Apo-Calcitonin Nasal Spray Product Monograph

ACTIONS AND CLINICAL PHARMACOLOGY

Salmon calcitonin (s-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. It is of physiological importance in the regulation of calcium metabolism in certain animal species and may also have physiological importance in certain extraskeletal systems (e.g., GI and renal function).

All calcitonin structures consist of 32 amino acids in a single chain, with a ring of seven amino-acid residues at the N-terminus, the sequence of which differs from species to species.

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. Due to the greater affinity of salmon calcitonin to receptor binding sites than calcitonins from mammalian species, including the synthetic human calcitonin, calcitonin (salmon) nasal solution is more potent and longer acting.

In terms of bioactivity, the potency of calcitonin (salmon) nasal solution was found to be about half that of the drug given by i.m. or s.c. injection.

Osteoporosis is a disease characterized by low bone mass and deterioration of bone tissue architecture leading to enhanced bone fragility and consequent increase in fracture risk. The most common type of osteoporosis occurs in postmenopausal females. Osteoporosis is a result of a disproportionate rate of bone resorption compared to bone formation which disrupts the structural integrity of bone, rendering it more susceptible to fracture. The most common sites of these fractures are the vertebrae, hip, and distal forearm (Colles’ fractures). Vertebral fractures occur with the highest frequency and are associated with back pain, spinal deformity and a loss of height.

Calcitonin (salmon) nasal solution markedly reduces the removal of calcium from bone in conditions with an increased rate of bone resorption such as osteoporosis. Osteoclast activity is inhibited, and osteoblast formation and activity seem to be stimulated. Calcitonin (salmon)

nasal solution inhibits bone resorption, thus lowering abnormally increased serum calcium.

Additionally, at the beginning of treatment it increases the urinary excretion of calcium, phosphorus, and sodium by reducing their tubular re-uptake. Serum calcium, however, is not reduced below the normal range.

Calcitonin (salmon) nasal solution has also been shown to be successful in reducing pain associated with osteolytic and osteopenic conditions, probably by action on the central nervous system.

Pharmacokinetics

The data on bioavailability of calcitonin (salmon) nasal solution obtained by various investigators using different methods show great variability, with a range varying between approximately 3 and 50% relative to intramuscular administration. As is the case with other polypeptide hormones, plasma levels of s-calcitonin are not predictive of the therapeutic response, and hence s-calcitonin activity should be evaluated by biochemical or clinical parameters. Calcitonin (salmon) nasal solution is absorbed rapidly by the nasal mucosa.

Maximum plasma concentrations occur within the first hour of administration. In the dose range 100-400 IU, area under the plasma concentration curve (AUC) increases roughly in proportion to the dose. However, administration of doses higher than 400 IU does not result in further increases in the AUC for the drug. The half-life of elimination of salmon calcitonin is calculated to be about 45 minutes. There is no accumulation of the drug on repeated administration at 10-hour intervals for up to 15 days.

INDICATIONS AND CLINICAL USE

APO-CALCITONIN Nasal Spray (Calcitonin [Salmon] Nasal Solution) is indicated for the treatment of postmenopausal osteoporosis in females greater than five years postmenopause with low bone mass relative to healthy premenopausal females. APO-CALCITONIN Nasal

Spray should be reserved for patients who refuse or cannot tolerate treatment with estrogens or in whom estrogens are contraindicated. APO-CALCITONIN Nasal Spray is recommended in conjunction with an adequate calcium (at least 1000 mg elemental calcium per day) and vitamin D (400 IU per day) intake to retard the progressive loss of bone mass.

CONTRAINDICATIONS

Known hypersensitivity to salmon calcitonin or to any component of the formulation (see

WARNINGS and ADVERSE REACTIONS sections.)

WARNINGS

Allergic Reactions

Because calcitonin is a polypeptide, the possibility of a systemic allergic reaction exists. In clinical trials with calcitonin (salmon) nasal solution, no serious allergic-type adverse reactions have been reported. However, in foreign marketing experience, there have been rare reports of serious allergic-type reactions, such as bronchospasm, swelling of the tongue or throat, tachycardia, hypotension, collapse and anaphylactic shock. The usual provisions should be made for the emergency treatment of such a reaction should it occur. For patients with a history of hypersensitivity, emergency self-injection therapy should be considered. Allergic reactions should be differentiated from generalized flushing and hypotension.

Skin testing should be considered prior to treatment with calcitonin (salmon) nasal solution for patients with suspected sensitivities to calcitonin. The following procedure is suggested:

Prepare a dilution of 10 IU per mL by withdrawing 0.05 mL of commercially available synthetic calcitonin (salmon) solution for injection in a tuberculin syringe and filling it to 1.0 mL with

Dextrose Injection 5%, USP (or Saline Injection, USP). Mix well, discard 0.9 mL and inject intracutaneously 0.1 mL (approximately 1 IU) on the inner aspect of the forearm. Observe the injection site 15 minutes after injection. The appearance of more than mild erythema or wheal constitutes a positive response.

