Calcitonin Salmon

1 INDICATIONS AND USAGE Calcitonin Salmon (synthetic origin) Nasal Spray is a calcitonin, indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause when alternative treatments are not suitable. Fracture reduction efficacy has not been demonstrated ( 1.1 ) Limitations of Use: Due to the possible association between malignancy and calcitonin salmon use, the need for continued therapy should be re-evaluated on a periodic basis ( 1.2 , 5.4 ) Calcitonin salmon nasal spray has not been shown to increase bone mineral density in early postmenopausal women ( 1.2 ) 1.1 Treatment of Postmenopausal Osteoporosis Calcitonin Salmon (synthetic origin) Nasal Spray is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. Fracture reduction efficacy has not been demonstrated. Calcitonin Salmon (synthetic origin) Nasal Spray should be reserved for patients for whom alternative treatments are not suitable (e.g., patients for whom other therapies are contraindicated or for patients who are intolerant or unwilling to use other therapies). 1.2 Important Limitations of Use Due to the possible association between malignancy and calcitonin salmon use, the need for continued therapy should be re-evaluated on a periodic basis [see Warnings and Precautions (5.4)] . Calcitonin Salmon (synthetic origin) Nasal Spray has not been shown to increase spinal bone mineral density in early postmenopausal women.

2 DOSAGE AND ADMINISTRATION For intranasal use only: one spray (200 USP Calcitonin Salmon Units) per day, alternating nostrils daily ( 2.1 ) Prior to first use, allow the bottle to reach room temperature and prime the pump ( 2.2 ) Ensure adequate calcium and vitamin D intake ( 2.3 ) 2.1 Basic Dosing Information The recommended dose of calcitonin salmon nasal spray is 1 spray (200 USP Calcitonin Salmon Units) per day administered intranasally, alternating nostrils daily. 2.2 Priming (Activation) of Pump Unopened calcitonin salmon nasal spray should be stored in the refrigerator. Before using the first dose of calcitonin salmon nasal spray, the patient should wait until it has reached room temperature. To prime the pump before it is used for the first time, the bottle should be held upright and the two white side arms of the pump depressed toward the bottle, repeat until a full spray is released. The pump is primed once the first full spray is emitted. To administer, the nozzle should first be carefully placed into the nostril while the patient’s head is in the upright position, then the pump should be firmly depressed toward the bottle. The pump should not be primed before each daily dose. 2.3 Recommendations for Calcium and Vitamin D Supplementation Patients who use calcitonin salmon nasal spray should receive adequate calcium (at least 1000 mg elemental calcium per day) and vitamin D (at least 400 International Units per day).

5 WARNINGS AND PRECAUTIONS Serious hypersensitivity reactions including anaphylactic shock have been reported. Consider skin testing prior to treatment in patients with suspected hypersensitivity to calcitonin salmon ( 5.1 ) Hypocalcemia has been reported. Ensure adequate intake of calcium and vitamin D ( 5.2 ) Nasal adverse reactions, including severe ulceration can occur. Periodic nasal examinations are recommended ( 5.3 ) Malignancy: A meta-analysis of 21 clinical trials suggests an increased risk of overall malignancies in calcitonin salmon-treated patients ( 5.4 , 6.1 ) Circulating antibodies to calcitonin salmon may develop, and may cause loss of response to treatment ( 5.5 ) 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions have been reported in patients receiving calcitonin salmon nasal spray, e.g., bronchospasm, swelling of the tongue or throat, anaphylaxis and anaphylactic shock. Reports of serious hypersensitivity reactions with injectable calcitonin salmon have also been reported, including reports of death attributed to anaphylaxis. The usual provisions should be made for emergency treatment if such a reaction occurs. Hypersensitivity reactions should be differentiated from generalized flushing and hypotension [see Contraindications (4)] . For patients with suspected hypersensitivity to calcitonin salmon, skin testing should be considered prior to treatment utilizing a dilute, sterile solution of a calcitonin salmon injectable product. Healthcare providers may wish to refer patients who require skin testing to an allergist. A detailed skin testing protocol is available from the Customer Service department of Apotex Corp. (1-800-706-5575). 5.2 Hypocalcemia Hypocalcemia associated with tetany (i.e., muscle cramps, twitching) and seizure activity has been reported with calcitonin therapy. Hypocalcemia must be corrected before initiating therapy with calcitonin salmon nasal spray. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with calcitonin salmon nasal spray. Use of calcitonin salmon nasal spray is recommended in conjunction with an adequate intake of calcium and vitamin D [see Dosage and Administration (2.3)] . 5.3 Nasal Adverse Reactions Adverse reactions related to the nose including rhinitis and epistaxis have been reported. Development of mucosal alterations may occur. Therefore, periodic nasal examinations with visualization of the nasal mucosa, turbinates, septum and mucosal blood vessels are recommended prior to start of treatment with calcitonin salmon nasal spray, periodically during the course of therapy, and at any time nasal symptoms occur. Calcitonin salmon nasal spray should be discontinued if severe ulceration of the nasal mucosa occurs, as indicated by ulcers greater than 1.5 mm in diameter or penetrating below the mucosa, or those associated with heavy bleeding. Although smaller ulcers often heal without withdrawal of calcitonin salmon nasal spray, medication should be discontinued temporarily until healing occurs [see Adverse Reactions (6.1)] . 5.4 Malignancy In a meta-analysis of 21 randomized, controlled clinical trials with calcitonin salmon (nasal spray or investigational oral formulations), the overall incidence of malignancies reported was higher among calcitonin salmon-treated patients (4.1%) compared with placebo-treated patients (2.9%). This suggests an increased risk of malignancies in calcitonin salmon-treated patients compared to placebo-treated patients. The benefits for the individual patient should be carefully considered against possible risks [see Adverse Reactions (6.1)] . 5.5 Antibody Formation Circulating antibodies to calcitonin salmon have been reported with calcitonin salmon nasal spray. The possibility of antibody formation should be considered in any patient with an initial respons…

