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).

3 DOSAGE FORMS AND STRENGTHS Calcitonin Salmon (synthetic origin) Nasal Spray consists of one glass bottle with attached pump. The bottle contains 2 mL or 3.7 mL of calcitonin salmon clear solution at a concentration of 2200 USP Calcitonin Salmon Units per mL. A primed pump delivers 0.09 mL (200 USP Calcitonin Salmon Units) calcitonin salmon per actuation. Nasal Spray: 2200 USP Calcitonin Salmon Units per mL of calcitonin salmon in a 2 mL or 3.7 mL fill glass bottle with attached pump. Each actuation delivers 200 USP Calcitonin Salmon Units of calcitonin salmon ( 3 )

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 )

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 Par Health at 1-800-828-9393 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 Solution 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 Solution (N=341) and to placebo nasal solution (N=131), and reported in greater than 3% of Calcitonin Salmon Nasal Solution 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 Solution has not been established. Table 1: Adverse Reactions Occurring in at Least 3% of Postmenopausal Patients Treated with Calcitonin Salmon Nasal Solution † 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 Solution Placebo Nasal Solution 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 Solution, 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 Solution 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 solution 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 …

7 DRUG INTERACTIONS No formal drug interaction studies have been performed with Calcitonin Salmon Nasal Solution. 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 USE IN SPECIFIC POPULATIONS There are no data to support use in children (8.4) Nasal reactions are more common in elderly patients ( 8.5 ) 8.1 Pregnancy Risk Summary Calcitonin Salmon Nasal Solution is not indicated for use in females of reproductive potential. There are no data with the use of Calcitonin Salmon Nasal Solution in pregnant women. In an animal reproduction study, subcutaneous administration of calcitonin-salmon to pregnant rabbits during organogenesis at 4 to 18 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 Solution were reported from maternal subcutaneous daily doses in rats up to 80 International Units/kg/day from gestation day 6 to 15. 8.2 Lactation Risk Summary Calcitonin Salmon Nasal Solution is not indicated for use in females of reproductive potential. There is no information on the presence of calcitonin-salmon in human milk, the effects on the breastfed child, or the effects on milk production. Calcitonin has been shown to inhibit lactation in rats. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In a multi-centered, double-blind, randomized clinical study of calcitonin-salmon nasal solution, 279 patients were less than 65 years old, while 467 patients were 65 to 74 years old and 196 patients were 75 years old and older. Compared to subjects less than 65 years old, the incidence of nasal adverse reactions (rhinitis, irritation, erythema, and excoriation) was higher in patients over the age of 65, particularly among those over the age of 75. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

12.1 Mechanism of Action Calcitonin salmon is a calcitonin receptor agonist. Calcitonin salmon acts primarily on bone, but direct renal effects and actions on the gastrointestinal tract are also recognized. Calcitonin salmon appears to have actions essentially identical to calcitonins of mammalian origin, but its potency per mg is greater and it has a longer duration of action. The actions of calcitonin on bone and its role in normal human bone physiology are still not completely elucidated, although calcitonin receptors have been discovered in osteoclasts and osteoblasts.

11 DESCRIPTION Calcitonin is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. Calcitonin Salmon (synthetic origin) Nasal Spray is a synthetic polypeptide of 32 amino acids in the same linear sequence that is found in calcitonin of salmon origin. This is shown by the following graphic formula: It is provided in a 2 mL or 3.7 mL fill glass bottle as a solution for nasal administration. This is sufficient medication for at least 14 doses (2 mL fill) or 30 doses (3.7 mL fill). Active Ingredient : calcitonin salmon 2200 USP Calcitonin Salmon Units per mL (corresponding to 200 USP Calcitonin Salmon Units per 0.09 mL actuation). Inactive Ingredients : benzalkonium chloride, hydrochloric acid (added as necessary to adjust pH), purified water and sodium chloride. The activity of calcitonin salmon nasal spray is stated in International Units based on bioassay in comparison with the International Reference Preparation of calcitonin salmon for Bioassay, distributed by the National Institute of Biological Standards and Control, Holly Hill, London. graphic-formula

10 OVERDOSAGE The pharmacologic actions of Calcitonin Salmon Nasal Solution suggest that hypocalcemic tetany could occur in overdose. Therefore, provisions for parenteral administration of calcium should be available for the treatment of overdose. Single doses of Calcitonin Salmon Nasal Solution up to 1600 International Units, doses up to 800 International Units per day for 3 days and chronic administration of doses up to 600 International Units per day have been studied without serious adverse effects.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Calcitonin Salmon (synthetic origin) Nasal Spray is available as a metered dose clear solution in a 2 mL or 3.7 mL fill clear glass bottle that contains 2,200 USP Calcitonin Salmon Units calcitonin salmon per mL. A pump is attached to the bottle. After priming, the pump will deliver 200 USP Calcitonin Salmon Units per activation (0.09 mL per spray) (2 mL fill: NDC 60505-0823-0; 3.7 mL fill: NDC 60505-0823-6). Storage and Handling Store unopened bottle in refrigerator between 2°C to 8°C (36°F to 46°F). Protect from freezing. Store bottle in use at room temperature between 20°C to 25°C (68°F to 77°F) in an upright position, for up to 30 days (2 mL fill) or 35 days (3.7 mL fill). Each bottle contains at least 14 doses (2 mL fill) or 30 doses (3.7 mL fill). Discard bottle after 14 doses (2 mL fill) or 30 doses (3.7 mL fill).