

The therapeutic response to isotretinoin is dose related and varies between patients. This necessitates individual adjustment of dosage according to the response of the condition and the patient's tolerance of the drug. In most cases complete or near complete suppression of acne is achieved with a 16 week course of treatment.
All patients should initially receive doses up to 0.5 mg/kg bodyweight daily for a period of two to four weeks, when their responsiveness to the drug will usually be apparent. It should be noted that the transient exacerbation of acne is occasionally seen during this initial period. Satisfactory initial responses have been reported from 0.05 mg/kg/day. Relapse rates on the lower doses are higher (a second course may be required in about two-thirds of patients on 0.1 mg/kg/day for 16 weeks), but there is decreased incidence and severity of adverse effects at lower doses.
The daily dosage should be taken with food in the nearest number of whole capsules, either as a single dose or in two divided doses during the day, whichever is more convenient.
Doses up to 1 mg/kg/day may be used in patient's refractory to initial treatment at lower doses.
The above daily dosages of isotretinoin should be continued for 16 weeks to complete the course of treatment.
After a period of two months off therapy, and if warranted by persistent severe cystic acne, a second course of therapy may be initiated.

4.3 Contraindications

Use in pregnancy (Category X).

Australian categorisation definition of Category X: Drugs which have such a high risk of causing permanent damage to the foetus that they should not be used in pregnancy or when there is a possibility of pregnancy.
Isotretinoin is highly teratogenic and should not be used during pregnancy.
Isotretinoin must not be used by females who are pregnant or who may possibly become pregnant while undergoing treatment.
Major human foetal abnormalities related to isotretinoin administration have been reported, including hydrocephalus, microcephalus, abnormalities of the external ear (micropinna, small or absent external auditory canals), eye abnormalities (including microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of great vessels, septal defects), facial dysmorphia, cleft palate, thymus gland abnormality, parathyroid gland abnormalities and cerebrellar malformation/ abnormalities. There is also an increased incidence of spontaneous abortion.
Women of childbearing potential should not be given isotretinoin until pregnancy is excluded. It is strongly recommended that a pregnancy test be performed within two weeks prior to isotretinoin therapy. Isotretinoin therapy should start on the second or third day of the next normal menstrual period. An effective form of contraception should be used for at least one month before and also throughout isotretinoin therapy.
It is recommended that contraception be continued for one month following discontinuation of Oratane therapy. Females should be fully counselled on the serious risk to the foetus should they become pregnant while undergoing treatment. If pregnancy does occur during treatment, the physician and patient should discuss the desirability of continuing the pregnancy.
Oratane is contraindicated in patients who are breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
Oratane is contraindicated in patients with severely impaired liver function and in patients with chronic abnormally elevated blood lipid values.
Oratane is contraindicated in patients who have pre-existing hypervitaminosis A.
Rare cases of benign intracranial hypertension have been reported after isotretinoin and after tetracyclines. Concomitant treatment with tetracyclines is, therefore, contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Oratane is also contraindicated in people who are hypersensitive to the drug or other ingredients in Oratane capsules or to other retinoids.

4.4 Special Warnings and Precautions for Use

Women of childbearing potential should be warned that the drug causes birth defects. They should be instructed that they must not be pregnant when isotretinoin therapy is initiated, and that they should use an effective form of contraception while taking isotretinoin and for one month after isotretinoin has been stopped (see Section 4.3 Contraindications).
Because of the relationship of isotretinoin to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
Oratane contains soya oil, therefore, caution should be taken with patients allergic to peanut or soya.
Donation of blood by patients during and within one month of cessation of isotretinoin treatment to women of childbearing potential should be avoided.

Skin and subcutaneous tissue disorders.

