Isotretinoin
10mg/20mg/40mg Capsules

What Isotretinoin is used for

• Isotretinoin contains isotretinoin – a substance related to vitamin A, and one of a group of medicines called retinoids.
• Isotretinoin is used to treat severe types of acne (such as nodular or conglobate acne, or acne that is at risk of causing permanent scarring). You will use Isotretinoin when your acne has not got better with anti-acne treatments, including antibiotics and skin treatments.
• Isotretinoin treatment must be supervised by a dermatologist (a doctor specialised in the treatment of skin problems).

Before you take Isotretinoin

Do not take Isotretinoin:

• If you are allergic to peanut or soya or any other ingredient of Isotretinoin. This medicine contains soya oil, as well as isotretinoin. See section 6 Further information at the end of this leaflet for a full list of ingredients.
• If you are pregnant or think you may be
• If you are breastfeeding
• If you have liver disease
• If you have very high levels of blood fats (e.g. high cholesterol or triglycerides)
• If you have very high levels of vitamin A in your body (hypervitaminosis A)
• If your doctor has told you that you have an intolerance to the sugars fructose or sorbitol.

If any of these apply to you, go back to your doctor before taking any Isotretinoin.

Do not use in children under 12.
Use in children over 12 only after puberty.

Special Precautions with Isotretinoin
Not to be taken when pregnant

Important advice for women
Isotretinoin is likely to damage an unborn baby (in medical language it is teratogenic). It also increases the risk of miscarriage.

• You must not take Isotretinoin when you’re pregnant.
• You must not take Isotretinoin if you are breastfeeding. The medicine is likely to pass into your milk and may harm your baby.
• You must not take it if you could get pregnant during treatment, or during the month after treatment.

Women who could get pregnant are only prescribed Isotretinoin under strict rules, because of the risk of birth defects (damage to the unborn baby).
These are the rules:

• You must only take Isotretinoin if you have severe acne that has not got better after any other anti-acne treatments, including antibiotics and skin treatments.
• Your doctor must have explained the risk of birth defects: you understand why you must not get pregnant and what you need to do to prevent it.
• You must have discussed contraception (birth control) with your doctor. They will give you information on preventing pregnancy. He or she may refer you to a specialist for contraceptive advice.
• You must agree to use one or preferably two effective methods of contraception, including condoms or a cap plus spermicide, for a month before taking Isotretinoin, during treatment and for a month afterwards. Before you start treatment your doctor will ask you to take a pregnancy test, which must be negative.
• You must use contraception even if you do not have periods or are not currently sexually active (unless your doctor decides this is not necessary).
• You must accept the need for monthly follow up visits and more pregnancy tests as decided by your doctor. You may have a test 5 weeks after stopping Isotretinoin. You must not get pregnant during treatment and for a month afterwards.
• Your doctor may ask you (or a guardian) to sign a form that confirms that you have been told about the risks, and that you accept the necessary precautions.

Prescriptions for women who could get pregnant are limited to 30 days treatment. A new prescription is needed for more treatment. Each prescription is only valid for 7 days.

If you do get pregnant while taking Isotretinoin, or in the month after treatment has stopped, stop taking the medicine straight away, and contact your doctor. He or she may refer you to a specialist for advice.

Your doctor has written information on pregnancy and contraception for the users of Isotretinoin which he should show you. If you haven’t seen this material already, ask your doctor.

Advice for men
Isotretinoin does not appear to damage sperm. Very low levels of isotretinoin are present in the semen of men taking Isotretinoin, but too little to harm the unborn baby of your partner. You must remember not to share your medication with anyone, particularly not women.

Advice for all patients

• Tell your doctor if you have ever had any mental illness (including depression, suicidal behaviour or psychosis), or if you take medicines for any of these conditions.
• Isotretinoin commonly increases blood fats, such as cholesterol or triglycerides. Your doctor will test these levels before, during and after Isotretinoin treatment. It is best that you do not drink alcoholic drinks or that you at least reduce the amount you usually drink while on treatment. Tell your doctor if you already have high blood fats, diabetes (high blood sugars), are overweight, or an alcoholic. You may need blood tests more often. If your blood fats stay high, your doctor may lower your dose, or take you off Isotretinoin.
• Isotretinoin may increase liver enzyme levels. Your doctor will do blood tests before, during and after Isotretinoin treatment to check these levels. If they stay high, your doctor may lower your dose or take you off of Isotretinoin.
• Isotretinoin may increase blood sugar levels. In rare cases, people become diabetic. Your doctor may monitor blood sugar levels during treatment, particularly if you already have diabetes, are overweight, or are an alcoholic.
• Your skin is likely to get dry. Use a skin moisturising ointment or cream and a lip balm during treatment. To prevent skin irritation you should avoid using exfoliating or anti-acne products.
• Avoid too much sun and do not use a sun-lamp or sun-bed. Your skin may become more sensitive to sunlight. Before you go out in the sun, use a sun-protection product with a high protection factor (SPF 15 or higher).
• Don’t have any cosmetic skin treatments. Isotretinoin may make your skin more fragile. Don’t have any waxing (hair removal), dermabrasion or laser treatments (removing horny skin or scars) during treatment, or for at least 6 months after treatment. They could cause scarring, skin irritation, or rarely, changes in the colour of your skin.
• Cut down on intensive exercise and physical activity. Isotretinoin can cause muscle and joint pain particularly in children and teenagers.
• Do not take vitamin A supplements while taking Isotretinoin. Taking both together may increase the risk of side effects.
• Do not donate blood while you are taking Isotretinoin or for one month afterwards. If someone who is pregnant is given your blood, the baby may be born with birth defects.

