Consumer medicine information

APO-Isotretinoin

Isotretinoin

BRAND INFORMATION

Brand name

APO-Isotretinoin

Active ingredient

Isotretinoin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Isotretinoin.

SUMMARY CMI

APO-Isotretinoin

Consumer Medicine Information (CMI) summary

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

1. Why am I using APO-Isotretinoin?

APO-Isotretinoin contains the active ingredient isotretinoin. APO-Isotretinoin is used to treat severe acne, where other treatments have not worked. For more information, see Section 1. Why am I using APO-Isotretinoin? in the full CMI.

2. What should I know before I use APO-Isotretinoin?

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

3. What if I am taking other medicines?

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

4. How do I use APO-Isotretinoin?

  • Your doctor will tell you how many APO-Isotretinoin capsules to take each day, take them exactly as your doctor has prescribed.
  • APO-Isotretinoin capsules should be swallowed whole with a glass of water or milk and must always be taken with food. More instructions can be found in Section 4. How do I use APO-Isotretinoin? in the full CMI.

5. What should I know while using APO-Isotretinoin?

Things you should do
  • Remind any doctor, dentist, or pharmacist you visit that you are using APO-Isotretinoin.
  • If you are about to start on any new medicine, tell your doctor and pharmacist that you are taking this medicine.
Things you should not do
  • Do not stop taking APO-Isotretinoin suddenly, change the dose or let yourself run out of medicine over the weekend or on holidays.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not take your medicine to treat any other complaint unless your doctor tell you to do.
  • Do not donate blood during treatment with APO-Isotretinoin or for at least 1 month after stopping treatment.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how APO-Isotretinoin affects you.
  • Isotretinoin usually does not affect your ability to drive a car or operate machinery. However, altered night vision and other visual disturbances may occur when taking isotretinoin.
Looking after your medicine
  • Keep your medicine in the pack until it is time to take it.
  • If you take your medicine out of the pack it may not keep well.
  • Keep your medicine in a cool dry place where the temperature stays below 25°C. Protect from light.

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

6. Are there any side effects?

APO-Isotretinoin helps most people with acne, but it may have unwanted side effects in a few people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects. Serious side effects may include nausea, vomiting, 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 diarrhea, severe bruising, sudden red or itchy spots, painful red areas, fever and chills, aching muscles, feeling depressed with or without suicidal thoughts and thinking, seeing or hearing things that are not real. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

APO-Isotretinoin

Active ingredient(s): Isotretinoin

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using APO-Isotretinoin?

APO-Isotretinoin contains the active ingredient isotretinoin. APO-isotretinoin belongs to a group of medicines called retinoids, which are like Vitamin A.

APO-Isotretinoin is used to treat severe acne, where other treatments have not worked.

Isotretinoin works by reducing the amount of the oil (sebum) made by glands in your skin.

It also reduces bacteria and inflammation and helps to open clogged pores.

2. What should I know before I use APO-Isotretinoin?

Warnings

Do not use APO-Isotretinoin if:

  • you are allergic to Isotretinoin, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • Do not take this medicine if you have an allergy to:
    - Isotretinoin
    - Vitamin A
    - Other retinoids
    - Soya
    - Any other ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • Shortness of breath
  • Wheezing or difficulty breathing
  • Swelling of the face, lips, tongue, throat, or other parts of the body
  • Rash, itching or hives on the skin.

Check with your doctor if you:

  • Do not take this medicine if you are taking tetracycline antibiotics (e.g., doxycycline, minocycline).
  • Do not take this medicine if you have the following medical conditions:
    - severe liver disease
    - very high fat levels (cholesterol, triglycerides) in your blood
    - hypervitaminosis A

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacists for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

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

Pregnancy and breastfeeding

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

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

Do not take this medicine if you are pregnant, or for at least one month before you plan to fall pregnant.

If you fall pregnant while taking this medicine, there is an extremely high risk of having a baby that is severely deformed. You must use effective contraception for one month before, during and one month after treatment.

Do not take this medicine if you are breastfeeding.