Acute exacerbation of acne is generally seen during the initial period of treatment; but this subsides with continued treatment, usually within 7-10 days, and usually does not require dose adjustments.
Wax epilation should be avoided in patients on Oratane and for a period of 5-6 months after treatment because of the risk of epidermal stripping, scarring or dermatitis.
Aggressive chemical dermabrasion and cutaneous laser treatment should be avoided in patients on Oratane and for a period of 5-6 months after the end of treatment because of risk of hypertrophic scarring in atypical areas and more rarely hyper- or hypopigmentation in treated areas.
Exposure to intense sunlight or UV rays should be avoided. Where necessary, a sun protection product with a high protection factor of at least SPF 15 should be used.
Patients should be advised to use a skin moisturising ointment or cream and a lip balm from the start of treatment as Oratane is likely to cause dryness of the skin and lips.
There have been postmarketing reports of severe skin reactions (e.g. erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis) associated with isotretinoin use. These events may be serious and result in death, life threatening events, hospitalisation or disability. Patients should be monitored closely for severe skin reactions and discontinuation of Oratane should be considered if warranted.

Benign intracranial hypertension.

Isotretinoin use has been associated with a number of cases of benign intracranial hypertension (pseudotumour cerebri), some of which involved the concomitant use of tetracyclines. Early signs and symptoms of benign intracranial hypertension include papilloedema, headache, nausea and vomiting, and visual disturbances. Patients who develop benign intracranial hypertension should discontinue Oratane immediately.

Eye disorders.

Dry eyes, corneal opacities, conjunctivitis, blepharitis, decreased night vision and keratitis usually resolve after discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Due to the possible occurrence of keratitis, patients with dry eyes should be monitored. Patients experiencing visual difficulties should be referred for an expert ophthalmological examination and withdrawal of isotretinoin considered. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment.
Corneal opacities have occurred in patients receiving isotretinoin for acne and more frequently when higher drug dosages were used in patients with disorders of keratinisation. All Oratane patients experiencing visual difficulties should discontinue the drug and have an ophthalmological examination.

Hearing impairment.

Impaired hearing has been reported in patients taking isotretinoin. Hearing impairment can be unilateral or bilateral, and symptoms include tinnitus, impaired hearing at certain frequencies and deafness. In some cases, hearing impairment has been reported to persist after therapy has been discontinued. Anyone who experiences these symptoms should immediately seek medical advice; the drug should be ceased and the patient should undergo urgent formal audiology assessment.

Biochemical abnormalities.

Rises in alanine and aspartate aminotransferases enzymes (ALT and AST) have been reported. Liver function tests, especially AST and blood lipids, should be measured before therapy and at monthly intervals during therapy and at the end of treatment. When transaminase levels exceed the normal levels, reduction of dose or discontinuation of treatment may be necessary.
Isotretinoin causes elevation of serum triglycerides and cholesterol as well as a decrease in high density lipoprotein (HDL) which appear to be related to duration of treatment and are reversible on cessation of treatment. The degree of elevation may also be dose dependent, although this has not been conclusively established.
At doses of greater than 1 mg/kg/day, approximately one in four patients have been found to develop elevated triglycerides while taking isotretinoin. At lower doses triglyceride levels elevated above the normal range are uncommon.
Some patients have been able to reverse triglyceride elevations by weight reduction and restriction of dietary fat and alcohol while continuing to take isotretinoin. Serum lipid values usually return to normal on reduction of dose or discontinuation of treatment.
Acute pancreatitis, which is potentially fatal, sometimes associated with serum triglyceride levels > 8 g/L has been reported. Hence, Oratane should be discontinued if uncontrolled hypertriglyceridemia or symptoms of pancreatitis occur.
Serum lipid (fasting value) should be determined one month prior to therapy and again about 4 weeks of therapy and subsequently at three month intervals unless more frequent monitoring is clinically indicated.
Predisposing factors such as a family history of lipid metabolism disorders, obesity, alcohol abuse, diabetes and smoking should be assessed. In high risk patients (with diabetes, obesity, alcoholism or lipid metabolism disorder) undergoing treatment with Oratane, more frequent checks of serum values for lipids and/or blood glucose may be necessary.

Musculoskeletal and connective tissue disorders.

