Fortical

FORTICAL — calcitonin salmon spray, metered
Physicians Total Care, Inc.

For Intranasal Use Only

Rx only

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.

The active ingredient in FORTICAL® calcitonin-salmon (rDNA origin) Nasal Spray is a polypeptide of 32 amino acids manufactured by recombinant DNA technology and is identical to calcitonin-salmon produced by chemical synthesis.

This is shown by the following graphic formula:

Chemical Structure

It is provided in a 3.7 mL fill glass bottle as a solution for intranasal administration with sufficient medication for at least 30 doses. Each spray delivers 200 International Units calcitonin-salmon in a volume of 0.09 mL.

Active Ingredient: Calcitonin-salmon 2200 International Units/mL, corresponding to 200 International Units per actuation (0.09 mL).

Inactive Ingredients: Sodium Chloride USP, Citric Acid USP, Phenylethyl Alcohol USP, Benzyl Alcohol NF, Polysorbate 80 NF, Hydrochloric Acid NF or Sodium Hydroxide NF (added as necessary to adjust pH) and Purified Water USP.

CLINICAL PHARMACOLOGY

Calcitonin 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 information below, describing the clinical pharmacology of calcitonin, has been derived from studies with injectable calcitonin. The mean bioavailability of calcitonin-salmon nasal spray is approximately 3% of the injectable calcitonin in normal subjects and, therefore, the conclusions concerning the CLINICAL PHARMACOLOGY of this preparation may be different.

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.

Single injections of calcitonin cause 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 vitro studies have shown that calcitonin-salmon causes inhibition of osteoclast function with loss of the ruffled osteoclast border responsible for resorption of bone. This activity resumes following removal of calcitonin-salmon from the test system. There is some evidence from in vitro studies that bone formation may be augmented by calcitonin through increased osteoblastic activity.

Animal studies indicate that endogenous calcitonin, primarily through its action on bone, participates with parathyroid hormone in the homeostatic regulation of blood calcium. Thus, high blood calcium levels cause increased secretion of calcitonin which, in turn, inhibits bone resorption. This reduces the transfer of calcium from bone to blood and tends to return blood calcium towards the normal level. The importance of this process in humans has not been determined. In normal adults, who have a relatively low rate of bone resorption, the administration of exogenous calcitonin results in only a slight decrease in serum calcium in the limits of the normal range. In normal children and in patients with Paget’s disease in whom bone resorption is more rapid, decreases in serum calcium are more pronounced in response to calcitonin.

Bone biopsy and radial bone mass studies at baseline and after 26 months of daily injectable calcitonin indicate that calcitonin therapy results in the formation of normal bone.

Postmenopausal Osteoporosis

Osteoporosis is a disease characterized by low bone mass and architectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk as patients approach or fall below a bone mineral density associated with increased frequency of fracture. The most common type of osteoporosis occurs in postmenopausal women. 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’ fracture). Vertebral fractures occur with the highest frequency and are associated with back pain, spinal deformity and a loss of height.

Calcitonin, given by the intranasal route, has been shown to increase spinal bone mass in postmenopausal women with established osteoporosis but not in early postmenopausal women.

Calcium Homeostasis

In two clinical studies designed to evaluate the pharmacodynamic response to calcitonin-salmon nasal spray, administration of 100-1600 International Units to healthy volunteers resulted in rapid and sustained small decreases (but still within the normal range) in both total serum calcium and serum ionized calcium. Single doses greater than 400 International Units did not produce any further biological response to the drug. The development of hypocalcemia has not been reported in studies in healthy volunteers or postmenopausal women.

Kidney

Studies with injectable calcitonin show increases in the excretion of filtered phosphate, calcium, and sodium by decreasing their tubular reabsorption. Comparable studies have not been conducted with FORTICAL® calcitonin-salmon (rDNA origin) Nasal Spray.

Gastrointestinal Tract

Some evidence from studies with injectable preparations suggests that calcitonin may have significant actions on the gastrointestinal tract. Short-term administration of injectable calcitonin 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 during chronic therapy has not been investigated. These studies have not been conducted with FORTICAL® calcitonin-salmon (rDNA origin) Nasal Spray.

Pharmacokinetics and Drug Metabolism

The pharmacokinetic properties of FORTICAL® calcitonin-salmon (rDNA origin) Nasal Spray after multiple dose administration were shown to be similar to that of a commercially available calcitonin-salmon product in healthy volunteers. The bioavailability of calcitonin-salmon nasal spray relative to intramuscular administration is between 3 and 5%. Calcitonin-salmon nasal spray is absorbed 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. Plasma exposure was higher following administration of 400 IU nasal spray compared to that after 200 IU dose. As is the case with other polypeptide hormones, there is very little value in monitoring plasma levels of salmon calcitonin since these are not directly predictive of the therapeutic response. Hence, Fortical® activity should be evaluated by using clinical parameters of efficacy.

Fortical Indications and Usage

Postmenopausal Osteoporosis

FORTICAL® calcitonin-salmon (rDNA origin) Nasal Spray is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause with low bone mass relative to healthy premenopausal women. Use of FORTICAL® calcitonin-salmon (rDNA origin) Nasal Spray is recommended in conjunction with an adequate calcium (at least 1000 mg elemental calcium per day) and Vitamin D (400 International Units per day) intake to retard the progressive loss of bone mass. The evidence of efficacy for calcitonin-salmon is based on increases in spinal bone mineral density (BMD) observed in clinical trials.

Two randomized, placebo-controlled trials were conducted in 325 postmenopausal women (227 treated with calcitonin-salmon nasal spray and 98 treated with placebo) with spinal, forearm or femoral BMD at least one standard deviation below the normal value for healthy premenopausal women. These studies conducted over two years demonstrated that 200 International Units daily of calcitonin-salmon nasal spray increases lumbar vertebral BMD relative to baseline and relative to placebo in osteoporotic women who were greater than 5 years postmenopause. Calcitonin-salmon nasal spray produced statistically significant increases in lumbar vertebral BMD compared to placebo as early as 6 months after initiation of therapy with persistence of this level for up to 2 years of observation.

No effects of calcitonin-salmon nasal spray on cortical bone of the forearm or hip were demonstrated. However, in one study, BMD of the hip showed a statistically significant increase compared with placebo in a region composed of predominantly trabecular bone after 1 year of treatment changing to a trend at 2 years that was no longer statistically significant.

CONTRAINDICATIONS

Clinical allergy to calcitonin-salmon.

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