CALCITONIN SALMON

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.

4 CONTRAINDICATIONS 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 )

11 DESCRIPTION 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 at least 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 Biologic Standards and Control, Holly Hill, London. formula

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 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).

1 INDICATIONS AND USAGE 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.

10 OVERDOSAGE The pharmacologic actions of Calcitonin Salmon Nasal Solutionsuggest that hypocalcemictetany could occur in overdose. Therefore, provisions for parenteral administration of calcium should be available for the treatment of overdose. Single doses of Calcitonin Salmon Nasal Solution up to 1600 International Units, doses up to 800 International Units per day for 3 days and chronic administration of doses up to 600 International Units per day have been studied without serious adverse effects.

7 DRUG INTERACTIONS 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 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Calcitonin-salmon is a 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 a 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. Bone Single injections of calcitonin-salmon caused a marked transient inhibition of the ongoing bone resorptive process. With prolonged use, there is a 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 a 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. Kidney Studies 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 Tract Some 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. CalciumHomeostasis In 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 3 and 5%. Calcitonin Salmon Nasal Solution is absorbed rapidly by the nasal mucosa with a mean T max 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. .

12.1 Mechanism of Action Calcitonin-salmon is a 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 a 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. Bone Single injections of calcitonin-salmon caused a marked transient inhibition of the ongoing bone resorptive process. With prolonged use, there is a 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 a 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. Kidney Studies 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 Tract Some 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. CalciumHomeostasis In 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 3 and 5%. Calcitonin Salmon Nasal Solution is absorbed rapidly by the nasal mucosa with a mean T max 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. .

20190330

17

3 DOSAGE FORMS AND STRENGTHS Calcitonin Salmon Nasal Solution consists of one glass bottle and one screw on pump. The bottle contains 3.7 mL of calcitonin-salmon clear solution at a concentration of 2200 International Units per mL. A primed pump delivers 0.09 mL (200 International Units) calcitonin-salmon per actuation. Nasal Spray: 2200 International Units per mL of calcitonin-salmon in a 3.7 mL fill glass bottle with screw on pump. Each actuation delivers 200 International Units of calcitonin-salmon (3 )

CALCITONIN SALMON CALCITONIN SALMON CALCITONIN SALMON CALCITONIN SALMON HYDROCHLORIC ACID NITROGEN SODIUM CHLORIDE WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity The 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 a 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 2 times the maximum recommended intranasal dose in humans (200International Units/day) based on body surface area conversion between rats and humansand a 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. Mutagenesis Synthetic calcitonin-salmon testednegative for mutagenicity using Salmonella typhimurium (5strains) and Escherichiacoli (2 strains), with and withoutrat liver metabolic activation, and was not clastogenic in a chromosome aberration test in Chinese Hamster V79cells. There was no evidence that calcitonin- salmon was clastogenic in the in vivo mouse micronucleustest. Fertility Effects ofcalcitonin-salmon on fertility have not been assessed in animals.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity The 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 a 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 2 times the maximum recommended intranasal dose in humans (200International Units/day) based on body surface area conversion between rats and humansand a 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. Mutagenesis Synthetic calcitonin-salmon testednegative for mutagenicity using Salmonella typhimurium (5strains) and Escherichiacoli (2 strains), with and withoutrat liver metabolic activation, and was not clastogenic in a chromosome aberration test in Chinese Hamster V79cells. There was no evidence that calcitonin- salmon was clastogenic in the in vivo mouse micronucleustest. Fertility Effects ofcalcitonin-salmon on fertility have not been assessed in animals.

ANDA076979

CALCITONIN SALMON

CALCITONIN SALMON

49884-161

HUMAN PRESCRIPTION DRUG

NASAL

PRINCIPAL DISPLAY PANEL - CARTON Calcitonin Salmon Carton Calcitonin Salmon Carton

RECENT MAJOR CHANGES Indications and Usage ( 1.2 ) 03/2014 Warnings and Precautions (5.4 ) 03/2014

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 D (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 a 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.

14 CLINICAL STUDIES Two randomized, placebo-controlled, two-year trials were conducted in 266 postmenopausal women who were greater than 5 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, a 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 2 years. Calcitonin Salmon Nasal Solution increased lumbar vertebral BMD relative to placebo in women with low bone mass who were greater than 5 years post menopause (see Table 3 below). Table 3. Calcitonin Salmon Nasal Solution: Lumbar Spine Bone Mineral Density in Women Greater Than 5 years Postmenopause With Low Bone Mass Lumber Spine Bone Mineral Density, Mean Change From Baseline (in %) at Month 24 Study 1 (with calcium supplement) n (ITT) = 100 Study 2 (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 p – 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.

8.5 Geriatric Use In a 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.

8.2 Lactation Risk Summary Calcitonin 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.

8.1 Pregnancy Risk Summary Calcitonin 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 4 to 18 times the recommended parenteral human dose caused a decrease in fetal birth weights. No adverse developmental outcome was observed in the rat with subcutaneous administration of calcitonin-salmon at 9 times the recommended human parenteral dose based on body surface area (see Data ). Data Animal Data Calcitonin-salmon has been shown to cause a decrease in fetal birth weights in rabbits when given by subcutaneous injection in doses 4 to 18 times the parenteral dose (of 54 International Units/m 2 ) 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 6 to 15.

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. 8.1 Pregnancy Risk Summary Calcitonin 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 4 to 18 times the recommended parenteral human dose caused a decrease in fetal birth weights. No adverse developmental outcome was observed in the rat with subcutaneous administration of calcitonin-salmon at 9 times the recommended human parenteral dose based on body surface area (see Data ). Data Animal Data Calcitonin-salmon has been shown to cause a decrease in fetal birth weights in rabbits when given by subcutaneous injection in doses 4 to 18 times the parenteral dose (of 54 International Units/m 2 ) 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 6 to 15. 8.2 Lactation Risk Summary Calcitonin 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 a 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.

16 HOW SUPPLIED/STORAGE AND HANDLING HOW SUPPLIED Available as a metered dose clear solution in a 3.7 mL fill clear glass bottle. It is available in a dosage strength of 200 International Units per activation (0.09 mL/spray). A screw-on pump is provided. The pump, following priming, will deliver 0.09 mL of solution. Calcitonin Salmon Nasal Solution contains 2200 International Units/mL calcitonin-salmon and is provided in an individual box containing one glass bottle and one screw-on pump (NDC 49884-161-11). Storage and Handling Store unopened bottle in refrigerator between 2°C to 8°C (36°F to 46°F). Freezing is to be avoided. Store bottle in use at room temperature between 20°C to 25°C (68°F to 77°F) in an upright position, for up to 35 days. Each bottle contains at least 30 doses. Discard bottle after 30 doses.