Consumer medicine information

Roaccutane

Isotretinoin

BRAND INFORMATION

Brand name

Roaccutane

Active ingredient

Isotretinoin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Roaccutane.

What is in this leaflet

This leaflet answers some common questions about Roaccutane. 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 Roaccutane against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Roaccutane is used for

Roaccutane contains the active ingredient isotretinoin.

Roaccutane is used to treat acne.

Roaccutane belongs to a group of medicines called retinoids, which are similar to vitamin A.

Retinoids work by reducing the amount of the oily substance (i.e. sebum) made by glands in your skin, reducing bacteria and inflammation and opening clogged pores.

There are many different types of medicines used to treat acne. Roaccutane is used for more severe cases.

Your doctor, however, may have prescribed Roaccutane for another purpose.

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

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

Roaccutane is not addictive.

Before you take Roaccutane

When you must not take it

Do not take Roaccutane if:

  1. you are pregnant, or for at least one month before you plan to fall pregnant
If you fall pregnant while taking Roaccutane 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.
  1. you are breastfeeding
You must stop breastfeeding before treatment begins. Do not breastfeed while taking Roaccutane.
  1. you have had an allergic reaction to Roaccutane, vitamin A, other retinoids or any of the ingredients listed at the end of this leaflet
  2. you are taking tetracycline antibiotics
  3. you have severe liver disease
  4. you have very high fat levels (cholesterol, triglycerides) in your blood
  5. you have hypervitaminosis A
This is a condition caused by an excessive amount of vitamin A in the diet.
  1. the packaging is torn or shows signs of tampering
  2. the expiry date (EXP) printed on the pack has passed.
If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure if you should start taking Roaccutane, contact your doctor.

Do not give Roaccutane to children. Roaccutane may be associated with slowing of growth when used in children before puberty. The use of Roaccutane in children less than 12 years of age is not recommended.

Before you start to take it

You must tell your doctor if:

  1. you have any allergies to any other medicines, foods, preservatives or dyes
Roaccutane capsules contain soya oil, which may contain traces of arachidic acid (a component of peanut oil)
  1. you have or have had any other health problems or issues including:
  • diabetes, or a history of diabetes in your family
  • depression
  • liver disease
  • kidney disease
  • lipid (cholesterol or triglyceride) disorder
  • hormone disorder
  • eye disorders
  • stomach or bowel disease
  1. you drink large amounts of alcohol.

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

Taking other medicines

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

Some medicines may interfere with Roaccutane. These include:

  • tetracycline antibiotics
  • vitamin A, or preparations containing vitamin A (including vitamin supplements)
  • other medicines you are using to treat your acne
  • the "mini-pill", a progestogen-only oral contraceptive pill.

These medicines may be affected by Roaccutane 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.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Roaccutane.

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

How to take Roaccutane

How much to take

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

Take Roaccutane exactly as your doctor has prescribed. Your doctor will tell you how many Roaccutane capsules to take each day.

The dose will be calculated to suit your individual needs and your body weight. This dose may be adjusted during treatment when your doctor knows how you respond to Roaccutane.

How to take it

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

Do not open the capsules and do not take any capsules that are damaged.

When to take it

Roaccutane may be taken once or twice a day and must always be taken with food.

Female patients should wait until the 2nd or 3rd day of the next normal menstrual period before starting Roaccutane treatment. This helps ensure that you aren't pregnant before you start taking Roaccutane.

How long to take Roaccutane

Continue taking Roaccutane for as long as your doctor prescribes.

Acne treatment with Roaccutane will usually last 4 to 8 months. In the first few weeks of treatment your acne may get a little worse before it gets better. Do not worry about this, it is a sign that Roaccutane is working.

At the end of this time your acne should have cleared up significantly. Most patients notice their skin condition continues to improve even after Roaccutane treatment is finished.

Please note that Roaccutane cannot improve scars or pitting that were present before treatment started, but it will help prevent such skin damage in the future.

If you forget to take Roaccutane

Do not try to make up for missed doses by taking an extra dose. This may increase the chance of getting an unwanted side effect.

If it is almost time for your next dose, skip the dose you 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.

If you take too much Roaccutane (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 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 much Roaccutane. 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 Roaccutane

Things you must do

If you become pregnant while taking Roaccutane, stop taking it and tell your doctor immediately.

