PRODUCT MONOGRAPH. Pr TOCTINO* Alitretinoin capsule, 10, 30 mg. Soft capsule 10 mg and 30 mg

Transcription

1 PRODUCT MONOGRAPH Pr TOCTINO* Alitretinoin capsule, 10, 30 mg Soft capsule 10 mg and 30 mg Therapeutic Classification: Immunomodulator/Anti-inflammatory agent Basilea Medical Ltd. 14/16 Frederick Sanger Road The Surrey Research Park Guildford Surrey, GU2 7YD UK Date of Revision: July 18, Distributed by: Actelion Pharmaceuticals Canada Inc Daniel-Johnson Blvd. Suite 701 Laval, Quebec H7T 2L1 Control number *Trademark of Basilea Pharmaceutica International AG, Basel, Switzerland Appendix E - Product Monograph Template - Standard Page 1 of 34

2 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION...3 SUMMARY PRODUCT INFORMATION...3 INDICATIONS AND CLINICAL USE...3 CONTRAINDICATIONS...4 WARNINGS AND PRECAUTIONS...5 ADVERSE REACTIONS...10 DRUG INTERACTIONS...14 OVERDOSAGE ACTION AND CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION...15 STORAGE AND STABILITY...18 SPECIAL HANDLING INSTRUCTIONS...18 DOSAGE FORMS, COMPOSITION AND PACKAGING...18 PART II: SCIENTIFIC INFORMATION...19 PHARMACEUTICAL INFORMATION...19 CLINICAL TRIALS... DETAILED PHARMACOLOGY...21 TOXICOLOGY...22 REFERENCES...24 PART III: CONSUMER INFORMATION...28 Appendix E - Product Monograph Template - Standard Page 2 of 34

3 Pr TOCTINO alitretinoin PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Oral Oral Dosage Form / Strength Soft capsule/ 10 mg Soft capsule/ 30 mg Clinically Relevant Nonmedicinal Ingredients None. For a complete listing see Dosage Forms, Composition and Packaging. None. For a complete listing, see Dosage Forms, Composition and Packaging. INDICATIONS AND CLINICAL USE TOCTINO (alitretinoin) is indicated for the treatment of severe chronic hand eczema refractory to high potency topical corticosteroids in adults. TOCTINO should only be prescribed by physicians knowledgeable in the use of retinoids systemically, who understand the risk of teratogenicity in females of child bearing potential (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS: Serious Warnings and Precautions and Special Populations, Women of Child Bearing Potential) Geriatrics Clinical trial experience has not identified differences in responses between elderly and other patients. However clinical studies of TOCTINO did not include sufficient numbers of subjects aged 65 years and over to determine with certainty whether they respond differently from younger subjects. Pediatrics TOCTINO is not recommended for use in patients under 18 years of age. CONTRAINDICATIONS TOCTINO (alitretinoin) is contraindicated in pregnancy. - Females must not become pregnant while taking TOCTINO and for at least one month after its discontinuation. TOCTINO can cause severe birth defects in infants born to women who become Appendix E - Product Monograph Template - Standard Page 3 of 34

4 pregnant during treatment with TOCTINO 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 WARNINGS AND PRECAUTIONS: Special populations, Women of child bearing potential). If pregnancy does occur during treatment with TOCTINO or within one month after its discontinuation, TOCTINO treatment must be immediately stopped and the physician and patient should discuss the desirability of continuing the pregnancy. - TOCTINO should only be prescribed by physicians knowledgeable in the use of retinoids systemically (see INDICATIONS AND CLINICAL USE). TOCTINO is contraindicated in breastfeeding women. TOCTINO is also contraindicated in patients: With hepatic insufficiency With severe renal insufficiency With uncontrolled hypercholesterolemia With uncontrolled hypertriglyceridemia With uncontrolled hypothyroidism With hypervitaminosis A With hypersensitivity either to alitretinoin, to other retinoids or to any of the excipients, in particular in case of allergies to peanut or soya. With rare hereditary problems of fructose intolerance Receiving concomitant treatment with tetracyclines (see WARNINGS AND PRECAUTIONS) Appendix E - Product Monograph Template - Standard Page 4 of 34

5 Serious Warnings and Precautions Pregnancy Prevention: TOCTINO (alitretinoin) is a known teratogen contraindicated in pregnancy (see boxed CONTRAINDICATIONS). Physicians should only prescribe TOCTINO to females of childbearing potential if ALL the conditions described below under Conditions of use are met. In addition, when prescribing this drug to female patients of childbearing potential, physicians must use the TOCTINO Pregnancy Prevention Program, which includes comprehensive information about the potential risks of this drug, a checklist for criteria which must be met prior to prescribing this drug to female patients of childbearing potential, detailed information on birth control options, a patient informed consent for review and signature, and monthly pregnancy reminders for physicians to use at each patient visit during the treatment period. Neurologic: Treatment with systemic retinoids, including alitretinoin, has been associated with the occurrence of benign intracranial hypertension, some of which involved concomitant use of tetracyclines (see CONTRAINDICATIONS AND WARNINGS AND PRECAUTIONS). Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop signs of benign intracranial hypertension should discontinue alitretinoin immediately (class effect). WARNINGS AND PRECAUTIONS Pregnancy Prevention and Conditions of Use: TOCTINO is contraindicated in females of childbearing potential unless ALL of the following conditions apply: 1. The patient has severe chronic hand eczema that is refractory to high potency topical corticosteroids 2. The patient is reliable in understanding and carrying out instructions. 3. The patient is able and willing to comply with the mandatory effective contraceptive measures. 4. The patient has received, and acknowledged understanding of, a careful oral and printed explanation of the hazards of fetal exposure to TOCTINO and the risk of possible contraception failure. 5. The patient has been informed and understands the need to rapidly consult her physician if there is a risk of pregnancy. 6. The patient understands the need for rigorous follow-up on a monthly basis. Appendix E - Product Monograph Template - Standard Page 5 of 34