4 CONTRAINDICATIONS Hypersensitivity to calcitonin salmon or any of the excipients. Reactions have included anaphylactic shock, anaphylaxis, bronchospasm, and swelling of the tongue or throat [see Warnings and Precautions (5.1)] . Hypersensitivity to calcitonin salmon or any of the excipients ( 4 )

7 DRUG INTERACTIONS No formal drug interaction studies have been performed with calcitonin salmon nasal spray. Concomitant use of calcitonin salmon and lithium may lead to a reduction in plasma lithium concentrations due to increased urinary clearance of lithium. The dose of lithium may require adjustment. Concomitant use of calcitonin salmon and lithium may lead to a reduction in plasma lithium concentrations due to increased urinary clearance of lithium. The dose of lithium may require adjustment ( 7 )

8.1 Pregnancy Risk Summary Calcitonin salmon nasal spray is not indicated for use in females of reproductive potential. There are no data with the use of calcitonin salmon nasal spray in pregnant women. In an animal reproduction study, subcutaneous administration of calcitonin-salmon to pregnant rabbits during organogenesis at 418 times the recommended parenteral human dose caused a decrease in fetal birth weights. No adverse developmental outcome was observed in the rat with subcutaneous administration of calcitonin-salmon at 9 times the recommended human parenteral dose based on body surface area (see Data). Data Animal Data Calcitonin salmon has been shown to cause a decrease in fetal birth weights in rabbits when given by subcutaneous injection in doses 4 to 18 times the parenteral dose (of 54 International Units/m 2 ) and 70 to 278 times the intranasal dose recommended for human use based on body surface area. No embryo/fetal toxicities related to calcitonin salmon nasal spray were reported from maternal subcutaneous daily doses in rats up to 80 International Units/kg/day from gestation day 6 to 15.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Hypersensitivity Reactions, including anaphylaxis [see Warnings and Precautions (5.1)] Hypocalcemia [see Warnings and Precautions (5.2)] Nasal Adverse Reactions [see Warnings and Precautions (5.3)] Malignancy [see Warnings and Precautions (5.4)] Most common adverse reactions (3% or greater) are rhinitis, epistaxis and other nasal symptoms, back pain, arthralgia, and headache ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of calcitonin salmon nasal spray in the treatment of postmenopausal osteoporosis was assessed in 5 randomized, double-blind, placebo controlled trials that enrolled postmenopausal women, aged 45 to 75 years. The duration of the trials ranged from 1 to 2 years. The incidence of adverse reactions reported in studies involving postmenopausal osteoporotic patients chronically exposed to calcitonin salmon nasal spray (N=341) and to placebo nasal spray (N=131), and reported in greater than 3% of calcitonin salmon nasal spray treated patients are presented in the following table. Other than flushing, nausea, possible allergic reactions, and possible local irritative effects in the respiratory tract, a relationship to calcitonin salmon nasal spray has not been established. Table 1: Adverse Reactions Occurring in at Least 3% of Postmenopausal Patients Treated with Calcitonin Salmon Nasal Spray †Symptom of nose includes: nasal crusts, dryness, redness or erythema, nasal sores, irritation, itching, thick feeling, soreness, pallor, infection, stenosis, runny/blocked, small wound, bleeding wound, tenderness, uncomfortable feeling and sore across bridge of nose. Calcitonin Salmon Nasal Spray Placebo Nasal Spray Adverse Reaction N=341 % of Patients N=131 % of Patients Rhinitis 12 7 Symptom of Nose† 11 16 Back Pain 5 2 Arthralgia 4 5 Epistaxis 4 5 Headache 3 5 Nasal Adverse Reactions In all postmenopausal patients treated with calcitonin salmon nasal spray, the most commonly reported nasal adverse reactions included rhinitis (12%), epistaxis (4%), and sinusitis (2%). Smoking did not have a contributory effect on the occurrence of nasal adverse reactions. Adverse reactions reported in 1% to 3% of patients treated with calcitonin salmon nasal spray include: influenza-like symptoms, erythematous rash, arthrosis, myalgia, sinusitis, upper respiratory tract infection, bronchospasm, abdominal pain, nausea, dizziness, paresthesia, abnormal lacrimation, conjunctivitis, lymphadenopathy, infection, and depression. Malignancy A meta-analysis of 21 randomized, controlled clinical trials with calcitonin salmon (nasal spray or investigational oral formulations) was conducted to assess the risk of malignancies in calcitonin salmon-treated patients compared to placebo-treated patients. The trials in the meta-analysis ranged in duration from 6 months to 5 years and included a total of 10883 patients (6151 treated with calcitonin salmon and 4732 treated with placebo). The overall incidence of malignancies reported in these 21 trials was higher among calcitonin salmon-treated patients (254/6151 or 4.1%) compared with placebo-treated patients (137/4732 or 2.9%). Findings were similar when analyses were restricted to the 18 nasal spray only trials [calcitonin salmon 122/2712 (4.5%); placebo 30/1309 (2.3%)]. The meta-analysis results suggest an increased risk of overall malignancies in calcitonin salmon-treated patients compared to placebo-treated patients when all 21 trials are included and when the analysis is restricted to the 18 nasal …