ADVERSE REACTIONS SECTION.

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)]. 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 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 randomized, double-blind, placebo controlled trials that enrolled postmenopausal women, aged 45 to 75 years. The duration of the trials ranged from to 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, 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 = 341 Placebo Nasal Spray = 131 Adverse Reaction of Patients of Patients Rhinitis 12 Symptom of Nose+ 11 16 Back Pain 2 Arthralgia 5 Epistaxis 5 Headache 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 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.MalignancyA 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 years and included 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 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. mechanism for these observations has not been identified. Although 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 (%) 95% Confidence Interval (%) 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) 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. risk difference of is suggestive of no difference in malignancy risks between the treatment groups. 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 causal relationship to drug exposure.The following adverse reactions have been reported during post-approval use of Calcitonin Salmon Nasal Solution.oAllergic/Hypersensitivity Reactions:Serious allergic reactions have been reported in patients receiving Calcitonin Salmon Nasal Solution, including anaphylaxis and anaphylactic shock.oHypocalcemia:Hypocalcemia with paresthesia has been reported.oBody as Whole: facial or peripheral edemaoCardiovascular: hypertension, vasodilatation, syncope, chest painoNervous system: dizziness, seizure, visual or hearing impairment, tinnitusoRespiratory/Special Senses: cough, bronchospasm, dyspnea, loss of taste/smelloSkin: rash/dermatitis, pruritus, alopecia, increased sweatingoGastrointestinal: diarrheaoNervous System Disorders: tremor. oAllergic/Hypersensitivity Reactions:Serious allergic reactions have been reported in patients receiving Calcitonin Salmon Nasal Solution, including anaphylaxis and anaphylactic shock.. oHypocalcemia:Hypocalcemia with paresthesia has been reported.. oBody as Whole: facial or peripheral edema. oCardiovascular: hypertension, vasodilatation, syncope, chest pain. oNervous system: dizziness, seizure, visual or hearing impairment, tinnitus. oRespiratory/Special Senses: cough, bronchospasm, dyspnea, loss of taste/smell. oSkin: rash/dermatitis, pruritus, alopecia, increased sweating. oGastrointestinal: diarrhea. oNervous 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 two-year Calcitonin Salmon Nasal Solution clinicalstudy that evaluated immunogenicity, 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 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 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityThe incidence of pituitary adenomas was increased in rats after one and two years of subcutaneous exposure to synthetic calcitonin-salmon. The significance of this finding to humansis unknown because pituitary adenomas are very common in rats as they age, the pituitary adenomas did not transforminto metastatic tumors, there were no other clear treatment-related neoplasms, and synthetic calcitonin salmon related neoplasms were not observed in mice after two years of dosing.Rat findings:The only clear neoplastic finding in rats dosed subcutaneously with synthetic calcitonin-salmon was an increase in the incidence of pituitary adenomas in male Fisher 344rats and female Sprague Dawley rats after one year of dosing and male Sprague Dawley rats dosed for one and two years. In female Sprague Dawley rats, the incidence of pituitary adenomas after two years was high in all treatment groups (between 80% and 92% including the control groups) such that treatment-related effectcould not be distinguished fromnatural backgroundincidence.Thelowestdosein male Sprague Dawley rats thatdeveloped an increased incidence of pituitary adenomas after two yearsof dosing (1.7 International Units/kg/day) is approximately times the maximum recommended intranasal dose in humans (200International Units/day) based on body surface area conversion between rats and humansand 20-fold conversion factor to account for decreased clinical exposure via the intranasal route. The findingssuggest that calcitonin-salmon reducedthe latency period for development of non-functioning pituitary adenomas.Mouse findings:No carcinogenicity potential was evident in male or female mice dosed subcutaneously for two years with synthetic calcitonin-salmon at dosesup to 800 International Units/kg/day. The 800 International Units/kg/day dose is approximately 390 times the maximum recommended intranasal dose in humans (200 International Units) basedon scaling for body surface area anda 20-foldconversion factor to account for low clinical exposure via the intranasal route.MutagenesisSynthetic calcitonin-salmon testednegative for mutagenicity usingSalmonella typhimurium(5strains) and Escherichiacoli (2 strains), with and withoutrat liver metabolic activation, and was not clastogenic in chromosome aberration test in Chinese Hamster V79cells. There was no evidence that calcitonin- salmon was clastogenic in the in vivo mouse micronucleustest.FertilityEffects ofcalcitonin-salmon on fertility have not been assessed in animals.