FDA label 773720d6-e217-4c25-b512-fd9daaeb6bd0

5 WARNINGS AND PRECAUTIONS Serious hypersensitivity reactions, including reports of fatal anaphylaxis 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 ) Malignancy: A meta-analysis of 21 clinical trials suggests an increased risk of overall malignancies in calcitonin-salmon-treated patients ( 5.3 , 6.1 ) Circulating antibodies to calcitonin-salmon may develop, and may cause loss of response to treatment ( 5.4 ) 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions have been reported in patients receiving Miacalcin injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis. Appropriate medical support and monitoring measures should be readily available when Miacalcin injection is administered. If anaphylaxis or other severe hypersensitivity/allergic reactions occur, initiate appropriate treatment [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 Miacalcin injection. Healthcare providers may wish to refer patients who require skin testing to an allergist. A detailed skin testing protocol is available from the Medical Services Department of Novartis Pharmaceuticals Corporation. 5.2 Hypocalcemia Hypocalcemia associated with tetany (i.e., muscle cramps, twitching) and seizure activity has been reported with Miacalcin injection therapy. Hypocalcemia must be corrected before initiating therapy. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients at risk for hypocalcemia, provisions for parenteral calcium administration should be available during the first several administrations of calcitonin-salmon and serum calcium and symptoms of hypocalcemia should be monitored. Use of Miacalcin injection for the treatment of Paget’s disease or postmenopausal osteoporosis is recommended in conjunction with an adequate intake of calcium and vitamin D [see Dosage and Administration (2.5)] . 5.3 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. It is not possible to exclude an increased risk when calcitonin-salmon is administered long-term subcutaneously, intramuscularly, or intravenously. The benefits for the individual patient should be carefully considered against possible risks [see Adverse Reactions (6.1)] . 5.4 Antibody Formation Circulating antibodies to calcitonin-salmon have been reported with Miacalcin injection. The possibility of antibody formation should be considered in any patient with an initial response to Miacalcin injection who later stops responding to treatment [see Adverse Reactions (6.3)] . 5.5 Urine Sediment Abnormalities Coarse granular casts and casts containing renal tubular epithelial cells were reported in young adult volunteers at bed rest who were given injectable calcitonin-salmon to study the effect of immobilization on osteoporosis. There was no other evidence of renal abnormality and the urine sediment normalized after calcitonin-salmon was stopped. Periodic examinations of urine sediment should be considered.

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)] Malignancy [see Warnings and Precautions (5.3)] Most common adverse reactions are nausea with or without vomiting (10%), injection site inflammation (10%), and flushing of the face or hands (2-5%) ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 injection was assessed in open-label trials several months to two years in duration. The most common adverse reactions are discussed below. Nausea : Nausea with or without vomiting has been noted in about 10% of patients treated with calcitonin-salmon. It is most evident when treatment is first initiated and tends to decrease or disappear with continued administration. Dermatologic Reactions : Local inflammatory reactions at the site of subcutaneous or intramuscular injection have been reported in about 10% of patients. Flushing of face or hands occurred in about 2%-5% of patients. Skin rashes and pruritus of the ear lobes have also been reported. Other Adverse Reactions : Nocturia, feverish sensation, pain in the eyes, poor appetite, abdominal pain, pedal edema, and salty taste have been reported in patients treated with calcitonin-salmon injection. 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 spray only trials (see Table 1). 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 1); 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 (5.3)] . Table 1: Risk Difference for Malignancies in Calcitonin-Salmon-Treated Patients Compared with Placebo-Treated Patients 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. 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) 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 Miacalcin injection. Allergic / Hypersensitivity Reactions : Serious hypersensitivity reactions have been reported in patients receiving calcitonin-salmon injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis. Skin and subcutaneous tissue disorders : Urticaria Hypocalcemia : Hypocalcemia with tetany (i.e. muscle cramps, twitching) and seizure activity have been reported. Body as a Whole : influenza-like symptoms, fatigue, edema (facial, peripheral, and generalized) Musculoskeletal : arthralgia, musculoskeletal pain Cardiovascular : hypertension Gastrointestinal : abdominal pain, diarrhea Urinary System : polyuria Nervous System : dizziness, headache, paresthesia, tremor Vision : visual disturbance 6.3 Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of Miacalcin may trigger the development of anti-calcitonin antibodies. Circulating antibodies to calcitonin-salmon after 2-18 months of treatment have been reported in about one-half of the patients with Paget’s disease in whom antibody studies were done. In some cases, high antibody titers are found; these patients usually will have a loss of response to treatment [see Warnings and Precautions (5.4)] . 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 among different calcitonin-salmon products may be misleading.

<table> <caption>Table 1: Risk Difference for Malignancies in Calcitonin-Salmon-Treated Patients Compared with Placebo-Treated Patients</caption> <col width="200"/> <col width="200"/> <col width="200"/> <col width="250"/> <tfoot> <tr> <td styleCode="Toprule " colspan="4"> 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.</td> </tr> </tfoot> <tbody> <tr> <td styleCode="Toprule Lrule Rrule "> <content styleCode="bold">Patients</content> </td> <td styleCode="Toprule Lrule Rrule "> <content styleCode="bold">Malignancies</content> </td> <td styleCode="Toprule Lrule Rrule " align="center"> <content styleCode="bold">Risk Difference¹ (%)</content> </td> <td styleCode="Toprule Lrule Rrule " align="center"> <content styleCode="bold">95% Confidence Interval² (%)</content> </td> </tr> <tr> <td styleCode="Toprule Lrule Rrule ">All (nasal spray + oral)</td> <td styleCode="Toprule Lrule Rrule ">All</td> <td styleCode="Toprule Lrule Rrule " align="center">1.0</td> <td styleCode="Toprule Lrule Rrule " align="center">(0.3, 1.6)</td> </tr> <tr> <td styleCode="Toprule Lrule Rrule ">All (nasal spray + oral)</td> <td styleCode="Toprule Lrule Rrule ">Excluding basal cell carcinoma</td> <td styleCode="Toprule Lrule Rrule " align="center">0.5</td> <td styleCode="Toprule Lrule Rrule " align="center">(-0.1, 1.2)</td> </tr> <tr> <td styleCode="Toprule Lrule Rrule ">All (nasal spray only)</td> <td styleCode="Toprule Lrule Rrule ">All</td> <td styleCode="Toprule Lrule Rrule " align="center">1.4</td> <td styleCode="Toprule Lrule Rrule " align="center">(0.3, 2.6)</td> </tr> <tr> <td styleCode="Toprule Lrule Rrule ">All (nasal spray only)</td> <td styleCode="Toprule Lrule Rrule ">Excluding basal cell carcinoma</td> <td styleCode="Toprule Lrule Rrule " align="center">0.8</td> <td styleCode="Toprule Lrule Rrule " align="center">(-0.2, 1.8)</td> </tr> </tbody> </table>