Calcitonin Salmon

1 INDICATIONS AND USAGE Calcitonin-salmon synthetic injection is a calcitonin, indicated for the following conditions: • Treatment of symptomatic Paget’s disease of bone when alternative treatments are not suitable ( 1.1 ) • Treatment of hypercalcemia ( 1.2 ) • Treatment of postmenopausal osteoporosis when alternative treatments are not suitable. Fracture reduction efficacy has not been demonstrated ( 1.3 ) 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 ( 1.4 , 5.3 ) 1.1 Treatment of Paget's Disease of Bone Calcitonin-salmon injec t ion is indicated for the treatment of symptomatic Paget’s disease of bone in patients with moderate to severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary hydroxyproline excretion. There is no evidence that the prophylactic use of calcitonin-salmon is beneficial in asymptomatic patients. Calcitonin-salmon injection should be used only in patients who do not respond to alternative treatments or for whom such 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 Treatment of Hypercalcemia Calcitonin-salmon injection is indicated for the early treatment of hypercalcemic emergencies, along with other appropriate agents, when a rapid decrease in serum calcium is required, until more specific treatment of the underlying disease can be accomplished. It may also be added to existing therapeutic regimens for hypercalcemia such as intravenous fluids and furosemide, oral phosphate or corticosteroids, or other agents. 1.3 Treatment of Postmenopausal Osteoporosis Calcitonin-salmon injection is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. The evidence of efficacy for calcitonin-salmon injection is based on increases in total body calcium observed in clinical trials. Fracture reduction efficacy has not been demonstrated. Calcitonin-salmon injection 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). 1.4 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 ( 5.3 )].

1.1 Treatment of Paget's Disease of Bone Calcitonin-salmon injec t ion is indicated for the treatment of symptomatic Paget’s disease of bone in patients with moderate to severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary hydroxyproline excretion. There is no evidence that the prophylactic use of calcitonin-salmon is beneficial in asymptomatic patients. Calcitonin-salmon injection should be used only in patients who do not respond to alternative treatments or for whom such 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 Treatment of Hypercalcemia Calcitonin-salmon injection is indicated for the early treatment of hypercalcemic emergencies, along with other appropriate agents, when a rapid decrease in serum calcium is required, until more specific treatment of the underlying disease can be accomplished. It may also be added to existing therapeutic regimens for hypercalcemia such as intravenous fluids and furosemide, oral phosphate or corticosteroids, or other agents.

1.3 Treatment of Postmenopausal Osteoporosis Calcitonin-salmon injection is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. The evidence of efficacy for calcitonin-salmon injection is based on incr …

2 DOSAGE AND ADMINISTRATION • Symptomatic Paget’s disease of bone: 100 International Units daily. Ensure adequate calcium and vitamin D intake ( 2.1 , 2.5 ) • Hypercalcemia: start with 4 International Units/kg body weight every 12 hours. Increase to 8 International Units/kg every 12 hours if no improvement in 1-2 days. Increase further to 8 International Units/kg every 6 hours if no improvement after 2 more days ( 2.2 ) • Postmenopausal osteoporosis: 100 International Units daily. Ensure adequate calcium and vitamin D intake ( 2.3 , 2.5 ) 2.1 Paget's Disease of Bone The recommended dose of calcitonin-salmon injection for treatment of symptomatic Paget’s disease of bone is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly. 2.2 Hypercalcemia The recommended starting dose of calcitonin-salmon injection for early treatment of hypercalcemia is 4 International Units/kg body weight every 12 hours by subcutaneous or intramuscular injection. If the response to this dose is not satisfactory after one or two days, the dose may be increased to 8 International Units/kg every 12 hours. If the response remains unsatisfactory after two more days, the dose may be further increased to a maximum of 8 International Units/kg every 6 hours. 2.3 Postmenopausal Osteoporosis The recommended dose of calcitonin-salmon injection for treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly. The minimum effective dose of calcitonin-salmon injection for the prevention of vertebral bone mineral density loss has not been established. 2.4 Preparation and Administration Visually inspect calcitonin-salmon vials. Calcitonin-salmon injection is a clear, colorless, solution. If the solution is not clear and colorless, or contains any particles, or if the vial is damaged, do not administer the solution. If the volume of calcitonin-salmon injection to be injected exceeds 2 mL, intramuscular injection is preferable and the total dose should be distributed across multiple sites of injection. Instruct patients to use sterile injection technique when administering calcitonin-salmon injection, and to dispose of needles properly. 2.5 Recommendations for Calcium and Vitamin D Supplementation Patients who use calcitonin-salmon injection for treatment of postmenopausal osteoporosis should receive adequate calcium (at least 1000 mg elemental calcium per day) and vitamin D (at least 400 International Units per day).