PRECAUTIONS

Nasal Examinations

Nasal adverse events were the most frequently reported adverse event, occurring in 17% of patients who received calcitonin (salmon) nasal solution and in 14% of patients who received placebo nasal solution in studies in postmenopausal females. Therefore, a nasal examination should be performed prior to start of treatment with nasal calcitonin and at any time nasal complaints occur. In all postmenopausal patients treated with calcitonin (salmon) nasal solution, the most commonly reported nasal adverse events included rhinitis (8.2%), nasal dryness (3.9%), epistaxis (2.4%), and sinusitis (1.6%). Smoking was shown not to have any contributory effect on the occurrence of nasal adverse events. In clinical trials in another disorder (Paget’s Disease), 2.8% of patients developed nasal ulcerations.

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, calcitonin

(salmon) nasal solution should be discontinued. Although smaller ulcers often heal without withdrawal of calcitonin (salmon) nasal solution, medication should be discontinued temporarily until healing occurs.

Pregnancy

Synthetic calcitonin (salmon) has been shown to cause a decrease in fetal birth weights without any fetal abnormalities in rabbits when given by injection in doses 70-278 times the intranasal dose recommended for human use based on body surface area. Since synthetic calcitonin (salmon) does not cross the placental barrier, this may be due to metabolic effects in the pregnant animal. There are no adequate and well controlled studies in pregnant women with s-calcitonin. Calcitonin (salmon) nasal solution is not indicated in pregnancy.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Synthetic calcitonin (salmon) has been shown to inhibit lactation in animals and should not be administered to nursing mothers.

Children

The safety and efficacy of calcitonin (salmon) nasal solution in children have not been established. Disorders of bone in children referred to as idiopathic juvenile osteoporosis have been reported rarely. The relationship of these disorders to postmenopausal osteoporosis has not been established and experience with the use of calcitonin with this disorder is very limited.

Use in the Elderly

Clinical trials using calcitonin (salmon) nasal solution have included postmenopausal women up to 77 years of age. No unusual adverse events or increased incidence of common adverse events have been noted in patients over 65 years of age.

Laboratory Tests

Urine sediment abnormalities have not been reported in ambulatory volunteers treated with calcitonin (salmon) nasal solution. Coarse granular casts containing renal tubular epithelial cells were reported in the urine of young adult volunteers at bed rest who were given injectable synthetic calcitonin (salmon) in order to determine the effect of calcitonin (salmon) nasal solution on immobilization osteoporosis. There was no other evidence of renal abnormality and the urine sediment became normal after salmon calcitonin therapy was stopped.

Instructions for the Patient

Instructions on priming of the pump upon first use of the device and nasal introduction of calcitonin (salmon) nasal solution should be given to the patient. Instructions for patients are supplied with individual bottles. Patients should be asked to notify their physician if they develop significant nasal irritation.

Patients should be advised of the following:

@ Store new, unopened bottles in the refrigerator between 2-8°C.

@ Protect the product from freezing.

@ Upon, first use only, the pump must be primed. The product should be allowed to reach room temperature before priming.

@ After priming and first use, the product should be stored at room temperature in an upright position. Each bottle contains 14 doses.

Drug Interactions

Formal studies designed to evaluate drug interactions with s-calcitonin have not been conducted. Currently no drug interactions with synthetic calcitonin (salmon) have been observed.

ADVERSE REACTIONS

Calcitonin (salmon) nasal solution has been evaluated for safety in more than 650 patients treated for osteoporosis for up to two years.

The most commonly reported adverse events with calcitonin (salmon) nasal solution were local effects such as rhinitis, nasal dryness with crusting, non-severe epistaxis and sinusitis.

Calcitonin (salmon) nasal solution was rarely associated with systemic effects, such as nausea, vomiting, dizziness, flushing accompanied by a sensation of heat and, uncommonly, polyuria and chills. These effects usually subsided spontaneously. Such systemic adverse events occur less frequently following intranasal administration of calcitonin (salmon) nasal solution than following i.v., i.m. or s.c. administration.

In very rare cases, calcitonin (salmon) nasal solution may give rise to hypersensitivity reactions such as generalized skin reactions. Isolated anaphylactic-type reactions including tachycardia, hypotension and collapse have been reported in post-marketing experience.

In approximately one-half of the patients tested after six months or more of treatment, indications of circulating antibodies to salmon calcitonin were obtained. In most patients the presence of antibodies does not reduce the clinical efficacy of exogenous salmon calcitonin.

The following table is based on controlled trials in patients treated with calcitonin (salmon)

nasal solution at doses of 50, 100, 200, or 400 IU/day for up to 2 years. The table includes all

AEs with an incidence of 1% or greater in the calcitonin (salmon) nasal solution all combined doses treatment group, irrespective of causal relationship to study drug.