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Calcitonin-salmon is 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 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 beendiscoveredin osteoclasts and osteoblasts.. 12.2 Pharmacodynamics. The information below, describing the clinical pharmacology of calcitonin, has been derived from studies with injectable calcitonin-salmon. The mean bioavailability of calcitonin-salmon nasal spray is approximately 3% of the injectable calcitonin-salmon in healthy subjects and, therefore, theconclusionsconcerningtheclinical pharmacology of this preparation may be different.BoneSingle injections of calcitonin-salmon caused marked transient inhibition of the ongoing bone resorptive process. With prolonged use, there is persistent, smaller decrease in the rate of bone resorption. Histologically, this is associated witha decreasednumber of osteoclasts and an apparent decrease in their resorptive activity.In healthy adults, who have relatively low rate of bone resorption, theadministration of exogenous calcitonin- salmon results in decreases in serumcalciumwithin thelimits of the normal range. In healthy children and in patients whose bone resorption is more rapid, decreasesin serumcalciumare more pronounced in response to calcitonin-salmon.KidneyStudies withinjectable calcitonin-salmon show increasesin the excretionof filtered phosphate, calcium, and sodiumby decreasing their tubular reabsorption. Comparable studieshave not been conducted with Calcitonin Salmon Nasal Solution.Gastrointestinal TractSome evidence fromstudies with injectable preparations suggests that calcitonin-salmon may have effects on the gastrointestinal tract.Short-termadministration of injectable calcitonin-salmon results in marked transient decreases in the volume and acidity ofgastric juice and in the volume andthe trypsin and amylase content of pancreatic juice. Whether these effects continue to beelicited after each injection of calcitonin-salmon during chronic therapy has not been investigated. These studies have not beenconducted with Calcitonin Salmon Nasal Solution.CalciumHomeostasisIn two clinical studies designed toevaluate the pharmacodynamic response to calcitonin-salmon nasal spray, administration of calcitonin-salmon 100 to 1600 International Unitsto healthy volunteers resulted in rapid and sustained decreases within the normal range for both total serumcalciumand serumionized calcium. Single doses of calcitonin-salmon greater than 400 International Units did notproduce any further biological response to the drug.. 12.3 Pharmacokinetics. The bioavailability of Calcitonin Salmon Nasal Solution relative to intramuscular administration in healthy volunteers is between and 5%. Calcitonin Salmon Nasal Solution is absorbed rapidly by the nasal mucosa with mean Tmax of about 13 minutes. The terminal half-life of calcitonin-salmon has been calculated to be around 18 minutes and no evidence of accumulation was observed with multiple dosing.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Two randomized, placebo-controlled, two-year trials were conducted in 266 postmenopausal women who were greater than years postmenopause with spinal, forearmor femoral bone mineral density (BMD) at least one standard deviation belowthe normal value for healthy premenopausal women (T-score -1). In both studies, total of 144 patients receivedCalcitonin Salmon Nasal Solution 200 International Units or placebodaily. The intent-to-treat population comprised 139 patients who had at least one follow-up BMD measurement. In study 1, patients also received 500 mg daily calciumsupplements, while in study 2, patients received no calciumsupplementation. The primary endpoint for both studieswas percent change in lumbar spine BMD at years. Calcitonin Salmon Nasal Solution increased lumbar vertebral BMD relative to placebo in women with low bone mass who were greater than years post menopause (see Table below).Table 3. Calcitonin Salmon Nasal Solution: Lumbar Spine Bone Mineral Density in Women Greater Than years Postmenopause With Low Bone Mass Lumber Spine Bone Mineral Density, Mean Change From Baseline (in %) at Month 24 Study (with calcium supplement) (ITT) 100 Study (no calcium supplement) n(ITT) 39 Calcitonin Salmon Nasal Solution 200 IU NS daily +1.56 +1.02 Placebo +0.20 -1.85 Treatment Difference +1.36 +2.87 p-value+ <0.05 <0.005 ITT: Intent To Treat IU: International Units NS: nasal spray - values by parametric testing (2 tailed 2-sample t-test) No effects of calcitonin salmon nasal spray on cortical bone of the forearm or hip were demonstrated.In clinical studies of postmenopausal osteoporosis, bone biopsy and radial bone mass assessments at baseline and after 26 months of daily injectable calcitonin-salmon indicate that calcitonin therapy results in the formation of normal bone.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 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 intake (2.3). 