Driving and using machines
You may not see as well at night during your treatment. This can happen suddenly. In rare cases this has continued after the treatment has stopped. Drowsiness and dizziness have been reported very rarely. If this happens to you, you should not drive or operate machinery.

Taking other medicines
Do not take vitamin A supplements or tetracyclines (a type of antibiotic), or use any skin treatments for acne while you are on Isotretinoin. It is fine to use moisturisers and emollients (skin creams or preparations that prevent water loss and have a softening effect on the skin).

Tell your doctor or pharmacist if you are taking any other medicines – including herbal and non-prescription products – or if you have taken any recently.

How to take Isotretinoin

• Always take Isotretinoin exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.
• The usual starting dose is 0.5 mg per kilogram body weight per day (0.5 mg/kg/day). So if you weigh 60 kg, your dose will usually start at 30 mg a day.
• Take the capsules once or twice daily.
• Take on a full stomach. Swallow them whole, with a drink or a mouthful of food.
• After a few weeks your doctor may adjust your dose. This depends on how you are getting on with your medicine. For most patients the dose will be between 0.5 and 1.0mg/kg/day. If you think that Isotretinoin is too strong or too weak, talk to your doctor or pharmacist.
• If you have severe kidney problems, you will usually start on a lower dose (such as 10 mg/day) which will be increased up to the highest dose your body can tolerate. If your body can’t tolerate the recommended dose, you may be prescribed a lower dose: that can mean you are treated for longer and your acne might be more likely to come back.
• A course of treatment usually lasts for 16 to 24 weeks. Most patients only need one course. Your acne may continue to improve for up to 8 weeks after treatment. You won’t usually start another course until then.
• Some people find their acne gets worse during the first weeks of treatment. It usually improves as treatment goes on.

If you take more Isotretinoin capsules than you should
If you take too many capsules or someone else accidentally takes your medicine, contact your doctor, pharmacist or nearest hospital immediately.

If you forget to take a dose
If you miss a dose take it as soon as you can. However, if it is nearly time for your next dose, skip the missed dose and carry on as before. Do not take a double dose (two doses close together).

Possible side effects

Isotretinoin can have side effects, though not everybody gets them. The effects often wear off, or stop when treatment is stopped. Your doctor can help you deal with them.

MENTAL PROBLEMS
Rare effects (may affect up to 1 in every 1000 people)

• Depression or related disorders. Signs of this include sad or empty mood, mood changes, anxiety, crying spells, irritability, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down or trouble concentrating.
• Existing depression getting worse.
• Becoming violent or aggressive.

Very rare effects (may affect up to 1 in every 10,000 people)

• Some people have had thoughts about hurting themselves or ending their own lives (suicidal thoughts), have tried to end their own lives (attempted suicide), or have ended their lives (suicide). These people may not appear to be depressed.
• Unusual behaviour.
• Signs of psychosis: a loss of contact with reality, such as hearing voices or seeing things that are not there.

Contact your doctor straight away if you get signs of any of these mental problems. Your doctor may tell you to stop taking Isotretinoin. That may not be enough to stop the effects: you may need more help, and your doctor can arrange this.

ALLERGIC REACTIONS
Rare effects (may affect up to 1 in every 1000 people)

• Serious (anaphylactic) reactions: difficulty breathing or swallowing caused by sudden swelling of the throat, face, lips and mouth. Also sudden swelling of the hands, feet and ankles.
• Allergic reactions such as rash, itchiness.

If you have a serious reaction, get emergency medical help immediately.
If you have any allergic reaction, stop taking Isotretinoin and contact your doctor.

SKIN AND HAIR PROBLEMS
Unknown frequency

• Serious skin rashes (erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), which are potentially life-threatening and require immediate medical attention. These appear initially as circular patches often with central blisters usually on arms and hands or legs and feet, more severe rashes may include blistering of the chest and back. Additional symptoms such as infection of the eye (conjunctivitis) or ulcers of the mouth, throat or nose may occur. Severe forms of rash may progress to widespread peeling of the skin which can be life threatening. These serious skin rashes are often preceded by headache, fever, body aches (flu-like symptoms).

If you develop a rash or these skin symptoms, stop taking Isotretinoin and contact your doctor immediately.

Very common effects (may affect more than 1 in every 10 people)

• Dryness of the skin, especially of the lips and face; inflamed skin, chapped and inflamed lips, rash, mild itching and slight peeling. Use a moisturising cream from the start of treatment.
• Skin becomes more fragile and redder than usual, especially the face.

Rare effects (may affect up to 1 in every 1000 people)

• Hair loss (alopecia). This is usually only temporary. Your hair should return to normal after the treatment ends.

Very rare effects (may affect up to 1 in every 10,000 people)

• Acne can get worse in the first few weeks, but symptoms should improve with time.
• Skin inflamed, swollen, and darker than usual, especially on the face.
• Excess sweating or itching.
• Increased sensitivity to light.
• Bacterial infections at the base of the nail, changes to nails.
• Swellings, discharging, pus.
• Thickened scarring after surgery.
• Increased body hair.

LIVER AND KIDNEY PROBLEMS
Unknown frequency

• Dark or cola-coloured urine

Very common effects (may affect more than 1 in every 10 people)

• Raised liver enzymes seen in blood tests.

Very rare effects (may affect up to 1 in every 10,000 people)

• Yellow skin or eyes, and feeling tired. These can be signs of hepatitis. Stop taking Isotretinoin straight away and contact your doctor.
• Difficulty urinating (passing water), swollen and puffy eyelids, feeling excessively tired. These may be signs of kidney inflammation. Stop taking Isotretinoin straight away and contact your doctor.

NERVOUS SYSTEM PROBLEMS
Common effects (may affect up to 1 in every 10 people)

• Headache.

Very rare effects (may affect up to 1 in every 10,000 people)

• Lasting headache, along with feeling sick (nausea), being sick (vomiting) and change in your eyesight including blurred vision. These may be signs of benign intracranial hypertension, especially if Isotretinoin is taken with antibiotics called tetracycline. Stop taking Isotretinoin straight away and contact your doctor.
• Convulsions, drowsiness, dizziness.

GUT AND STOMACH PROBLEMS
Very rare effects (may affect up to 1 in every 10,000 people)

• Severe abdominal (tummy) pain, with or without severe bloody diarrhoea, feeling sick (nausea) and being sick (vomiting). These can be signs of serious gut conditions. Stop taking Isotretinoin straight away and contact your doctor.

BLOOD PROBLEMS
Very common effects (may affect more than 1 in every 10 people)

• Bruising, bleeding or clotting more easily - if clotting cells are affected.
• Anaemia – weakness, dizziness, pale skin – if red blood cells are affected.
• More liable to get infections - if the white blood cells are affected.

Very rare effects (may affect up to 1 in every 10,000 people)

• Lymph glands may become swollen.

EYE DISORDERS
Very common effects (may affect more than 1 in every 10 people)

• Inflammation of the eye (conjunctivitis) and eyelid area; eyes feel dry and irritated. Ask a pharmacist for suitable eye drops. If you get dry eyes and wear contact lenses, you may need to wear glasses instead.

Very rare effects (may affect up to 1 in every 10,000 people)

• You may see less well at night; colour blindness and colour vision gets worse.
• Sensitivity to light may increase; you may find that you need to wear sunglasses to protect your eyes from too bright sunlight.
• Other sight problems including blurred vision, distorted vision, cloudy surface on the eye (corneal opacity, cataracts).

If you get blurred vision, stop taking Isotretinoin straight away and contact your doctor. If your sight is affected in any other way tell a doctor as soon as you can.

Ear, nose and throat problems
Common effects (may affect up to 1 in every 10 people)

• Inside of the nose becomes dry and crusted, causing mild nosebleeds.
• Sore or inflamed throat and nose.

Very rare effects (may affect up to 1 in every 10,000 people)

• Dry throat, hoarseness.
• Sudden tight chest, shortness of breath and wheezing, particularly if you have asthma.
• Hearing difficulties.

DIABETES
Very rare effects (may affect up to 1 in every 10,000 people)

• Excessive thirst; frequent need to urinate; blood tests show an increase in your blood sugar. These can all be signs of diabetes.

BONES AND MUSCLES
Unknown frequency

• Muscle weakness

Very common effects (may affect more than 1 in every 10 people)

• Back pain; muscle pain; joint pain particularly in children and teenagers.

Very rare effects (may affect up to 1 in every 10,000 people)

• Arthritis; bone disorders (delayed growth, extra growth and changes to bone density); growing bones may stop growing.
• Calcium deposits in soft tissue, sore tendons, high levels of muscle breakdown products in your blood if you exercise vigorously.

To avoid making any bone or muscle problems worse, cut down on intensive physical activity while you’re on Isotretinoin.

OTHER TYPES OF REACTION
Very common effects (may affect more than 1 in every 10 people)

• Changed levels of fats in the blood (including HDL or triglycerides).

Common effects (may affect up to 1 in every 10 people)

• Higher levels of cholesterol in the blood.
• Protein or blood in the urine.

Very rare effects (may affect up to 1 in every 10,000 people)

• Generally feeling unwell.
• High levels of uric acid in the blood.
• Bacterial infections.
• Inflammation of the blood vessels (sometimes with bruising, red patches).

If you notice any side effects that you are worried about, whether they are listed in this leaflet or not, talk to your doctor.

Storing Isotretinoin

• Keep out of the reach and sight of children.
• Do not store above 25°C.
• Store in the original package and keep blister in the outer carton in order to protect from moisture and light.
• Do not use after the expiry date (EXP) stated on the pack and blister.
• Return left over capsules to your pharmacist. Only keep them if your doctor tells you to.

Further information

What Isotretinoin contains:

• The active substance in Isotretinoin is isotretinoin.
• Other ingredients are refined soya-bean oil, hydrogenated soya-bean oil, partially hydrogenated soya-bean oil, yellow beeswax, gelatin, glycerol, sorbitol, mannitol, hydrogenated hydrolysed starch, titanium dioxide (E171), red iron oxide (E172), printing ink containing shellac, black iron oxide (E172) and propylene glycol.

What Isotretinoin looks like and contents of the pack:
Isotretinoin comes in soft capsules containing either 10 mg or 20 mg isotretinoin.

• The 10 mg capsules are oval, opaque, coloured brown-red and marked TAJ.
• The 20 mg capsules are oval, opaque, coloured brown-red and white and marked TAJ.

The capsules come in blister packs of 20, 30, 50 or 100 capsules. Not all pack sizes may be marketed.

Isotretinoin
10mg/20mg/40mg Capsules

DESCRIPTION

Isotretinoin, a retinoid, is available as Isotretinoin in 10-mg, 20-mg and 40-mg soft gelatin capsules for oral administration. Each capsule contains yellow wax, butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil, tocopherol, and soybean oil. Gelatin capsules contain gelatin, glycerin and non-crystallizing sorbitol solution, with the following dye systems: 10 mg — ferric oxide (yellow) and titanium dioxide; 20 mg — titanium dioxide; 40 mg — FD&C Yellow No.6 and titanium dioxide.

The edible imprinting ink for all the capsules contains: shellac glaze, dehydrated alcohol, isopropyl alcohol, iron oxide black, N-butyl alcohol, propylene glycol, and ammonium hydroxide.

USP Dissolution Test Pending.
Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural formula is:

CLINICAL PHARMACOLOGY

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown.

Nodular Acne
Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and 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.1

Pharmacokinetics
Absorption
Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of Isotretinoin under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with Isotretinoin given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Isotretinoin capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

Distribution
Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism
Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.

After a single 80 mg oral dose of Isotretinoin to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (=18 years), the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.

Elimination
Following oral administration of an 80 mg dose of 14C- isotretinoin as a liquid suspension, 14C- activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of Isotretinoin to 74 healthy adult subjects under fed conditions, the mean ±SD elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were 21 ± 8.2 hours and 24 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne.

Special Patient Populations
Pediatric Patients
The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (=18 years) who received Isotretinoin for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.

In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.

INDICATIONS AND USAGE

Severe Recalcitrant Nodular Acne
Isotretinoin is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition,2 means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, Isotretinoin should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Isotretinoin is indicated only for those female patients who are not pregnant, because Isotretinoin can cause severe birth defects.

A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off Isotretinoin. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth.

CONTRAINDICATIONS

Pregnancy: Category X. See Boxed CONTRAINDICATIONS AND WARNINGS.

Allergic Reactions
Isotretinoin is contraindicated in patients who are hypersensitive to this medication or to any of its components (see PRECAUTIONS: Hypersensitivity).

WARNINGS

Psychiatric Disorders
Isotretinoin may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these events. Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Isotretinoin therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults”), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop Isotretinoin and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of Isotretinoin therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient’s family. A referral to a mental health professional may be necessary. The physician should consider whether Isotretinoin therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Isotretinoin therapy.

Pseudotumor Cerebri
Isotretinoin use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue Isotretinoin immediately and be referred to a neurologist for further diagnosis and care.

Serious Skin Reactions
There have been post-marketing reports of erythema multiforme and severe skin reactions [eg, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These events may be serious and result in death, life-threatening events, hospitalization, or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of Isotretinoin should be considered if warranted.

Pancreatitis
Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Isotretinoin should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.

Lipids
Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Isotretinoin. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Isotretinoin in clinical trials. In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects on triglycerides, HDL, and cholesterol were reversible upon cessation of Isotretinoin therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing Isotretinoin.5

Blood lipid determinations should be performed before Isotretinoin is given and then at intervals until the lipid response to Isotretinoin is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk during Isotretinoin therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Isotretinoin therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended.

The cardiovascular consequences of hypertriglyceridemia associated with Isotretinoin are unknown.

Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).

Hearing Impairment
Impaired hearing has been reported in patients taking Isotretinoin; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this event have not been established. Patients who experience tinnitus or hearing impairment should discontinue Isotretinoin treatment and be referred for specialized care for further evaluation.

Hepatotoxicity
Clinical hepatitis considered to be possibly or probably related to Isotretinoin therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with Isotretinoin, the drug should be discontinued and the etiology further investigated.

Inflammatory Bowel Disease
Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after Isotretinoin treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Isotretinoin immediately.

Skeletal
Bone Mineral Density
Effects of multiple courses of Isotretinoin on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. In an open-label clinical trial (N=217) of a single course of therapy with Isotretinoin for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range –1.6% to –7.6%) in five of eight patients (62.5%).

In a separate open-label extension study of ten patients, ages 13-18 years, who started a second course of Isotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25%.

Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been seen in the Isotretinoin population. While causality to Isotretinoin has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Isotretinoin be given at the recommended doses for no longer than the recommended duration.

Hyperostosis
A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in six of eight patients in a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple Isotretinoin treatment courses for acne are unknown.

In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of Isotretinoin given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown.

Premature Epiphyseal Closure
There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of Isotretinoin. The effect of multiple courses of Isotretinoin  on epiphyseal closure is unknown.

Vision Impairment
Visual problems should be carefully monitored. All Isotretinoin patients experiencing visual difficulties should discontinue Isotretinoin treatment and have an ophthalmological examination.

Corneal Opacities
Corneal opacities have occurred in patients receiving Isotretinoin for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with Isotretinoin have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug.

Decreased Night Vision
Decreased night vision has been reported during Isotretinoin therapy and in some instances the event has persisted after therapy was discontinued. Because 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.

PRECAUTIONS

Isotretinoin must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Isotretinoin must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE. Registered and activated pharmacies must receive Isotretinoin only from wholesalers registered with iPLEDGE.

iPLEDGE program requirements for wholesalers, prescribers, and pharmacists are described below:

Wholesalers:
For the purpose of the iPLEDGE program, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute Isotretinoin, wholesalers must be registered with iPLEDGE, and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of isotretinoin. These include:

• Registering prior to distributing isotretinoin and re-registering annually thereafter
• Distributing only FDA approved isotretinoin product
• Only shipping isotretinoin to
  • wholesalers registered in the iPLEDGE program with prior written consent from the manufacturer or
  • pharmacies licensed in the US and registered and activated in the iPLEDGE program
• Notifying the isotretinoin manufacturer (or delegate) of any non-registered and/or non-activated pharmacy or unregistered wholesaler that attempts to order isotretinoin
• Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE program by the isotretinoin manufacturer (or delegate)
• Returning to the manufacturer (or delegate) any undistributed product if registration is revoked by the manufacturer or if the wholesaler chooses to not re-register annually

Prescribers:
To prescribe isotretinoin, the prescriber must be registered and activated with the pregnancy risk management program iPLEDGE. Prescribers can register by signing and returning the completed registration form. Prescribers can only activate their registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy.
• I have the expertise to provide the patient with detailed pregnancy prevention counseling or I will refer her to an expert for such counseling, reimbursed by the manufacturer.
• I will comply with the iPLEDGE program requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program and The iPLEDGE Program Prescriber Contraception Counseling Guide.
• Before beginning treatment of female patients of childbearing potential with isotretinoin and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously one month before, during, and one month after isotretinoin therapy, unless the patient commits to continuous abstinence.
• I will not prescribe isotretinoin to any female patient of childbearing potential until verifying she has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of isotretinoin and another pregnancy test 1 month later.
• I will report any pregnancy case that I become aware of while the female patient is on isotretinoin or one month after the last dose to the pregnancy registry.

To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the internet www.ipledgeprogram.com):

1. Register each patient in the iPLEDGE program.
2. Confirm monthly that each patient has received counseling and education
3. For female patients of childbearing potential:
   • Enter patient’s two chosen forms of contraception each month.
   • tretinoin must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test.

Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE program. Meeting the requirements for a female patient of childbearing potential signifies that she:

Has been counseled and has signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin. The patient must sign the informed consent form before starting treatment and patient counseling must also be done at that time and on a monthly basis thereafter.

Has had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests should be at least 19 days.

- For patients with regular menstrual cycles, the second pregnancy test should be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used two forms of contraception for one month.

- For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used two forms of contraception for one month.

Has had a negative result from a urine or serum pregnancy test in a CLIA-certified laboratory before receiving each subsequent course of isotretinoin. A pregnancy test must be repeated every month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription.

Has selected and has committed to use two forms of effective contraception simultaneously, at least one of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use two forms of effective contraception for at least one month prior to initiation of isotretinoin therapy, during isotretinoin therapy, and for one month after discontinuing isotretinoin therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis.

