Source: FDA, National Drug Code (US) Revision Year: 2022
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 beendiscoveredin osteoclasts and osteoblasts.
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, theconclusionsconcerningtheclinical pharmacology of this preparation may be different.
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 witha decreasednumber of osteoclasts and an apparent decrease in their resorptive activity.
In healthy adults, who have a relatively low rate of bone resorption, theadministration of exogenous calcitonin‑ salmon results in decreases in serumcalciumwithin thelimits of the normal range. In healthy children and in patients whose bone resorption is more rapid, decreasesin serumcalciumare more pronounced in response to calcitonin-salmon.
Studies withinjectable calcitonin-salmon show increasesin the excretionof filtered phosphate, calcium, and sodiumby decreasing their tubular reabsorption. Comparable studieshave not been conducted with Calcitonin Salmon Nasal Solution.
Some evidence fromstudies with injectable preparations suggests that calcitonin-salmon may have effects on the gastrointestinal tract.Short-termadministration of injectable calcitonin-salmon results in marked transient decreases in the volume and acidity ofgastric juice and in the volume andthe trypsin and amylase content of pancreatic juice. Whether these effects continue to beelicited after each injection of calcitonin-salmon during chronic therapy has not been investigated. These studies have not beenconducted with Calcitonin Salmon Nasal Solution.
In two clinical studies designed toevaluate the pharmacodynamic response to calcitonin-salmon nasal spray, administration of calcitonin-salmon 100 to 1600 International Unitsto healthy volunteers resulted in rapid and sustained decreases within the normal range for both total serumcalciumand serumionized calcium. Single doses of calcitonin-salmon greater than 400 International Units did notproduce any further biological response to the drug.
The bioavailability of Calcitonin Salmon Nasal Solution relative to intramuscular administration in healthy volunteers is between 3 and 5%. Calcitonin Salmon Nasal Solution 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.
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 humansis unknown because pituitary adenomas are very common in rats as they age, the pituitary adenomas did not transforminto 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.
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 344rats 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 effectcould not be distinguished fromnatural backgroundincidence.Thelowestdosein male Sprague Dawley rats thatdeveloped an increased incidence of pituitary adenomas after two yearsof dosing (1.7 International Units/kg/day) is approximately 2 times the maximum recommended intranasal dose in humans (200International Units/day) based on body surface area conversion between rats and humansand a 20-fold conversion factor to account for decreased clinical exposure via the intranasal route. The findingssuggest that calcitonin-salmon reducedthe latency period for development of non-functioning pituitary adenomas.
No carcinogenicity potential was evident in male or female mice dosed subcutaneously for two years with synthetic calcitonin-salmon at dosesup 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) basedon scaling for body surface area anda 20-foldconversion factor to account for low clinical exposure via the intranasal route.
Synthetic calcitonin-salmon testednegative for mutagenicity using Salmonella typhimurium (5 strains) and Escherichia coli (2 strains), with and withoutrat liver metabolic activation, and was not clastogenic in a chromosome aberration test in Chinese Hamster V79cells. There was no evidence that calcitonin- salmon was clastogenic in the in vivo mouse micronucleustest.
Effects ofcalcitonin-salmon on fertility have not been assessed in animals.
Two randomized, placebo-controlled, two-year trials were conducted in 266 postmenopausal women who were greater than 5 years postmenopause with spinal, forearmor femoral bone mineral density (BMD) at least one standard deviation belowthe normal value for healthy premenopausal women (T-score < -1). In both studies, a total of 144 patients receivedCalcitonin Salmon Nasal Solution 200 International Units or placebodaily. The intent-to-treat population comprised 139 patients who had at least one follow-up BMD measurement. In study 1, patients also received 500 mg daily calciumsupplements, while in study 2, patients received no calciumsupplementation. The primary endpoint for both studieswas percent change in lumbar spine BMD at 2 years. Calcitonin Salmon Nasal Solution increased lumbar vertebral BMD relative to placebo in women with low bone mass who were greater than 5 years post menopause (see Table 3 below).
Table 3. Calcitonin Salmon Nasal Solution: Lumbar Spine Bone Mineral Density in Women Greater Than 5 years Postmenopause With Low Bone Mass
| Lumber Spine Bone Mineral Density, Mean Change From Baseline (in %) at Month 24 | ||
|---|---|---|
| Study 1 (with calcium supplement) n (ITT) = 100 | Study 2 (no calcium supplement) n(ITT) = 39 | |
| Calcitonin Salmon Nasal Solution 200 IU NS daily | +1.56 | +1.02 |
| Placebo | +0.20 | -1.85 |
| Treatment Difference | +1.36 | +2.87 |
| p-value † | <0.05 | <0.005 |
ITT: Intent To Treat
IU: International Units
NS: nasal spray
p–values by parametric testing (2–tailed 2-sample t-test)
No effects of calcitonin salmon nasal spray on cortical bone of the forearm or hip were demonstrated.
In clinical studies of postmenopausal osteoporosis, bone biopsy and radial bone mass assessments at baseline and after 26 months of daily injectable calcitonin-salmon indicate that calcitonin therapy results in the formation of normal bone.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
