Consumer medicine information

Rocta Capsules

Isotretinoin

BRAND INFORMATION

Brand name

Rocta Capsules

Active ingredient

Isotretinoin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rocta Capsules.

What is in this leaflet

This leaflet answers some common questions about Rocta capsules. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Rocta capsules against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine.

You may need to read it again.

What Rocta is used for

Rocta contains the active ingredient isotretinoin.

Rocta is used to treat acne.

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

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

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

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

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

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

Rocta is not addictive.

Before you take it

When you must not take it

Do not take Rocta if:

  1. you are pregnant, or for at least one month before you plan to fall pregnant
    If you fall pregnant while taking Rocta 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.
  2. you are breastfeeding
    Breastfeeding must stop before treatment begins. Do not breastfeed while taking Rocta.
  3. you have had an allergic reaction to Rocta, vitamin A, other retinoids or any other ingredients of Rocta (listed at the end of this leaflet)
  4. you are taking tetracycline antibiotics (such as Akamin®, Vibramycin®, Doxycycline hydrochloride, Doryx®, Frakas®, Minomycin®)
  5. you have severe liver disease
  6. you have very high fat levels (cholesterol, triglycerides) in your blood
  7. you have hypervitaminosis A
    This is a condition caused by an excessive amount of vitamin A in the diet.
  8. the packaging is torn or shows signs of tampering
  9. 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 Rocta, contact your doctor.

Do not give Rocta to children.

There is limited information on the use of Rocta in children before puberty.

Before you start to take it

Tell your doctor if:

  1. you have any allergies to any other medicines, foods, preservatives or dyes
    Rocta capsules contain soya oil, which may contain traces of arachidic acid (a component of peanut oil)
  2. 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
  • 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 Rocta.

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 Rocta. These include:

  • tetracycline antibiotics (such as Akamin, Doxycycline hydrochloride, Frakas, Vibramycin, Doryx, Minomycin)
  • 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 Rocta, 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 Rocta.

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

How to take it

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 Rocta exactly as your doctor has prescribed.

Your doctor will tell you how many Rocta capsules to take each day.

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

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

Rocta may be taken once or twice a day and must always be taken with meals.

Female patients should wait until the 2nd or 3rd day of the next normal menstrual period before starting Rocta treatment.

This helps ensure that you aren't pregnant before you start taking Rocta.

How long to take it

Continue taking Rocta for as long as your doctor prescribes.

Acne treatment with Rocta will usually last 4 to 8 months. In the first few weeks of treatment your acne will probably get a little worse before it gets better.

Do not worry about this, it is a sign that Rocta 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 Rocta treatment is finished. Please note that Rocta 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 it

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 (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 Rocta. 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 it

Things you must do

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

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

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 Rocta.

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 Rocta 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 Rocta.

Things you must not do

Do not stop taking Rocta 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 Rocta to anyone else even if their symptoms seem similar to yours.

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

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

Things to be careful of

Be careful driving or operating machinery until you know how Rocta affects you.

Normally Rocta would not affect your ability to drive a car or operate machinery. However altered night vision and other visual disturbances may occur when taking Rocta. Make sure you know how you react to Rocta 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 Rocta may cause discomfort.

Rocta 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 a sunscreen while taking Rocta.

Your skin may be more prone to sunburn while on Rocta.

Avoid waxing and dermabrasion while taking Rocta and for 5 to 6 months after stopping Rocta treatment.

Your skin may be more sensitive while on Rocta. Waxing may cause dermatitis and dermabrasion may cause scarring during and for several months after Rocta 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 Rocta treatment.

Side effects

Rocta 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
  • sweating
  • changes to the nails
  • eye problems such as dry, sore, swollen or itchy eyes, discharge or trouble seeing at night
  • 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 Rocta 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
  • blood in stools or severe diarrhoea
  • severe bruising
  • sudden red, often itchy spots, similar to the rash of measles starting on the face, hands or feet. The spots may blister or change to flat round raised, red, pale-centred marks. Also, you may have fever, sore throat, headache and/or diarrhoea
  • painful red areas, that change to large blisters and end with peeling of layers of skin, that may occur on 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 it

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 well.