This medicine passes into breastmilk and your baby may be affected.

3. What if I am taking other medicines?

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

If you have peanut allergy, discuss with your doctor the risks and benefits of taking this product.

Some people who are allergic to peanuts may also be allergic to the soya oil in these capsules.

In addition, the soya oil in this product is manufactured in a facility which produces other products containing peanut oil. It cannot be guaranteed that this product does not contain traces of peanut oil.

Tell your doctor if you have or have had any of the following medical conditions:

  • diabetes or a family history of diabetes
  • high fat (lipid) levels or a family history of lipid disorders
  • kidney problems
  • stomach or bowel disease
  • excessive body weight or a family history of obesity
  • depression or a history of depression

Tell your doctor if you drink large amounts of alcohol or if you smoke.

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

Tell your doctor or pharmacist if you are taking any other medicine including that you get without your pharmacy prescription from your pharmacy, supermarket, or health food shop.

Some medicines may interact with isotretinoin. These include:

  • tetracycline antibiotics (e.g., doxycycline, minocycline)
  • vitamin A, or preparation containing vitamin A
  • other acne treatments (e.g., strong creams, ointments, or gels)
  • the ‘mini-pill’, a progesterone-only oral contraceptive pill
  • contraceptives containing norethisterone or norethisterone acetate.
  • phenytoin, used to treat epilepsy.
  • oral or injectable corticosteroids

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

Your doctor and pharmacists have more information on medicines to be careful with or avoid while taking this medicine.

Other medicine not listed above may also interact with isotretinoin.

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

4. How do I use APO-Isotretinoin?

How much to take / use

  • Follow all directions given to you by your doctor or pharmacists carefully.
  • They may be different to the information contained in the leaflet.
  • If you do not understand the instructions on the box, ask your doctor or pharmacist for help.
  • Your doctor will tell you how much of this medicine you should take, depending on your body weight and how well you respond to isotretinoin.
  • Swallow the capsules whole with a glass of water or milk.
  • Do not open the capsules or take any capsules that are damaged.

When to take / use APO-Isotretinoin

  • APO-Isotretinoin should be used at about the same time each day, either once or twice a day.
  • Taking it at the same time each day will have the best effect. It will also help you remember when to take it.
  • Isotretinoin must always be taken with food.
  • Female patients should wait until the 2nd or 3rd day of the normal menstrual period before starting isotretinoin therapy.
  • This helps ensure that you aren't pregnant before you start taking isotretinoin.

How long to take APO-Isotretinoin

  • Continue taking your medicine for as long as your doctor tells you.
  • Isotretinoin treatment usually lasts around four months. In some cases, a second course may be needed, usually with a gap of two months between courses.
  • In the first few weeks of treatment your acne may worsen, but this will usually stop within seven to ten days. This is a sign that isotretinoin is working.
  • At the end of the course, your acne should have cleared up significantly. Most patients notice their skin condition continues to improve even after isotretinoin treatment is finished. Isotretinoin cannot improve scars or pitting that were present before treatment started, but it will help prevent future skin damage.
  • Make sure you have enough to last over weekends and holidays.

If you forget to use APO-Isotretinoin

APO-Isotretinoin should be used regularly at the same time each day.

If you miss your dose at the usual time, take it as soon as you remember and then go back to taking your medicine as you would normally.

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

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

This may increase the chance of you experiencing side effects.

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

If you use too much APO-isotretinoin

If you think that you have used too much APO-Isotretinoin, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

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

You may need urgent medical attention.

If you take too much isotretinoin you may experience a severe but short-lived headache, nausea, vomiting, facial flushing, reddened lips, stomach pain, drowsiness, irritability, itching, dizziness, or unsteady walking.

For one month following an overdose:

  • You must not donate blood.
  • females must not become pregnant.
  • males must not father a child, as there is a chance that isotretinoin may be present in higher levels in semen.

