FDA label 8690b869-d9ef-4fd3-9588-0afe6dab8be7

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 Solution, 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 CONTRAINDICATION ( 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 Medical Services Department of Par Pharmaceutical at 1-800-828-9393. 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 Solution. 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 Solution. Use of Calcitonin Salmon Nasal Solution 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 mucus, turbinates, septum and mucosal blood vessels are recommended prior to start of treatment with Calcitonin Salmon Nasal Solution, periodically during the course of therapy, at any time nasal symptoms occur. Calcitonin Salmon Nasal Solution 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 Solution, 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 Solution. The possibility of antibody formation should be considered in any patient with an initial response to Calcitonin Salmon Nasal Solution who later stops responding to treatment [see ADVERSE REACTIONS ( 6.3 )]. 5.6 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. Urine sediment abnormalities have not been reported in ambulatory volunteers treated with calcitonin salmon nasal spray.

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 Pharmaceutical 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 spray (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 N = 341 Placebo Nasal Spray N = 131 Adverse Reaction % of Patients % 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 spray or investigational oral formulations) was conducted to assess the risk ofmalignancies in calcitonin-salmon treated patients compared to placebo-treatedpatients. The trialsin the meta-analysis ranged in duration from6 months to 5 years and included a total of10883 patients (6151 treated with calcitonin-salmon and 4732 treated with placebo). The overall incidence of malignancies reportedin 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 anincreased risk of overall malignanciesin calcitonin-salmon-treated patients compared to placebo-treated patientswhen all 21trials 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 seenwith the meta-analysis was heavily influenced by a single large 5-year trial, which had an observed riskdifference of 3.4% [95% CI (0.4%, 6.5%)]. Imbalances in risks were still observed when analysesexcluded 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 Post Marketing Experience Because postmarketing adversereactions are reported voluntarily froma population of uncertain size, it is not always possible to reliably estimate their frequencyor 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 potentiallyimmunogenic properties of medicinal products containing peptides, administration of Calcitonin Salmon Nasal Solution may trigger the development ofanti-calcitonin antibodies.In a two-year Calcitonin Salmon Nasal Solution clinicalstudy that evaluated immunogenicity, a measurable antibodytiter 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 antibodytest result may be influenced by several factors, including assay methodology, sample handling, timing ofsample 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.

<table><caption>Table 1. Adverse Reactions Occurring in at Least 3% Of Postmenopausal Patients Treated with Calcitonin Salmon Nasal Solution</caption><col width="1px"/><col width="1px"/><col width="1px"/><tfoot><tr><td valign="top" colspan="3" styleCode=" Botrule "> &#x2020; 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.</td></tr></tfoot><tbody><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule "/></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule "><paragraph><content styleCode="bold"/></paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph><content styleCode="bold">Calcitonin Salmon Nasal Solution N = 341</content></paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph><content styleCode="bold">Placebo Nasal Spray N = 131</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule "><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph><content styleCode="bold">% of Patients</content></paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph><content styleCode="bold">% of Patients</content></paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule "><paragraph>Rhinitis</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule "><paragraph>Symptom of Nose&#x2020;</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>11</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule "><paragraph>Back Pain</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>5</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule "><paragraph>Arthralgia</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>4</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule "><paragraph>Epistaxis</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>4</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule "><paragraph>Headache</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>3</paragraph></td><td align="center" styleCode=" Botrule Rrule "><paragraph>5</paragraph></td></tr></tbody></table>

<table><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph><content styleCode="bold">Patients</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph><content styleCode="bold">Malignancies</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph><content styleCode="bold">Risk Difference ¹ (%)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph><content styleCode="bold">95% Confidence Interval ² (%)</content></paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule "><paragraph>All (nasal spray + oral)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>All</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>1.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>(0.3, 1.6)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule "><paragraph>All (nasal spray + oral)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>Excluding basal cell carcinoma</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>0.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>(-0.1, 1.2)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule "><paragraph>All (nasal spray only)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>All</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>1.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>(0.3, 2.6)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule "><paragraph>All (nasal spray only)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>Excluding basal cell carcinoma</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>0.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>(-0.2, 1.8)</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule "><paragraph>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.</paragraph><paragraph>²The corresponding 95% confidence interval for the overall adjusted risk difference also based on MH fixed-effect method.</paragraph></td></tr></tbody></table>