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

Do not store Rocta, 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 Rocta 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 Rocta from light.

Disposal

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

Product description

Availability

Rocta capsules come in two strengths, 10 mg and 20 mg.

Rocta 10 mg and 20 mg capsules are available in packs of 60 capsules.

What the tablets look like

  • 10 mg - red-orange, size 3, oval, soft gelatin capsules marked P10
  • 20 mg - red-orange, size 6, oval, soft gelatin capsules marked P20

Ingredients

Active ingredient - isotretinoin

  • each 10 mg capsule contains 10 mg isotretinoin
  • each 20 mg capsule contains 20 mg isotretinoin.

Inactive ingredients -
The capsules also contain:

  • Soya oil,
  • beeswax - yellow,
  • soya oil - hydrogenated and - partially hydrogenated.

The capsule shell contains

  • gelatin,
  • glycerol,
  • titanium dioxide,
  • ferrous oxide red and yellow.

The printing uses Videojet Inksource 16-9000 ink, which contains Brilliant Blue FCF and shellac.

Manufacturer

Rocta is distributed in Australia by:
Aspen Pharma Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065

Registration Number
10 mg: AUST R 165124
20 mg: AUST R 165125

Sponsor

Southern Cross Pharma Pty Ltd
56 Illabunda Drive
Malua Bay NSW 2536
ABN 47 094 447 677

Date of Information:
December 2012

BRAND INFORMATION

Brand name

Rocta Capsules

Active ingredient

Isotretinoin

Schedule

S4

 

1 Name of Medicine

Isotretinoin.

6.7 Physicochemical Properties

Chemical name: (2Z, 4E, 6E, 8E)- 3,7-dimethyl- 9- (2,6,6 trimethylcyclohex- 1-enyl)nona- 2,4,6,8- tetraenoic acid. Molecular Formula: C20H28O2. Molecular Weight: 300.44.

Chemical structure.


CAS number.

4759-48-2.
Isotretinoin is related to both retinoic acid and retinol (vitamin A). 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.

2 Qualitative and Quantitative Composition

Rocta 10 mg capsules contain 10 mg isotretinoin.
Rocta 20 mg capsules contain 20 mg isotretinoin.

Excipients with known effect.

Rocta contains Soya oil, hydrogenated soya oil and partially hydrogenated soya oil, gelatin, for the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Rocta 10 mg Capsules is a soft gelatin, oval (red-orange, size 3) marked P10.
Rocta 20 mg Capsules is a soft gelatin, oval (red-orange, size 6) marked P20.

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 (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 1.5 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 one 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 six hours.
The mean ± SD minimum steady-state blood concentrations of isotretinoin were 160 ± 19 nanogram/mL in ten patients receiving 40 mg twice daily. After single and multiple doses, the mean ratio of areas under the curves of isotretinoin to 4-oxo-isotretinoin is 3 to 3.5.

Excretion.

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

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

In Fischer 344 rats given isotretinoin at dosages of 32 or 8 mg/kg/day for greater than 18 months, there was dose related increased incidence of 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.

4 Clinical Particulars

4.1 Therapeutic Indications

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.

4.3 Contraindications

Severely impaired liver function and in patients with chronic abnormally elevated blood lipid values.
Hypersensitivity to the drug or other ingredients in isotretinoin capsules or to other retinoids.
Pre-existing hypervitaminosis A.
Rare cases of benign intracranial hypertension have been reported after isotretinoin and after tetracyclines. Concomitant treatment with tetracyclines is, therefore, contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in pregnancy (Category X).

Isotretinoin must not be used by females who are pregnant or who may possibly become pregnant while undergoing treatment.
Major human fetal 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 fetus should they become pregnant while undergoing treatment. If pregnancy does occur during treatment, the doctor and patient should discuss the desirability of continuing the pregnancy.

Use in lactation.

Isotretinoin is contraindicated in patients who are breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).

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.

Identified precautions. 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 seven to ten days, and usually does not require dose adjustments.
Wax epilation should be avoided in patients on isotretinoin and for a period of five to six 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 five to six months after treatment because of the risk of hypertrophic scarring in atypical areas and more rarely hyperpigmentation or hypopigmentation in treated areas.
Exposure to intense sunlight or ultraviolet 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 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 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 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 isotretinoin immediately.

Eye disorders.

Dry eyes, corneal opacities, conjunctivitis, blepharitis, decreased night vision and keratitis usually resolve after discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Due to the possible occurrence of keratitis, patients with dry eyes should be monitored. Patients experiencing visual difficulties should be referred for an expert ophthalmological examination and withdrawal of isotretinoin considered. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment.
Corneal opacities have occurred in patients receiving isotretinoin for acne and more frequently when higher drug dosages were used in patients with disorders of keratinisation. All 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 and restriction of dietary fat and alcohol 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 triglyceride levels > 8 g/L, has been reported. Hence isotretinoin should be discontinued if uncontrolled hypertriglyceridaemia or symptoms of pancreatitis occur.
Serum lipids (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 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 isotretinoin, 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.
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.

Psychiatric disorders.

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

Gastrointestinal disorders.

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

Allergic reactions.

Anaphylactic reactions have been 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 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.

Use in renal impairment.

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

Use in the elderly.

No data available.

Paediatric use.

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

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 (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 antiacne agents should be avoided as local irritation may increase.
Concurrent treatment with vitamin A must be avoided, as symptoms of hypervitaminosis A may be intensified (see Section 4.8 Adverse Effects (Undesirable Effects)).
Cases of pseudotumour cerebri and/or papilloedema have been reported in association with the use of isotretinoin. Four out of ten of these patients had retinal haemorrhages. Symptoms appeared after 21 days to six months therapy with 40 to 120 mg daily. Concomitant tetracycline or minocycline was administered in five out of ten 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; 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)1
Isotretinoin must not be used by females who are pregnant or who may possibly become pregnant while undergoing treatment.
Major human fetal 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 fetus should they become pregnant while undergoing treatment. If pregnancy does occur during treatment, the doctor and patient should discuss the desirability of continuing the pregnancy.
Isotretinoin is a known human teratogen and should not, under any circumstances, be administered during pregnancy, see Section 4.3 Contraindications.
Isotretinoin should only be prescribed by doctors who are experienced in the use of systemic retinoids and understand the risk of teratogenicity.
Isotretinoin was teratogenic in rats and rabbits, although sensitivity differed. 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 postnatal 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. Bodyweight 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 four litters.
1 Category X - Drugs which have such a high risk of causing permanent damage to the fetus 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 into human milk is very likely. Because of the potential for adverse effects, the use of isotretinoin 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 isotretinoin are similar to those described in patients taking very high doses of vitamin A.

Postmarketing experience.

Symptoms associated with hypervitaminosis A.

The most common side effects are mucocutaneous. The most frequently reported effects are dryness of the skin, in particular peeling of the palms and soles, dryness of the mucosa, e.g. 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 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 disorder.

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, have been reported, particularly in those undertaking vigorous physical activity. None of the cases was associated with renal failure. All cases recovered.

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, papilloedema as a sign of intracranial hypertension, impaired hearing at certain frequencies.

Gastrointestinal system disorders.

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

Liver and biliary system disorders.

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

Respiratory system disorders.

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

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.

Laboratory findings.

Increase in serum triglyceride and cholesterol levels, decrease in HDL, hyperuricaemia. 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 (e.g. Wegener's granulomatosis, allergic vasculitis), allergic responses, systemic hypersensitivity, glomerulonephritis.

Reporting suspected adverse effects.

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

4.2 Dose and Method of Administration

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

4.9 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 Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Soya oil, yellow beeswax, hydrogenated soya oil and partially hydrogenated soya oil. The capsule shell contains gelatin, glycerol, titanium dioxide, iron oxide red CI77491 and iron oxide yellow CI77492. The printing ink used is Proprietary Ingredient Number 4632, which is Videojet Inksource 16-9000 ink and contains Brilliant Blue FCF and 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 in the original packaging. Protect from light and moisture.

6.5 Nature and Contents of Container

Isotretinoin capsules are available in PVC/PE/PVDC/Al blister packs.
10 mg and 20 mg in blister packs of 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