2.1 Paget's Disease of Bone The recommended dose of calcitonin-salmon injection for treatment of symptomatic Paget’s disease of bone is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly.

2.2 Hypercalcemia The recommended starting dose of calcitonin-salmon injection for early treatment of hypercalcemia is 4 International Units/kg body weight every 12 hours by subcutaneous or intramuscular injection. If the response to this dose is not satisfactory after one or two days, the dose may be increased to 8 International Units/kg every 12 hours. If the response remains unsatisfactory after two more days, the dose may be further increased to a maximum of 8 International Units/kg every 6 hours.

2.3 Postmenopausal Osteoporosis The recommended dose of calcitonin-salmon injection for treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly. The minimum effective dose of calcitonin-salmon injection for the prevention of vertebral bone mineral density loss has not been established.

2.4 Preparation and Administration Visually inspect calcitonin-salmon vials. Calcitonin-salmon injection is a clear, colorless, solution. If the solution is not clear and colorless, or contains any particles, or if the vial is damaged, do not administer the solution. If the volume of calcito …

3 DOSAGE FORMS AND STRENGTHS Calcitonin salmon injection USP, synthetic, 400 USP Units/2 mL (200 USP Units/mL) is available as a sterile, clear, colorless solution filled in individual 2 mL multiple-dose clear glass vials. Calcitonin salmon injection, USP, synthetic: 200 USP Units per mL, sterile solution in 2 mL multiple-dose clear glass vials. ( 3 )

4 CONTRAINDICATIONS Hypersensitivity to calcitonin salmon or any of the excipients. Reactions have included anaphylaxis with death, bronchospasm, and swelling of the tongue or throat [see Warnings and Precautions ( 5.1 )] . Hypersensitivity to calcitonin salmon or any of the excipients ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Hypersensitivity Reactions, including anaphylaxis [see Warnings and Precautions ( 5.1 )] Hypocalcemia [see Warnings and Precautions ( 5.2 )] Malignancy [see Warnings and Precautions ( 5.3 )] Most common adverse reactions are nausea with or without vomiting (10%), injection site inflammation (10%), and flushing of the face or hands (2% to 5%) ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of calcitonin-salmon injection was assessed in open-label trials several months to two years in duration. The most common adverse reactions are discussed below. Nausea: Nausea with or without vomiting has been noted in about 10% of patients treated with calcitonin-salmon. It is most evident when treatment is first initiated and tends to decrease or disappear with continued administration. Dermatologic Reactions: Local inflammatory reactions at the site of subcutaneous or intramuscular injection have been reported in about 10% of patients. Flushing of face or hands occurred in about 2% to 5% of patients. Skin rashes and pruritus of the ear lobes have also been reported. Other Adverse Reactions: Nocturia, feverish sensation, pain in the eyes, poor appetite, abdominal pain, pedal edema, and salty taste have been reported in patients treated with calcitonin-salmon injection. Malignancy A meta-analysis of 21 randomized, controlled clinical trials with calcitonin-salmon (nasal spray or investigational oral formulations) was conducted to assess the risk of malignancies in calcitonin-salmon-treated patients compared to placebo-treated patients. The trials in the meta- analysis ranged in duration from 6 months to 5 years and included a total of 10,883 patients (6,151 treated with calcitonin-salmon and 4,732 treated with placebo). The overall incidence of malignancies reported in these 21 trials was higher among calcitonin-salmon-treated patients (254/6,151 or 4.1%) compared with placebo-treated patients (137/4,732 or 2.9%). Findings were similar when analyses were restricted to the 18 nasal spray only trials [calcitonin-salmon 122/2,712 (4.5%); placebo 30/1,309 (2.3%)]. The meta-analysis results suggest an increased risk of overall malignancies in calcitonin-salmon­ treated patients compared to placebo-treated patients when all 21 trials are included and when the analysis is restricted to the 18 nasal spray only trials (see Table 1). It is not possible to exclude an increased risk when calcitonin-salmon is administered by the subcutaneous, intramuscular, or intravenous route because these routes of administration were not investigated in the meta- analysis. The increased malignancy risk seen with the meta-analysis was heavily influenced by a single large 5-year trial, which had an observed risk difference of 3.4% [95% CI (0.4%, 6.5%)]. Imbalances in risks were still observed when analyses excluded basal cell carcinoma (see Table 1); the data were not sufficient for further analyses by type of malignancy. A mechanism for these observations has not been identified. Although a definitive causal relationship between calcitonin-salmon use and malignancies cannot be established from this meta-analysis, the benefits for the individual patient should be carefully evaluated against all possible risks [see Warnings and Precautions ( 5.3 )]. Table 1: Risk Difference for Malignancies in Calcitonin-Salmon-Treated Patients Compared with Placebo-Treated Patients Patients Malignancies Risk Difference 1 (%) 95% Confidence Interval 2 (%) All (nas …

