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WARNINGS Allergic Reactions Because calcitonin is a polypeptide, the possibility of a systemic allergic reaction exists. A few cases of serious allergic-type reactions have been reported in patients receiving calcitonin-salmon nasal spray, including cases of anaphylaxis and anaphylactic shock. With injectable calcitonin-salmon there have been a few reports of serious allergic-type reactions (e.g. bronchospasm, swelling of the tongue or throat, anaphylactic shock), including very rare reports of death attributed to anaphylaxis. The usual provisions should be made for emergency treatment if such a reaction should occur. Allergic reactions should be differentiated from generalized flushing and hypotension. For patients with suspected sensitivity to calcitonin, skin testing should be considered prior to treatment utilizing a dilute, sterile solution of a calcitonin-salmon injectable product. Physicians may wish to refer patients who require skin testing to an allergist. A detailed skin testing protocol is available from Upsher-Smith Laboratories, Inc. by calling toll-free at 1-800-654-2299.

ADVERSE REACTIONS 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. Most adverse reactions were mild to moderate in severity. Nasal adverse events were most common with 70% mild, 25% moderate, and 5% severe in nature (placebo rates were 71% mild, 27% moderate, and 2% severe). Adverse Reactions Occurring in at Least 3% of Postmenopausal Patients Treated Chronically Adverse Reaction Calcitonin-Salmon Nasal Spray N=341 % of Patients Placebo N=131 % of Patients Rhinitis 12.0 6.9 Symptom of Nose 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. 10.6 16.0 Back Pain 5.0 2.3 Arthralgia 3.8 5.3 Epistaxis 3.5 4.6 Headache 3.2 4.6 In addition, the following adverse events were reported in fewer than 3% of patients during chronic therapy with calcitonin-salmon nasal spray. Adverse events reported in 1%-3% of patients are identified with an asterisk(*). The remainder occurred in less than 1% of patients. 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. Body as a whole – General Disorders: influenza-like symptoms*, fatigue*, edema (facial, peripheral, and generalized), fever Integumentary: erythematous rash*, skin ulceration, eczema, alopecia, pruritus, increased sweating Musculoskeletal/Collagen: arthrosis*, myalgia*, arthritis, polymyalgia rheumatica, stiffness Respiratory/Special Senses: sinusitis*, upper respiratory tract infection*, bronchospasm*, pharyngitis, bronchitis, pneumonia, coughing, dyspnea, taste perversion, parosmia, nasal congestion, sneezing, allergic rhinitis, nasal odor, mucosal excoriation, rhinitis ulcerative Cardiovascular: hypertension*, angina pectoris*, tachycardia, palpitation, bundle branch block, myocardial infarction Gastrointestinal: dyspepsia*, constipation*, abdominal pain*, nausea*, diarrhea*, vomiting, flatulence, increased appetite, gastritis, dry mouth Liver/Metabolic: cholelithiasis, hepatitis, thirst, weight increase Endocrine: goiter, hyperthyroidism Urinary System: cystitis*, pyelonephritis, hematuria, renal calculus Central and Peripheral Nervous System: dizziness*, paresthesia*, vertigo, migraine, neuralgia, agitation Hearing/Vestibular: tinnitus, hearing loss, earache Vision: abnormal lacrimation*, conjunctivitis*, blurred vision, vitreous floater, visual disturbance Vascular: flushing, cerebrovascular accident, thrombophlebitis Hematologic/Resistance Mechanisms: lymphadenopathy*, infection*, anemia Psychiatric: depression*, insomnia, anxiety, anorexia Immune System Disorders : hypersensitivity, anaphylaxis and anaphylactic shock Common adverse reactions associated with the use of injectable calcitonin-salmon occurred less frequently in patients treated with calcitonin-salmon nasal spray than in those patients treated with injectable calcitonin. Nausea, with or without vomiting, which occurred in 1.8% of patients treated with the nasal spray (and 1.5% of those receiving placebo nasal spray) occurs in about 10% of patients who take injectable calcitonin-salmon. Flushing, which occurred in less than 1% of patients treated with the nasal spray, occurs in 2-5% of patients treated with injectable calcitonin-salmon. Although the administered dosages of injectable and nasal spray calcitonin-salmon are comparable (50-100 units daily of injectable versus 200 units daily of nasal spray), the nasal dosage form has a mean bioavailability of about 3% (range 0.3%-30.6%) and therefore provides less drug to the systemic circulation, possibly accounting for the decrease in frequency of adverse reactions. The collective foreign marketing experience with calcitonin-salmon nasal spray does not show evidence of any notable difference in the incidence profile of reported adverse reactions when compared with that seen in the clinical trials.

<table width="70%" ID="i8079b3db-8a9f-457c-837b-f4206121f7c8"> <caption>Adverse Reactions Occurring in at Least 3% of Postmenopausal Patients Treated Chronically</caption> <col width="40%" align="left" valign="bottom"/> <col width="30%" align="center" valign="bottom"/> <col width="30%" align="center" valign="bottom"/> <thead> <tr> <th>Adverse Reaction</th> <th>Calcitonin-Salmon Nasal Spray N=341 % of Patients</th> <th>Placebo N=131 % of Patients</th> </tr> </thead> <tbody> <tr> <td>Rhinitis</td> <td>12.0</td> <td>6.9</td> </tr> <tr> <td>Symptom of Nose<footnote>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.</footnote> </td> <td>10.6</td> <td>16.0</td> </tr> <tr> <td>Back Pain</td> <td>5.0</td> <td>2.3</td> </tr> <tr> <td>Arthralgia</td> <td>3.8</td> <td>5.3</td> </tr> <tr> <td>Epistaxis</td> <td>3.5</td> <td>4.6</td> </tr> <tr> <td>Headache</td> <td>3.2</td> <td>4.6</td> </tr> </tbody> </table>