5. What should I know while using APO-Isotretinoin?

Things you should do

Call your doctor straight away if you:

  • If you become pregnant while taking isotretinoin, stop taking it and tell your doctor immediately.
  • Isotretinoin causes birth defects in females taking isotretinoin.
  • You must use strict birth control for at least 1 month before, during and for 1 month after taking isotretinoin.
  • There is no known risk to males who wish to father children (except after overdosing; see previously).
  • If you are about to start on any new medicine, tell your doctor and pharmacist that you are taking this medicine.
  • Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.
  • Tell your doctor if you are about to have any blood tests.
  • Tell your doctor if you are planning to do a lot of vigorous exercise while taking isotretinoin.
  • Your muscles and joints may be prone to tenderness or stiffness if you do a lot of exercise.
  • Tell your doctor if you have not taken your medicine exactly as prescribed.
  • Tell your doctor if you feel APO-Isotretinoin are not helping your condition.
  • Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.
  • Keep all your doctors' appointments so that your progress can be checked.
  • Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects.
  • Tell your doctor if you experience persistent pain in your lower back or buttocks during treatment with APO-Isotretinoin. These symptoms may be signs of sacroiliitis, a type of inflammatory back pain. Your doctor may discontinue treatment with APO-Isotretinoin and refer you to a specialist for treatment of inflammatory back pain. Further evaluation may be needed including imaging modalities such as MRI.

Things you should not do

  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not take your medicine to treat any other complaint unless your doctor tell you to do.
  • Do not stop taking you medicine or change the dosage without first checking with your doctor.
  • Do not donate blood during treatment with isotretinoin or for at least four weeks after stopping treatment.

Things to be careful of

  • Tell your doctor if your skin condition does not improve within one to two months of starting this medicine, or if your skin irritation becomes severe.
  • During the first three weeks of taking isotretinoin, your skin may become irritated. Your acne may seem to get worse before it gets better.
  • Full improvement continues after you stop taking isotretinoin and may take up to six months.
  • If you develop any new skin rash (e.g. redness, hives, spots, blisters or flaking skin) during isotretinoin treatment, contact your doctor immediately.
  • There have been reports of skin rash associated with this medicine. Some of these rashes may be serious and can cause severe illness. These serious rashes may be accompanied or preceded by flu-like symptoms.
  • Isotretinoin may cause hearing problems in one or both ears (ringing in the ears, unable to hear certain sounds, deafness).
    This may occur during or after finishing a course of isotretinoin. No more isotretinoin should be taken, and medical attention sought immediately.
    Isotretinoin may cause bowel problems. Contact your doctor immediately if you have severe stomach pains, bleeding from the rectum or bloody diarrhea.
  • Isotretinoin may cause dryness of the mouth and nose.
    For temporary relief of mouth dryness, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if dry mouth continues for more than two weeks, check with your doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay and gum disease. Moisturizer or petroleum jelly can be used to soften the lining of the nose, lips and the skin areas not affected by acne.
  • Isotretinoin may cause mood or behavior problems, including having thoughts about self-harm or suicide. Tell your doctor immediately if unusual mood or behavior problems occur.
    Symptoms of depression may include:
    - feeling sad, having crying spells
    - losing interest in activities you once enjoyed
    - sleeping too much or having trouble sleeping
    - changes in appetite or body weight
    - having trouble concentrating
    - withdrawing from friends or family
    - feeling like you have no energy
    - feelings of worthlessness or inappropriate guilt.
  • Isotretinoin may cause bone or muscle problems, including joint pain, muscle pain or stiffness, or difficulty moving. Tell your doctor if these problems are bothersome. Your doctor will monitor you for signs of raised lipid (fat) levels in your blood.
  • You may be able to manage these with diet, weight loss, restricting alcohol intake and stopping smoking. Tell your doctor straight away if you have severe pains in your upper abdomen.
  • This medicine may affect blood sugar levels.
  • Tell your doctor if you have diabetes and you notice a change in the results of blood or urine sugar tests.

Isotretinoin may cause dry eyes.