6 7. The patient uses effective contraception without any interruption for one month before beginning TOCTINO therapy, during TOCTINO therapy and for one month following discontinuation of TOCTINO therapy. It is recommended that two reliable forms of contraception be used simultaneously. 8. The patient has had two negative pregnancy tests with a sensitivity of at least 25 miu/ml before starting TOCTINO therapy with the first pregnancy test conducted at initial assessment when the patient is qualified for TOCTINO 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 TOCTINO therapy is initiated. 9. 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 TOCTINO. (Re items 2 to 9, see WARNINGS AND PRECAUTIONS: Special Populations, Women of Child Bearing Potential.) Even female patients who normally do not employ contraception due to a history of infertility, or claim absence of sexual activity must be advised to employ contraception while taking TOCTINO, following the above guidelines. Even female patients who have amenorrhea must follow all the advice on effective contraception. Special Populations 1. Women of child bearing potential: There is an extremely high risk that major human fetal abnormalities will occur if pregnancy occurs during treatment with TOCTINO or up to one month following its discontinuation. Potentially any exposed fetus can be affected. Pregnancy Tests: Female patients of childbearing potential must not be given TOCTINO until pregnancy is excluded. The patient must have two negative pregnancy tests before starting TOCTINO therapy with the first pregnancy test conducted at initial assessment when the patient is qualified for TOCTINO therapy by the physician. A second pregnancy test must be performed within 11 days prior to starting TOCTINO treatment. TOCTINO 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 TOCTINO 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. These pregnancy tests will: Serve primarily to reinforce to the patient the necessity of avoiding pregnancy. 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 TOCTINO and the desirability of continuing the pregnancy in view of the potential teratogenic Appendix E - Product Monograph Template - Standard Page 6 of 34

7 effect of TOCTINO (see CONTRAINDICATIONS and TOXICOLOGY: Reproduction and Teratology Studies). Contraception: Effective contraception must be used for at least one month before starting TOCTINO treatment, during treatment and for at least one month following the discontinuation of TOCTINO 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. Microdosed progesterone preparations (minipills) are not a suitable method of contraception during Toctino therapy (see DRUG INTERACTIONS; Drug-Drug Interactions). 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. Pregnancy: Pregnancy occurring during treatment with TOCTINO and for one month after its discontinuation, carries the risk of fetal malformation and the increased risk of spontaneous abortion (see CONTRAINDICATIONS and TOXICOLOGY: Reproduction and Teratology Studies). TOCTINO, treatment must be stopped and the patient should be fully counselled regarding 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. Breastfeeding Women: Alitretinoin is highly lipophilic, therefore the passage of alitretinoin into human milk is very likely. Due to the potential risk for the exposed child, the use of alitretinoin is contraindicated in breast feeding mothers. (see CONTRAINDICATIONS). 2. Male patients Small amounts of alitretinoin have been detected in the semen of healthy volunteers receiving 40 mg of alitretinoin and there is no indication of drug accumulation in semen. Assuming complete vaginal absorption of these amounts would have a negligible effect on the endogenous plasma levels of the female partner and therefore does not appear to pose a risk to the fetus if the partner is pregnant. Based on non-clinical findings, the male fertility may be compromised by treatment with TOCTINO. Male patients should be reminded that they must not share their medication with anyone, particularly not females. General Appendix E - Product Monograph Template - Standard Page 7 of 34

8 TOCTINO should not be prescribed if the patient's eczema (dermatitis) can be adequately controlled by standard measures, including skin protection, avoidance of allergens and irritants, and treatment with potent topical corticosteroids. Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment. Blood Donations: Patients should not donate blood during therapy and for 1 month following discontinuation of TOCTINO because of the potential risk to the foetus of a pregnant transfusion recipient. Carcinogenesis and Mutagenesis Alitretinoin was tested in 2-year carcinogenicity studies in rats and mice. Dose-related retinoidspecific toxicity was seen at higher doses, but no carcinogenic potential was noted. Cardiovascular / Lipid Metabolism Alitretinoin has been associated with an increase in plasma cholesterol and triglyceride levels. 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, serum cholesterol and triglycerides (fasting values) should be monitored. Alitretinoin should be discontinued if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Triglyceride levels in excess of 800mg/dL (9mmol/L) are sometimes associated with acute pancreatitis, which may be fatal. Patients at high risk for cardiac events should start on the lowest possible dose of altitretinoin and be carefully monitored due to increases in lipid levels. Endocrine and Metabolism Changes in thyroid function tests have been observed in patients receiving alitretinoin, most often noted as a reversible reduction in thyroid stimulating hormone (TSH) levels and T4 [free thyroxine]. Gastrointestinal Isotretinoin, which belongs to the same chemical class as alitretinoin, has been associated with inflammatory bowel disease (IBD), including regional ileitis, in patients without a history of intestinal disorders. If severe diarrhea is observed diagnosis of IBD should be considered. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue TOCTINO immediately. Hepatic/Biliary/Pancreatic Appendix E - Product Monograph Template - Standard Page 8 of 34