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 intake (2.3). 2.1 Basic Dosing Information. The recommended dose of Calcitonin Salmon Nasal Solution is 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 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 patients 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 Supplementation. Patients who use Calcitonin Salmon Nasal Solution should receive adequate calcium (at least 1000 mg elemental calcium per day) and vitamin (at least 400 International Units per day).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Calcitonin Salmon Nasal Solution is calcitonin, indicated for the treatment of postmenopausal osteoporosis in women greater than 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 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). Due to the possible association between malignancy and calcitonin-salmon use, the need for continued therapy should be re-evaluated on 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 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 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.. Due to the possible association between malignancy and calcitonin-salmon use, the need for continued therapy should be re-evaluated on 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information and Instructions for Use).Instruct patients on pump assembly, priming of the pump, and nasal introduction of Calcitonin Salmon Nasal Solution. Although instructions for patients are supplied with the individual bottle, procedures for use should be demonstrated to each patient [see DOSAGE AND ADMINISTRATION (2.2)]. Patients should notify their healthcare provider if they develop significant nasal irritation [see WARNINGS AND PRECAUTIONS (5.3)] Inform patients of the potential increase in risk of malignancy [see WARNINGS AND PRECAUTIONS (5.4)]. Advise patients to maintain an adequate calcium (at least 1000 mg elemental calcium per day) and vitamin (at least 400 International Units per day) intake [see DOSAGE AND ADMINISTRATION (2.3)]. Instruct patients to seek emergency medical help or go to the nearest hospital emergency room right away if they develop any signs or symptoms of serious allergic reaction.Advise patients how to correctly store unopened and opened product [see HOW SUPPLIED/STORAGE AND HANDLING (16)]. Advise patients that the bottle should be discarded after 30 doses, because after 30 doses, each spray may not deliver the correct amount of medication even if the bottle is not completely empty.. Instruct patients on pump assembly, priming of the pump, and nasal introduction of Calcitonin Salmon Nasal Solution. Although instructions for patients are supplied with the individual bottle, procedures for use should be demonstrated to each patient [see DOSAGE AND ADMINISTRATION (2.2)]. Patients should notify their healthcare provider if they develop significant nasal irritation [see WARNINGS AND PRECAUTIONS (5.3)] . Inform patients of the potential increase in risk of malignancy [see WARNINGS AND PRECAUTIONS (5.4)]. Advise patients to maintain an adequate calcium (at least 1000 mg elemental calcium per day) and vitamin (at least 400 International Units per day) intake [see DOSAGE AND ADMINISTRATION (2.3)]. Instruct patients to seek emergency medical help or go to the nearest hospital emergency room right away if they develop any signs or symptoms of serious allergic reaction.. Advise patients how to correctly store unopened and opened product [see HOW SUPPLIED/STORAGE AND HANDLING (16)]. Advise patients that the bottle should be discarded after 30 doses, because after 30 doses, each spray may not deliver the correct amount of medication even if the bottle is not completely empty.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityThe incidence of pituitary adenomas was increased in rats after one and two years of subcutaneous exposure to synthetic calcitonin-salmon. The significance of this finding to humansis unknown because pituitary adenomas are very common in rats as they age, the pituitary adenomas did not transforminto metastatic tumors, there were no other clear treatment-related neoplasms, and synthetic calcitonin salmon related neoplasms were not observed in mice after two years of dosing.Rat findings:The only clear neoplastic finding in rats dosed subcutaneously with synthetic calcitonin-salmon was an increase in the incidence of pituitary adenomas in male Fisher 344rats and female Sprague Dawley rats after one year of dosing and male Sprague Dawley rats dosed for one and two years. In female Sprague Dawley rats, the incidence of pituitary adenomas after two years was high in all treatment groups (between 80% and 92% including the control groups) such that treatment-related effectcould not be distinguished fromnatural backgroundincidence.Thelowestdosein male Sprague Dawley rats thatdeveloped an increased incidence of pituitary adenomas after two yearsof dosing (1.7 International Units/kg/day) is approximately times the maximum recommended intranasal dose in humans (200International Units/day) based on body surface area conversion between rats and humansand 20-fold conversion factor to account for