Miacalcin - Calcitonin Salmon injection, Solution

Miacalcin 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 Paget’s Disease of Bone

  Miacalcin injection 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. Miacalcin 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).
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• •Treatment of hypercalcemia (
  1.2 Treatment of Hypercalcemia

  Miacalcin 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.
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• •Treatment of postmenopausal osteoporosis when alternative treatments are not suitable. Fracture reduction efficacy has not been demonstrated (
  1.3 Treatment of Postmenopausal Osteoporosis

  Miacalcin 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. Miacalcin 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).
  )

• •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 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)]

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  5.3 Malignancy

  In a 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. It is not possible to exclude an increased risk when calcitonin salmon is administered long-term subcutaneously, intramuscularly, or intravenously. The benefits for the individual patient should be carefully considered against possible risks

  [see Adverse Reactions (6.1)]

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• •Symptomatic Paget’s disease of bone: 100 USP Units daily. Ensure adequate calcium and vitamin D intake (
  2.1 Paget’s Disease of Bone

  The recommended dose of Miacalcin injection for treatment of symptomatic Paget’s disease of bone is 100 USP Units (0.5 mL) per day administered subcutaneously or intramuscularly.
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  2.5 Recommendations for Calcium and Vitamin D Supplementation

  Patients who use Miacalcin 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).
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• •Hypercalcemia: start with 4 USP Units/kg body weight every 12 hours. Increase to 8 USP Units/kg every 12 hours if no improvement in 1-2 days. Increase further to 8 USP Units/kg every 6 hours if no improvement after 2 more days (
  2.2 Hypercalcemia

  The recommended starting dose of Miacalcin 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: 100 USP Units daily. Ensure adequate calcium and vitamin D intake (
  2.3 Postmenopausal Osteoporosis

  The recommended dose of Miacalcin 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 Miacalcin injection for the prevention of vertebral bone mineral density loss has not been established.
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  2.5 Recommendations for Calcium and Vitamin D Supplementation

  Patients who use Miacalcin 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).
  )

Miacalcin injection is available as a clear, colorless, sterile solution of synthetic calcitonin salmon, USP in individual 2 mL multi-dose vials containing 200 USP Units per mL.

There are no data to support use in children (

• •Serious hypersensitivity reactions, including reports of fatal anaphylaxis have been reported. Consider skin testing prior to treatment in patients with suspected hypersensitivity to calcitonin salmon (
  5.1 Hypersensitivity Reactions

  Serious hypersensitivity reactions have been reported in patients receiving Miacalcin injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis. Appropriate medical support and monitoring measures should be readily available when Miacalcin injection is administered. If anaphylaxis or other severe hypersensitivity/allergic reactions occur, initiate appropriate treatment

  [see Contraindications (4)]

  .

  For patients with suspected hypersensitivity to calcitonin salmon, skin testing should be considered prior to treatment utilizing a dilute, sterile solution of Miacalcin injection. Healthcare providers may wish to refer patients who require skin testing to an allergist. A detailed skin testing protocol is available from the Mylan Pharmaceuticals Inc. Product Safety Department.
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• •Hypocalcemia has been reported. Ensure adequate intake of calcium and vitamin D (
  5.2 Hypocalcemia

  Hypocalcemia associated with tetany (i.e., muscle cramps, twitching) and seizure activity has been reported with Miacalcin injection therapy. Hypocalcemia must be corrected before initiating therapy. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients at risk for hypocalcemia, provisions for parenteral calcium administration should be available during the first several administrations of calcitonin salmon and serum calcium and symptoms of hypocalcemia should be monitored. Use of Miacalcin injection for the treatment of Paget’s disease or postmenopausal osteoporosis is recommended in conjunction with an adequate intake of calcium and vitamin D

  [see Dosage and Administration (2.5)]

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• •Malignancy: A meta-analysis of 21 clinical trials suggests an increased risk of overall malignancies in calcitonin salmon-treated patients (
  5.3 Malignancy

  In a 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. It is not possible to exclude an increased risk when calcitonin salmon is administered long-term subcutaneously, intramuscularly, or intravenously. The benefits for the individual patient should be carefully considered against possible risks

  [see Adverse Reactions (6.1)]

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  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 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 [calcitonin salmon 122/2712 (4.5%); placebo 30/1309 (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)]

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  Table 1: Risk Difference for Malignancies in Calcitonin Salmon-Treated Patients Compared with Placebo-Treated Patients

  Patients	Malignancies	Risk Difference 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. (%)	95% Confidence Interval The corresponding 95% confidence interval for the overall adjusted risk difference also based on MH fixed-effect method. (%)
  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)
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• •Circulating antibodies to calcitonin salmon may develop, and may cause loss of response to treatment (
  5.4 Antibody Formation

  Circulating antibodies to calcitonin salmon have been reported with Miacalcin injection. The possibility of antibody formation should be considered in any patient with an initial response to Miacalcin injection who later stops responding to treatment

  [see Adverse Reactions (6.3)]

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