9 Treatment with other systemic retinoids has been associated with transient and reversible increases in liver transaminases. In the event of persistent clinically relevant elevation of transaminase levels, reduction of the dose or discontinuation of treatment should be considered. Musculo-skeletal and connective tissue disorders Treatment with other systemic retinoids has been associated with bone changes including premature epiphyseal closure, hyperostosis, and calcification of tendons and ligaments. Myalgia, arthralgia and increased serum creatinine phosphokinase values have been observed in patients treated with alitretinoin. Neurologic Treatment with systemic retinoids, including alitretinoin, has been associated with the occurrence of benign intracranial hypertension, some of which involved concomitant use of tetracyclines (see CONTRAINDICATIONS AND DRUG INTERACTIONS). Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop signs of benign intracranial hypertension should discontinue alitretinoin immediately. Ophthamologic Treatment with alitretinoin has been associated with dry eyes. The symptoms usually resolve after discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment. Decreased night vision has been reported in patients treated with alitretinoin and other retinoids. These effects usually resolve after discontinuation of therapy. Patients should be advised of this potential problem and warned to be cautious when driving or operating machines. Psychiatric Depression, aggravated depression, anxiety, aggressive tendencies, mood alterations, psychotic symptoms, and very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with systemic retinoids including alitretinoin. Particular care needs to be taken in patients with a history of depression and patients on alitretinoin treatment should therefore be observed for signs of depression and referred for appropriate treatment if necessary. However, discontinuation of alitretinoin may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary. Skin The effects of UV light are enhanced by retinoid therapy, therefore patients should avoid excessive exposure to sunlight and the unsupervised use of sun lamps. Where necessary a sunprotection product with a high protection factor of at least SPF 15 should be used. Appendix E - Product Monograph Template - Standard Page 9 of 34

10 Patients who experience dryness of the skin and lips should be advised to use a skin moisturizing ointment or cream and a lip balm. Monitoring and Laboratory Tests Pregnancy tests: The patient should have two negative pregnancy tests (β-hcg in urine or serum) with a sensitivity of at least 25 miu/ml before starting TOCTINO therapy with the first pregnancy test conducted at initial assessment when the patient is qualified for TOCTINO 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 must wait until the second or third day of their next normal menstrual period before starting TOCTINO. Pregnancy testing must be repeated monthly for pregnancy detection during TOCTINO treatment and at one month after discontinuation of treatment. The dates and results of the pregnancy tests should be documented. The following tests are required before starting TOCTINO, at first month, then as clinically indicated: Serum blood lipid determinations (under fasting conditions) should be performed before TOCTINO is given and then at intervals (one month after the start of therapy) until the lipid response to TOCTINO is established (which usually occurs within four weeks), and also at the end of treatment. (See WARNINGS AND PRECAUTIONS; General; Cardiovascular/Lipid Metabolism) Blood glucose level: patients with known or suspected diabetes should have periodic blood sugar determinations. ADVERSE REACTIONS Adverse Drug Reaction Overview In blinded studies, 1382 patients with CHE received alitretinoin (1101 patients) or placebo (281 patients). Of these, 426 patients received alitretinoin at 30 mg per day (182 for 24 weeks) and 514 received 10 mg per day (240 for 24 weeks). The most frequent adverse drug reactions (ADRs) observed under alitretinoin therapy are headache (30mg: 21%; 10mg: 11%), and flushing (30mg: 5.9%, 10mg: 1.6% ). The percentage of patients who discontinued therapy due to adverse events was: 5.4% (placebo), 5.3% (10 mg), 9.3% (30 mg) in Study BAP The most common reason for discontinuation was headache (0.5% placebo, 1.4% 10 mg, 4.1% 30 mg), which typically occurred within the first 10 days of therapy, and was transient. These reversible ADRs are dose dependent and may therefore be alleviated by dose reduction. Clinical Trial Adverse Drug Reactions Appendix E - Product Monograph Template - Standard Page 10 of 34

11 Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Table 1: Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term Reported by 1% of Patients in Any Treatment Group: Blinded Patient Studies Population (Studies BAP00003, BAP00089 and BAP00200) Alitretinoin 30mg 10mg Placebo Number of Patients in Safety 426 (100.0%) 514 (100.0%) 281 (100.0%) Population SKIN AND SUBCUTANEOUS TISSUE DISORDERS ECZEMA 15 ( 3.5%) 18 ( 3.5%) 11 ( 3.9%) ERYTHEMA 31 ( 7.3%) 8 ( 1.6%) 4 ( 1.4%) DRY SKIN* 12 ( 2.8%) 14 ( 2.7%) 3 ( 1.1%) DERMATITIS 7 ( 1.6%) 7 ( 1.4%) 5 ( 1.8%) PRURITUS 6 ( 1.4%) 5 ( 1.0%) 5 ( 1.8%) RASH 4 ( 0.9%) 6 ( 1.2%) 4 ( 1.4%) ALOPECIA* 7 ( 1.6%) 0 0 NERVOUS SYSTEM DISORDER HEADACHE* DIZZINESS 92 (21.6%) 3 ( 0.7%) 58 (11.3%) 9 ( 1.8%) 22 ( 7.8%) 3 ( 1.1%) INFECTIONS AND INFESTATIONS NASOPHARYNGITIS 26 ( 6.1%) 26 ( 5.1%) 14 ( 5.0%) INFLUENZA 6 ( 1.4%) 11 ( 2.1%) 4 ( 1.4%) UPPER RESPIRATORY TRACT INFECTION 9 ( 2.1%) 5 ( 1.0%) 5 ( 1.8%) PHARYNGITIS 6 ( 1.4%) 5 ( 1.0%) 1 ( 0.4%) HERPES SIMPLEX 5 ( 1.2%) 1 ( 0.2%) 3 ( 1.1%) RHINITIS 3 ( 0.7%) 2 ( 0.4%) 4 ( 1.4%) FOLLICULITIS 0 2 ( 0.4%) 3 ( 1.1%) GASTROINTESTINAL DISORDERS LIP DRY* 24 ( 5.6%) 19 ( 3.7%) 9 ( 3.2%) DRY MOUTH* 12 ( 2.8%) 13 ( 2.5%) 3 ( 1.1%) NAUSEA 14 ( 3.3%) 12 ( 2.3%) 5 ( 1.8%) CHEILITIS 7 ( 1.6%) 6 ( 1.2%) 1 ( 0.4%) DIARRHOEA 4 ( 0.9%) 7 ( 1.4%) 4 ( 1.4%) ABDOMINAL PAIN UPPER 5 ( 1.2%) 4 ( 0.8%) 1 ( 0.4%) VOMITING 5 ( 1.2%) 3 ( 0.6%) 1 ( 0.4%) DYSPEPSIA 6 ( 1.4%) 2 ( 0.4%) 0 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS BACK PAIN 6 ( 1.4%) 11 ( 2.1%) 3 ( 1.1%) ARTHRALGIA 8 ( 1.9%) 5 ( 1.0%) 3 ( 1.1%) MYALGIA 5 ( 1.2%) 4 ( 0.8%) 3 ( 1.1%) PAIN IN EXTREMITY 1 ( 0.2%) 6 ( 1.2%) 4 ( 1.4%) GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 9 ( 2.1%) 10 ( 1.9%) 5 ( 1.8%) EYE DISORDERS CONJUNCTIVITIS* 8 ( 1.9%) 6 ( 1.2%) 3 ( 1.1%) DRY EYE* 11 ( 2.6%) 9 ( 1.8%) 1 ( 0.4%) ABNORMAL EYE SENSATION 5 (1.2%) 1 (0.2%) 0 Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term Reported by 1% of Patients in Any Treatment Group: Blinded Patient Studies Population (Studies BAP00003, BAP00089 and BAP00200) cont'd Alitretinoin Appendix E - Product Monograph Template - Standard Page 11 of 34