Myalgia, arthralgia and increased serum creatine phosphokinase may occur and may be associated with reduced tolerance to vigorous exercise (see Section 4.8 Adverse Effects (Undesirable Effects)).
In clinical trials of disorders of keratinisation with a mean dose of 2.24 mg/kg/day, a high prevalence of skeletal hyperostosis was noted. Bone changes including premature epiphyseal closure and calcifications of tendons and ligaments have occurred after administration of high doses for long periods for treating disorders of keratinisation. The dose levels, duration of treatment and total cumulative dose in these patients generally far exceeded those recommended for the treatment of acne.
Minimal skeletal hyperostosis has also been observed by X-rays in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses.
Due to the possible occurrence of these bone changes, a careful evaluation of the risk/ benefit ratio should be carried out in every patient and isotretinoin administration should be restricted to severe cases.

Psychiatric disorders.

Depression, psychotic symptoms and, rarely, suicide, suicidal ideation and attempts have been reported with isotretinoin. Particular care needs to be taken in patients with a history of depression and all patients should be monitored for signs of depression. Although no mechanism of action for these events has been established, discontinuation of Oratane may not alleviate symptoms and, therefore, further psychiatric or psychological evaluation may be necessary.

Gastrointestinal disorders.

Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing abdominal pain, rectal bleeding or severe (haemorrhagic) diarrhoea should discontinue isotretinoin immediately.

Allergic reactions.

Anaphylactic reactions have been reported rarely and only after previous topical exposure to retinoids. Allergic cutaneous reactions are reported infrequently. Serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement have been reported. Severe allergic reactions necessitate interruption of therapy and careful monitoring.

Use in hepatic impairment.

Several cases of clinical hepatitis have been noted which are considered to be possibly or probably related to isotretinoin therapy. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalised with dosage reduction or continued administration of the drug. If normalisation does not readily occur or if hepatitis is suspected during treatment with isotretinoin, the drug should be discontinued and the etiology further investigated.

Use in renal impairment.

Renal insufficiency and renal failure do not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin can be given to patients with renal insufficiency. Isotretinoin should be started at a lower dose in patients with severe renal insufficiency and afterwards dose adjusted according to tolerance.

Use in the elderly.

No data available.

Paediatric use.

The approved therapeutic indication does not involve use in children and safety in prepubertal children has not been established (see Section 4.4 Special Warnings and Precautions for Use, Hyperostosis).

Effects on laboratory tests.

Elevation of lipid (triglycerides and cholesterol) levels occurs with isotretinoin therapy. These are usually mild in doses less than 1 mg/kg/day and elevations above the normal range are unusual at 0.5 mg/kg/day. At doses above 1 mg/kg/day, elevation (above normal range) occurs in 25% of patients.
These changes are seen more frequently in patients where a family history of lipid disorders, or obesity, alcohol abuse, diabetes mellitus or smoking is present. The changes are dose related and may be controlled by dietary means (including alcohol restriction) or dosage reduction (see Section 4.4 Special Warnings and Precautions for Use, Biochemical abnormalities).
Elevated ESR values occur in about 40% of patients treated with isotretinoin.
A rise in aspartate aminotransferase (AST) levels may occur, especially with higher doses of isotretinoin. Although the changes have usually been within the normal range, and may return to baseline levels despite continued treatment, significant increases have occurred in a few cases, necessitating dosage reduction or discontinuation of isotretinoin.
Certain patients receiving isotretinoin have experienced problems in the control of their blood sugar. Therefore, known or suspected diabetics should have frequent blood sugar determinations performed during isotretinoin therapy. New cases of diabetes have been diagnosed.
A small number of patients have shown proteinuria, microscopic or gross hematuria and elevated CPK.