Roaccutane can cause birth defects (damage to unborn babies). You must use strict birth control, starting at least 1 month before you begin taking Roaccutane, for the whole time you are taking Roaccutane and for 1 month after you finish taking Roaccutane.

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 taking Roaccutane.

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

Tell your doctor if you feel Roaccutane capsules are not helping your condition.

Be sure to keep all of your appointments with your doctor so that your progress can be checked. Your doctor may ask you to have regular blood tests to monitor your liver function, blood sugar levels and blood cholesterol levels.

If you are intending to do a lot of heavy lifting or exercise, tell your doctor. Your muscles and joints may be more prone to tenderness or stiffness if you do a lot of heavy exercise while taking Roaccutane.

Things you must not do

Do not stop taking Roaccutane or change the dose without first checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays.

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

Do not use Roaccutane to treat other complaints unless your doctor says to.

Do not donate blood during treatment with Roaccutane or for at least 1 month after stopping treatment.

Things to be careful of

Be careful driving or operating machinery until you know how Roaccutane affects you. Normally Roaccutane would not affect your ability to drive a car or operate machinery. However, altered night vision and other visual disturbances may occur when taking Roaccutane. Make sure you know how you react to Roaccutane 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 Roaccutane may cause discomfort. Roaccutane may cause dry eyes. An eye lubricant or artificial tears, available from your pharmacist, should relieve this problem. Otherwise, you may temporarily need to wear your lenses for shorter periods or wear glasses instead.

Avoid excessive sun exposure and solariums and apply sunscreen whilst taking Roaccutane. Your skin may be more prone to sunburn while on Roaccutane.

Avoid waxing and dermabrasion whilst taking Roaccutane and for 5 to 6 months after stopping Roaccutane treatment. Your skin may be more sensitive while on Roaccutane. Waxing may cause dermatitis and dermabrasion may cause scarring during and for several months after Roaccutane treatment.

Avoid using facial peels, electrolysis and some hair treatments.

Your skin and hair may be more delicate during treatment and for a while after Roaccutane treatment.

Side Effects

Roaccutane helps most people with acne but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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 and skin
    A moisturiser or petroleum jelly can be used to soften the lining of the nose, lips and the skin areas not affected by the acne
  • fragile skin
  • change in colour of the skin
  • peeling palms of the hands and soles of the feet
  • itchy skin rash
  • an increased susceptibility to sunburn
  • flaring of acne, usually at the start of treatment
  • sweating
  • changes to the 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 or stiffness in your bones, joints or muscles
  • tiredness
  • headache
  • 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. Most of them disappear completely in a few days to a few weeks after the dose of Roaccutane is lowered or stopped.

Tell your doctor immediately if you experience any of the following:

  • 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 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. You may also have a 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 lips, mouth, eyes, nose and genitals. Those affected may have fever and chills, aching muscles 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;

  • feeling sad or having crying spells
  • losing interest in activities you once enjoyed
  • sleeping too much or having trouble sleeping
  • changes in your appetite or body weight
  • having trouble concentrating
  • withdrawing from your friends or family
  • feeling like you have no energy
  • feelings of worthlessness or inappropriate guilt

These may be serious side effects. You may need 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 side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don't understand anything in this list.

After taking Roaccutane

Storage

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

Keep the blister pack in a cool dry place where the temperature stays below 25°C.

Do not store Roaccutane, or any other medicine, in a bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep Roaccutane 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.

Protect Roaccutane from light.

Disposal

If your doctor tells you to stop taking Roaccutane, or the capsules have passed their expiry date, ask your pharmacist what to do with any capsules that are left over.

Product Description

Availability

Roaccutane is available as a 20 mg capsule in a pack of 60 capsules.

What Roaccutane looks like

Roaccutane 20 mg capsule is soft, oval, half brown-red and half opaque white in colour and has "ROA 20" printed on it.

Ingredients

Active ingredient - isotretinoin

Each Roaccutane 20 mg capsule contains 20 mg isotretinoin.

Inactive ingredients -

The capsules also contain:

  • soya oil
  • yellow beeswax
  • partially hydrogenated soya oil
  • hydrogenated soya oil.