decreased clinical exposure via the intranasal route. The findingssuggest that calcitonin-salmon reducedthe latency period for development of non-functioning pituitary adenomas.Mouse findings:No carcinogenicity potential was evident in male or female mice dosed subcutaneously for two years with synthetic calcitonin-salmon at dosesup to 800 International Units/kg/day. The 800 International Units/kg/day dose is approximately 390 times the maximum recommended intranasal dose in humans (200 International Units) basedon scaling for body surface area anda 20-foldconversion factor to account for low clinical exposure via the intranasal route.MutagenesisSynthetic calcitonin-salmon testednegative for mutagenicity usingSalmonella typhimurium(5strains) and Escherichiacoli (2 strains), with and withoutrat liver metabolic activation, and was not clastogenic in chromosome aberration test in Chinese Hamster V79cells. There was no evidence that calcitonin- salmon was clastogenic in the in vivo mouse micronucleustest.FertilityEffects ofcalcitonin-salmon on fertility have not been assessed in animals.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The information below, describing the clinical pharmacology of calcitonin, has been derived from studies with injectable calcitonin-salmon. The mean bioavailability of calcitonin-salmon nasal spray is approximately 3% of the injectable calcitonin-salmon in healthy subjects and, therefore, theconclusionsconcerningtheclinical pharmacology of this preparation may be different.BoneSingle injections of calcitonin-salmon caused marked transient inhibition of the ongoing bone resorptive process. With prolonged use, there is persistent, smaller decrease in the rate of bone resorption. Histologically, this is associated witha decreasednumber of osteoclasts and an apparent decrease in their resorptive activity.In healthy adults, who have relatively low rate of bone resorption, theadministration of exogenous calcitonin- salmon results in decreases in serumcalciumwithin thelimits of the normal range. In healthy children and in patients whose bone resorption is more rapid, decreasesin serumcalciumare more pronounced in response to calcitonin-salmon.KidneyStudies withinjectable calcitonin-salmon show increasesin the excretionof filtered phosphate, calcium, and sodiumby decreasing their tubular reabsorption. Comparable studieshave not been conducted with Calcitonin Salmon Nasal Solution.Gastrointestinal TractSome evidence fromstudies with injectable preparations suggests that calcitonin-salmon may have effects on the gastrointestinal tract.Short-termadministration of injectable calcitonin-salmon results in marked transient decreases in the volume and acidity ofgastric juice and in the volume andthe trypsin and amylase content of pancreatic juice. Whether these effects continue to beelicited after each injection of calcitonin-salmon during chronic therapy has not been investigated. These studies have not beenconducted with Calcitonin Salmon Nasal Solution.CalciumHomeostasisIn two clinical studies designed toevaluate the pharmacodynamic response to calcitonin-salmon nasal spray, administration of calcitonin-salmon 100 to 1600 International Unitsto healthy volunteers resulted in rapid and sustained decreases within the normal range for both total serumcalciumand serumionized calcium. Single doses of calcitonin-salmon greater than 400 International Units did notproduce any further biological response to the drug.

USE IN SPECIFIC POPULATIONS SECTION.

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)See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.. 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 SummaryCalcitonin 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 to 18 times the recommended parenteral human dose caused decrease in fetal birth weights. No adverse developmental outcome was observed in the rat with subcutaneous administration of calcitonin-salmon at times the recommended human parenteral dose based on body surface area (see Data). DataAnimal DataCalcitonin-salmon has been shown to cause decrease in fetal birth weights in rabbits when given by subcutaneous injection in doses to 18 times the parenteral dose (of 54 International Units/m2) 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 to 15.. 8.2 Lactation. Risk SummaryCalcitonin 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 multi-centered, double-blind, randomized clinical study of calcitonin salmon nasal spray, 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.

WARNINGS AND PRECAUTIONS SECTION.

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: 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). 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: 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 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 dilute, sterile solution of calcitonin-salmon injectable product. Healthcare providers may wish to refer patients who require skin testing to an allergist. 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 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 [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 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.