4.5 Interactions with Other Medicines and Other Forms of Interactions

As a rule concomitant therapy is not indicated but nonirritant topical preparations may be used if required. Concurrent administration of isotretinoin with topical keratolytic or exfoliative antiacne agents should be avoided as local irritation may increase.
Concurrent treatment with vitamin A must be avoided, as symptoms of hypervitaminosis A may be intensified (see Section 4.8 Adverse Effects (Undesirable Effects)).
Cases of pseudotumour cerebri and/or papilloedema have been reported in association with the use of isotretinoin. Four out of ten of these patients had retinal haemorrhages. Symptoms appeared after 21 days to 6 months therapy with 40 to 120 mg daily. Concomitant tetracycline or minocycline was administered in 5 out of 10 cases; both of these drugs have been implicated in causing intracranial hypertension. Concomitant therapy with tetracyclines is contraindicated (see Section 4.3 Contraindications).
Since acne is an androgen dependent disease, contraceptives containing an androgen progestational substance, such as one derived from 19-nortestosterone (norsteroid), particularly in the presence of gynaecoendocrinological problems, should be avoided.
The effect of microdosed progesterone preparations may be diminished by interaction with isotretinoin. Therefore, microdosed progesterone preparations or "minipills" should not be used.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In the reproductive studies in rats (2, 8 or 32 mg/kg/day; 2-generation), no adverse effects were noted on gonadal function, fertility, gestation or neonatal viability, although the average weight in the high dose group was slightly reduced.
In dogs, testicular atrophy was noted after treatment with isotretinoin for approximately 30 weeks at dosages of 60 or 20 mg/kg/day. In general, there was microscopic evidence for appreciable depression of spermatogenesis, but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen. In studies in 66 human males, 30 of whom were patients with cystic acne, no significant changes were noted in the count or motility of spermatozoa in the ejaculate.
(Category X)
Australian categorisation definition of Category X: Drugs which have such a high risk of causing permanent damage to the foetus that they should not be used in pregnancy or when there is a possibility of pregnancy.
Isotretinoin is a known human teratogen and should not, under any circumstances, be administered during pregnancy (see Section 4.3 Contraindications).
Isotretinoin should only be prescribed by physicians who are experienced in the use of systemic retinoids and understand the risk of teratogenicity.
Isotretinoin is teratogenic in rats and rabbits although sensitivity differs. In the rat, doses up to 50 mg/kg/day were not teratogenic but 150 mg/kg/day was teratogenic. At lower doses in the rat perinatal and post-natal studies (5, 15, 32 mg/kg/day) increased pup mortality was noted in all treatment groups. This was attributed to a dose-related reduction in maternal food intake. Body weight development of pups was significantly impaired in high dose groups.
In the rabbit, a dose of 10 mg/kg/day caused abortions in 9 out of 13 animals and teratogenicity and embryotoxicity were observed in the remaining 4 litters.
 As isotretinoin is highly lipophilic, the passage of the drug in human milk is very likely. Because of the potential for adverse effects, the use of isotretinoin is contraindicated in breastfeeding mothers.

4.7 Effects on Ability to Drive and Use Machines

Decreased night vision has occurred during isotretinoin therapy and in rare instances has persisted after discontinuation of therapy. As the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night.

4.8 Adverse Effects (Undesirable Effects)

Most adverse effects appear to be dose related with the more pronounced effects occurring at doses above 1 mg/kg/day. The adverse effects may recede during continued therapy and the mucocutaneous effects were reversible with dosage reduction or discontinuation of therapy. Exacerbation of the cystic acne may occur during the initial stages of therapy.
Many of the adverse effects seen in patients receiving isotretinoin are similar to those described in patients taking very high doses of vitamin A.

Postmarketing experience.

Symptoms associated with hypervitaminosis A.

The most common side effects are mucocutaneous. The most frequently reported effects are dryness of the skin, in particular peeling of the palms and soles, dryness of the mucosa, e.g. lips (cheilitis which occurs in over 90% of patients), the nasal mucosa (epistaxis is seen in up to 30% of patients), the pharynx (hoarseness) and eyes (conjunctivitis, reversible corneal opacities and intolerance to contact lenses).

Skin and appendages disorders.

Exanthema, pruritus, facial erythema/ dermatitis, sweating, pyogenic granuloma, paronychia, nail dystrophy, increased formation of granulation tissue, persistent hair thinning, reversible alopecia, acne fulminans, hirsutism, hyperpigmentation, photosensitivity, photoallergic effects, skin fragility. Acne flare occurs at the start of treatment and persists for several weeks.
During the postmarketing period, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with isotretinoin (see Section 4.4 Special Warnings and Precautions for Use).

Musculoskeletal system disorders.