Soya oil may contain traces of arachidic acid (a component of peanut oil).

The capsule shell contains:

  • gelatin
  • glycerol
  • sorbitol
  • mannitol
  • maize starch product
  • titanium dioxide
  • iron oxide, red

The printing ink contains:

  • shellac
  • iron oxide, black.

Roaccutane does not contain sucrose or gluten.

Manufacturer

Roaccutane is distributed by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney, NSW 2000

Medical enquiries: 1800 233 950

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

Australian Registration Numbers:

Roaccutane 20 mg capsules - AUST R 50839

This leaflet was prepared on 14 May 2019

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Roaccutane

Active ingredient

Isotretinoin

Schedule

S4

 

1 Name of Medicine

Isotretinoin.

6.7 Physicochemical Properties

Chemically, isotretinoin is (2Z, 4E, 6E, 8E)-3,7-dimethyl-9-(2,6,6 trimethylcyclohex 1 enyl)nona-2,4,6,8-tetraenoic acid and is also known as 13 cis retinoic acid. Isotretinoin is related to both retinoic acid and retinol (vitamin A). The molecular formula is C20H28O2. Isotretinoin has a molecular weight of 300.44.
Isotretinoin is a yellow orange to orange crystalline powder, 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.

Chemical structure.


CAS number.

4759-48-2.

2 Qualitative and Quantitative Composition

Each Roaccutane 20 mg capsule contains isotretinoin 20 mg.

Excipients with known effect.

Contains soya bean oil (refined, hydrogenated and partially hydrogenated).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Roaccutane 20 mg - half brown-red soft capsule half opaque white, imprinted with ROA 20.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Retinoid for treatment of acne, ATC code: D10B A01.

Mechanism of action.

Isotretinoin is a retinoid that inhibits sebaceous gland function and keratinisation. The exact mechanism of action of Roaccutane is unknown.

Pharmacodynamic effect.

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 Roaccutane 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 (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 Roaccutane 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 10 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.

Elimination.

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 65-83% 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

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 man, 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 leukemia.

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).

4 Clinical Particulars

4.1 Therapeutic Indications

Roaccutane 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 drug. Because of significant adverse effects associated with its use, Roaccutane should be reserved for patients with severe cystic acne who are unresponsive to conventional therapy, including systemic antibiotics.

4.3 Contraindications

Use in pregnancy (Category X): Roaccutane must not be used by females who are pregnant or who may possibly become pregnant while undergoing treatment.
Major human fetal abnormalities related to Roaccutane 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 Roaccutane until pregnancy is excluded. It is strongly recommended that a pregnancy test be performed within two weeks prior to Roaccutane therapy. Roaccutane 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 Roaccutane therapy.
It is recommended that contraception be continued for one month following discontinuation of Roaccutane therapy. Females should be fully counseled on the serious risk to the fetus 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.
Roaccutane is contraindicated in patients who are breast-feeding (see Section 4.4 Special Warnings and Precautions for Use).
Roaccutane is contraindicated in patients with severely impaired liver function and in patients with chronic abnormally elevated blood lipid values.
Roaccutane is contraindicated in patients who have pre-existing hypervitaminosis A.
Rare cases of benign intracranial hypertension have been reported after Roaccutane and after tetracyclines. Concomitant treatment with tetracyclines is therefore contraindicated. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)
Roaccutane is also contraindicated in people who are hypersensitive to the drug or other ingredients in Roaccutane capsules listed in Section 6.1 List of Excipients or to other retinoids.

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 Roaccutane therapy is initiated, and that they should use an effective form of contraception while taking Roaccutane and for one month after Roaccutane has been stopped. (See Section 4.3 Contraindications.)
Because of the relationship of Roaccutane to Vitamin A, patients should be advised against taking vitamin supplements containing Vitamin A to avoid additive toxic effects.
Roaccutane 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 Roaccutane 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 Roaccutane and for a period of 5 to 6 months after treatment because of risk of epidermal stripping, scarring or dermatitis.
Aggressive chemical dermabrasion and cutaneous laser treatment should be avoided in patients on Roaccutane 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 hypo-pigmentation 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 Roaccutane is likely to cause dryness of the skin and lips.
There have been post-marketing reports of severe skin reactions (e.g. erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis) associated with Roaccutane 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 Roaccutane should be considered if warranted.