Calcitonin (salmon) nasal solution has also been evaluated for safety in more than 900 patients, who were at least 1-year postmenopausal, treated for up to 5 years in the Prevent

Recurrence of Osteoporotic Fractures (P.R.O.O.F.) Trial. Similar types of adverse reactions were reported in this study. However, the incidence for adverse reactions in this trial, involving

942 patients exposed to calcitonin (salmon) nasal solution and 307 patients exposed to placebo nasal solution, were generally higher than in the 2 year trials due to the longer observation period. In addition, these events were reported with a similar frequency in both the calcitonin (salmon) nasal solution and placebo groups.

In the P.R.O.O.F. trial, nasal adverse events assessed as definitely, probably, possibly, or unlikely drug related by the investigators included:

Less frequently reported nasal adverse events occurring in less than 1% of patients included nasal polyp, nasal septum ulceration, and nasoseptal deviation. Most of the nasal events were mild to moderate in severity and did not prompt discontinuation. Calcitonin (salmon)

nasal solution nasal adverse event rates were 73.5% mild, 24.3% moderate, and 2.2% severe

(placebo nasal solution adverse event rates were 69.5% mild, 24.3% moderate, and 6.2% severe).

In addition, during the P.R.O.O.F. trial, edema (e.g. tongue, extremity, face, generalized)

occurred in 3.1% and 2.6% of patients who received calcitonin (salmon) nasal solution and placebo nasal solution, respectively. Allergy occurred in 1.6% and 1.4% of patients who received calcitonin (salmon) nasal solution and placebo nasal solutions, respectively.

Additional adverse reactions that occurred in the P.R.O.O.F. trial and not included in the 2 year trials data are: pain (i.e. musculoskeletal, general), arthropathy, hot flushes, accidental trauma, asthenia, chest pain, skin disorder (e.g. fissures, lesions, sores), dry skin, leg pain, cramps, chest sounds abnormal (e.g. basilar, crepitations, rales), arrhythmia, hypercalcemia, dysphonia, somnolence, ear disorder (e.g. sensation of fullness, stuffiness, blockage), vision abnormal, cataract, eye abnormality (e.g. dryness, infection, irritation), glaucoma, purpura.

The collective foreign marketing experience with calcitonin (salmon) nasal solution does not show evidence of any notable difference in the profile of reported adverse reactions when compared with that seen in the clinical trials.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

No instances of overdose with calcitonin (salmon) nasal solution have been reported and no serious adverse reactions have been associated with high doses. There is no known potential for drug abuse for synthetic calcitonin (salmon).

Single doses of calcitonin (salmon) nasal solution up to 1600 IU and doses up to 800 IU per day for three days and chronic administration of doses up to 600 IU per day have been studied without serious adverse effects. A dose of 1000 IU of synthetic calcitonin (salmon) injectable solution given subcutaneously may produce nausea and vomiting. A dose of synthetic calcitonin (salmon) injectable solution of 32 IU per kg per day for one or two days demonstrated no additional adverse effects.

There have been no reports of hypocalcemic tetany. However, the pharmacologic actions of calcitonin (salmon) nasal solution suggest that this could occur in overdose. Therefore, provisions for parenteral administration of calcium should be available for the treatment of overdose.

DOSAGE AND ADMINISTRATION

The recommended dose of APO-CALCITONIN Nasal Spray (Calcitonin [Salmon] Nasal

Solution) in postmenopausal women is one spray (200 IU) per day administered intranasally, alternating nostrils daily.

Drug effect may be monitored by periodic measurements of lumbar vertebral bone mass to document stabilization of bone mass or increases in bone density.

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper/Common Name: Calcitonin (salmon)

Chemical Name: L-Cysteinyl-L-seryl-L-asparaginyl-L-leucyl-L-seryl-L-threonyl-L-cysteinyl-L-valyl-L-leucyl-glycyl-L-lysyl-L-leucyl-L-seryl-L-glutaminyl-L-glutamyl-L-leucyl-L-histidyl-L-lysyl-L-leucyl-L-glutaminyl-L-threonyl-L-tyrosyl-L-prolyl-L-arginyl-L-threonyl-L-asparaginyl-L-threonyl-glycyl-L-seryl-glycyl-L-threonyl-L-proline amide 3,7-3,1 disulfide

Structural Formula:

H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH₂

Molecular Formula: C₁₄₅H₂₄₀N₄₄O₄₈S₂

Molecular Weight: 3431.9

Description:

It is a white or almost white powder. Freely soluble in water.

COMPOSITION

Each spray of APO-CALCITONIN Nasal Spray (Calcitonin [Salmon] Nasal Solution) contains

200 IU of synthetic calcitonin (salmon) as the active ingredient and the following non-medicinal ingredients: Benzalkonium chloride (as a preservative), hydrochloric acid and/or sodium hydroxide (for pH adjustment), sodium chloride and purified water.

STABILITY AND STORAGE RECOMMENDATIONS

Unopened APO-CALCITONIN Nasal Spray (Calcitonin [Salmon] Nasal Solution) should be stored in the refrigerator between 2 and 8°C and protected from freezing.

After priming, APO-CALCITONIN Nasal Spray should be stored at room temperature (below

25°C) and used within 4 weeks. To ensure correct delivery, the bottle should be kept in an upright position.