Wearing contact lenses during treatment with isotretinoin may cause discomfort. You may temporarily need to wear your lenses for shorter periods or wear glasses instead. An eye lubricant or artificial tears, available from your pharmacist, should relieve this problem. Make sure your doctor or eye specialist know if you have dry eyes, so they can monitor you.

Eye infections, inflammation and hazy vision may also occur and should be monitored closely by your doctor and eye specialist.

Your skin will be more prone to sunburn, dryness, or irritation, especially during the first two or three weeks of treatment. It is advised to:

  • avoid excessive exposure to the sun, UV, sunlamp or solarium, wind or cold weather
  • use sunscreen with at least SPF15
  • wear protective clothing and hats
  • use skin moisturizer and lip balm
    Avoid waxing, dermabrasion and laser treatment while taking isotretinoin and for five to six months after stopping isotretinoin.
  • Your skin may be more sensitive while on isotretinoin. Waxing may cause dermatitis and dermabrasion may lift the skin's surface and cause scarring during and for several months after isotretinoin therapy.
  • Avoid using facial peels, electrolysis and some hair treatments.
    Your skin and hair may be more delicate during treatment and for a while after taking isotretinoin. Using mild creams and ointments may help

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APO-Isotretinoin affects you.

Isotretinoin usually does not affect your ability to drive a car or operate machinery. However, altered night vision and other visual disturbances may occur when taking isotretinoin. Some people may also feel drowsy or dizzy. Make sure you know how you react to isotretinoin before you drive a car, operate machinery or do anything else that may be dangerous.

Looking after your medicine

Storage

Keep your medicine in the pack until it is time to take it.

If you take your medicine out of the pack it may not keep well.

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

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

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

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

Heat and dampness can destroy some medicines.

Keep it 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.

When to discard your medicine

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine leftover.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
  • Dry lips (scaling, redness burning, pain or other signs of inflammation), mouth, nose and skin (including rash).
  • Nosebleeds
  • Peeling palms of the hands and soles of feet
  • Nail infection or inflammation
  • Dry throat or hoarse voice
  • Infection., cold sores
  • Muscle, back, or tendon pain or stiffness
  • Bleeding or red, swollen gums
  • Feeling lethargic, tired or having no energy.
  • Mild headache
  • Feeling dizzy, drowsy or nervous
  • Weight loss
  • Abnormal periods
  • Feeling sick (nausea)
  • Sweating, flushing
  • Bony growths
  • Itchy skin, bruising, mild rash or peeling change in skin color.
  • Sexual dysfunction including impaired sexual function in males, decreased libido and gynaecomastia
  • An increased chance of sunburn
  • Initial worsening of acne
  • Hair loss (usually temporary but persisted in rare cases)
  • Changes in hair growth
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Eye problem (burning, redness itching or other signs of eye inflammation or infections; problem wearing contacts lenses
  • loss of appetite, dark urine, pale stools, yellowing of the skin or eyes (jaundice), bleeding or bruising more easily than normal (signs of liver disease)
  • bloody or cloudy urine
  • severe diarrhea
  • chest infection
  • swollen or itchy veins
  • frequent infections, fever severe chills, sore throat, or mouth ulcers
  • tenderness or stiffness in your bones or joints, fractures
  • sleep problems
  • blurred or unusual vision
  • a change in your blood glucose levels, especially if you are diabetic.
  • Wounds not healing properly.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Very Serious Side Effects

Very Serious side effectsWhat to do
  • shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; muscle pain or tenderness or joint pain or rash, itching or hives on the skin (signs of an allergic reaction)
  • severe skin reactions with painful red areas, large blisters, peeling of skin layers; fever, chills, aching muscles, feeling unwell (signs of erythema multiforme, Stevens-Johnson Syndrome or toxic epidermal necrolysis)
  • severe diarrhoea, rectal bleeding, black, bloody or tarry stools
  • severe pain in your upper stomach spreading to your back, nausea, vomiting, fast heart rate
  • brown or dark coloured urine, with severe muscle aching and weakness (signs of muscle breakdown)
  • sudden and severe headache or pain behind your eyes, nausea, vomiting
  • hearing problems, hearing loss, or ringing in your ears
  • psychosis, hallucinations (thinking, seeing or hearing things that are not there)
  • feeling anxious or agitated, or acting aggressively
  • seizures
  • fast or unusual heart rate, fainting
  • feeling unable to think and judge clearly
  • changing emotions or mood, including crying, self-harm, thoughts of suicide, attempting suicide
  • feeling depressed, with or without suicidal thoughts
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