7 DRUG INTERACTIONS No formal drug interaction studies have been performed with calcitonin-salmon injection. 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 )

8 USE IN SPECIFIC POPULATIONS There are no data to support use in children ( 8.4 ) 8.1 Pregnancy Risk Summary There are no studies with calcitonin salmon injection in pregnant women to inform a drug associated risk for birth defects or miscarriage. 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 D ata ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 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 recommended for human use (of 54 International Units/m 2 ). No embryo/fetal toxicities related to calcitonin salmon injection 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 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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for calcitonin salmon injection and any potential adverse effects on the breastfed infant from calcitonin salmon injection or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of calcitonin salmon injection did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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 been discovered in osteoclasts and osteoblasts.

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 injection USP, synthetic 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: Calcitonin salmon, USP is a white to off-white powder. It is soluble in water and 1% aqueous acetic acid. Its chemical name is L-cysteinyl-L-seryl-L-asparginyl-L-leucyl-L-seryl-L-threonyl-L-cysteinyl-L-valyl-L-leucyl-glycyl-L-lysyl-L-leucyl-L-seryl-L-glutaminyl-L-alpha-glutamyl-L-leucyl-L-histidyl-L-lysyl-L-leucyl-L-glutaminyl-Lthreonyl-L-tyrosyl-L-prolyl-L-arginyl-L-threonyl-L-asparginyl-L-threonyl-glycyl-L-seryl-glycyl-Lthreonyl-L-prolinamide (1->7)-disulfide and chemical structure is: Its molecular formula is C 145 H 240 N 44 O 48 S 2 and its molecular weight is 3432 Daltons. Calcitonin salmon injection, USP, synthetic, 400 USP Units/2 mL (200 USP Units/mL) is available as a sterile, clear, colorless solution filled in individual 2 mL multiple-dose clear glass vials for subcutaneous or intramuscular injection. Each 1 mL contains: Active: Calcitonin salmon, USP ........................................0.03333 mg (equivalent to 200 USP calcitonin salmon units) Inactives: Acetic acid, USP ............................................................... 2.25 mg Phenol, USP ...................................................................... 5.00 mg Sodium acetate trihydrate, USP.................................. 2.00 mg Sodium chloride, USP ....................................................... 7.50 mg Water for injection, USP, q.s. to ........................................ 1.00 mL The activity of calcitonin salmon injection, USP 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 for Biological Standards and Control, Holly Hill, London. graphic 1

10 OVERDOSAGE The pharmacologic actions of calcitonin salmon injection suggest that hypocalcemic tetany could occur in overdose. Therefore, provisions for parenteral administration of calcium should be available for the treatment of overdose. A dose of calcitonin salmon l,000 International Units subcutaneously may produce nausea and vomiting. Doses of 32 International Units per kg per day for 1 to 2 days demonstrate no other adverse effects. Data on chronic high-dose administration are insufficient to assess toxicity.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Calcitonin Salmon Injection, USP Synthetic is available as a sterile solution as follows: Calcitonin Salmon Injection, USP Synthetic NDC (Preservative) (200 USP Units per mL) Package Factor 25021-473-02 400 USP Units per 2 mL Multi-Dose Vial 1 vial per carton Storage Conditions Store in a refrigerator between 2° to 8°C (36° to 46°F). Protect from freezing. Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex.

How Supplied Calcitonin Salmon Injection, USP Synthetic is available as a sterile solution as follows: Calcitonin Salmon Injection, USP Synthetic NDC (Preservative) (200 USP Units per mL) Package Factor 25021-473-02 400 USP Units per 2 mL Multi-Dose Vial 1 vial per carton