12 30mg 10mg Placebo Number of Patients in Safety 426 (100.0%) 514 (100.0%) 281 (100.0%) Population INVESTIGATIONS BLOOD CREATINE PHOSPHOKINASE INC. 13 ( 3.1%) 8 ( 1.6%) 4 ( 1.4%) BLOOD TRIGLYCERIDES INCREASED 12 ( 2.8%) 3 ( 0.6%) 0 WEIGHT INCREASED 5 ( 1.2%) 4 ( 0.8%) 2 ( 0.7%) VASCULAR DISORDERS FLUSHING 25 ( 5.9%) 8 ( 1.6%) 3 ( 1.1%) HYPERTENSION 7 ( 1.6%) 6 ( 1.2%) 1 ( 0.4%) HOT FLUSH 5 ( 1.2%) 2 ( 0.4%) 1 ( 0.4%) PSYCHIATRIC DISORDERS DEPRESSION* 11 ( 2.6%) 9 ( 1.8%) 5 ( 1.8%) INSOMNIA 3 ( 0.7%) 5 ( 1.0%) 3 ( 1.1%) SLEEP DISORDER 3 ( 0.7%) 1 ( 0.2%) 3 ( 1.1%) RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS PHARYNGOLARYNGEAL PAIN 5 ( 1.2%) 5 ( 1.0%) 3 ( 1.1%) METABOLISM AND NUTRITION DISORDERS HYPERCHOLESTEROLAEMIA 5 ( 1.2%) 3 ( 0.6%) 1 ( 0.4%) *similar Medra terms were combined in this calculation Headache was the most common AE and clearly showed a dose effect. Erythema and dry lips were also more frequent with alitretinoin 30 mg than with alitretinoin 10 mg. Additional AEs occurring with highest incidence in the 30 mg alitretinoin arm included dry skin, conjunctivitis, hypercholesterolemia, and flushing. Other commonly occurring AEs without strong apparent dose effect included nasopharyngitis, and eczema. All other treatment-emergent AEs were of similar frequency in the two alitretinoin groups and with the placebo group. Psychiatric effects, in particular depression, and mood changes and suicidal ideation, have been associated with retinoids including alitretinoin. In alitretinoin clinical studies, patients have been monitored for depression using the CES-D (Center for Epidemiological Studies-Depression) score. Treatment with alitretinoin was not associated with changes in the CES-D score. The following adverse events were not observed in clinical trials with alitretinoin, but have been observed with other retinoids: Inflammatory bowel disease, diabetes mellitus, color blindness (color vision deficiencies), contact lens intolerance and decreased night vision. Changes in bone mineralization and extra-osseous calcifications have been associated with systemic retinoid treatment. In clinical studies with alitretinoin, degenerative changes of the spine and ligamentous calcifications were frequent findings in patients with chronic hand eczema before treatment (baseline), with minor progression in a small number of patients during treatment. These observations were consistent with age dependent degenerative changes. Assessments of bone density (DXA) did not indicate a dose dependent effect on bone mineralization. The most common laboratory changes consisted of increased levels of triglycerides (30mg: 35.4%; 10mg: 17.0% ), increased cholesterol (30mg: 27.8%; 10mg 16.7%), decreased levels of thyroid stimulating hormone (TSH, 30mg: 8.4%, 10mg: 6.0%) and decreased levels of free T4 (30mg: 10.5%; 10mg: 2.9%). Appendix E - Product Monograph Template - Standard Page 12 of 34

13 Less Common Clinical Trial Adverse Drug Reactions (<1%) Nervous system disorders: Benign intracranial hypertension Eye disorders: Blurred vision, cataract Vascular disorders: Vasculitis Respiratory, thoracic and mediastinal disorders: Epistaxis Skin and subcutaneous tissues disorders: Pruritus, rash, skin exfoliation, asteatotic eczema Musculo-skeletal and connective tissue disorders: exostosis, (hyperostosis), ankylosing spondylosis Table 2: Abnormal Hematologic and Clinical Chemistry Findings) Number of Patients in Safety population >10% of patients outside marked reference range 5-10% of patients outside marked reference range 1-5% of patients outside marked reference range 30 mg 10 mg Placebo LDL calculated high Total cholesterol high Triglycerides high HDL low Iron low, Total iron binding capacity high; Neutrophils absolute count low; Eosinophils high; Creatinine kinase high; Low density lipoproteins high; Thyroid stimulating hormone low LDL calculated high Reticulocyte count low; Eosinophils high Creatinine kinase high HDL low TSH low Leucocytes high; Lymphocytes absolute count high; Neutrophils absolute count low; Eosinophils high; Creatinine kinase high Total cholesterol high HDL low; LDL calculated high Thyroid stimulating hormone low The most frequent and relevant changes in individual laboratory values included elevated levels of fasting cholesterol and triglycerides with corresponding changes in high density lipoproteins (HDL) and low density lipoproteins (LDL), and lowered levels of thyroxin and TSH, predominantly in the 30 mg dose group. Other frequently reported changes were reductions in hemoglobin, hematocrit, and red blood cell (RBC) counts, which were more frequent in the 30 mg dose group. Elevated levels of creatinine phosphokinase were frequent in both alitretinoin groups. Post-Market Adverse Drug Reactions Appendix E - Product Monograph Template - Standard Page 13 of 34

