CALCITONIN SALMON

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 Nasal Solution 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 3.7 mL fill glass bottle as a solution for nasal administration. This is sufficient medication for 30 doses. Active Ingredient: calcitonin-salmon, 2200 International Units per mL (corresponding to 200 International Units per 0.09 mL actuation). Inactive Ingredients: sodium chloride, chlorobutanol (possesses a characteristic odor), hydrochloric acid (added as necessary to adjust pH), purified water and nitrogen. The activity of Calcitonin Salmon Nasal Solution 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. formula

Calcitonin Salmon Nasal Solution 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 Solution has not been shown to increase bone mineral density in early postmenopausal women ( 1.2 ) 1.1 Treatment of Postmenopausal Osteoporosis Calcitonin Salmon Nasal Solution is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. Fracture reduction efficacy has not been demonstrated. Calcitonin Salmon Nasal Solution 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 Nasal Solution has not been shown to increase spinal bone mineral density in early postmenopausal women.

For intranasal use only: one spray (200 International 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 Solution is 1 spray (200 International Units) per day administered intranasally, alternating nostrils daily. 2.2 Priming (Activation) of Pump Unopened Calcitonin Salmon Nasal Solution should be stored in the refrigerator. Before using the first dose of Calcitonin Salmon Nasal Solution, 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 Solution should receive adequate calcium (at least 1000 mg elemental calcium per day) and vitamin D (at least 400 International Units per day).

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 )

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 Endo 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 and when the analysis is restricted to the 18 nasal spray only trials (see Table 2 ). It is not possible to exclude an increased risk when calcitonin-salmon is administered by the subcutaneous, intramuscular, or intravenous route because these routes of administration were not investigated in the meta-analysis. The increased malignancy risk seen with the meta-analysis was heavily influenced by a single large 5-year trial, which had an observed risk difference of 3.4% [95% CI (0.4%, 6.5%)]. Imbalances in risks were still observed when analyses excluded basal cell carcinoma (see Table 2 ); the data were not sufficient for further analyses by type of malignancy. A mechanism for these observations has not been identified. Although a definitive causal relationship between calcitonin-salmon use and malignancies cannot be established from this meta-analysis, the benefits for the individual patient should be carefully evaluated against all possible risks [see Warnings and Precautions ( 5.4 ) ]. Table 2: Risk Difference for Malignancies in Calcitonin-Salmon-Treated Patients Compared with Placebo-Treated Patients Patients Malignancies Risk Difference 1 (%) 95% Confidence Interval 2 (%) All (nasal spray + oral) All 1.0 (0.3, 1.6) All (nasal spray + oral) Excluding basal cell carcinoma 0.5 (-0.1, 1.2) All (nasal spray only) All 1.4 (0.3, 2.6) All (nasal spray only) Excluding basal cell carcinoma 0.8 (-0.2, 1.8) 1 The overall adjusted risk difference is the difference between the percentage of patients who had any malignancy (or malignancy excluding basal cell carcinoma) in calcitonin-salmon and placebo treatment groups, using the Mantel-Haenszel (MH) fixed-effect method. A risk difference of 0 is suggestive of no difference in malignancy risks between the treatment groups. 2 The corresponding 95% confidence interval for the overall adjusted risk difference also based on MH fixed-effect method. 6.2 Postmarketing Experience Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been reported during post-approval use of Calcitonin Salmon Nasal Solution. Allergic/Hypersensitivity Reactions: Serious allergic reactions have been reported in patients receiving Calcitonin Salmon Nasal Solution, including anaphylaxis and anaphylactic shock. Hypocalcemia : Hypocalcemia with paresthesia has been reported. Body as a whole : facial or peripheral edema Cardiovascular: hypertension, vasodilatation, syncope, chest pain Nervous system: dizziness, seizure, visual or hearing impairment, tinnitus Respiratory/Special Senses : cough, bronchospasm, dyspnea, loss of taste/smell Skin : rash/dermatitis, pruritus, alopecia, increased sweating Gastrointestinal: diarrhea Nervous system disorders: tremor 6.3 Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of Calcitonin Salmon Nasal Solution may trigger the development of anti-calcitonin antibodies. In a two-year Calcitonin Salmon Nasal Solution clinical study that evaluated immunogenicity, a measurable antibody titer was found in 69% of patients treated with Calcitonin Salmon Nasal Solution and 3% of placebo-treated patients. Antibody formation may be associated with a loss of response to treatment [see Warnings and Precautions (5.5 ) ]. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to Calcitonin Salmon Nasal Solution with the incidence of antibodies to other calcitonin-containing products may be misleading.

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 )