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

7. Product details

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

What APO-Isotretinoin contains

Active ingredient
(main ingredient)		Isotretinoin
Other ingredients
(inactive ingredients)
  • soya oil
  • beeswax - yellow
  • soya oil - hydrogenated and partially hydrogenated
  • gelatin (phenylalanine & sulfites)
  • glycerol
  • titanium dioxide
  • iron oxide red
  • iron oxide yellow
  • brilliant blue FCF
  • shellac
Potential allergenscontains sulfites, phenylalanine and soybean products

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

What APO-Isotretinoin looks like

10 mg capsules: Red-orange, size 3, oval, soft gelatin capsules marked P10. AUST R 190940.

20 mg capsules: Red-orange, size 6, oval, soft gelatin capsules marked P20. AUST R 190941.

Available in blister strips of 60 capsules.

* Not all strengths may be available.

Who distributes APO-Isotretinoin

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in July 2024

Published by MIMS September 2024

BRAND INFORMATION

Brand name

APO-Isotretinoin

Active ingredient

Isotretinoin

Schedule

S4

 

1 Name of Medicine

Isotretinoin.

2 Qualitative and Quantitative Composition

Each capsule contains 10 mg or 20 mg of isotretinoin as the active ingredient.

Excipients with known effect.

Sulfites, phenylalanine, and soy bean products.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APO-Isotretinoin 10 mg capsule.

Red-orange, size 3, oval, soft gelatin capsules marked P10.

APO-Isotretinoin 20 mg capsule.

Red-orange, size 6, oval, soft gelatin capsules marked P20.

4 Clinical Particulars

4.1 Therapeutic Indications

Isotretinoin is indicated for the treatment of severe cystic acne. 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

APO-Isotretinoin capsules are intended for oral administration.

Dosage.

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 reactions 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 patients 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

(Category X)
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 cerebellar 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 isotretinoin 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.
 Isotretinoin is contraindicated in patients who are breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation.).
Isotretinoin is contraindicated in patients with severely impaired liver function and in patients with chronic abnormally elevated blood lipid values.
Isotretinoin is contraindicated in patients who have pre-existing hypervitaminosis A.
Hypersensitivity to the drug or any of the other ingredients or to other retinoids. Isotretinoin contains soya oil and partially hydrogenated soya oil, therefore isotretinoin is contraindicated in patients allergic to soya.
Rare cases of benign intracranial hypertension have been reported after isotretinoin and after tetracyclines. Concomitant treatment with tetracyclines is therefore contraindicated (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Information for patients.

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.
Isotretinoin 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.

Patients should be informed that transient exacerbation of acne has been seen, generally during the initial period of therapy. 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 isotretinoin 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 isotretinoin and for a period of 5-6 months after the end of treatment because of the 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 isotretinoin 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 therapy. These reactions 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 isotretinoin 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 with 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 isotretinoin immediately.

Eye disorders.

Dry eyes, corneal opacities, conjunctivitis, blepharitis, intolerance to contact lenses, 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 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 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 isotretinoin 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 aminotransferase 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 the 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, restriction of dietary fat and alcohol and reduction in dose while continuing to take isotretinoin. Serum lipid values usually return to normal on reduction of the dose or discontinuation of treatment.
Acute pancreatitis, which is potentially fatal, sometimes associated with serum triglycerides levels > 8 g/L, has been reported. Hence isotretinoin should be discontinued if uncontrolled hypertriglyceridaemia or symptoms of pancreatitis occur.
Serum lipid levels (fasting value) should be determined one month prior to therapy and again after about four 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 disorders, obesity, alcoholism, diabetes and smoking should be assessed. In high risk patients (with diabetes, obesity, alcoholism or lipid metabolism disorder) undergoing treatment with isotretinoin, more frequent checks of serum values for lipids and/or blood glucose may be necessary.