14 Not applicable. DRUG INTERACTIONS Overview Alitretinoin is metabolized by cytochrome P450 3A4 (CYP3A4). No drug interactions were observed when alitretinoin was co-administered with the oral contraceptive ethinyl estradiol and norgestimate. Co-administration with strong CYP3A4 or PgP inhibitors, such as ketoconazole, increases levels of alitretinoin, and dose reduction of alitretinoin may be considered in patients experiencing adverse events. Substrates of CYP3A4, such as cyclosporin or simvastatin, do not affect the pharmacokinetics of alitretinoin. Alitretinoin did not affect the pharmacokinetics of cyclosporin or ketoconazole. A slight reduction of simvastatin plasma levels was observed when co-administered with alitretinoin. Patients should not take vitamin A or other retinoids as concurrent medication due to the risk of developing hypervitaminosis A. Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported with concomitant use of retinoids and tetracyclines. Therefore, concomitant treatment with tetracyclines must be avoided (see Serious Warnings and Precautions). Drug-Drug Interactions Table 3: Established or Potential Drug-Drug Interactions Ref Effect Clinical Comment Simvastatin CT Decrease =16% in simvastatin levels Ketoconazole CT Increase 40% alitretinoin levels Legend: C = Case Study; CT = Clinical Trial; T = Theoretical Dose adjustment of simvastatin during routine monitoring of CL and TG, if appropriate Dose reduction of alitretinoin guided by the appearance of typical retinoids side effects such as headache and flushing Microdosed progesterone preparations (minipills) are not a suitable method of contraception during Toctino therapy. An increased risk of liver toxicity may be seen if retinoids are taken concomitantly with methotrexate. Appendix E - Product Monograph Template - Standard Page 14 of 34

15 Drug-Food Interactions Clinical pharmacology studies with various formulations of alitretinoin demonstrated that when alitretinoin is taken with food, the systemic exposure is significantly enhanced. All subsequent clinical studies were done in a fed state. Therefore, alitretinoin must be taken with a meal. DOSAGE AND ADMINISTRATION Recommended Dose and Dosage Adjustment The recommended dose range for TOCTINO is 10mg-30mg once daily with a meal. The recommended start dose is 30 mg once daily. Dose reduction to 10 mg once daily may be considered in patients with unacceptable side effects. Patients at high risk for cardiac events should start on the lowest possible dose of altitretinoin and be carefully monitored due to increases in lipid levels (see WARNINGS and PRECAUTIONS). In studies investigating 10mg and 30mg daily doses, both doses resulted in clearing of the disease. The 30mg dose provided a more rapid response and a higher response rate. The 10mg daily dose was associated with fewer adverse events (see ADVERSE REACTIONS AND PART II, CLINICAL TRIALS). A treatment course of TOCTINO may be given for 12 to 24 weeks depending on response. Discontinuation of therapy should be considered for patients who still have severe disease after the initial 12 weeks of treatment. In the event of relapse, patients may benefit from further treatment courses of TOCTINO. Children TOCTINO is not recommended for use in patients under 18 years of age. Missed Dose The missed dose should be taken as soon as it is remembered, and then the regular dosing schedule should be continued. Two doses of TOCTINO should not be taken on the same day. Administration The capsules should be taken once daily and must be taken with a meal. OVERDOSAGE Appendix E - Product Monograph Template - Standard Page 15 of 34

16 For management of suspected overdose, contact your regional poison control centre. Alitretinoin is a derivative of vitamin A. Alitretinoin has been administered in oncological clinical studies at dosages of more than the 10-fold of the therapeutic dosage given for chronic hand eczema. The toxicity observed was consistent with vitamin A toxicity, and included severe headache, diarrhea, facial flushing, hypertriglyceridaemia. These effects were reversible. Please contact the Poison Control Centre in case of overdose. The following precautions should be taken with all female patients of childbearing potential who have taken an overdose of TOCTINO. 1. At the time of the overdose, a pregnancy test must be performed. 2. One complete menstrual cycle or one month after the overdose, a second pregnancy test must be performed. 3. Effective contraception must be used for at least one complete menstrual cycle after the overdose. Patients who present with a positive pregnancy test at the time of the overdose, or one complete menstrual cycle / one month after the overdose, should be fully counselled on the serious risk to the fetus from this exposure to TOCTINO and the physician and the patient should discuss the desirability of continuing the pregnancy. (See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Special Populations, Women of Child Bearing Potential, and TOXICOLOGY: Reproduction and Teratology Studies). Canadian Regional Poison Information Centres have been advised on the management of TOCTINO overdoses and on the teratogenic potential of exposure to TOCTINO. ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action The pharmacological action of retinoids may be explained by their effects on cell proliferation, cell differentiation, apoptosis, angiogenesis, keratinization, sebum secretion and immunomodulation. Unlike other retinoids, which are specific agonists of either RAR or RXR receptors, alitretinoin binds to members of both receptor families. The mechanism of action of alitretinoin in chronic hand dermatitis is unknown. Alitretinoin has demonstrated immunomodulatory and anti-inflammatory effects that are relevant to skin inflammation. CXCR3 ligands and CCL20 chemokines, expressed in eczematous skin lesions, are downregulated by alitretinoin in cytokine-stimulated keratinocytes and dermal endothelial cells. In Appendix E - Product Monograph Template - Standard Page 16 of 34

17 addition, alitretinoin suppresses the expansion of cytokine activated leucocytes subsets and antigen presenting cells. It has been observed that in humans alitretinoin only minimally affects sebum secretion. Pharmacokinetics Absorption The absorption of alitretinoin from the gastro-intestinal tract is variable and dose-proportional over the therapeutic range from mg. The absolute bioavailability of alitretinoin has not been determined. When alitretinoin is taken with food, the exposure is increased and the variability in exposure is decreased. Therefore, alitretinoin should be taken with a meal. Distribution Alitretinoin is 99% bound to plasma proteins. The volume of distribution of alitretinoin in man has not been determined, but animal studies indicate a volume of distribution greater than the extracellular volume. Metabolism Alitretinoin is metabolized by oxidation in the liver by CYP3A4 isoenzymes into 4-oxoalitretinoin. Both compounds undergo isomerization into all-trans retinoic acid and 4-oxo-alltrans retinoic acid. After oral administration, the contribution of the metabolites in plasma to the systemic exposure of alitretinoin is approximately 35% to 80% for 4-oxo-alitretinoin. The major metabolite 4-oxo-alitretinoin is further glucuronidated and eliminated in urine. Alitretinoin is degraded similarly to vitamin A by sequential cleavage of the carbon-side chain. During a 12-to 24-week treatment period with 10 or 30 mg dose, the exposure to alitretinoin remained stable. There is no indication of auto-induction of metabolizing enzymes. Elimination Alitretinoin is an endogenous retinoid. Alitretinoin concentrations return to normal range within 1 to 3 days treatment cessation. Excretion of radio-labeled alitretinoin, was complete with approximately 94% of the dose recovered. Radio-labeled material was eliminated mainly in urine and a smaller fraction (approx. 30%) in feces. The most abundant excretion compound is the glucuronide of 4-oxo-alitretinoin amounting to 6.5% of the dose in urine. Elimination half-life of unchanged alitretinoin ranges between 2 to 10 hours. Alitretinoin and its 4-oxo-metabolite do not accumulate. Special Populations and Conditions Pharmacokinetics in special populations Appendix E - Product Monograph Template - Standard Page 17 of 34

18 Gender, weight and age did not affect the pharmacokinetics of alitretinoin. See INDICATIONS AND CLINICAL USE: Geriatrics The pharmacokinetics of alitretinoin in CHE patients was similar to that in healthy volunteers. Alitretinoin kinetics have not been studied in patients with hepatic or with severe renal insufficiency or in patients below 18 years (see CONTRAINDICATIONS). STORAGE AND STABILITY TOCTINO should be stored between 15 and 30 ºC. SPECIAL HANDLING INSTRUCTIONS Store in the original package. Keep the blister in the outer carton to protect from light. DOSAGE FORMS, COMPOSITION AND PACKAGING 10 mg soft capsule: Each capsule contains 10mg alitretinoin. The nonmedical ingredients are : Soybean oil, Partially hydrogenated soybean oil, Medium chain triglycerides, Yellow wax, DLalpha-tocopherol. The capsule shell contains: Gelatin, Glycerol, Sorbitol, Water, Iron oxide. 30 mg soft capsule: Each capsule contains 30mg alitretinoin. The nonmedical ingredients are : Soybean oil, Partially hydrogenated soybean oil, Medium chain triglycerides, Yellow wax, DLalpha-tocopherol. The capsule shell contains: Gelatin, Glycerol, Sorbitol, Water, Iron oxide. Availability: Capsules are available in blister packs of 10 capsules. Each box contains 3 blister packs. Appendix E - Product Monograph Template - Standard Page 18 of 34

19 PHARMACEUTICAL INFORMATION Drug Substance PART II: SCIENTIFIC INFORMATION Common name: Alitretinoin Chemical name: (2E, 4E, 6Z, 8E)-3,7-Dimethyl-9-(2,6,6-tri-methyl-cyclohex-1-en-yl)- nona-2,4,6,8-tetraen-1-oic acid Molecular formula and molecular mass: C 20 H 28 O 2 (300.44) Structural formula: COOH Physicochemical properties: Alitretinoin is a light green/light yellow to yellow powder, with a melting point above 150 C. Alitretinoin is only very slightly soluble in aqueous solutions. Alitretinoin is soluble (to different degrees) in various organic solvents. Alitretinoin has a pka value of 5.1 (calculated by the Perrin method). Alitretinoin has a ph of 6.1 (1 % suspension in water). The n-octanol/water partition coefficient (P ow ) is >1.6 x 10 6 (log P ow > 6.5) CLINICAL TRIALS The safety and efficacy of TOCTINO in patients with severe chronic hand eczema (CHE) refractory to high potency topical corticosteroids has been established in double blind, placebocontrolled Phase 3 studies. In these trials, the term Chronic Hand Dermatitis (CHaD) was used and is considered to be synonymous with Chronic Hand Eczema (CHE). The primary endpoint in these studies was the proportion of patients achieving Physicians Global Assessment (PGA) ratings of clear or almost clear hands at the end of therapy. The treatment duration was 12 to 24 weeks. The BACH (Benefit of Alitretinoin in Chronic Hand Dermatitis Study) included 1032 severe CHE patients who had no response or a transient response (initial improvement and worsening of disease despite continued treatment) to potent topical corticosteroids or were intolerant of potent topical corticosteroids. All phenotypes of CHE were included: hyperkeratosis (87%), pompholyx (27%) and fingertip dermatitis (43%) and other (15%). Essentially all patients had signs of skin Appendix E - Product Monograph Template - Standard Page 19 of 34

20 inflammation, comprising of erythema and/or vesicles. Treatment with alitretinoin led to a significantly higher proportion of patients with clear/almost clear hands, compared to placebo. The response was dose dependent (see Table 5). Response rates for different CHE subtypes were also dose dependent, except for patients with pomphlyx. Table 4: Response rate by CHE subtype CHE subtype Hyperkeratotic (% of ITT population) (64%) Response rate (PGA) 30mg: 54% 10 mg: 30% Placebo: 12% Hyperkeratotic/Pompholyx (22%) 30mg: 33% 10 mg: 23% Placebo: 12% Pompholyx (5%) 30mg: 33% 10 mg: 22% Placebo: 30% Table 5: Primary Efficacy Parameter - Results Alitretinoin Primary Endpoint 10 mg 30 mg Placebo ITT Population N=418 N=409 N=205 PGA at end of study Total Response Rate Clear Almost clear 115 (27.5%) 39 ( 9.3%) 76 (18.2%) Secondary endpoints included the proportion of patients achieving at least mild disease, time to achieving clear to almost clear hands, reduction in total lesion symptom score, patient global assessment (PaGA) of disease severity, reduction in extent of disease (see Table 6). Patients with clear/almost clear hands at end of treatment were followed up for 24 weeks. During that period no active drug treatment for CHE was allowed. Relapse was defined as 75% of the initial total lesion symptom score. Table 6: Secondary Efficacy Parameters - Results 195 (47.7%) 90 (22.0%) 105 (25.7%) Comparison to placebo P=0.004 P=< (16.6%) 6 ( 2.9%) 28 (13.7%) Appendix E - Product Monograph Template - Standard Page 20 of 34

21 Alitretinoin Efficacy Variable 10 mg 30 mg Placebo ITT Population N=418 N=409 N=205 Partial Response Rate 207 (49.5%) 254 (62.1%) 74 (36.1%) (clear, almost clear or mild disease) PaGA (clear or almost clear) 101 (24.2%) 163 (39.9%) 31 (15.1%) mtlss (mean % change from (n=411) (n=408) (n=204) baseline) mtlss (median % change from baseline) Time to response (first quartile) 171 days 85 days - Extent of disease (mean % change from baseline) Re-treatment Study (n=418) (n=402) (n=409) (n=391) (n=205) (n=197) The objective of the study was to assess the safety and efficacy of a 12 to 24-week course of alitretinoin in patients with chronic hand eczema refractory to topical therapy, who had been previously treated with alitretinoin or placebo in the BACH study. The numbers of responding patients without observed relapse at the end of the 24-weeks follow-up period was 62.6% (30 mg), and 70.4% (10 mg). Responding patients from Study BAP00089 who relapsed within 24 weeks after the end of treatment were enrolled into Cohort A in a double-blind, randomized, placebo-controlled, multicenter study design. Relapse was defined as an mtlss score 75% of the original baseline value (at baseline of Study BAP00089). Eligible patients were assigned to the same dose they had previously received in Study BAP00089 or placebo in a 2:1 ratio for 12 to 24 weeks. The efficacy results from this study confirm that patients who had previously responded to active alitretinoin can benefit from re-treatment (see Table 7). Appendix E - Product Monograph Template - Standard Page 21 of 34

22 Table 7: Summary of Primary Efficacy Variable - PGA (BAP00091 Cohort A ) Dose Group in BAP mg 30 mg Placebo Dose group in BAP mg Placebo 30 mg Placebo Placebo ITT Population N=21 N=10 N=49 N=24 N=13 PGA at end of study Total Response Rate Clear Almost clear 10 (47.6%) 2 ( 9.5%) 8 (28.1%) 1 (10%) 1 (10%) 0 39 (79.6%) 21 (42.9%) 18 (36.7%) 2 (8.3%) 0 2 (8.3%) 9 (69.2%) 3 (23.1%) 6 (46.2%) Patients in Cohort A who were treated with alitretinoin responded more frequently than those given placebo. In the alitretinoin 30 mg arm, 79.6% of patients responded (clear or almost clear in Physician s Global Assessment) compared with 8.3% on placebo. In the 10 mg arm 47.6% responded on active re-treatment compared to 10% on placebo. The placebo response rate in patients who previously responded to placebo was 69.2%. It thus appears that patients who responded to placebo treatment can respond again (intervention effect). Patients who had previously responded to active treatment, however, did not generally respond to placebo. Non-responding patients with mostly mild or moderate CHE (following protocol amendment to exclude patients with severe disease) following 12 or 24 weeks of trial treatment in Study BAP00089 were enrolled into Cohort B in an open-label, multicenter study. All non-responding patients (Cohort B) were assigned to alitretinoin 30 mg once daily for 12 to 24 weeks. Results for Cohort B indicate that either a higher dose or a longer treatment period can benefit patients who have residual mild or moderate CHE at the end of a course of 24 weeks of alitretinoin treatment. The overall response rate for the alitretinoin 30 mg group was 47.3% which is comparable to the response rate for the 30 mg arm in Study BAP ECG Safety In a double-blind, placebo-controlled, crossover study in 48 healthy volunteers, alitretinoin was associated with statistically significant increases in the ECG-derived heart rate. In subjects receiving alitretinoin 30 mg for 3 days, the maximum mean increase was 4.4 bpm (90% CI 2.0,6.7 bpm) at 3 hours post-dosing. In subjects receiving a single dose of alitretinoin 60 mg, significant increases in heart rate were observed from 3 to 12 h post-dosing, with a maximum mean increase of 10.6 bpm (90% CI 7.2, 14.0 bpm) at 8 h post-dosing. The incidence of heart rate values greater than 100 bpm and =25% higher than baseline was 8.7% for the placebo treatment, 8.3% for the alitretinoin 30 mg treatment, and 23.9% for the alitretinoin 60 mg treatment. Comparative Bioavailability Studies Bioavailability study No. BAP00300 compared the commercial formulations (30 mg and 10 mg capsules) with the corresponding formulations used in the pivotal Phase 3 studies (20+10 mg and 10 mg capsules). Appendix E - Product Monograph Template - Standard Page 22 of 34