Benign intracranial hypertension.

Roaccutane 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 Roaccutane 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 Roaccutane considered. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment.
Corneal opacities have occurred in patients receiving Roaccutane for acne and more frequently when higher drug dosages were used in patients with disorders of keratinisation. All Roaccutane patients experiencing visual difficulties should discontinue the drug and have an ophthalmological examination.

Hearing impairment.

Impaired hearing has been reported in patients taking Roaccutane. 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 H.D.L., 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 Roaccutane. 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 Roaccutane. 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, Roaccutane should be discontinued if uncontrolled hypertriglyceridemia or symptoms of pancreatitis occur.
Serum lipids (fasting value) should be determined one month prior to therapy and again after 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, alcoholism, diabetes and smoking should be assessed. In high risk patients (with diabetes, obesity, alcoholism or lipid metabolism disorder) undergoing treatment with Roaccutane, 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.
Roaccutane 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 Roaccutane 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 Roaccutane 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 Roaccutane, the drug should be discontinued and the etiology further investigated.

Psychiatric disorders.

Depression, psychotic symptoms, and rarely, suicide, suicidal ideation and attempts have been reported with Roaccutane. 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 Roaccutane may not alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary.

Gastrointestinal disorders.

Roaccutane 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 Roaccutane immediately.

Allergic reactions.

Anaphylactic reactions have been rarely reported 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, Roaccutane can be given to patients with renal insufficiency. Roaccutane should be started at a lower dose in patients with severe renal insufficiency and 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 Roaccutane in paediatric patients less than 12 years of age is not recommended.
Roaccutane may stop long bone growth in children who are still growing. The use of Roaccutane 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 Roaccutane 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. (See Section 4.4 Special Warnings and Precautions for Use.)
Elevated ESR values occur in about 40% of patients treated with Roaccutane.
A rise in aspartate aminotransferase (AST) levels may occur, especially with the higher dosages of Roaccutane. 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 Roaccutane.
Certain patients receiving Roaccutane have experienced problems in the control of their blood sugar. Therefore, known or suspected diabetics should have frequent blood sugar determinations performed during Roaccutane 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 Roaccutane 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 hemorrhages. 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 who 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. For more details, see Section 4.3 Contraindications.
Roaccutane 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 and 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 the 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 Roaccutane is contraindicated in breastfeeding mothers.

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 Roaccutane 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. of the lips (cheilitis, which occurs in over 90% of patients), the nasal mucosa (epistaxis, which is seen in up to 30% of patients), the pharynx (hoarseness), the 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 reactions, skin fragility. Acne flare occurs at the start of treatment and persists for several weeks.
During the post-marketing period, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported with Roaccutane (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, 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 hospitalization 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), 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 intracranial hypertension, impaired hearing at certain frequencies.

Gastrointestinal system disorders.

Nausea, severe diarrhea, inflammatory bowel disease such as colitis, ileitis, and hemorrhage have been reported to occur. Patients treated with Roaccutane, 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 hematocrit), elevation of sedimentation rate, increase or decrease in platelet count (thrombocytopenia), 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, haematuria and proteinuria, vasculitis (for example Wegener's granulomatosis, allergic vasculitis), allergic responses, systemic hypersensitivity, glomerulonephritis.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dose.

The therapeutic response to Roaccutane 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 initially should receive Roaccutane at doses up to 0.5 mg/kg/day 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 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 Roaccutane 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.

4.7 Effects on Ability to Drive and Use Machines

Decreased night vision has occurred during Roaccutane 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.

4.9 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).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsule filling.

Soya oil, yellow beeswax, partially hydrogenated soya oil, hydrogenated soya oil.

Capsule shell.

Gelatin, glycerol, titanium dioxide (CI77891), iron oxide red (CI77491), Karion 83 (by R.P. Scherer GmbH, ARTG No. 2072).

Printing ink.

Black ink edible S-1-27794 (ARTG No. 12104) which contains shellac and iron oxide black CI77499.

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 degrees Celsius.
Protect from light.

6.5 Nature and Contents of Container

Roaccutane 20 mg is available in a blister pack of 30 or 60 capsules.

6.6 Special Precautions for Disposal

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

Summary Table of Changes