Myalgia (muscle pain) with or without elevated serum CPK values (see Section 4.4 Special Warnings and Precautions for Use), arthralgia (joint pain), tenderness or stiffness of bones, hyperostosis, arthritis, calcification of ligaments and tendons and other bone changes, reduced bone density, back pain, epiphyses, premature fusion, tendinitis.
Serious cases of rhabdomyolysis, often leading to hospitalisation and some with fatal outcome have been reported, particularly in those undertaking vigorous physical activity.

Psychiatric and central nervous system disorders.

Behavioural disorders, depression, suicide attempt, suicide (see Section 4.4 Special Warnings and Precautions for Use), headache, increased intracranial pressure (pseudotumour cerebri), and seizures.

Sensory disorders.

Visual disturbances, photophobia, decreased night vision, colour vision disturbances (reversible upon discontinuation), lenticular cataracts, keratitis, blurred vision, blepharitis, conjunctivitis, eye irritation, papilledema as a sign of benign intracranial hypertension, impaired hearing at certain frequencies.

Gastrointestinal system disorders.

Nausea, severe diarrhoea, inflammatory bowel disease such as colitis, ileitis and haemorrhage have been reported to occur. Patients on isotretinoin, especially those with high triglyceride levels, are at risk of developing pancreatitis. Fatal pancreatitis has been rarely reported (see Section 4.4 Special Warnings and Precautions for Use).

Liver and biliary system disorders.

Transient and reversible increases in liver transaminases, some cases of hepatitis.

Respiratory system disorders.

Bronchospasm has been rarely reported; sometimes in patients with a prehistory of asthma.

Reproductive system and breast disorders.

Sexual dysfunction including erectile dysfunction and decreased libido, gynaecomastia. A causal association with these adverse effects has not been established.

Disorders of the blood.

Decrease in white blood cell count, neutropenia, disorders of red blood cell parameters (such as decrease in red blood cell count and haematocrit), elevation of sedimentation rate increase or decrease in platelet count (thrombocytopenia) and anaemia.

Laboratory findings.

Increase in serum triglyceride and cholesterol levels, decrease in HDL, hyperuricemia. Rare cases of elevated blood glucose have been reported, and new cases of diabetes have been diagnosed (see Section 4.4 Special Warnings and Precautions for Use).

Resistance mechanism disorders.

Local or systemic infections due to Gram positive microorganisms (Staphylococcus aureus).

Miscellaneous reactions.

Decreases in haematocrit, lymphadenopathy, hematuria and proteinuria, vasculitis (for example Wegener's granulomatosis, allergic vasculitis), allergic responses, systemic hypersensitivity and glomerulonephritis.

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.

4.9 Overdose

Signs of hypervitaminosis A could appear in cases of overdose. Clinically, overdose has been associated with transient headache, vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness and ataxia. All symptoms quickly resolved without apparent residual effects.
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.

Oratane contains isotretinoin; this is a retinoid that inhibits sebaceous gland function and keratinisation. The exact mechanism of action of isotretinoin is unknown.
Clinical improvement in cystic acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is reversible and the extent is related to the dose and duration of treatment with Oratane and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

There is considerable interindividual variation in the bioavailability of oral isotretinoin. After oral administration of 80 mg isotretinoin (2 x 40 mg capsules) given in the fasting state, peak plasma concentrations ranged from 167 to 459 nanogram/mL and mean time to peak was 3.2 hours in healthy volunteers, while in acne patients peak concentrations ranged from 98 to 535 nanogram/mL (mean 262 nanogram/mL) with a mean time to peak of 2.9 hours.
The bioavailability of isotretinoin capsules taken with food is 1½ to 2 times greater than when taken in a fasting state.

Distribution.

Tissue distribution in animals.

Tissue distribution of 14C-isotretinoin in rats revealed high concentrations of radioactivity in many tissues after 15 minutes, with a maximum in 1 hour and declining to nondetectable levels by 24 hours in most tissues. After seven days, however, low levels of radioactivity were detected in the liver, ureter, adrenal, ovary and lacrimal gland.
The drug is 99.9% bound in human plasma almost exclusively to albumin.

Metabolism.

