Source: FDA, National Drug Code (US) Revision Year: 2018
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.
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.
Studies with injectable calcitonin salmon show increases in the excretion of filtered phosphate, calcium, and sodium by decreasing their tubular reabsorption.
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.
The absolute bioavailability of calcitonin salmon is approximately 66% and 71% after intramuscular or subcutaneous injection, respectively. After subcutaneous administration, peak plasma levels are reached in approximately 23 minutes. The terminal half-life is approximately 58 minutes for intramuscular administration and 59 to 64 minutes for subcutaneous administration. The apparent volume of distribution is 0.15 to 0.3 L/kg.
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.
The only clear neoplastic finding in rats dosed subcutaneously with 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 1/6th of the maximum recommended subcutaneous dose in humans (100 International Units/day) based on body surface area conversion between rats and humans. The findings suggest that calcitonin salmon reduced the 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 doses up to 800 International Units/kg/day. The 800 International Units/kg/day dose is approximately 39 times the maximum recommended subcutaneous dose in humans (100 International Units/day) based on body surface area conversion between mice and humans.
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.
Effects of calcitonin salmon on fertility have not been assessed in animals.
The trials used for the basis of approval for calcitonin salmon injection for treatment of Paget’s disease of bone were conducted in patients with moderate to severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary hydroxyproline excretion. In open-label clinical trials of several months to two years duration with historical controls, biochemical abnormalities were substantially improved (more than 30% reduction) in about ⅔ of patients studied and bone pain was improved in a similar fraction. A small number of documented instances of reversal of neurologic deficits have occurred, including improvement in the basilar compression syndrome, and improvement of spinal cord and spinal nerve lesions. There is too little experience to predict the likelihood of improvement of any given neurologic lesion. Hearing loss is improved infrequently (4 of 29 patients studied by audiometry). Patients with increased cardiac output due to extensive Paget’s disease of bone have had measured decreases in cardiac output while receiving calcitonin salmon. The number of treated patients in this category is too small to predict how likely such a result will be.
There is no evidence that the prophylactic use of calcitonin salmon is beneficial in asymptomatic patients.
In four open-label clinical trials enrolling 53 patients, calcitonin salmon has been shown to lower elevated serum calcium levels of patients with carcinoma (with or without metastases), multiple myeloma, and primary hyperparathyroidism (lesser response). These patients were treated with calcitonin salmon only when other methods of lowering serum calcium (hydration, oral phosphate, corticosteroids) were unsuccessful or unsuitable. With patients' pre-therapy serum calcium levels as controls, reduction in serum calcium was evident within 1 to 2 hours of administration. The peak effect occurred within 24 to 48 hours of injection and administration of calcitonin salmon every 12 hours maintained a hypocalcemic effect for approximately 5 to 8 days, the time period evaluated for most patients in the clinical trials. The average reduction of 8-hour post-injection serum calcium was approximately 9% (2 to 3 mg/dL). Patients with higher values of serum calcium tended to show greater reductions during calcitonin salmon treatment.
The trials used for the basis of approval for calcitonin salmon injection for treatment of postmenopausal osteoporosis were two randomized, open-label, 2-year studies in postmenopausal women 50 to 74 years of age with total body calcium < 85% of expected normal, and vertebral osteopenia (by x-ray criteria) and/or at least one atraumatic compression fracture. The primary efficacy endpoint was total body calcium measured by neutron activation analysis. Patients were randomized to calcitonin salmon injection 100 International Units daily (subcutaneously or intramuscularly) at bedtime, or control. All subjects received daily supplements of 1200 mg calcium carbonate and 400 International Units of vitamin D.
In both studies, total body calcium increased from baseline with calcitonin salmon therapy at 1 year, followed by a trend to decreasing total body calcium (still above baseline) at 2 years.
Thoracic and lumbar spine X-rays (AP/lateral) were obtained yearly. For the two studies combined (34 calcitonin salmon and 35 control subjects), in the first year there was a total of 6 new vertebral compression fractures in the calcitonin salmon group and 5 in the control group. In the second year there were 7 new fractures in each group.
No evidence currently exists to indicate whether Miacalcin injection decreases the risk of osteoporotic fracture. A controlled study, which was prematurely discontinued, failed to demonstrate any benefit of calcitonin salmon on fracture rate.
No adequate controlled trials have examined the effect of calcitonin salmon injection on vertebral bone mineral density beyond 1 year of treatment. Therefore, the minimum effective dose of Miacalcin injection for prevention of vertebral bone mineral density loss has not been established.
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.
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