Calcitonin Salmon Drug Information

Paget’s Disease of Bone

The recommended dose of Calcitonin salmon injection for treatment of symptomatic Paget's disease of bone is 100 USP Units (0.5 mL) per day administered subcutaneously or intramuscularly.

Hypercalcemia

The recommended starting dose of Calcitonin salmon injection for early treatment of hypercalcemia is 4 USP 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 USP 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 USP Units/kg every 6 hours.

Postmenopausal Osteoporosis

The recommended dose of Calcitonin salmon injection for treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause is 100 USP 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.

Preparation and

Administration Visually inspect calcitonin salmon injection 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.

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).

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 10883 patients (6151 treated with calcitonin salmon and 4732 treated with placebo). The overall incidence of malignancies reported in 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. 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%. 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.

Table 1: Risk Difference for Malignancies in Calcitonin Salmon-Treated Patients Compared with Placebo-Treated Patients * 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. † The corresponding 95% confidence interval for the overall adjusted risk difference also based on MH fixed-effect method. Patients Malignancies Risk Difference * (%) 95% Confidence Interval † (%) All (nasal spray + oral) All

All (nasal spray + oral) Excluding basal cell carcinoma 0.5 (-0.1, 1.2)

All (nasal spray only) All

All (nasal spray only) Excluding basal cell carcinoma 0.8 (-0.2, 1.8) 6.2

Postmarketing Experience Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been reported during post-approval use of calcitonin salmon injection. Allergic / Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving calcitonin salmon injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis.

Skin and subcutaneous tissue disorders : Urticaria Hypocalcemia : Hypocalcemia with tetany (i.e. muscle cramps, twitching) and seizure activity have been reported. Body as a Whole: influenza-like symptoms, fatigue, edema (facial, peripheral, and generalized) Musculoskeletal: arthralgia, musculoskeletal pain Cardiovascular: hypertension Gastrointestinal: abdominal pain, diarrhea Urinary System: polyuria Nervous System: dizziness, headache, paresthesia, tremor Vision: visual disturbance

Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing peptides

administration of calcitonin salmon may trigger the development of anti-calcitonin antibodies. Circulating antibodies to calcitonin salmon after 2 to 18 months of treatment have been reported in about one-half of the patients with Paget's disease in whom antibody studies were done. In some cases, high antibody titers are found; these patients usually will have a loss of response to treatment.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies among different calcitonin salmon products may be misleading.

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

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 4-18 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). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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 were reported from maternal subcutaneous daily doses in rats up to 80 International Units/kg/day from gestation day 6 to 15.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Hypersensitivity to calcitonin salmon or any of the excipients. Reactions have included anaphylaxis with death, bronchospasm, and swelling of the tongue or throat. Hypersensitivity to calcitonin salmon or any of the excipients

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 l000 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.