The major identified metabolite in blood and urine is 4-oxo-isotretinoin. Tretinoin and 4-oxo-tretinoin were also observed. After two 40 mg capsules of isotretinoin, maximum concentrations of the metabolite of 87 to 399 nanogram/mL occurred at 6 to 20 hours. The blood concentration of the major metabolite generally exceeded that of isotretinoin after 6 hours.
The mean ± SD minimum steady-state blood concentrations of isotretinoin were 160 ± 19 nanogram/mL in ten patients receiving 40 mg twice daily. After single and multiple doses, the mean ratio of areas under the curves of isotretinoin to 4-oxo-isotretinoin is 3 to 3.5.

Excretion.

The terminal elimination half-life of isotretinoin ranged from 10 to 20 hours in volunteers and patients. Following an 80 mg liquid suspension oral dose of 14C-isotretinoin, 14C activity in blood declined with a half-life of 90 hours. Relatively equal amounts of radioactivity were recovered in the urine and faeces with 65 to 83% of the dose recovered. The apparent half-life for elimination of the 4-oxo-metabolite ranged from 11 to 50 hours with a mean of 29 hours. This metabolite is subject to recycling in the enterohepatic circulation.

5.3 Preclinical Safety Data

Genotoxicity.

Isotretinoin was negative in tests for gene mutation (histidine reversion in S. typhimurium), chromosomal damage in vitro (Chinese hamster lung cell and S. cervisiae D7 assays) and in vivo (mouse micronucleus test), and unscheduled DNA synthesis in vitro (rat hepatocytes).

Carcinogenicity.

In Fischer 344 rats given isotretinoin at dosages of 32 or 8 mg/kg/day for greater than 18 months, there was dose related increased incidence of pheochromocytoma. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage. There is doubt as to the validity of this animal model as a predictor of tumorigenicity in humans, as the Fischer rat is genetically predisposed to the multiple endocrine neoplasia syndrome which includes spontaneous occurrence of pheochromocytoma. In these studies there was also a dose related decrease in the incidence of liver adenomata, liver angiomata and leukaemia.

6 Pharmaceutical Particulars

6.1 List of Excipients

Oratane capsules contain isotretinoin, beeswax - yellow, disodium edetate, butylated hydroxyanisole, dl-alpha-tocopherol, soya oil - partially hydrogenated, soya oil, vegetable oil - hydrogenated (5 mg, 10 mg and 20 mg only), soya oil - hydrogenated (30 mg and 40 mg only).
The capsule shell contains sorbitol solution (70% non-crystallising), glycerol, gelatin, titanium dioxide, water - purified, brilliant scarlet 4R CI16255 (10 mg and 20 mg only), sunset yellow FCF CI15985 (40 mg only), indigo carmine CI73015 (20 mg only), iron oxide black CI177499 (10 mg only), iron oxide red (30 mg only).

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 30°C in the closed carton to protect from light and moisture:
Oratane 20 mg capsules AUST R 69868.
Store below 25°C in the closed carton to protect from light and moisture:
Oratane 5 mg capsules AUST R 127499;
Oratane 10 mg capsules AUST R 75034;
Oratane 30 mg capsules AUST R 303071;
Oratane 40 mg capsules AUST R 117206.

6.5 Nature and Contents of Container

Oratane 5 mg capsules are available in PVC/PVDC/Al blister packs of 15 (sample pack)*, 30*, 60 and 90* capsules.
Oratane 10 mg capsules are available in PVC/PVDC/Al blister packs of 15 (sample pack)*, 30*, 60 and 90* capsules.
Oratane 20 mg capsules are available in PVC/PVDC/Al blister packs of 15 (sample pack)*, 30*, 60 and 90* capsules.
Oratane 30 mg capsules are available in PVC/PVDC/Al blister packs of 15 (sample pack)*, 30*, 60 and 90* capsules.
Oratane 40 mg capsules are available in PVC/PVDC/Al or PVC/PCTFE/Al blister packs of 15 (sample pack)*, 30, 60* and 90* capsules.
*Currently not 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.

Structurally it is represented as:
Isotretinoin, C20H28O2.

CAS number.

CAS 4759-48-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes