Epuris Product Monograph

Recent Major Label Changes

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Table of Contents

Recent Major Label Changes .............................................................................................................. 2

Table of Contents ............................................................................................................................... 2

Part 1: Healthcare Professional Information ....................................................................................... 5

1. 1.

   Indications ............................................................................................................................. 5

   1.1. Pediatrics............................................................................................................................. 5

   1.2. Geriatrics ............................................................................................................................. 5

2. 2. Contraindications ................................................................................................................... 5
3. 3. Serious Warnings and Precautions Box ................................................................................... 6
4. 4.

   Dosage and Administration .................................................................................................... 8

   4.1. Dosing Considerations ........................................................................................................ 8

   4.2. Recommended Dose and Dosage Adjustment ................................................................... 8

   4.4. Administration .................................................................................................................... 9

   4.5. Missed Dose ........................................................................................................................ 9

5. 5. Overdose ............................................................................................................................... 9
6. 6. Dosage Forms, Strengths, Composition and Packaging .......................................................... 10
7. 7.

   Warnings and Precautions .................................................................................................... 11

   General ........................................................................................................................................... 11

   Blood Donation .............................................................................................................................. 12

   Cardiovascular ................................................................................................................................ 12

   Ear/Nose/Throat ............................................................................................................................ 13

   Endocrine and Metabolism ............................................................................................................ 13

   Gastrointestinal.............................................................................................................................. 13

   Hepatic/Biliary/Pancreatic ............................................................................................................. 13

   Immune .......................................................................................................................................... 14

   Monitoring and Laboratory Tests .................................................................................................. 14

   Musculoskeletal ............................................................................................................................. 15

   Neurologic ...................................................................................................................................... 17

   Ophthalmologic.............................................................................................................................. 17

   Psychiatric ...................................................................................................................................... 17

   Renal .............................................................................................................................................. 17

   Reproductive Health: Female and Male Potential ......................................................................... 18

   Skin 19

   7.1. Special Populations ........................................................................................................... 20

   7.1.1. Pregnant Women ......................................................................................................... 20

   7.1.2. Breastfeeding ............................................................................................................... 21

   7.1.3. Pediatrics ...................................................................................................................... 21

   7.1.4. Geriatrics ...................................................................................................................... 21

8. 8.

   Adverse Reactions ............................................................................................................... 21

   8.1. Adverse Reaction Overview .............................................................................................. 21

   8.2. Clinical Trial Adverse Reactions ........................................................................................ 22

   8.2.1. Clinical Trial Adverse Reactions – Pediatrics ................................................................ 25

   8.3. Less Common Clinical Trial Adverse Reactions ................................................................. 25

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data 27

   8.5. Post-Market Adverse Reactions ........................................................................................ 27

9. 9.

   Drug Interactions ................................................................................................................. 28

   9.1. Serious Drug Interactions ................................................................................................. 28

   9.2. Drug Interactions Overview .............................................................................................. 28

   9.4. Drug-Drug Interactions ..................................................................................................... 28

   9.5. Drug-Food Interactions ..................................................................................................... 29

   9.6. Drug-Herb Interactions ..................................................................................................... 29

   9.7. Drug-Laboratory Test Interactions .................................................................................... 30

10. 10.

    Clinical Pharmacology .......................................................................................................... 30

    10.1. Mechanism of Action ........................................................................................................ 30

    10.2. Pharmacodynamics ........................................................................................................... 30

    10.3. Pharmacokinetics .............................................................................................................. 30

11. 11. Storage, Stability and Disposal ............................................................................................. 32
12. 12. Special Handling Instructions................................................................................................ 32

Part 2: Scientific Information ............................................................................................................ 33

1. 13. Pharmaceutical Information ................................................................................................. 33
2. 14.

   Clinical Trials ........................................................................................................................ 33

   14.1. Clinical Trials by Indication ............................................................................................... 33

3. 15. Microbiology ....................................................................................................................... 35
4. 16. Non-Clinical Toxicology ........................................................................................................ 35

Patient Medication Information ....................................................................................................... 39

Part 1: Healthcare Professional Information

1. INDICATIONS

EPURIS^® (isotretinoin) is indicated for the treatment of:

• Severe Nodular and/or Inflammatory Acne
• Acne Conglobata
• Recalcitrant Acne

Because of significant adverse reactions associated with its use, EPURIS^® should be reserved for patients where the conditions listed above are unresponsive to conventional first line therapies. EPURIS® should not be substituted with other marketed formulations of isotretinoin.

EPURIS^® should only be prescribed by physicians knowledgeable in the use of retinoids systemically, who understand the risk of teratogenicity in females of child bearing age and who are experienced in counselling young adults for whom isotretinoin is generally indicated (see 2. Contraindications, 3. Serious Warnings and Precautions Box and 7.1.1. Pregnant Women).

A careful assessment of the patient’s mental state should be made, including whether or not they have a history of previous psychiatric illness (see 3. Serious Warnings and Precautions)

It is strongly recommended that each EPURIS^® prescription be limited to a one-month supply in order to encourage patients to return for follow-up to monitor side effects.

The pharmacist must ensure that:

• Prescriptions of EPURIS^® for women of childbearing potential be limited to 30 days of treatment and continuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescription and dispensing of EPURIS® should occur on the same day.
• Dispensing of EPURIS^® occur within a maximum of 7 days of the prescription.

1.1. Pediatrics

Pediatrics (< 12 years of age): The safety and efficacy of EPURIS^® in pediatric patients less than 12 years of age have not been established. The use of EPURIS^® in these patients is not recommended.

Pediatrics (12 to 17 years of age): 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 (see 7.1.3. Pediatrics).

1.2. Geriatrics

Geriatrics (≥ 65 years of age): Clinical studies of isotretinoin-containing products did not include sufficient numbers of geriatric 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 (see 7.1.4. Geriatrics).

2. Contraindications

EPURIS® (isotretinoin) is contraindicated in pregnancy.

• Females must not become pregnant while taking EPURIS^® or for at least one month after its discontinuation. Isotretinoin causes severe birth defects in a very high percentage of infants born to women who became pregnant during treatment with isotretinoin in any amount, even for a short period of time.
• Potentially any exposed fetus can be affected. There are no accurate means of determining whether an exposed fetus has been affected (see 7.1.1. Pregnant Women).
• If pregnancy does occur during treatment with EPURIS^® or for one month after its discontinuation, EPURIS® treatment must be immediately stopped and the physician and patient should discuss the desirability of continuing the pregnancy.
• EPURIS^® should only be prescribed by physicians knowledgeable in the use of retinoids systemically (see 1. Indications).

EPURIS^® is also contraindicated in:

• breast-feeding women
• hepatic insufficiency
• renal insufficiency
• hypervitaminosis A
• patients with excessively elevated blood lipid values
• patients taking tetracyclines (see 3. Serious Warnings and Precautions Box and 9.4. Drug-Drug Interactions)
• patients who are sensitive to isotretinoin or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Table 2.
• Serious Warnings and Precautions Box

Serious Warnings and Precautions

4. Dosage and Administration

4.1. Dosing Considerations

• Carefully assess the patient’s mental state, including whether or not they have a history of previous psychiatric illness (see 3. Serious Warnings and Precautions Box and 7. Warnings and Precautions, Psychiatric).
• 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 single 12 to 16 week course of therapy. If a second course of therapy is needed, it can be initiated eight or more weeks after completion of the first course, since experience has shown that patients may continue to improve while off the drug.
• Due to possible differences in pharmacokinetic properties, EPURIS® capsules are not interchangeable with other isotretinoin-containing products

The following laboratory testing must be completed prior to EPURIS^® use:

• Pregnancy testing: Ensure patient is not pregnant prior to administering EPURIS^® (see 2. Contraindications, Monitoring and Laboratory Tests, and 7.1.1. Pregnant Women)
• A fasting lipid profile including triglycerides
• Liver function tests
• Renal function tests
• Blood glucose levels (see 2. Contraindications, Monitoring and Laboratory Tests)

4.2. Recommended Dose and Dosage Adjustment

Initial Therapy: The initial dose of EPURIS® should be individualized according to the patient’s weight and severity of the disease.

In general, patients initially should receive EPURIS® 0.5 mg/kg body weight 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. For optimal absorption, the daily dose of EPURIS® should be taken with food. Taking EPURIS® without food decreases the rate and extent of absorption by 21% and 33% (Cmax and AUCt). EPURIS® should be taken in the nearest number of whole capsules, either as a single dose or in two divided doses during the day, whichever is more convenient.

Maintenance Therapy: Maintenance dose should be adjusted between 0.1 and 1 mg/kg body weight daily and, in exceptional instances, up to 2 mg/kg body weight daily, depending upon individual patient response and tolerance to the drug.

A complete course of therapy consists of 12-16 weeks of EPURIS® administration.

Patients may show additional improvement for up to several months after a course of EPURIS® has been completed. With effective treatment, appearance of new lesions will not normally be evident for a period of at least three to six months.

4.4. Administration

EPURIS^® is for oral use only.

4.5. Missed Dose

If a patient misses a dose of EPURIS^®, it may be taken later the same day, but, the patient should be instructed to not take more EPURIS^® in one day than what has been prescribed. The patient should then administer the next dose on the usual scheduled dosing day. The patient should not take a double dose to make up for a missed dose.

5. Overdose

In the event of acute EPURIS overdose, evacuation of the stomach should be considered during the first few hours after this overdose. Signs and symptoms of acute overdose of isotretinoin have been associated with headache, vomiting, facial flushing, cheilitis, abdominal pain, dizziness and ataxia. To date, all symptoms have quickly resolved without apparent residual effects and usually without treatment. Elevated intracranial pressure has been reported with patients receiving therapeutic doses of isotretinoin. Patients with an EPURIS overdose should be monitored closely for signs of increased intracranial pressure. Signs of hypervitaminosis A could appear in cases of overdose.

Limited data exists on the pharmacokinetic characteristics of isotretinoin in an overdose situation.

Following the oral administration of single 80, 160, 240 and 340 mg doses to 12 healthy male subjects C_max was 366, 820, 1,056 and 981 ng/mL, and t_1/2 was 13.6, 14.1, 14.4 and 16.5 hours for isotretinoin, respectively. Twenty-three compromised cancer patients received weekly oral doses of 200 (3 patients); 400 (7 patients); 660 (2 patients); 1,000 (3 patients); 1,400 (6 patients) and 1,800 (1 patient) mg/m².

Normal body surface area for healthy subjects is 1.73 m². After the first dose, C_max was 1.5, 3.8, 3.5, 2.5, 2.7 and 4.6 µg/mL, and t_1/2 was 45, 9.1, 14.5, 57, 13.1 and 6.1 hours for isotretinoin, respectively.

The absorption of isotretinoin appears to be a saturable process.

Since it is difficult to extrapolate from the results of these studies to the overdose situation, the following precautions should be taken with all female patients of childbearing potential who have taken an overdose of EPURIS^®.

After a patient has been treated for an isotretinoin overdose, consideration should be given to the teratogenic potential of the drug. Female patients should be given pregnancy tests and advised that they need to use a designated method of birth control for at least 30 days after the overdose (the average half life of the drug is ~25 hours). Female patients who test positive on a pregnancy screen after an overdose should be fully counseled on the serious risk to the fetus from this exposure to isotretinoin and the physician and patient should discuss the desirability of continuing the pregnancy (See 2. Contraindications, 7.1.1. Pregnant Women and 16. Non-Clinical Toxicology, Reproductive and Developmental Toxicology).

Patients who test positive on a pregnancy screen after an overdose should be fully counselled on the serious risk to the fetus from this exposure to isotretinoin and the physician and patient should discuss the desirability of continuing the pregnancy (see 2. Contraindications, 7.1.1. Pregnant Women and 16. Non-Clinical Toxicology, Reproductive and Developmental Toxicology).

Canadian Regional Poison Information Centres have been advised on the proper collection and handling of isotretinoin blood samples and also on the laboratory(s) equipped to assay these samples.

6. Dosage Forms, Strengths, Composition and Packaging

Table 1: Dosage Forms, Strengths, Composition and Packaging

Table 2: Hard Gelatin Capsule Shell: Description

7. Warnings and Precautions

Please see 3. Serious Warnings and Precautions Box

General

EPURIS^® is contraindicated in females of childbearing potential unless ALL of the following conditions apply:

Conditions of Use

1. 1. The patient has severe disfiguring nodular and/or inflammatory acne, acne conglobata or recalcitrant acne that has not responded to standard therapy, including systemic antibiotics.
2. 2. The patient is reliable in understanding and carrying out instructions.
3. 3. All patients must sign the informed consent form prior to initiating therapy. This form is provided to the physician via the www.epuris.ca website or by contacting Cipher Pharmaceuticals Inc.’s Information line at 1-855-437-8747 (1-855-4EPURIS).
4. 4. The patient is able and willing to comply with the mandatory effective contraceptive measures.
5. 5. The patient has received, and acknowledged understanding of, a careful oral and printed explanation of the hazards of fetal exposure to isotretinoin and the risk of possible contraception failure. This explanation may include showing a line drawing to the patient of an infant with the characteristic external deformities resulting from isotretinoin exposure during pregnancy.
6. 6. The patient has been informed and understands the need to rapidly consult her physician if there is a risk of pregnancy.
7. 7. The patient understands the need for rigorous follow-up on a monthly basis.
8. 8. The patient uses effective contraception without any interruption for one month before beginning EPURIS^® therapy, during EPURIS^® therapy and for one month following discontinuation of EPURIS^® therapy. It is recommended that two reliable forms of contraception be used simultaneously (see 7.1.1. Pregnant Women).
9. 9. The patient has had two negative pregnancy tests before starting EPURIS^® therapy with the first pregnancy test conducted at initial assessment when the patient is qualified for EPURIS^® therapy by the physician. The patient has had a second serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL with a negative result, performed in a licensed laboratory, within 11 days prior to initiating therapy. The patient has had two or three days of the next normal menstrual period before EPURIS^® therapy is initiated.
10. 10. In the event of relapse treatment, the patient must also use the same uninterrupted and effective contraceptive measures one month prior to, during and for one month after EPURIS^®.

(For items 4 to 9 above, please see 7.1.1. Pregnant Women).

It is mandatory that all female patients of childbearing potential treated with EPURIS^® have regular negative monthly pregnancy tests prior to receiving each 30-day EPURIS^® prescription and an additional test one month after the discontinuation of treatment.

Even female patients who normally do not employ contraception due to a history of infertility, or claim absence of sexual activity should be advised to employ contraception while taking EPURIS^®, following the above guidelines. Even female patients who have amenorrhea must follow all the advice on effective contraception.

Information concerning the EPURIS^® PEER™ Program (see 3. Serious Warnings and Precautions Box) has also been provided directly to patients via the EPURIS^® compliance packaging or could be found via www.epuris.ca website. This “Patient Information” asks female patients of childbearing potential, who have not been counseled using the EPURIS^® PEER™ Program, to contact their physician for further information.

Patients should also be informed that confidential contraception counseling (provided by a health care professional) is available from Cipher Pharmaceuticals Inc.

Blood Donation

It is recommended that blood donation for transfusion purposes be deferred during therapy with EPURIS^® and for one month after discontinuation of treatment. Theoretically, blood from such donors could present a small risk to the fetus if transfused to a pregnant mother during the first trimester of pregnancy.

Cardiovascular

Approximately 25% of patients receiving isotretinoin experienced an elevation in plasma triglycerides. Approximately 15% developed a decrease in high density lipoproteins and about 7% showed an increase in cholesterol levels. These effects on triglycerides, HDL and cholesterol were reversible upon cessation of isotretinoin therapy (see 8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data).

Patients with increased tendency to develop hypertriglyceridemia include those with diabetes mellitus, obesity, increased alcohol intake and familial history.

The cardiovascular consequences of hypertriglyceridemia are not well understood, but may increase the patient’s risk status. Therefore, every attempt should be made to control significant triglyceride elevation (see 7. Warnings and Precautions, Monitoring and Laboratory Tests). 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. An obese male patient with Darier’s disease developed elevated triglycerides and subsequent eruptive xanthomas.

Ear/Nose/Throat

Impaired hearing at certain frequencies has been reported in some patients treated with isotretinoin. Patients who experience tinnitus or hearing impairment should discontinue EPURIS^® treatment and be referred for specialized care for further evaluation.

Endocrine and Metabolism

Patients with diabetes or a family history of diabetes may experience problems with the control of their blood sugar during EPURIS^® therapy. Therefore, known or suspected diabetics should have periodic blood sugar determinations. Although no causal relationship has been established, elevated fasting blood sugars have been reported, and new cases of diabetes have been diagnosed during isotretinoin therapy (see 8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data)

Gastrointestinal

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

Hepatic/Biliary/Pancreatic

Liver function tests should be monitored before treatment and at regular intervals during treatment (one month after the start of treatment and at least three month intervals thereafter) unless more frequent monitoring is clinically indicated. 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 normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur, or if hepatitis is suspected during treatment with EPURIS^®, the drug should be discontinued and the etiology further investigated (see 7. Warnings and Precautions, Monitoring and Laboratory Tests).

There have been some reports of acute pancreatitis, which is known to be potentially fatal. This is sometimes associated with elevation of serum triglycerides in excess of 800 mg/dL or 9 mmol/L (see 7. Warnings and Precautions, Monitoring and Laboratory Tests). Therefore, every attempt should be made to control significant triglyceride elevation (see 7. Warnings and Precautions, Cardiovascular). EPURIS^® should be discontinued if uncontrolled hypertriglyceridemia or symptoms of pancreatitis occur.

Immune

Anaphylactic reactions have been reported with isotretinoin. These reactions were more serious after prior exposure to topical retinoids. Allergic cutaneous reactions and 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.

Monitoring and Laboratory Tests

In high risk patients (with diabetes, obesity, alcoholism or lipid metabolism disorder) undergoing treatment with EPURIS®, more frequent checks of serum values for lipids (see 7. Warnings and Precautions, Endocrine and Metabolism and Hepatic/Biliary/Pancreatic) and/or blood glucose may be necessary.

Pregnancy tests: The patient should have two negative pregnancy tests (β-hCG in urine or serum) before starting EPURIS^® therapy with the first pregnancy test conducted at initial assessment when the patient is qualified for EPURIS^® therapy by the physician. The patient then should have a second pregnancy test with a sensitivity of at least 25 mIU/mL with a negative result, performed in a licensed laboratory, within 11 days prior to initiating therapy. The patient has had two or three days of the next normal menstrual period before EPURIS^® therapy is initiated. Pregnancy test must be repeated monthly for pregnancy detection during EPURIS^® treatment and at one month after discontinuation of treatment. The dates and results of the pregnancy tests should be documented.

Signs of Depression: sad mood, hopelessness, feeling of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, changes 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. If symptoms of depression develop or worsen during treatment with EPURIS^®, the drug should be discontinued promptly and the patient referred for appropriate psychiatric treatment.

The following tests are required before starting EPURIS^®, at first month, then as clinically indicated:

• Serum blood lipid determinations (under fasting conditions) should be performed before EPURIS^® is given and then at intervals (one month after the start of therapy) until the lipid response to EPURIS^® is established (which usually occurs within four weeks), and also at the end of treatment.
• Complete blood count and differential: for early detection of leukopenia, neutropenia, thrombocytopenia and anemia.
• Liver function tests: Increases in about 15% of ALT, AST, ALP baseline levels have been reported. Liver function tests should be monitored before treatment and at regular intervals during treatment (one month after the start of treatment and at least three-month intervals thereafter) unless more frequent monitoring is clinically indicated.
• Blood glucose levels: all patients and in particular patients with known or suspected diabetes should have periodic blood sugar determinations.

A Psychiatric Screening Checklist is available to assist physicians in screening patients for depression/suicidality prior to treatment and in monitoring for the development of psychiatric symptoms during treatment.

Musculoskeletal

Effects of multiple courses of EPURIS^® 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 (see also 7.1.3. Pediatrics).

In the pivotal clinical trial (ISOCT 08.01) in 924 patients, adverse events related to the musculoskeletal system and connective tissue were reported in approximately 37% of patients, and musculoskeletal symptoms in approximately 24% of the patients. Elevations in levels of serum creatine kinase (≥350 U/L) were reported in approximately 29% of patients, and the AE “blood creatine kinase increase” in 6% of patients. In the same trial, 27/306 (8.8%) of adolescents had BMD declines, defined as ≥ 4% lumbar spine or total hip, or ≥ 5% femoral neck, during the 20-week treatment period. Repeat scans conducted within 2-3 months after the post-treatment scan showed no recovery of BMD. Longer term data at 4-11 months showed that 3 out of 7 patients had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population.

In an open-label clinical trial (N=217) of a single course of therapy with ACCUTANE for severe recalcitrant nodular acne in pediatric patients 12 to 17 years, 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 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumber spine, while the other 3 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 5 of 8 patients (62.5%).

In this clinical trial 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.

In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second course of ACCUTANE 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 isotretinoin treated population. While causality to EPURIS^® has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that EPURIS^® be given at the recommended doses for no longer than the recommended duration.

Physicians should use caution when prescribing EPURIS^® 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 treatment with EPURIS^® or following cessation of treatment with EPURIS^® while involved in these activities. While causality to EPURIS^® has not been established, an effect cannot be ruled out.

There have been post-marketing serious reports of rhabdomyolysis, often leading to hospitalization and some with fatal outcome, particularly in those undergoing strenuous physical activity. Patients should abstain from vigorous exercise activity during isotretinoin treatment (see 8.5. Post-Market Adverse Reactions, Musculoskeletal).

Sacroiliitis has been reported in patients exposed to isotretinoin. To differentiate sacroiliitis from other causes of back pain, in patients with clinical signs of sacroiliitis, further evaluation may be needed including imaging modalities such as MRI. In cases reported post-marketing, sacroiliitis improved after discontinuation of isotretinoin and appropriate treatment.

Hyperostosis: Due to possible occurrence of bone changes, a careful evaluation of the risk/benefit ratio should be carried out in every patient and EPURIS^® administration should be restricted to severe cases of acne. Bone changes including, premature epiphyseal closure, hyperostosis and calcification of tendons and ligaments have occurred after several years of administration at high doses for treating disorders of keratinization. The dose levels, duration of treatment and total cumulative dose in these patients generally far exceeded those recommended for the treatment of acne.

In clinical trials of disorders of keratinization, with a mean dose of 2.24 mg/kg/day, a high prevalence of skeletal hyperostosis was noted. Two children showed x-ray findings suggestive of premature closure of the epiphysis. Additionally, skeletal hyperostosis was noted in six of eight patients in a prospective study of disorders of keratinization.

Minimal skeletal hyperostosis and calcification of tendons have also been observed by x-rays in prospective studies of cystic acne patients treated with a single course of therapy at recommended doses. 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.

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.

Myalgia and arthralgia (mild to moderate) may occur and may be associated with reduced tolerance to vigorous exercise (see 8.2. Clinical Trial Adverse Reactions and 8.5. Post-Market Adverse Drug Reactions, Musculoskeletal). Instances of raised serum creatine phosphokinase (CPK) values have been reported in patients receiving isotretinoin, particularly those undertaking vigorous physical activity. Discontinuation of EPURIS^® may be required.

Neurologic

See 3. Serious Warnings and Precautions Box.

Ophthalmologic

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. Dry eyes, corneal opacities, decreased night vision, keratitis, blepharitis and conjunctivitis usually resolve after discontinuation of therapy. Due to the possible occurrence of keratitis, patients with dry eyes should be monitored. All EPURIS^® patients experiencing visual difficulties should discontinue the drug and have an ophthalmological examination. Approximately 3% of patients experienced a decrease in visual acuity that did not fully recover at the end of the study (see 8.2. Clinical Trial Adverse Reactions and 8.5. Post-Market Adverse Drug Reactions, Eye Disorders). Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment

A number of cases of decreased night vision have occurred during isotretinoin therapy and in rare instances have persisted after therapy (see 8.2. Clinical Trial Adverse Reactions and 8.5. Post-Market Adverse Drug Reactions, Eye Disorders). 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. EPURIS^® patients experiencing visual impairment should discontinue treatment and have an ophthalmological examination. Visual problems should be carefully monitored.

Psychiatric

See 7. Warning and Precautions, Signs of Depression and 3. Serious Warnings and Precautions Box.

A Mental Health Questionnaire is available to assist physicians in screening patients for depression/suicidality prior to treatment and in monitoring for the development of psychiatric symptoms during treatment.

Renal

EPURIS^® is contraindicated in patients with renal insufficiency (see 2. Contraindications).

Reproductive Health: Female and Male Potential

Both male and female patients should be given a copy of the Patient Medication Information.

• Contraception Females: Effective contraception must be used for at least one month before starting EPURIS^® treatment, during treatment and for at least one month following the discontinuation of EPURIS^® treatment. It is recommended that two reliable forms of contraception be used simultaneously. At least 1 of these forms of contraception must be a primary form, unless the patient has undergone a hysterectomy. Effective forms of contraception include: tubal ligation, partner’s vasectomy, intrauterine devices, birth control pills, and topical/injectable/insertable hormonal birth control products. Barrier forms of contraception include diaphragms, latex condoms, and cervical caps; each must be used with a spermicide. Any birth control method can fail. Therefore, it is critically important that women of childbearing potential use 2 effective forms of contraception simultaneously (see 9.4 Drug-Drug Interactions).

  Even female patients who normally do not employ contraception due to a history of infertility, or claim absence of sexual activity should be advised to employ contraception while taking EPURIS^®, following the above guidelines. Even female patients who have amenorrhea must follow all the advice on effective contraception.

  Information concerning the EPURIS^® PEER™ Program (see 3 Serious Warnings and Precautions Box) has also been provided directly to patients via the EPURIS^® compliance packaging. This “Patient Information” asks female patients of childbearing potential, who have not been counseled using the EPURIS^® PEER™ Program, to contact their physician for further information.

  Patients should also be informed that confidential contraception counseling (provided by a health care professional) is available from Cipher Pharmaceuticals Inc.

• Fertility

  Male Patients: The available data suggest that the level of maternal exposure from the semen of the patients receiving isotretinoin is not of a sufficient magnitude to be associated with the teratogenic effects of isotretinoin. The threshold dose of isotretinoin exposure causing birth defects is not known. Postmarketing reports through 20 years include 4 with isolated defects compatible with features of retinoid exposed fetus; however, 2 of these reports were incomplete and 2 had other possible explanations for the defects observed.

  Male patients should be reminded that they must not share their medication with anyone, particularly not females.

  Isotretinoin, in therapeutic dosages, does not affect the number, motility and morphology of sperm.

  Both male and female patients should be given a copy of the Patient Medication Information.

• Function

  Risk of Sexual Side Effects

  Cases of sexual dysfunction including erectile dysfunction, decreased/loss of libido, vulvovaginal dryness, orgasm difficulties, and genital hypoaesthesia have been reported in patients with the use of isotretinoin. There have been reports of persistence of these events following drug discontinuation. While causality to isotretinoin could not be definitively established, an effect cannot be ruled out. When deciding on treatment with isotretinoin, patients, and where appropriate, parents or caregivers, should be informed about this potential risk. All patients should be screened and monitored, and advised to monitor themselves, for signs and symptoms of sexual dysfunction before and during therapy.

• Teratogenic Risk

  Embryo-Fetal Toxicity

  EPURIS^® is contraindicated in pregnancy (see 2 Contraindications). Based on human data, there is an extremely high risk EPURIS^® can cause fetal harm when administered to a pregnant patient (see 3 Serious Warnings and Precautions Box, Conditions of Use, and 7.1.1 Pregnant Women).

  Male Patients

  The threshold dose of isotretinoin exposure causing birth defects is not known. Since the extent to which isotretinoin may be found in semen is not known, it is recommended that male patients being treated with EPURIS^® use a condom or avoid reproductive sexual activity to avoid possible transmission to a female partner.

  Male patients should be reminded that they must not share their medication with anyone, particularly not females.

Skin

Acute exacerbation of acne is occasionally seen during the initial period, but this subsides with continued treatment, usually 7-10 days, and usually does not require dose adjustment.

Exposure to intense sunlight or to UV rays should be avoided. When necessary, a sun-protection product with a high protection factor of a least SPF 15 should be used.

It is recommended that aggressive chemical dermabrasion and cutaneous laser treatment be avoided in patients on EPURIS^® and for a period of 5-6 months after the end of treatment because of the risk of hypertrophic scarring in atypical areas, and more rarely hyper- or hypopigmentation in treated areas.

It is recommended that wax epilation be avoided in patients on EPURIS^® therapy and for a period of 5-6 months after treatment because of the risk of epidermal stripping, scarring or dermatitis.

Concurrent administration of EPURIS^® with keratolytic or exfoliative anti-acne agents should be avoided as local irritation may increase.

Patients should be advised to use a skin-moisturizing ointment or cream and a lip balm from the start of treatment as isotretinoin is likely to cause dryness of the skin and lips.

Serious Skin Reactions

There have been very rare post-marketing reports of severe skin reactions. (e.g., erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN)) associated with isotretinoin use. These events may be serious and result in hospitalization, life threatening events, disfiguration, disability and/or death. Patients treated with EPURIS^® should be monitored closely for severe skin reactions. Treatment should be discontinued if the patient develops any of the following reactions: rash, especially if associated with fever and/or malaise, conjunctivitis (red or inflamed eyes); blisters on legs, arms or face and/or sores in mouth, throat, nose or eyes; peeling skin or other serious skin reactions.

7.1. Special Populations

7.1.1. Pregnant Women

There is an extremely high risk (25% or greater) that major human fetal abnormalities will occur if pregnancy occurs during treatment with isotretinoin or up to one month following its discontinuation. Potentially any exposed fetus can be affected. These abnormalities, associated with isotretinoin administration during pregnancy, have been reported and include:

CNS (hydrocephalus, hydranencephaly, microcephaly, posterior fossa abnormalities, cranial nerve dysfunction, cerebellar malformation); craniofacial (anotia, microtia, low set ears, small or absent external auditory canals, microphthalmia, facial dysmorphia, cleft palate); cardiac (septal defects, aortic arch abnormalities, tetralogy of Fallot); thymus gland abnormalities; and parathyroid hormone deficiency. Cases of IQ scores less than 85 with or without other abnormalities have been reported.

Pregnancy Tests: Female patients of childbearing potential must not be given EPURIS^® until pregnancy is excluded. The patient must have two negative pregnancy tests before starting EPURIS^® therapy with the first pregnancy test conducted at initial assessment when the patient is qualified for EPURIS^® therapy by the physician. A second pregnancy test must be performed within 11 days prior to starting EPURIS^® treatment. EPURIS^® treatment should start on the second or third day of the next normal menstrual period following this negative pregnancy test.

It is mandatory that all female patients of childbearing potential treated with EPURIS^® have regular monthly pregnancy tests during treatment and one month after the discontinuation of treatment. The dates and results of pregnancy tests should be documented. The blood monitoring chart can be used to document these results as well as to serve as a reminder of all the tests that should be carried out and their frequency.

These pregnancy tests will:

1. 1. Serve primarily to reinforce to the patient the necessity of avoiding pregnancy.
2. 2. In the event of accidental pregnancy, provide the physician and patient an immediate opportunity to discuss the serious risk to the fetus from this exposure to EPURIS^® and the desirability of continuing the pregnancy in view of the potential teratogenic effect of EPURIS^® (see 2. Contraindications and 16. Toxicology, Reproduction and Developmental Toxicology).

Pregnancy occurring during treatment with isotretinoin and for one month after its discontinuation carries the risk of fetal malformation and the increased risk of spontaneous abortion (see 2. Contraindications and 16. Toxicology, Reproduction and Developmental Toxicology). EPURIS^® treatment must be stopped and the patient should be fully counseled on the serious risk to the fetus should they become pregnant while undergoing treatment. If pregnancy does occur during this time the physician and patient should discuss the desirability of continuing the pregnancy.

7.1.2. Breastfeeding

It is not known whether isotretinoin is excreted in human milk. As isotretinoin is highly lipophilic, the passage of the drug in human milk is very likely. Because of the potential for adverse effects, women should not breastfeed if they are receiving EPURIS^® (see 2. Contraindications).

7.1.3. Pediatrics

Pediatrics (< 12 years of age): The safety and efficacy of EPURIS^® in pediatric patients less than 12 years of age have not been established. The use of EPURIS^® in these patients is not recommended.

Pediatrics (12 to 17 years of age): In studies with isotretinoin adverse reactions reported in pediatric patients ages 12 to 17 years 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 (see 8. Adverse Reactions).

Pediatric patients and their caregivers should be informed that approximately 29% of pediatric patients treated with isotretinoin developed back pain. Back pain was severe in 13.5% 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 EPURIS^®. Consideration should be given to discontinuation of EPURIS^® if any significant abnormality is found.

7.1.4. Geriatrics

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 geriatric and younger adults, effects of aging may increase some risks associated with EPURIS^®.

1. 8. Adverse Reactions

8.1. Adverse Reaction Overview

The adverse events listed below reflect the experience from the clinical studies conducted with EPURIS^® (isotretinoin) and the post-marketing experience. The relationship of some of these events to EPURIS^® therapy is unknown.

Many of the side effects and adverse events seen or expected in patients receiving isotretinoin are similar to those described in patients taking high doses of vitamin A.

Adverse reactions were generally reversible when therapy was discontinued; however, some have persisted after cessation of therapy.

See 7. Warnings and Precautions regarding psychiatric events (Signs of Depression), Gastrointestinal events (association with inflammatory bowel disease), impact on Hepatic/Biliary/Pancreatic function (acute pancreatitis), Neurologic (benign intracranial hypertension), Skin.

The following adverse reactions have been identified in a double-blind, randomized, Phase III, parallel group study of EPURIS® compared to a Reference Product dosed under fed conditions, in 925 patients with severe recalcitrant nodular acne. The most commonly reported adverse events with EPURIS^® use were dry lip (45%) and dry skin (44.2%). Adverse events related to the musculoskeletal system and connective tissues were reported in approximately 37% of the patients.

Adverse events leading to discontinuation were reported in 4.1% of patients with EPURIS®, and 3.3% of patients with the Reference Product. These AEs were classified as psychiatric events and gastrointestinal events in the EPURIS® group, and as psychiatric events and musculoskeletal/connective tissue events in the Reference Product group.

No deaths were reported during the study, and the rate of serious adverse events (SAE) was relatively low in both groups (1.1% to 1.5%). Three serious AEs were considered to be possibly related to EPURIS® and recovered completely: severe abdominal pain, severe upper abdominal pain and moderate migraine.

Discontinuation: Adverse events leading to discontinuation were reported in 4.1% of patients with EPURIS^®, and 3.3% of patients with the Reference Product. These AEs were classified as psychiatric events and gastrointestinal events in the EPURIS^® group, and as psychiatric events and musculoskeletal/connective tissue events in the Reference Product group.

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Table 3 presents common adverse events (≥ 1%) reported in a double-blind, randomized, Phase III, parallel group study of EPURIS^® compared to a Reference Product dosed under fed conditions, in 925 patients with severe recalcitrant nodular acne.

In the above-described study (ISOCT.08.01) almost all patients experienced at least one adverse event (AE) in both groups at similar rates (92% with EPURIS^® and 90% with the Reference Product (a marketed formulation of isotretinoin)). Most of these AEs were treatment related (87% with EPURIS^® and 84% with the reference drug).

Adverse events related to the musculoskeletal system and connective tissues were reported in approximately 37% of the patients, and musculoskeletal symptoms in approximately 24% of the patients. Elevations in levels of serum creatine kinase were reported as high alert laboratory values (≥ 350 u/L) in approximately 29% of patients, and incidence of the AE “blood phosphocreatine kinase increased” in 6% of patients.

Systematic assessment of visual acuity (Snellen chart) was performed in most patients and revealed that 20% of patients in the EPURIS^® group and 15% of patients in the Reference group experienced VA worsening that was reversible for most. However, 3.7% (17/464) of patients in the EPURIS^® group and 3% (14/460) of patients in the Reference group did not fully recover baseline visual acuity values.

No deaths were reported during the study, and the rate of serious adverse events (SAE) was relatively low in both groups (1.1% to 1.5%). Three serious AEs were considered to be possibly related to EPURIS^® and recovered completely: severe abdominal pain, severe upper abdominal pain and moderate migraine.

Adverse events leading to discontinuation were reported in 4.1% of patients with EPURIS^®, and 3.3% of patients with the Reference Product. These AEs were classified as psychiatric events and gastrointestinal events in the EPURIS^® group, and as psychiatric events and musculoskeletal/connective tissue events in the Reference Product group.

Table 3: Adverse Events Reported in ≥ 1% of Patients in the EPURIS^® group versus the Reference Product Group in the Double-Blind, Phase III Study

Adverse Reactions

Some adverse events tended to be reported with a differential in frequency according to gender in both treatment groups: For example, triglycerides increased, arthralgia, pain, and blurred vision tended to be more often reported in females, while chapped lips, cheilitis, epistaxis, creatine kinase increased, and bone density decreased tended to be more reported in males.

Reduced visual acuity, blurred vision, increased triglycerides, headache and fatigue tended to be more often reported in adults as compared to adolescents (12 to 17 years).

Decreased bone density was reported in adolescents of both treatment groups (4% to 8%) but not in adults.

8.2.1. Clinical Trial Adverse Reactions – Pediatrics

See 8.2. Clinical Trial Adverse Reactions.

8.3. Less Common Clinical Trial Adverse Reactions

Less Common (<1%) Adverse Reactions in subjects receiving EPURIS^® in any clinical trial are listed below.

Blood and lymphatic system disorders: lymphadenopathy

Cardiac Disorders: Palpitations, tachycardia and coronary artery disease.

Ear and labyrinth disorders: Tinnitus, ear pain, hypoacusis, ear discomfort, external ear inflammation, cerumen impaction, hyperacusis and vertigo.

Eye disorders: Ocular hyperaemia, lacrimation increased, photophobia, xerophthalmia, blepharitis, eye pain, visual impairment, blepharospasm, conjunctival haemorrhage, conjunctival hyperaemia, conjunctivitis allergic, diplopia, eczema eyelids, eye haemorrhage, eye swelling, eyelid oedema, foreign body sensation in eyes, keratitis, myopia, orbital edema, photopsia, pinguecula and punctate keratitis.

Gastrointestinal disorders: Bleeding and inflammation of the gums, dry mouth, abdominal discomfort, dyspepsia, haemorrhoids, rectal haemorrhage, abdominal pain lower, lip swelling, mouth ulceration, oral pain, tooth impacted, abdominal distension, abdominal tenderness, anal fissure, frequent bowel movement, gastroesophageal reflux disease, gingival recession, haematochezia, hypoaesthesia oral, lip haemorrhage, lip ulceration, oesophageal pain, painful defaecation, rectal fissure, tooth disorder and toothache.

General disorders and administration site conditions: oedema peripheral, thirst, chest pain, cyst, impaired healing, influenza like illness, xerosis, discomfort, oedema, gravitational oedema, mucous membrane disorder and swelling.

Metabolism and nutrition disorders: Increased appetite and thyroid disorder.

Musculoskeletal and connective tissue disorders: Tendonitis, muscle spasms, arthropathy, joint stiffness, joint swelling, joint pain, muscle tightness, musculoskeletal chest pain, arthritis, bone pain, fibromyalgia, groin pain, intervertebral disc space narrowing, joint crepitation, limb discomfort, muscle atrophy, myositis, spinal osteoarthritis, synovial cyst and tendon pain.

Nervous system disorders: Dizziness, drowsiness, malaise, memory impairment, nervousness, paresthesia, presyncope, sinus headache, syncope, weakness.

Psychiatric Disorders: Depression, attention deficit hyperactivity disorder, mood swings, sleep disorder, panic attack, restlessness, stress, adjustment disorder, affect lability, anger, bradyphrenia, delusion, depressed mood, disorientation, dysthymic disorder, emotional distress, hallucination auditory, libido decreased, middle insomnia, obsessive thoughts, paranoia, substance abuse and irritability.

Renal and urinary disorders: Proteinuria, haematuria, dysuria, nephrolithiasis and polyuria

Reproductive system and breast disorders: Metrorrhagia, menstruation irregular, vulvovaginal bleeding, vulvovaginal discomfort, amenorrhoea, breast cyst, dysmenorrhoea, epididymitis, erectile dysfunction, menorrhagia, ovarian cyst, ovarian cyst ruptured, pruritus genital, testicular cyst, vaginal discharge and vulva cyst.

Respiratory, thoracic and mediastinal disorders: Rhinorrhoea, sinus congestion, asthma, respiratory tract congestion, dry throat, nasal mucosal disorder, rales, rhinitis seasonal, sleep apnoea syndrome, throat irritation, voice hoarseness and wheezing.

Skin and subcutaneous tissue disorders: Bruising, pruritus, alopecia, eczema nummular, scar, eczema asteatotic, acne, rash papular, skin exfoliation, acne cystic, blister, hair texture abnormal, intertrigo, pain of skin, photosensitivity reaction, pyogenic granuloma, skin discolouration, acrodermatitis, alopecia effluvium, androgenic alopecia, dermatitis atopic, dermatitis exfoliative, exfoliative rash, livedo reticularis, onycholysis, pityriasis rosea, psoriasis, rash follicular, paronychia, seborrhoea, skin depigmentation, skin fissures, skin irritation, skin infections, skin lesion, skin ulcer, swelling face and telangiectasia.

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Blood potassium increased, blood alkaline phosphatase increased, blood bilirubin increased, blood urea increased, elevated platelet counts, eosinophil count increased, false positive tuberculosis test, gamma-glutamyltransferase abnormal, blood cholesterol increased, glucose urine present, haematocrit decreased, protein urine, thrombocytopenia, white blood cell count decreased.

8.5. Post-Market Adverse Reactions

The following additional adverse reactions have been identified during post-approval use of EPURIS^®.

Blood and lymphatic system disorders: anemia.

Ear and labyrinth disorders: Impaired hearing at certain frequencies.

Eye disorders: Visual disturbances.

Gastrointestinal disorders: Pancreatitis (see WARNINGS AND PRECAUTIONS: Hepatic/Biliary/Pancreatic). Inflammatory bowel disease, colitis, esophagitis/esophageal ulceration and other nonspecific gastrointestinal symptoms (see WARNINGS AND PRECAUTIONS: Gastrointestinal).

General disorders and administration site conditions: chest pain.

Immune system disorders: allergic responses

Investigations: Elevated fasting blood sugar and red blood cells in the urine.

Metabolism and nutrition disorders: New cases of diabetes (see Warnings and Precautions: Endocrine and Metabolism), hypertriglyceridemia.

Nervous system disorders: Seizures and benign intracranial hypertension, seizures (see Warnings and Precautions: Serious Warnings and Precautions, Neurologic).

Psychiatric Disorders: Emotional instability, suicidal ideation, suicide attempt, suicide, aggression and violent behaviors.

Renal and urinary disorders: Nonspecific urogenital findings.

Reproductive system: Sexual dysfunction.

Skin and subcutaneous tissue disorders: Acne flare, hair loss, hypopigmentation, sweating and urticaria.

Vascular disorders: vascular thrombotic disease.

The following additional adverse reactions have been identified during the use of other isotretinoin products.

Eye disorders: Cataracts, colour vision disorder, optic neuritis, papilledema as a sign of benign intracranial hypertension and colour vision disturbances. Corneal opacity were reported in nodular and/or inflammatory acne patients (see 7. Warnings and Precautions: Ophthalmologic). Decreases in night vision were reported and, in rare instances, persisted after cessation of therapy (see 7. Warnings and Precautions: Ophthalmologic).

Gastrointestinal disorders: Ileitis, cheilitis and other nonspecific gastrointestinal symptoms. Patients treated with isotretinoin, especially those with high triglyceride levels are at risk of developing pancreatitis. Rare cases of fatal pancreatitis have been reported (see 7. Warnings and Precautions: Hepatic/Biliary/Pancreatic).

Hepatobiliary disorders: Several cases of clinical hepatitis have been reported (see 7. Warnings and Precautions: Hepatic/Biliary/Pancreatic).

Immune system disorders: systemic hypersensitivity

Investigations: Decreases in red blood cell parameters, decrease in serum high density lipoprotein (HDL), hyperuricemia, elevated sedimentation rates, white blood cells in the urine and blood protein present.

A rise in serum levels of liver enzymes may occur, especially with higher dosages. 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 (see 7. Warnings and Precautions: Hepatic/Biliary/Pancreatic).

Metabolism and nutrition disorders: hypertriglyceridemia (usually was dose-related).

Musculoskeletal and connective tissue disorders: Calcification of tendons and ligaments, premature epiphyseal closure, skeletal hyperostosis (see Warnings and Precautions: Musculoskeletal, Hyperostosis) and other types of bone abnormalities. There have been post-marketing serious reports of rhabdomyolysis, often leading to hospitalization, particularly in those undergoing strenuous physical activity.

Renal and urinary disorders: Glomerulonephritis.

Reproductive system: Sexual dysfunction.

Respiratory, thoracic and mediastinal disorders: Voice alteration and bronchospasm, sometimes in patients with pre-history of asthma.

Skin and subcutaneous tissue disorders: Acne fulminans, desquamation, eruptive xanthomas, facial erythema, nail dystrophy, flushing, fragility of skin, hirsutism, hyperpigmentation, peeling of palms and soles, photoallergic, vasculitis (including Wegener’s granulomatosis), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting), erythema nodosum and exanthema. Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported to be associated with isotretinoin (see 7. Warnings and Precautions: Serious Skin Reactions).

9. Drug Interactions

9.1. Serious Drug Interactions

9.2. Drug Interactions Overview

Tetracyclines (e.g., minocycline, tetracycline), vitamin A-type drugs and supplements, phenytoin, and systemic corticosteroids (e.g., prednisone) may interact with isotretinoin (see 9.4. Drug-Drug Interactions).

9.4. Drug-Drug Interactions

The drugs listed below are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Tetracyclines: Rare cases of benign intracranial hypertension ‘pseudotumor cerebri’ have been reported after use of isotretinoin and/or tetracyclines. Therefore, concomitant treatment with tetracyclines must be avoided (see 7. Warnings and Precautions, Neurologic).

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.

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.

Norethindrone/ethinyl estradiol: In a study of 31 premenopausal women with severe recalcitrant nodular acne receiving OrthoNovum®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). A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for isotretinoin.

Microdosed progesterone preparations (minipills): Are not a suitable method of contraception during EPURIS^® therapy.

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.

9.5. Drug-Food Interactions

Following administration of a single capsule of 40 mg EPURIS^® with a high fat high calorie meal in healthy subjects, the mean (CV%) for isotretinoin AUC_T was 6095.2 ng•hr/mL (26%). The isotretinoin C_max was 394.3 ng/mL (39%), and the median time to peak of 4.5 hours.

When a single capsule of 40 mg EPURIS^® was administered under fasting conditions the mean (CV%) for extent of isotretinoin exposure AUC_T was 4045 ng•hr/mL (20%) representing a decrease of 33% relative to high fat-fed conditions. The isotretinoin peak plasma concentration mean (CV%) for C_max was 313 ng/mL (26%) or a decrease of 20% over fed, with a median time to peak of 2.5 hours in healthy volunteers, representing a decrease of 45% over fasting.

9.6. Drug-Herb Interactions

St. John’s Wort: Isotretinoin use is associated with depression in some patients (see 7. Warnings and Precautions, Psychiatric and 8.3. Less Common Clinical Trial Adverse Reactions, Psychiatric Disorders). 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.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

The mechanism of action of isotretinoin is unknown. Vitamin A is important for functional integrity of the skin and is known to affect the keratinization process. In acne patients, improvement occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to either the dose or duration of isotretinoin administration and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.

10.2. Pharmacodynamics

The pharmacodynamics of EPURIS^® is unknown.

10.3. Pharmacokinetics

Absorption

Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high fat meal. EPURIS^® is equivalent in rate and extent of absorption to Accutane^® (isotretinoin) capsule (Roche, USA) when both drugs are taken with a high-fat meal. EPURIS^® is more bioavailable than Accutane^® (isotretinoin) capsules (Roche, USA) when both drugs are taken fasted; the AUC_0-t of EPURIS^® is approximately 83% greater than that of Accutane^® (isotretinoin) capsules (Roche, USA). EPURIS^® is therefore not interchangeable with other marketed isotretinoin products.

A single dose two-way crossover pharmacokinetic trial was conducted in healthy adult subjects comparing EPURIS^® 40 mg (1 x 40 mg capsules), dosed under fasted and fed conditions. Under fasted conditions, it was observed that the mean AUC_0-t and C_max were approximately 33% and 20% lower than that observed under high fat-fed conditions (Table 4). The observed elimination half-life (T_1/2) was slightly lower in the fed state versus fasted. The time to peak concentration (T_max) increased with food and this may be related to a longer absorption phase. In a single dose 4-way cross over study conducted in normal healthy adult subjects, a 40 mg dose of Accutane^® (isotretinoin) capsules (Roche, USA) was administered under fasted conditions the mean AUC_0-t and C_max were approximately 62% and 64% lower than that observed under high fat-fed conditions.

Table 4: Pharmacokinetic parameters of EPURIS^® mean (%CV) following administration of 40 mg strength, N=14

Published clinical literature has 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 99.9% protein bound in human plasma, almost exclusively to 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 40 mg oral dose of EPURIS^® to 57 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.

Following 40 mg of EPURIS^® administered orally, maximum plasma concentrations of the 4-oxo-isotretinoin was 51 to 463 ng/mL and maximum concentrations were observed between 7 and 36 hours.

The mean minimum steady-state blood concentrations of EPURIS^® were 171 ng/mL in 40 patients receiving 40 mg (2 x 20 mg) twice daily doses. After single and multiple doses, the mean ratio of areas under the curves of 4-oxo-isotretinoin to isotretinoin was between 3.2 and 3.8.

Elimination

After a single 40 mg (2 x 20 mg) oral dose of EPURIS^® to 57 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t_1/2) of isotretinoin and 4-oxo-isotretinoin under fed states were 18 hours and 38 hours, respectively. Following oral administration of ¹⁴ C-isotretinoin, ¹⁴C activity in blood declined with a mean half-life of 90 hours. Approximately equal amounts of radioactivity were recovered in the urine and feces, with 65-83% of the dose recovered.

Special Populations and Conditions

Pediatrics

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 5 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.

Table 5: Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (SD), N=38¹

In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t_1/2) 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.

11. Storage, Stability and Disposal

EPURIS^® (isotretinoin) 10 mg, 20 mg, 30 mg and 40 mg capsules: Store at 20 - 25°C. Protect from light. Keep in a safe place out of the reach of children.

12. Special Handling Instructions

The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established “collection systems” if available in your location.

Return any unused EPURIS^® (isotretinoin) capsules to the pharmacist.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Proper name: Isotretinoin, USP

Chemical name: 3-7-dimethyl-9-(2,6,6-trimethyl-1-cyclo-hexen-1-yl)-2-cis-4-trans-6- trans-8-trans- nonatetraenoic acid

Molecular formula and molecular mass: C₂₀H₂₈O₂ 300.44

Structural formula:

Physicochemical properties: Orange crystalline powder, insoluble in water; soluble in chloroform (10g / 100 mL).

Melting point: approximately 175ºC;

pKa: approximately 4.

14. Clinical Trials

14.1. Clinical Trials by Indication

Treatment of Severe Recalcitrant Nodule Acne

Study demographics and trial design

A double-blind, randomized, phase III, parallel group study was conducted under fed conditions, in patients with severe recalcitrant nodular acne to evaluate the efficacy and safety of EPURIS^® compared to a Reference Product (currently marketed formulation of isotretinoin). A total of 925 (EPURIS^®: 464 / Reference Product: 461) male and female patients between the ages of 12 and 54 years with at least 10 or more nodular lesions on the face and/or trunk were randomized into the study; 813 patients completed the full duration of the study. Patients were treated with EPURIS^® or the Reference Product in a 1:1 ratio at an initial titration dose of 0.5 mg/kg/day for the first 4 weeks followed by 1 mg/kg/day for the following 16 weeks. The ITT population was defined as all randomized patients who were dispensed the study drug. The per protocol population was defined as patients in the ITT population who completed the study without any major protocol deviations.

Safety assessments during the study included monitoring of adverse events, laboratory tests, psychiatric evaluations, bone mineral density and bone age assessments, questions about musculoskeletal symptoms, ophthalmic and audiology testing.

Results with both of the primary efficacy outcomes, change from Baseline to Week 20 in total nodular lesion count and the proportion of patients with at least a 90% reduction from Baseline in total nodular lesion count are shown below (Table 6).

Table 6: Efficacy Results in the Phase III clinical study (ISOCT.08.01): Total nodular lesion count (facial and truncal)

Figure 1: Total Nodular (Facial and Truncal) Lesion Count by Visit [ITT Population (LOCF)]

15. Microbiology

No microbiological information is required for this drug product.

1. 16. Non-Clinical Toxicology

General Toxicology

Isotretinoin exerts a specific action on the sebaceous glands of the hamster flank organs. Subcutaneous administration of isotretinoin to female hamsters treated simultaneously with testosterone enanthate prevents the androgen-induced growth of flank organ sebaceous glands without affecting other androgen dependent cells (i.e. does not inhibit development of pigment or larger hair follicles).

Doses up to 300 mg/kg orally of isotretinoin have no effect upon circulation and respiratory parameters in the anesthetized cat. A dose of 1 g/kg results in respiratory stimulation and a slight decrease in blood pressure, pulse rate, blood flow to the extremities as well as oxygen saturation.

Toxicology

Acute Toxicity Studies:

Table 7: Acute Toxicity Studies

Pyramiding doses of 4.8, 13.1, 41.2 and 79.8 mg/kg of isotretinoin were administered to dogs. All dogs survived. Diarrhea occurred in dogs treated with doses of 13.1 mg/kg or higher.

Long-Term Toxicity Studies:

55-week Oral Toxicity -Dog

In a 55-week toxicity study conducted in beagle dogs (9/sex/group), isotretinoin was administered as a dietary admix at doses of 3, 20 or 120 mg/kg/day. Severe toxicity developed in the high-dose group and administration was stopped at the end of week 4. Isotretinoin was restarted in this group at the end of 12 weeks, but at a reduced dosage of 60 mg/kg/day. After 7 weeks, administration again had to be stopped for 6 weeks. Administration continued uninterrupted until week 30. Thereafter, the high-dose group was maintained on a cycle of 2 weeks no treatment followed by 6 weeks of treatment with 60 mg/kg/day.

In the high-dose group (60/120 mg/kg/day), the following toxic manifestations were observed: weight loss, skin lesions, visible blood in feces, ophthalmological changes (epiphora, superficial punctate corneal opacities in the subepithelial stroma, vascularization of the subepithelial corneal stroma and congestion or hyperemia of the palpebral and/or bulbar conjunctiva), decreases in hematocrit and hemoglobin, decreased mean serum glucose levels, slight alterations in mean serum transaminase activity, elevations in mean serum alkaline phosphatase activity, and qualitative albuminuria.

Most clinical signs of toxicity disappeared or diminished when isotretinoin was withdrawn and reappeared when treatment was reactivated. Pathological changes in the high-dose group included: increased incidence of focal gross lesions in the gastrointestinal tract, testicular atrophy with evidence of spermatogenic arrest, increased mean liver weight, microscopic evidence for edema and/or erythrophago-cytosis of the lymph nodes, encephalomalacia limited to single microscopic foci in the brain of two dogs, and degeneration of elastic fibre in four dogs.

Many of the clinical and pathological signs, except for weight loss and corneal opacities, seen in the high dosage group were also evident in the dogs treated with 20 mg/kg/day. However, a tendency towards a decreased frequency and a longer time to first appearance than in the high-dose group was noted.

The low dosage (3 mg/kg/day) was well tolerated, but microscopic changes in the lymph nodes were observed in the same number of dogs as was recorded for the mid-dose group.

Two-year Oral Toxicity - Rat

Isotretinoin was administered to rats (80/sex/group) as a dietary admix for two years. All groups received 1 mg/kg/day for 13 weeks in order to avoid excessive bone fractures during the major period of growth. Thereafter, doses of 2, 8 and 32 mg/kg/day were administered. In the high-dose group, administration of drug was discontinued during weeks 29-41 and 67-73 due to long bone fracture.

All observed side effects of hypervitaminosis A syndrome were spontaneously reversible after withdrawal of isotretinoin. Even experimental animals in a poor general state had largely recovered within 1-2 weeks.

32 mg/kg/day

Upon completion of the study, the following clinical and laboratory findings were observed in the high dose group: increased mortality, decreased body weight gain and food consumption; altered gait (related to possible long bone fracture); decreased hemoglobin and hematocrit; elevated serum alkaline phosphatase, serum triglycerides, serum phosphate, and serum urea nitrogen; exacerbated age- and sialodacryoadenitis (SDA) virus-related eye changes; skin lesions; some increased organ weights. The following histopathological findings were noted: reduplication of small bile ducts; focal fibrosis and focal chronic inflammation of the heart; focal dilation of renal tubules and focal chronic inflammation of the kidney; adrenal medullary lesions (hyperplasia and pheochromocytomas); arteritis; calcification of arteries; focal calcification in tissues; focal osteolysis of bone.

8 mg/kg/day

When isotretinoin was administered to rats at 8 mg/kg/day as a dietary admix for two years, the clinical and laboratory findings were: increased mortality; decreased body weight gain; decreased hemoglobin and hematocrit; elevated serum alkaline phosphatase and serum triglycerides; exacerbated age- and SDA virus-related eye changes; skin lesions; some increased organ weights. The histopathological findings were: reduplication of small bile ducts; focal fibrosis and focal chronic inflammation in the heart; renal tubular dilation and focal chronic inflammation in the kidney; adrenal medullary lesions (hyperplasia and pheochromocytomas); arteritis; calcification of arteries; focal calcification in tissues; focal osteolysis of bone.

2 mg/kg/day

When isotretinoin was administered to rats at 2 mg/kg/day as a dietary admix for two years, the clinical and laboratory findings were: elevated serum alkaline phosphatase values, some increased organ weights. The histopathological findings were: reduplication of small bile ducts; increased focal chronic inflammation of the kidneys; arteritis; calcification of arteries; focal calcification in tissues.

Although an increased incidence of pheochromocytomas and adrenal medullary hyperplasia were observed at the high and mid doses, no increase was observed at the low dose. It is very likely that this increase in number of adrenal medullary proliferative lesions was mediated by an effect upon hormonal status in rats that were already hormonally abnormal because of their genetic origin and overfeeding, as well as other aspects of the environment of laboratory rats. Dose-related decreases in the incidence of liver adenomas and angiomas in male rats and leukemia in female rats were also noted.

Carcinogenicity:

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.

Genotoxicity:

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 1.6 x background) was noted in S. typhimurium TA 100 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.

Reproductive and Developmental Toxicology:

Like other Vitamin A derivatives, isotretinoin has been shown in animal experiments to be teratogenic and embryotoxic; however, there is a large species variation in the teratogenic effect. Rats have been reported to be less sensitive to the teratogenic effects of isotretinoin; whereas, humans have been reported to be the most sensitive. Differences in sensitivity are a result of interspecies differences in the pharmacokinetics and placental transfer of isotretinoin.

Table 8 provides the low dose (mg/kg) reported to elicit teratogenesis in animal models.

Table 8: Low dose (mg/kg) reported to elicit teratogenesis in animal models

Fertility and General Reproductive Performance - Rat

Isotretinoin at doses of 2, 8 or 32 mg/kg/day was administered orally to male rats for 63 days prior to mating and through the mating period and to females for 14 days prior to mating and through day 13 of gestation or day 21 of gestation or day 21 of lactation. No adverse effects on fertility and general reproductive performance were observed except for a slight reduction in the weight of weanlings in the high-dose group.

Teratology - Rat

A teratology study was conducted in rats with 5, 15 or 50 mg/kg/day of isotretinoin administered orally on gestation days 7 through 15. Doses of up to 50 mg/kg/day of isotretinoin were found to be nonteratogenic. In an earlier study a dose of 150 mg/kg/day was observed to be teratogenic.

Teratology - Rabbit

New Zealand white rabbits were administered isotretinoin at doses of 1, 3 or 10 mg/kg/day on days 7 through 18 of gestation. No teratogenic or embryotoxic effects were observed at 1 and 3 mg/kg/day. At 10 mg/kg/day, 9/13 does aborted and teratogenicity and embryotoxicity were observed in the remaining four litters.

Perinatal and Postnatal Evaluation - Rat

Rats were administered isotretinoin at doses of 5, 15 or 32 mg/kg/day orally from gestation day 14 through day 21 of lactation. Increased pup mortality, considered secondary to reduced maternal food intake, was noted in all treated groups and particularly in the high-dose group. Body weight development of pups was impaired significantly in the high-dose group. Similarly, this effect was considered due to a reduced food intake by the dams.