If the patient has unprotected heterosexual intercourse at any time one month before, during, or one month after therapy, she must:

1. Stop taking Isotretinoin immediately, if on therapy
2. Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse
3. Start using two forms of effective contraception simultaneously again for one month before resuming Isotretinoin therapy
4. Have a second pregnancy test after using two forms of effective contraception for one month as described above depending on whether she has regular menses or not.

Effective forms of contraception include both primary and secondary forms of contraception:

Any birth control method can fail. There have been reports of pregnancy from female patients who have used oral contraceptives, as well as transdermal patch/injectable/ implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking Isotretinoin. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that female patients of childbearing potential use two effective forms of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits).

Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for Isotretinoin. Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.

Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John’s Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John’s Wort.

If a pregnancy does occur during Isotretinoin treatment, Isotretinoin must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or one month after Isotretinoin therapy must be reported immediately to the FDA and also to the iPLEDGE pregnancy registry via the internet (www.ipledgeprogram.com).

All Patients
Isotretinoin is contraindicated in female patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions:

• Must be registered with the iPLEDGE program by the prescriber
• Must understand that severe birth defects can occur with the use of isotretinoin by female patients
• Must be reliable in understanding and carrying out instructions
• Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings about the potential risks associated with isotretinoin
• Must fill and pick up the prescription within 7 days of the date of specimen collection for the pregnancy test for female patients of childbearing potential
• Must fill and pick up the prescription within 30 days of the office visit for male patients and female patients not of childbearing potential
• Must not donate blood while on isotretinoin and for one month after treatment has ended
• Must not share isotretinoin with anyone, even someone who has similar symptoms

Female Patients of Childbearing Potential
Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, female patients of childbearing potential must meet the following conditions:

• Must NOT be pregnant or breast-feeding
• Must comply with the required pregnancy testing at a CLIA-certified laboratory
• Must fill and pick up the prescription within 7 days of the date of specimen collection for the pregnancy test
• Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence from heterosexual intercourse, and understand behaviors associated with an increased risk of pregnancy
• Must understand that it is her responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy
• Must have signed an additional Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin
• Must access the iPLEDGE system via the internet, before starting isotretinoin, on a monthly basis during therapy, and one month after the last dose to answer questions on the program requirements and to enter the patient’s two chosen forms of contraception
• Must have been informed of the purpose and importance of providing information to the iPLEDGE program should she become pregnant while taking isotretinoin or within one month of the last dose

Pharmacists:
To dispense isotretinoin, pharmacies must be registered and activated with the pregnancy risk management program iPLEDGE.

The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I will train all pharmacists, who participate in the filling and dispensing of isotretinoin prescriptions, on the iPLEDGE program requirements.
• I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE program requirements described in the booklet entitled Pharmacist Guide for the iPLEDGE Program.
• I will obtain Isotretinoin product only from iPLEDGE registered wholesalers.
• I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another pharmacy.
• I will return to the manufacturer (or delegate) any unused product if registration is revoked by the manufacturer or if the pharmacy chooses to not reactivate annually.
• I will not fill isotretinoin for any party other than a qualified patient.

To dispense isotretinoin, the pharmacist must:

1. be trained by the Responsible Site Pharmacist concerning the iPLEDGE program requirements.
2. obtain authorization from the iPLEDGE program via the internet for every isotretinoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive Isotretinoin.
3. write the Risk Management Authorization (RMA) number on the prescription.

Isotretinoin must only be dispensed:

• in no more than a 30-day supply
• with a Isotretinoin Medication Guide
• after authorization from the iPLEDGE program
• prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 30 days of the office visit for male patients and female patients not of childbearing potential and within 7 days of the date of specimen collection for female patients of childbearing potential)
• with a new prescription for refills and another authorization from the iPLEDGE program (No automatic refills are allowed)

A Isotretinoin Medication Guide must be given to the patient each time Isotretinoin is dispensed, as required by law. This Isotretinoin  Medication Guide is an important part of the risk management program for the patients.

Isotretinoin must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved Isotretinoin products must be distributed, prescribed, dispensed, and used. Patients must fill Isotretinoin prescriptions only at US licensed pharmacies.

A description of the iPLEDGE program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE program requirements and to reinforce the educational messages.

1. The Guide to Best Practices for the iPLEDGE Program includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified Isotretinoin prescription.
2. The iPLEDGE Program Prescriber Contraception Counseling Guide includes: specific information about effective contraception, the limitations of contraceptive methods, behaviors associated with an increased risk of contraceptive failure and pregnancy and the methods to evaluate pregnancy risk.
3. The Pharmacist Guide for the iPLEDGE Program includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription.
4. The iPLEDGE program is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE program includes information on the risks and benefits of Isotretinoin which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription.
5. Female patients not of childbearing potential and male patients, and female patients of childbearing potential are provided with separate booklets. Each booklet contains information on isotretinoin therapy including precautions and warnings, a Patient Information/Informed Consent (for all patients) form, and a toll-free line which provides Isotretinoin information in two languages.
6. The booklet for female patients not of childbearing potential and male patients, The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, also includes information about male reproduction and a warning not to share isotretinoin with others or to donate blood during Isotretinoin therapy and for one month following discontinuation of isotretinoin.
7. The booklet for female patients of childbearing potential, The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant, includes a referral program that offers female patients free contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; and a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form concerning birth defects.
8. The booklet, The iPLEDGE Program Birth Control Workbook includes information on the types of contraceptive methods, the selection and use of appropriate, effective contraception, the rates of possible contraceptive failure and a toll-free contraception counseling line.
9. In addition, there is a patient educational DVD with the following videos —"Be Prepared, Be Protected" and "Be Aware: The Risk of Pregnancy While on Isotretinoin".

General
Although an effect of Isotretinoin on bone loss is not established, physicians should use caution when prescribing Isotretinoin to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant.

Patients may be at increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with Isotretinoin or following cessation of therapy with Isotretinoin while involved in these activities. While causality to Isotretinoin has not been established, an effect must not be ruled out.

Information for Patients
Patients must be instructed to read the Medication Guide supplied as required by law when Isotretinoin is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional information, patients must also be instructed to read the iPLEDGE program patient educational materials. All patients must sign the Patient Information/Informed Consent (for all patients) form.

Female patients of childbearing potential must be instructed that they must not be pregnant when Isotretinoin therapy is initiated, and that they should use two forms of effective contraception simultaneously for one month before starting Isotretinoin, while taking Isotretinoin, and for one month after Isotretinoin has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning Isotretinoin therapy. They should be given an opportunity to view the patient DVD provided by the manufacturer to the prescriber. The DVD includes information about contraception, the most common reasons that contraception fails, and the importance of using two forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes Isotretinoin at any time during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another Isotretinoin prescription is written.

Isotretinoin is found in the semen of male patients taking Isotretinoin, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of postmarketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete, and two had other possible explanations for the defects observed.

Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Isotretinoin treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop Isotretinoin and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of Isotretinoin treatment may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient’s family. A referral to a mental health professional may be necessary. The physician should consider whether Isotretinoin therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Isotretinoin therapy.

Patients must be informed that some patients, while taking Isotretinoin or soon after stopping Isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking Isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on Isotretinoin becoming aggressive or violent. No one knows if Isotretinoin caused these behaviors or if they would have happened even if the person did not take Isotretinoin. Some people have had other signs of depression while taking Isotretinoin.

Patients must be informed that they must not share Isotretinoin with anyone else because of the risk of birth defects and other serious adverse events.

Patients must be informed not to donate blood during therapy and for one month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Isotretinoin.

Patients should be reminded to take Isotretinoin with a meal. To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.

Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy.

Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during Isotretinoin therapy and for at least 6 months thereafter due to the possibility of scarring.

Patients should be advised to avoid prolonged exposure to UV rays or sunlight.

Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy.

Patients should be informed that approximately 16% of patients treated with Isotretinoin in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of Isotretinoin, but in some cases persisted. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity.

Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with Isotretinoin developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of Isotretinoin. Consideration should be given to discontinuation of Isotretinoin if any significant abnormality is found.

Neutropenia and rare cases of agranulocytosis have been reported. Isotretinoin should be discontinued if clinically significant decreases in white cell counts occur.

Patients should be advised that severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in post-marketing data. Isotretinoin should be discontinued if clinically significant skin reactions occur.

Hypersensitivity
Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.

Drug Interactions
Vitamin A:
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.

Tetracyclines:
Concomitant treatment with Isotretinoin and tetracyclines should be avoided because Isotretinoin use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines.

Micro-dosed Progesterone Preparations:
Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during Isotretinoin therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Isotretinoin. Therefore, it is critically important for female patients of childbearing potential to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form.

Norethindrone/ethinyl estradiol:
In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving 7/7/7 Tablets as an oral contraceptive agent, Isotretinoin at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.

St. John’s Wort:   Isotretinoin use is associated with depression in some patients. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John’s Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John’s Wort.

Phenytoin:
Isotretinoin has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Isotretinoin. Therefore, caution should be exercised when using these drugs together.

Systemic Corticosteroids:
Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Isotretinoin. Therefore, caution should be exercised when using these drugs together.

Laboratory Tests
Pregnancy Test:
-Female patients of childbearing potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue
qualification of the patient for Isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days.

-For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of Isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month.

-For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of Isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month.

-Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription.

Lipids:
Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to Isotretinoin is established. The incidence of hypertriglyceridemia is one patient in four on Isotretinoin therapy.

Liver Function Tests:
Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to Isotretinoin has been established.

Glucose:
Some patients receiving Isotretinoin have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Isotretinoin therapy, although no causal relationship has been established.

CPK:
Some patients undergoing vigorous physical activity while on Isotretinoin therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial.

Carcinogenesis, Mutagenesis and Impairment of Fertility
In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain.

The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6x background) was noted in S.typhimurium TA100 when the assay was conducted with metabolic activation. No dose response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative.

In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).

In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). 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 of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving Isotretinoin therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.

Pregnancy: Category X. See Boxed CONTRAINDICATIONS AND WARNINGS.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive Isotretinoin.

Pediatric Use
The use of Isotretinoin in pediatric patients less than 12 years of age has not been studied. The use of Isotretinoin for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists. Use of Isotretinoin in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients (=18 years). Results from this study demonstrated that Isotretinoin, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe recalcitrant nodular acne in both pediatric and adult patients.

In studies with Isotretinoin, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients.

In an open-label clinical trial (N=217) of a single course of therapy with Isotretinoin for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range -1.6% to -7.6%) in five of eight patients (62.5%).

In a separate open-label extension study of ten patients, ages 13 to 18 years, who started a second course of Isotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25%.

Geriatric Use
Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with isotretinoin therapy.

ADVERSE REACTIONS

Clinical Trials and Postmarketing Surveillance
The adverse reactions listed below reflect the experience from investigational studies of Isotretinoin, and the postmarketing experience. The relationship of some of these events to Isotretinoin therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Isotretinoin are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, eg, of the lips, nasal passage, and eyes).

Dose Relationship
Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy.

Body as a Whole
allergic reactions, including vasculitis, systemic hypersensitivity, edema, fatigue, lymphadenopathy, weight loss

Cardiovascular
palpitation, tachycardia, vascular thrombotic disease, stroke

Endocrine/Metabolic
hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests).

Gastrointestinal
inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms.

Hematologic
allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PRECAUTIONS: Information for Patients). See PRECAUTIONS: Laboratory Tests for other hematological parameters.

skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PRECAUTIONS: Information for Patients), transient pain in the chest (see PRECAUTIONS: Information for Patients), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests).

Neurological
pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness.

Psychiatric
suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability.

Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System
Abnormal menses.

Respiratory
bronchospasms (with or without a history of asthma), respiratory infection, voice alteration

Skin and Appendages
acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic /photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener’s granulomatosis; see PRECAUTIONS: Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PRECAUTIONS: Information for Patients)

Special Senses
Hearing
hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.

Vision
corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist (see WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances

Urinary System
glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters)

Laboratory
Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment

Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS: Hepatotoxicity)

Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests), hyperuricemia

Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PRECAUTIONS: Information for Patients), elevated sedimentation rates, elevated platelet counts, thrombocytopenia

White cells in the urine, proteinuria, microscopic or gross hematuria

OVERDOSAGE

The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice (>600 times the recommended clinical dose of 1 mg/kg/day after normalization of the rat dose for total body surface area and >300 times the recommended clinical dose of 1 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects.

Isotretinoin causes serious birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS). Female patients of childbearing potential who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the Boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for one month after the overdose. All patients with isotretinoin overdose should not donate blood for at least one month.

DOSAGE AND ADMINISTRATION

Isotretinoin should be administered with a meal (see PRECAUTIONS: Information for Patients).

The recommended dosage range for Isotretinoin is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1 mg/kg/day,8 it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects — some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated. Failure to take Isotretinoin with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions.

The safety of once daily dosing with Isotretinoin has not been established. Once daily dosing is not recommended.

If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Isotretinoin, even in low doses, has not been studied, and is not recommended. It is important that Isotretinoin be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Isotretinoin on bone loss is unknown .

Contraceptive measures must be followed for any subsequent course of therapy.

HOW SUPPLIED

Soft gelatin capsules, 10 mg (pale yellow), imprinted in black ink with “V10”. Boxes of 30 containing 3 Prescription Packs of 10 capsules. Boxes of 100 containing 10 Prescription Packs of 10 capsules.

Soft gelatin capsules, 20 mg (white to slight pink), imprinted in black ink with “V20”. Boxes of 30 containing 3 Prescription Packs of 10 capsules. Boxes of 100 containing 10 Prescription Packs of 10 capsules.

Soft gelatin capsules, 40 mg (orange), imprinted in black ink with “V40”. Boxes of 30 containing 3 Prescription Packs of 10 capsules. Boxes of 100 containing 10 Prescription Packs of 10 capsules.

Storage
Store at 20°-25°C (68° to 77°F). [See USP controlled room temperature]. Protect from light.

REFERENCES

1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979.

2. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991.

3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid: evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980.

4. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet 2:1048-1049, 1980.

5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980.

6. Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ. Isotretinoin therapy is associated with early skeletal radiographic changes. J Am Acad Dermatol 10:1024-1029, 1984.

7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.

8. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 10:490-496, 1984.