23 The comparative bioavailability study was an open-label, single-dose, randomized, replicate 4-way crossover trial conducted in 138 healthy male subjects at a single centre, under fed conditions. Subjects were randomly allocated to 4 groups of similar size, receiving either doses of 10 mg (test and reference) or 30 mg (test and reference) alitretinoin. Pharmacokinetic analysis was performed on plasma concentration data of alitretinoin and its 4-oxo-metabloite (primary plasma metabolite). The comparative bioavailability assessment was based on the AUC T and C max parameters of alitretinoin. Parameter AUC T (ng.h/ml) AUC I Test * (Commercial formulation) (26.6%) C max (ng/ml) 64.7 Table 8 Alitretinoin (BAL4079) (1 x 10 mg capsule) From measured data uncorrected for potency Geometric Mean Arithmetic Mean (CV %) Reference (Phase 3 formulation) (33.0%) % Ratio of Geometric Means 90% Confidence Interval (47.6%) (56.1%) T max (h) 3.0 ( ) 3.0 ( ) T ½ (h) 6.63 (168%) 4.60 (69.3%) * 10 mg TOCTINO capsule intended for market 10 mg Phase 3 clinical capsule Expressed as the median (range) only Expressed as the arithmetic mean (CV%) only The AUC I parameter cannot be reliably characterized Appendix E - Product Monograph Template - Standard Page 23 of 34

24 Parameter AUC T (ng.h/ml) AUC I Table 9 Alitretinoin (BAL4079) (30 mg dose as either 1 x 10 mg plus 1 x 20 mg clinical capsules or 1 x 30 mg commercial capsule) From measured data uncorrected for potency Geometric Mean Arithmetic Mean (CV %) Test * (Commercial formulation) (45.2%) C max (ng/ml) Reference (Phase 3 formulation) (42.7%) % Ratio of Geometric Means 90% Confidence Interval (65.3%) (56.8%) T max (h) 3.0 ( ) 3.0 ( ) T ½ (h) 7.15 (166%) 7.39 (194%) * 30 mg TOCTINO capsule intended for market 10 mg plus 20 mg Phase 3 clinical capsules Expressed as the median (range) only Expressed as the arithmetic mean (CV%) only Alitretinoin is an endogenous compound and therefore concentrations cannot be reliably extrapolated to infinity DETAILED PHARMACOLOGY Retinoids include natural compounds such as retinol (vitamin A), as well as synthetic compounds, such as etretinate and acitretin, and have been proven to be useful agents in the treatment of a variety of dermatological diseases. Alitretinoin (9-cis retinoic acid, BAL4079) is a naturally occurring endogenous retinoid, structurally related to vitamin A. It is a highly lipophilic compound, and in humans is protein bound in plasma (>99%). Alitretinoin, and to a lesser extent its 4-oxo-metabolite, are known to bind and activate both the retinoic acid (RA) receptors (RARs) α, β, and γ, and the retinoid X receptors (RXRs) α, β, and γ. However, the actual mechanisms and the significance of this receptor binding capacity remain to be established. Recent studies demonstrated that in contact dermatitis (allergic and chemical), alitretinoin plays an anti-inflammatory and immunomodulatory role, by down-regulation of the production of Appendix E - Product Monograph Template - Standard Page 24 of 34

25 chemokines in cytokine-induced dermal cells and suppression of the expansion of cytokineinduced leucocytes and antigen presenting cells. Safety Pharmacology Mice receiving single doses of alitretinoin up to 2000 mg/kg showed no drug-related CNS effects. Similarly, single oral doses of 10 and 30 mg/kg, resulting in mean plasma concentrations of 886 and 2101 ng/ml at 2 hours after administration, had no effect on cardiovascular or respiratory function in dogs, nor was locomotor activity affected. Induction of CYP450 isozymes as seen in the 13-week interim sacrifice of the 26-week oral toxicity study in rats did not lead to decreased exposures to alitretinoin or the 4-oxo metabolite in this species. TOXICOLOGY Acute Toxicity Studies The acute toxicity of alitretinoin was low in mice after intraperitoneal administration with an LD 50 >4000 mg/kg at 24 hours after administration and approximately 1400 mg/kg after a 10-day observation period. The acute toxicity of BAL4079 was in line with the established low acute toxicity of retinoids in general and lower than that of all-trans and 13-cis retinoic acid. Long-Term Toxicity Studies The toxicity profile of alitretinoin is consistent with the typical retinoid effects and reflects the known features of hypervitaminosis A. Toxicity findings were generally reversible upon discontinuation of treatment. Hypervitaminosis A associated with the administration of alitretinoin or its isomers isotretinoin and tretinoin was assessed in mice. The study showed comparable findings for alitretinoin and tretinoin, thus confirming the typical retinoid class effects with alitretinoin. In another comparative study in rats, alitretinoin and isotretinoin produced characteristic dose-dependent signs and symptoms of hypervitaminosis A at >10 and 50 mg/kg, respectively. In all species, retinoid-specific toxicity was time- and dose-dependent and findings were generally reversible or at least showed a trend towards reversibility during the respective recovery periods. The dose-limiting toxic effects of alitretinoin were bone fractures in rats, and skin and mucus membrane effects in dogs. In mice, the main findings included increased liver weight (adaptive centrilobular hypertrophy) and degenerative changes of male reproductive organs. In rats, findings included impaired general condition, minor changes in hematological and clinical chemistry parameters (e.g. reduced red blood parameters, increased platelet count and increased triglycerides), hypertrophy, increased glycogen storage and fatty change of the liver, bone fractures, thickening of epiphyseal cartilage, hyperplasia and hyperkeratosis of the forestomach and esophagus, degenerative changes in the female reproductive organs and eyes, Appendix E - Product Monograph Template - Standard Page 25 of 34