1.1 Treatment of Postmenopausal Osteoporosis

Miacalcin nasal spray is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. Fracture reduction efficacy has not been demonstrated. Miacalcin nasal spray 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)].
• Miacalcin nasal spray has not been shown to increase spinal bone mineral density in early postmenopausal women.

2.1 Basic Dosing Information

The recommended dose of Miacalcin nasal spray is 1 spray (200 International Units) per day administered intranasally, alternating nostrils daily.

2.2 Priming (Activation) of Pump

Unopened Miacalcin nasal spray should be stored in the refrigerator. Before using the first dose of Miacalcin nasal spray, 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 Miacalcin nasal spray should receive adequate calcium (at least 1000 mg elemental calcium per day) and vitamin D (at least 400 International Units per day).

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions have been reported in patients receiving Miacalcin nasal spray, 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 a reaction occurs. Hypersensitivity reactions should be differentiated from generalized flushing and hypotension [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 a calcitonin-salmon injectable product. Healthcare providers may wish to refer patients who require skin testing to an allergist. A detailed skin testing protocol is available from the Medical Services Department of Novartis Pharmaceuticals Corporation.

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 Miacalcin nasal spray. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with Miacalcin nasal spray. Use of Miacalcin nasal spray is recommended in conjunction with an adequate intake of calcium and vitamin D [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 mucosal blood vessels are recommended prior to start of treatment with Miacalcin nasal spray, periodically during the course of therapy, and at any time nasal symptoms occur.

Miacalcin nasal spray 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 Miacalcin nasal spray, medication should be discontinued temporarily until healing occurs [see Adverse Reactions (6.1)].

5.4 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. 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 Miacalcin nasal spray. The possibility of antibody formation should be considered in any patient with an initial response to Miacalcin nasal spray 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.

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 Miacalcin (calcitonin-salmon) nasal spray in the treatment of postmenopausal osteoporosis was assessed in 5 randomized, double-blind, placebo controlled trials that enrolled postmenopausal women, aged 45–75 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 Miacalcin nasal spray (N=341) and to placebo nasal spray (N=131), and reported in greater than 3% of Miacalcin 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 Miacalcin nasal spray has not been established.

Nasal Adverse Reactions: In all postmenopausal patients treated with Miacalcin nasal spray, 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%–3% of patients treated with Miacalcin nasal spray 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 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 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 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 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)].

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 Miacalcin nasal spray.

Allergic/Hypersensitivity Reactions: Serious allergic reactions have been reported in patients receiving calcitonin-salmon nasal spray, 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 potentially immunogenic properties of medicinal products containing peptides, administration of Miacalcin may trigger the development of anti-calcitonin antibodies. In a two-year Miacalcin nasal spray clinical study that evaluated immunogenicity, a measurable antibody titer was found in 69% of patients treated with Miacalcin 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 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 to Miacalcin nasal spray with the incidence of antibodies to other calcitonin-containing products may be misleading.

8.1 Pregnancy

Pregnancy Category C:

Risk Summary

There are no adequate and well-controlled studies in pregnant women. Miacalcin nasal spray should be used during pregnancy only if the potential benefit justifies the use as compared with potential risks to the patient and fetus. Based on animal data, Miacalcin is predicted to have low probability of increasing the risk of adverse developmental outcomes above background risk.

Animal Data

Calcitonin-salmon has been shown to cause a decrease in fetal birth weights in rabbits when given by subcutaneous injection in doses 4–18 times the parenteral dose (of 54 International Units/m2) and 70–278 times the intranasal dose recommended for human use based on body surface area.

No embryo/fetal toxicities related to Miacalcin were reported from maternal subcutaneous daily doses in rats up to 80 International Units/kg/day from gestation day 6 to 15.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. No studies have been conducted to assess the impact of Miacalcin on milk production in humans, its presence in human breast milk, or its effects on the breastfed child. Because many drugs are excreted in human milk, caution should be exercised when Miacalcin is administered to a nursing woman. 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 multicentered, 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.

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.

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, the conclusions concerning the clinical 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 with a decreased number of osteoclasts and an apparent decrease in their resorptive activity.

In healthy adults, who have a relatively low rate of bone resorption, the administration of exogenous calcitonin-salmon results in decreases in serum calcium within the limits of the normal range. In healthy children and in patients whose bone resorption is more rapid, decreases in serum calcium are more pronounced in response to calcitonin-salmon.

Kidney

Studies with injectable calcitonin-salmon show increases in the excretion of filtered phosphate, calcium, and sodium by decreasing their tubular reabsorption. Comparable studies have not been conducted with Miacalcin nasal spray.

Gastrointestinal Tract

Some evidence from studies with injectable preparations suggests that calcitonin-salmon may have effects on the gastrointestinal tract. Short-term administration of injectable calcitonin-salmon results in marked transient decreases in the volume and acidity of gastric juice and in the volume and the trypsin and amylase content of pancreatic juice. Whether these effects continue to be elicited after each injection of calcitonin-salmon during chronic therapy has not been investigated. These studies have not been conducted with Miacalcin nasal spray.

Calcium Homeostasis

In two clinical studies designed to evaluate the pharmacodynamic response to calcitonin-salmon nasal spray, administration of calcitonin-salmon 100–1600 International Units to healthy volunteers resulted in rapid and sustained decreases within the normal range for both total serum calcium and serum ionized calcium. Single doses of calcitonin-salmon greater than 400 International Units did not produce any further biological response to the drug.

12.3 Pharmacokinetics

The bioavailability of Miacalcin nasal spray relative to intramuscular administration in healthy volunteers is between 3% and 5%. Miacalcin nasal spray is absorbed rapidly by the nasal mucosa with a 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.

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 humans is unknown because pituitary adenomas are very common in rats as they age, the pituitary adenomas did not transform into 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 344 rats 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 effect could not be distinguished from natural background incidence. The lowest dose in male Sprague Dawley rats that developed an increased incidence of pituitary adenomas after two years of dosing (1.7 International Units/kg/day) is approximately 2 times the maximum recommended intranasal dose in humans (200 International Units/day) based on body surface area conversion between rats and humans and a 20-fold conversion factor to account for decreased clinical exposure via the intranasal route. The findings suggest that calcitonin-salmon reduced the 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 doses up 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) based on scaling for body surface area and a 20-fold conversion factor to account for low clinical exposure via the intranasal route.

Mutagenesis

Synthetic calcitonin-salmon tested negative for mutagenicity using Salmonella typhimurium (5 strains) and Escherichia coli (2 strains), with and without rat liver metabolic activation, and was not clastogenic in a chromosome aberration test in Chinese Hamster V79 cells. There was no evidence that calcitonin-salmon was clastogenic in the in vivo mouse micronucleus test.

Fertility

Effects of calcitonin-salmon on fertility have not been assessed in animals.