Musculoskeletal and connective tissue disorders.

Sacroiliitis has been reported in patients exposed to isotretinoin. To differentiate sacroiliitis from other causes of back pain, in patients with clinical signs of sacroiliitis, further evaluation may be needed including imaging modalities such as MRI. In cases reported post-marketing, sacroiliitis improved after discontinuation of APO-Isotretinoin and appropriate treatment.
Myalgia, arthralgia and increased serum creatine phosphokinase may occur and be associated with reduced tolerance to vigorous exercise (see Section 4.8 Adverse Effects (Undesirable Effects)). Isolated instances of raised CPK levels have been reported in patients receiving isotretinoin, particularly those undergoing vigorous physical activity.
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, hyperostosis, and calcification 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 cystic acne patients treated with a single course of therapy at recommended doses.
Isotretinoin may be associated with growth retardation in prepubertal children.
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.

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 aetiology further investigated.

Psychiatric disorders.

Depression, depression aggravated, psychotic symptoms, anxiety, aggressive tendencies, mood alterations, psychosis and, rarely, suicide, suicidal ideation and suicide 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 and referred for appropriate treatment if necessary. Although no mechanism of action for these events has been established, discontinuation of therapy may be insufficient to 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 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 then afterwards, dose adjusted according to tolerance.

Paediatric use.

The approved therapeutic indication does not involve use in children and safety in prepubertal children has not been established (also see Section 4.4 Special Warnings and Precautions for Use).
The use of isotretinoin in paediatric patients less than 12 years of age is not recommended.
Isotretinoin may stop long bone growth in children who are still growing. The use of isotretinoin for the treatment of severe cystic acne in paediatric patients aged 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists.

Use in the elderly.

No data available.

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 the 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. (Also 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 the higher dosages 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 haematuria 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 anti-acne 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 gynaeco-endocrinological 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.
In a study of 31 premenopausal female patients with severe recalcitrant nodular acne, isotretinoin at a dose of 1 mg/kg/day did not induce clinically relevant changes in the pharmacokinetics of ethinyl oestradiol and norethindrone and in the serum levels of progesterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the Product Information of the medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.
Isotretinoin has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and isotretinoin. Therefore, caution should be exercised when using these drugs together.
Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and isotretinoin. Therefore, caution should be exercised when using these drugs together.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In the reproductive studies in rats (2, 8 or 32 mg/kg/day; two 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)
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 were teratogenic. At lower doses in the rat perinatal and postnatal 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. Bodyweight 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.
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.
 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.
Drowsiness, dizziness and visual disturbances have been reported very rarely. Patients should be warned that if they experience these effects, they should not drive, operate machinery or take part in any other activities where the symptoms could put either themselves or others at risk.

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.

Post-marketing experience.

Blood glucose.

Certain patients receiving isotretinoin have experienced problems in the control of their blood sugar. New cases of diabetes have been diagnosed.

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), nasopharyngitis, the pharynx (hoarseness) and eyes (conjunctivitis, reversible corneal opacities and intolerance to contact lenses).

Skin and appendages disorders.

Exanthema, pruritus, facial erythema/ dermatitis, dry skin, localized exfoliation, sweating, pyogenic granuloma, paronychia, nail dystrophy, abnormal wound healing (delayed healing or increased formation of granulation tissue with crusting, persistent hair thinning, reversible alopecia (which in some cases persists), bruising, dry mouth, epistaxis, eruptive xanthomas, flushing, infections (including disseminated herpes simplex), peeling of palms and soles, rash (including seborrhea, and eczema), sunburn susceptibility increased, urticaria, acne fulminans, hirsutism, hyperpigmentation and hypopigmentation, photosensitivity, photoallergic reactions, skin fragility. Acne flare occurs at 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), hyperostosis, exostosis, arthritis, calcification of ligaments and tendons and other bone changes, reduced bone density, musculoskeletal symptoms (sometimes severe) including back pain, epiphyses, premature fusion, tendinitis, transient pain in the chest, arthritis and elevations of CPK.
Serious cases of rhabdomyolysis, often leading to hospitalization some with fatal outcome have been reported, particularly in those undertaking vigorous physical activity.
Cases of sacroiliitis have been observed in patients treated with isotretinoin (see Section 4.4 Special Warnings and Precautions for Use).

Renal and urinary disorders.

Cases of urethritis have been reported.

Psychiatric and central nervous system disorders.

Behavioural disorders, depression, depression aggravated, suicide attempt, suicidal ideation, suicide, (see Section 4.4 Special Warnings and Precautions for Use), psychosis, violent behaviour, emotional instability, aggressive tendencies, anxiety, mood alterations, headache, increased intracranial pressure (pseudotumour cerebri), seizures, insomnia, lethargy, malaise, nervousness, paraesthesia, syncope, hoarseness, drowsiness and dizziness.
Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Sensory disorders.

Visual disturbances, photophobia, decreased night vision, colour vision disturbances (reversible upon discontinuation), lenticular cataracts, keratitis, blurred vision, blepharitis, conjunctivitis, eye irritation, contact lens intolerance, corneal opacities, eyelid inflammation, optic neuritis, eye irritation, papilloedema as a sign of benign intracranial hypertension, tinnitus, impaired hearing at certain frequencies and deafness.

Gastrointestinal system disorders.

Nausea, severe diarrhoea, bleeding and inflammation of the gums, oesophagitis/ oesophageal ulceration, (haemorrhagic), dry throat, pancreatitis, 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.

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

Respiratory system disorders.

Bronchospasm (with or without a history of asthma), respiratory infection, voice alteration 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), anaemia.

Cardiovascular disorders.

Palpitation, tachycardia, vascular thrombotic disease, stroke. Vasculitis (for example Wegener's granulomatosis, allergic vasculitis).

Urinary disorders.

Haematuria, proteinuria and glomerulonephritis.

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, haematuria, and proteinuria, vasculitis (for example Wegener's granulomatosis, allergic vasculitis), allergic responses, systemic hypersensitivity, 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 and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Isotretinoin is a derivative of vitamin A. Although acute toxicity of isotretinoin is low, signs of hypervitaminosis A could appear in cases of accidental overdose. Clinically, overdose has been associated with transient headache, (severe), nausea or vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, drowsiness, irritability, pruritus and ataxia. All symptoms quickly resolved without apparent residual effects.
The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice and approximately 1960 mg/kg in rabbits.

Treatment.

Treatment of overdose should consist of general supportive measures.
Isotretinoin causes serious birth defects at any dosage (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). Female patients of childbearing potential who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counselling about the risks to the foetus. Nonpregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counselling. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for 1 month after the overdose.
All patients with isotretinoin overdose should not donate blood for at least one month.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Isotretinoin 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 isotretinoin 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. cerevisiae 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 phaeochromocytoma. 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 phaeochromocytoma. 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

Soya oil, yellow beeswax, hydrogenated soya oil and partially hydrogenated soya oil, gelatin, glycerol, titanium dioxide, iron oxide red, iron oxide yellow, brilliant blue FCF, shellac.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light and moisture.

6.5 Nature and Contents of Container

APO-Isotretinoin 10 mg capsule.

Blister pack (PVC/PE/PVDC/Al) of 60 capsules. AUST R number 190940.

APO-Isotretinoin 20 mg capsule.

Blister pack (PVC/PE/PVDC/Al) of 60 capsules. AUST R number 190941.
Not all strengths may be available.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

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. It is related to both retinoic acid and retinol (vitamin A).

Chemical structure.


Chemical name: (2Z, 4E, 6E, 8E)- 3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic acid (also known as 13-cis-retinoic acid).
Molecular formula: C20H28O2.
Molecular weight: 300.44.

CAS number.

4759-48-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes