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Calcitonin (salmon)
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. Calcitonin (salmon) is a synthetic polypeptide of 32 amino acids in the same linear sequence that is found in calcitonin of salmon origin. Injection: It is provided in sterile solution for subcutaneous or intramuscular injection. Each milliliter contains 200 IU (MRC) of calcitonin (salmon), 5 mg phenol (as preservative), with sodium chloride, sodium acetate, acetic acid, and sodium hydroxide to adjust tonicity and pH. Nasal Spray: It is provided in 2 ml fill glass bottles as a solution for nasal administration. This is sufficient medication for 14 doses. Each milliliter contains calcitonin (salmon) 2200 IU (corresponding to 200 IU per 0.09 ml actuation), sodium chloride 8.5 mg, benzalkonium chloride 0.10 mg, nitrogen, hydrochloric acid (added as necessary to adjust pH) and purified water. The activity of calcitonin (salmon) nasal
spray is stated in International Units based on bioassay in comparison
with the International Reference Preparation of calcitonin (salmon) for
Bioassay, distributed by the National Institute of Biologic Standards
and Control, Holly Hill, London.
Injection 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 actions of calcitonin on bone and its role in normal human bone physiology are still incompletely understood. Bone: 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. Decreased osteocytic resorption may also be involved. There is some evidence that initially bone formation may be augmented by calcitonin through increased osteoblastic activity. However, calcitonin will probably not induce a long-term increase in bone formation. 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 to 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 normal children and in patients with generalized Paget's disease, bone resorption is more rapid and decreases in serum calcium are more pronounced in response to calcitonin. Paget's Disease of Bone (Osteitis Deformans): Paget's disease is a disorder of uncertain etiology characterized by abnormal and accelerated bone formation and resorption in one or more bones. In most patients only small areas of bone are involved and the disease is not symptomatic. In a small fraction of patients, however, the abnormal bone may lead to bone pain and bone deformity, cranial and spinal nerve entrapment, or spinal cord compression. The increased vascularity of the abnormal bone may lead to high output congestive heart failure. Active Paget's disease involving a large mass of bone may increase the urinary hydroxyproline excretion (reflecting breakdown of collagen-containing bone matrix) and serum alkaline phosphatase (reflecting increased bone formation). Calcitonin (salmon), presumably by an initial blocking effect on bone resorption, causes a decreased rate of bone turnover with a resultant fall in the serum alkaline phosphatase and urinary hydroxyproline excretion in approximately 2/3 of patients treated. These biochemical changes appear to correspond to changes toward more normal bone, as evidenced by a small number of documented examples of: 1) radiologic regression of Pagetic lesions, 2) improvement of impaired auditory nerve and other neurologic function, 3) decreases (measured) in abnormally elevated cardiac output. These improvements occur extremely rarely, if ever, spontaneously (elevated cardiac output may disappear over a period of years when the disease slowly enters a sclerotic phase; in the cases treated with calcitonin, however, the decreases were seen in less than one year.) Some patients with Paget's disease who have good biochemical and/or symptomatic responses initially, later relapse. Suggested explanations have included the formation of neutralizing antibodies and the development of secondary hyperparathyroidism, but neither suggestion appears to explain adequately the majority of relapses. Although the parathyroid hormone levels do appear to rise transiently during each hypocalcemic response to calcitonin, most investigators have been unable to demonstrate persistent hypersecretion of parathyroid hormone in patients treated chronically with Calcitonin (salmon). Circulating antibodies to calcitonin after 2-18 months of treatment have been reported in about half of the patients with Paget's disease in whom antibody studies were done, but calcitonin treatment remained effective in many of these cases. Occasionally, patients with high antibody titers are found. These patients usually will have suffered a biochemical relapse of Paget's disease and are unresponsive to the acute hypocalcemic effects of calcitonin. Hypercalcemia: In clinical trials, Calcitonin (salmon) has been shown to lower the elevated serum calcium of patients with carcinoma (with or without demonstrated metastases), multiple myeloma or primary hyperparathyroidism (lesser response). Patients with higher values for serum calcium tend to show greater reduction during calcitonin therapy. The decrease in calcium occurs about 2 hours after the first injection and lasts for about 6-8 hours. Calcitonin (salmon) given every 12 hours maintained a calcium lowering effect for about 5-8 days, the time period evaluated for most patients during the clinical studies. The average reduction of 8-hour post-injection serum calcium during this period was about 9 percent. Kidney: Calcitonin increases the excretion of filtered phosphate, calcium, and sodium by decreasing their tubular reabsorption. In some patients, the inhibition of bone resorption by calcitonin is of such magnitude that the consequent reduction of filtered calcium load more than compensates for the decrease in tubular reabsorption of calcium. The result in these patients is a decrease rather than an increase in urinary calcium. Transient increases in sodium and water excretion may occur after the initial injection of calcitonin. In most patients, these changes return to pretreatment levels with continued therapy. Gastrointestinal Tract: Increasing evidence indicates that calcitonin has significant actions on the gastrointestinal tract. Short-term administration 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. Metabolism: The metabolism of Calcitonin (salmon) has not yet been studied clinically. Information from animal studies with Calcitonin (salmon) and from clinical studies with calcitonins of porcine and human origin suggest that Calcitonin (salmon) is rapidly metabolized by conversion to smaller inactive fragments, primarily in the kidneys, but also in the blood and peripheral tissues. A small amount of unchanged hormone and its inactive metabolites are excreted in the urine. It appears that Calcitonin (salmon) cannot cross the placental barrier and its passage to the cerebrospinal fluid or to breast milk has not been determined. Nasal Spray 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 that of 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 the 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 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 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, 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 IU 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 IU 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 females. Kidney: Studies with injectable calcitonin wshow increases in the excretion of filtered phosphate, calcium, and sodium by decreasing their tubular reabsorption. Comparable studies have not been carried out with Calcitonin (salmon) nasal spray. Gastrointestinal Tract: Some evidence from studies with injectable preparations suggest 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 Calcitonin (salmon) nasal spray. Pharmacokinetics and Metabolism: The data on bioavailability
of Calcitonin (salmon) nasal
spray obtained by various investigators using different methods show great
variability. Calcitonin (salmon) nasal
spray is absorbed rapidly by the nasal
mucosa. Peak plasma concentrations
of drug appear 31-39 minutes after nasal
administration compared
to 16-25 minutes following parenteral
dosing. In normal volunteers
approximately 3% (range 0.3%-30.6%) of a nasally administered dose
is bioavailable compared to the same dose
administered by intramuscular
injection. The half-life of elimination
of calcitonin- salmon is calculated to be 43 minutes. There is no accumulation
of the drug on repeated nasal
administration at 10
hour intervals for up to 15 days. Absorption of nasally administered calcitonin
has not been studied in postmenopausal
women.
Paget's Disease Calcitonin (salmon) injection, synthetic is indicated for the treatment of symptomatic Paget's disease of bone, for the treatment of hypercalcemia, and for the treatment of postmenopausal osteoporosis. Injection: At the present time, effectiveness has been demonstrated principally in patients with moderate to severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary hydroxyproline excretion. In these patients, the biochemical abnormalities were substantially improved (more than 30% reduction) in about 2/3 of patients studied, and bone pain was improved in a similar fraction. A small number of documented instances of reversal of neurologic deficits has occurred, including improvement in the basilar compression syndrome, and improvement of spinal cord and spinal nerve lesions. At present, there is too little experience to predict the likelihood of improvement of any given neurologic lesion. Hearing loss, the most common neurologic lesion of Paget's disease, is improved infrequently (4 of 29 patients studied audiometrically). Patients with increased cardiac output due to extensive Paget's disease have had measured decreases in cardiac output while receiving calcitonin. The number of treated patients in this category is still too small to predict how likely such a result will be. The large majority of patients with localized, especially monostotic disease do not develop symptoms and most patients with mild symptoms can be managed with analgesics. There is no evidence that the prophylactic use of calcitonin is beneficial in asymptomatic patients, although treatment may be considered in exceptional circumstances in which there is extensive involvement of the skull or spinal cord with the possibility of irreversible neurologic damage. In these instances, treatment would be based on the demonstrated effect of calcitonin on Pagetic bone, rather than on clinical studies in the patient population in question. Hypercalcemia Injection: Calcitonin (salmon) injection, synthetic is indicated for early treatment of hypercalcemic emergencies, along with other appropriate agents, when a rapid decrease in serum calcium is required, until more specific treatment of the underlying disease can be accomplished. It may also be added to existing therapeutic regimens for hypercalcemia such as intravenous fluids and furosemide, oral phosphate or corticosteroids, or other agents. Postmenopausal Osteoporosis Injection: Calcitonin (salmon) injection, synthetic is indicated for the treatment of postmenopausal osteoporosis in conjunction with adequate calcium and vitamin Dy intake to prevent the progressive loss of bone mass. No evidence currently exists to indicate whether or not Calcitonin (salmon) decreases the risk of vertebral crush fractures or spinal deformity. A recent controlled study, which was discontinued prior to completion because of questions regarding its design and implementation, failed to demonstrate any benefit of salmon calcitonin on fracture rate. No adequate controlled trials have examined the effect of salmon calcitonin injection on vertebral bone mineral density beyond 1 year of treatment. Two placebo-controlled studies with salmon calcitonin have shown an increase in total body calcium at 1 year, followed by a trend to decreasing total body calcium (still above baseline) at 2 years. The minimum effective dose of Calcitonin (salmon) for prevention of vertebral bone mineral density loss has not been established. It has been suggested that those postmenopausal patients having increased rates of bone turnover may be more likely to respond to anti-resorptive agents such as Calcitonin (salmon). Nasal Spray: Calcitonin (salmon) nasal spray is indicated for the treatment of postmenopausal osteoporosis in females greater than 5 years postmenopause with low bone mass relative to healthy premenopausal females. Calcitonin (salmon) nasal spray should be reserved for patients who refuse or cannot tolerate estrogens or in whom estrogens are contraindicated. Use of Calcitonin (salmon) 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. The evidence of efficacy is based on increases in spinal bone mineral density observed in clinical trials. Two randomized, placebo controlled trials were conducted in 325 postmenopausal females [227 Calcitonin (salmon) nasal spray treated and 98 placebo treated] with spinal, forearm or femoral bone mineral density (BMD) at least one standard deviation below normal for healthy premenopausal females. These studies conducted over two years demonstrated that 200 IU daily of Calcitonin (salmon) nasal spray increases lumbar vertebral BMD relative to baseline and relative to placebo in osteoporotic females 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 six months after initiation of therapy with persistance 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 one year of treatment changing to a trend at 2 years that was no longer statistically significant.
Paget's Disease Injection: The recommended starting dose of Calcitonin (salmon) in Paget's disease is 100 IU (0.5 ml) per day administered subcutaneously (preferred for outpatient self-administration) or intramuscularly. Drug effect should be monitored by periodic measurement of serum alkaline phosphatase and 24-hour urinary hydroxyproline (if available) and evaluations of symptoms. A decrease toward normal of the biochemical abnormalities is usually seen, if it is going to occur, within the first few months. Bone pain may also decrease during that time. Improvement of neurologic lesions, when it occurs, requires a longer period of treatment, often more than one year. In many patients, doses of 50 IU (0.25 ml) per day or every other day are sufficient to maintain biochemical and clinical improvement. At the present time, however, there are insufficient data to determine whether this reduced dose will have the same effect as the higher dose on forming more normal bone structure. It appears preferable, therefore, to maintain the higher dose in any patient with serious deformity or neurological involvement. In any patient with a good response initially who later relapses, either clinically or biochemically, the possibility of antibody formation should be explored. The patient may be tested for antibodies by an appropriate specialized test or evaluated for the possibility of antibody formation by critical clinical evaluation. Patient compliance should also be assessed in the event of relapse. In patients who relapse, whether because of antibodies or for unexplained reasons, a dosage increase beyond 100 IU per day does not usually appear to elicit an improved response. Hypercalcemia Injection: The recommended starting dose of Calcitonin (salmon) injection, synthetic in hypercalcemia is 4 IU/kg body weight every 12 hours by subcutaneous or intramuscular injection. If the response to this dose is not satisfactory after one or two days, the dose may be increased to 8 IU/kg every 12 hours. If the response remains unsatisfactory after two more days, the dose may be further increased to a maximum of 8 IU/kg every 6 hours. Postmenopausal Osteoporosis Injection: The minimum effective dose of salmon calcitonin for the prevention of vertebral bone mineral density loss has not been established. Data from a single one-year placebo-controlled study with salmon calcitonin injection suggested that 100 IU (subcutaneously or intramuscularly) every other day might be effective in preserving vertebral bone mineral density. Baseline and interval monitoring of biochemical markers of bone resorption/turnover (e.g., fasting AM, second-voided urine hydroxyproline to creatinine ratio) and of bone mineral density may be useful in achieving the minimum effective dose. The recommended dose of calcitonin is 100 IU per day administered subcutaneously or intramuscularly. Patients should also receive supplemental calcium such as calcium carbonate 1.5 g daily and an adequate vitamin Dy intake (400 units daily). An adequate diet is also essential. If the volume of Calcitonin (salmon) injection, synthetic to be injected exceeds 2 ml, intramuscular injection is preferable and multiple sites of injection should be used. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Nasal Spray: The recommended dose of Calcitonin (salmon) nasal spray in postmenopausal osteoporotic females is 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 loss or increases in bone density. Effects of Calcitonin (salmon) nasal spray on biochemical markers of bone turnover have not been consistently demonstrated in studies in postmenopausal osteoporosis. Therefore, these parameters should not be solely utilized to determine clinical response to Calcitonin (salmon) nasal spray therapy in these patients. Activation of Pump: Before the first dose, it is necessary to activate the pump. The bottle should be held upright and the two white side arms depressed toward the bottle six times until a faint spray is emitted. The pump is activated once this first faint spray has been emitted. At this point, the nozzle should be placed firmly into the nostril with the head in the upright position, and the pump depressed toward the bottle. It is not necessary to reactivate the pump before each daily dose. HOW SUPPLIED Nasal Spray: Available as a metered dose solution in 2 ml fill glass bottles. It is available in a dosage strength of 200 IU per activation (0.09 ml/puff). A screw-on pump is provided. This pump, following activation, will deliver 0.09 ml of solution. Miacalcin Nasal Spray contains 2200 IU/ml Calcitonin (salmon). Store unopened in refrigerator between 36°-46°F (2°-8°C). Protect from freezing. Once the pump has been activated, the bottle may be maintained at room temperature until the medication has been finished, which is a period of 2 weeks. Injection: Store in Refrigerator - Between 2°-8°C
(36°-46°F).
Gastrointestinal System Injection: Nausea with or without vomiting has been noted in about 10% of patients treated with calcitonin. It is most evident when treatment is first initiated and tends to decrease or disappear with continued administration. Dermatologic/Hypersensitivity Injection: Local inflammatory reactions at the site of subcutaneous or intramuscular injection have been reported in about 10% of patients. Flushing of face or hands occurred in about 2%-5% of patients. Skin rashes, nocturia, pruritus of the ear lobes, feverish sensation, pain in the eyes, poor appetite, abdominal pain, edema of feet, and salty taste have been reported in patients treated with Calcitonin (salmon). Administration of Calcitonin (salmon) has been reported in a few cases to cause serious allergic-type reactions (e.g., bronchospasm, swelling of the tongue or throat, and anaphylactic shock), and in one case, death attributed to anaphylaxis (see WARNINGS). Nasal Spray: The incidence of adverse reactions reported in studies involving postmenopausal osteoporotic patients chronically exposed to Calcitonin (salmon) nasal spray (N=341) and to placebo nasal spray (N=131) and reported in greater than 3% of Calcitonin (salmon) nasal spray treated patients are presented below in the following table (TABLE 1). Most adverse reactions were mild to moderate in severity. Nasal adverse events were most common with 70% mild, 25% moderate, and 5% severe in nature (placebo rates were 71% mild, 27% moderate, and 2% severe).
Body as a Whole (General Disorders): Influenza-like
symptoms*, fatigue*, periorbital
edema, fever.
Common adverse reactions associated with the use of injectable Calcitonin (salmon) occurred less frequently in patients treated with Calcitonin (salmon) nasal spray than in those patients treated with injectable calcitonin. Nausea, with or without vomiting, which occurred in 1.8% of patients treated with the nasal spray (and 1.5% of those receiving placebo nasal spray) occurs in about 10% of patients who take injectable Calcitonin (salmon). Flushing, which occurred in less than 1% of patients treated with the Nasal Spray, occurs in 2%-5% of patients treated with injectable Calcitonin (salmon). Although the administered dosages of injectable and nasal spray Calcitonin (salmon) are comparable (50-100 units daily of injectable versus 200 units daily of nasal spray), the nasal dosage form has a mean bioavailability of about 3% (range 0.3%- 30.6%) and therefore provides less drug to the systemic circulation, possibly accounting for the decrease in frequency of adverse reactions. The collective foreign marketing experience with Miacalcin (Calcitonin (salmon)) Nasal Spray does not show evidence of any notable difference in the incidence profile of reported adverse reactions when compared with that seen in the clinical trials.
Nasal Spray: Formal studies designed to evaluate drug interactions with Calcitonin (salmon) have not been done. No drug interaction studies have been performed with Calcitonin (salmon) nasal spray ingredients. Currently, no drug interactions
with Calcitonin (salmon) have been observed. The effects of prior use
of diphosphonates in postmenopausal
osteoporosis patients have not been assessed; however, in patients with
Paget's Disease prior diphosphonate use appears to reduce
the anti-resorptive response to Calcitonin (salmon) nasal
spray.
Allergic REACTIONS Injection: Because calcitonin is protein in nature, the possibility of a systemic allergic reaction exists. Administration of Calcitonin (salmon) has been reported in a few cases to cause serious allergic-type reactions (e.g., bronchospasm, swelling of the tongue or throat, and anaphylactic shock), and in one case, death attributed to anaphylaxis. The usual provisions should be made for the emergency treatment of such a reaction should it occur. Allergic reactions should be differentiated from generalized flushing and hypotension. Skin testing should be considered prior to treatment with calcitonin, particularly for patients with suspected sensitivity to calcitonin. The following procedure is suggested: Prepare a dilution at 10 IU per ml by withdrawing 1/20 ml (0.05 ml) in a tuberculin syringe and filling it to 1.0 ml with Sodium Chloride Injection. 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. The incidence of osteogenic sarcoma is known to be increased in Paget's disease. Pagetic lesions, with or without therapy, may appear by x-ray to progress markedly, possibly with some loss of definition of periosteal margins. Such lesions should be evaluated carefully to differentiate these from osteogenic sarcoma. Nasal Spray: Because calcitonin is a polypeptide, the possibility of a systemic allergic reaction exists. In clinical trials with Calcitonin (salmon) nasal spray and foreign marketing experience, no serious allergic-type adverse reactions have been reported. However, with injectable Calcitonin (salmon) there have been a few reports of serious allergic-type reactions (e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and in one case death attributed to anaphylaxis). The usual provisions should be made for the emergency treatment of such a reaction should it occur. Allergic reactions should be differentiated from generalized flushing and hypotension. Skin testing should be considered prior to treatment with nasal calcitonin for patients with suspected sensitivity to calcitonin. The following procedure is suggested: Prepare a dilution at 10 IU per ml by withdrawing 1/20 ml (0.05 ml) of injectable Calcitonin (salmon) in a tuberculin syringe and filling it to 1.0 ml with Sodium Chloride Injection. 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.
Injection General: The administration of calcitonin possibly could lead to hypocalcemic tetany under special circumstances although no cases have yet been reported. Provisions for parenteral calcium administration should be available during the first several administrations of calcitonin. Laboratory Tests: Periodic examinations of urine sediment of patients on chronic therapy are recommended. Coarse granular casts and casts containing renal tubular epithelial cells were reported in young adult volunteers at bed rest who were given Calcitonin (salmon) to study the effect of immobilization on osteoporosis. There was no other evidence of renal abnormality and the urine sediment became normal after calcitonin was stopped. Urine sediment abnormalities have not been reported by other investigators. Information for the Patient: Careful instruction in sterile injection technique should be given to the patient, and to other persons who may administer Calcitonin (salmon) injection, synthetic. Carcinogenesis, Mutagenesis, and Impairment of Fertility: An increased incidence of pituitary adenomas has been observed in one-year toxicity studies in Sprague-Dawley rats administered Calcitonin (salmon) at dosages of 20 and 80 IU/kg/day and in Fisher 344 rats given 80 IU/kg/day. The relevance of these findings to humans is unknown. Calcitonin (salmon) was not mutagenic in tests using Salmonella typhimurium, Escherichia coli, and Chinese Hamster V79 cells. Pregnancy, Teratogenic Effects, Pregnancy Category C: Calcitonin (salmon) has been shown to cause a decrease in fetal birth weights in rabbits when given in doses 14-56 times the dose recommended for human use. Since calcitonin does not cross the placental barrier, this finding may be due to metabolic effects of calcitonin on the pregnant animal. There are no adequate and well-controlled studies in pregnant women. Calcitonin (salmon) injection, synthetic should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be undertaken while a patient is on this drug since many drugs are excreted in human milk. Calcitonin has been shown to inhibit lactation in animals. Pediatric Use: Disorders of bone in children referred to as juvenile Paget's disease have been reported rarely. The relationship of these disorders to adult Paget's disease has not been established and experience with the use of calcitonin in these disorders is very limited. There are no adequate data to support the use of Calcitonin (salmon) injection, synthetic in children. Nasal Spray Periodic Nasal Examinations: Periodic nasal examinations with visualization of the nasal mucosa, turbinates, septum and mucosal blood vessel status are recommended. The development of mucosal alterations or transient nasal conditions occurred in up to 9% of patients who received Calcitonin (salmon) nasal spray and in up to 12% of patients who received placebo nasal spray in studies in postmenopausal females. The majority of patients (approximately 90%) in whom nasal abnormalities were noted also reported nasally related complaints/symptoms as adverse events. 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 spray, the most commonly reported nasal adverse events included rhinitis (12%), epistaxis (3.5%), and sinusitis (2.3%). Smoking was shown not to have any contributory effect on the occurrence of nasal adverse events. One patient (0.3%) treated with Calcitonin (salmon) nasal spray who was receiving 400 IU daily developed a small nasal wound. 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 spray should be discontinued. Although smaller ulcers often heal without withdrawal of Calcitonin (salmon) nasal spray, medication should be discontinued temporarily until healing occurs. Information for the Patient: Careful instructions on pump assembly, priming of the pump and nasal introduction of Calcitonin (salmon) nasal spray should be given to the patient. Although instructions for patients are supplied with individual bottles, procedures for use should be demonstrated to each patient. Patients should notify their physician if they develop significant nasal irritation. Carcinogenesis, Mutagenesis, and Impairment of Fertility: An increased incidence of non-functioning pituitary adenomas has been observed in one-year toxicity studies in Sprague-Dawley and Fischer 344 Rats administered (subcutaneously) Calcitonin (salmon) at dosages of 80 IU per kilogram per day (16-19 times the recommended human parenteral dose and about 130-160 times the human intranasal dose based on body surface area). The findings suggest that Calcitonin (salmon) reduced the latency period for development of pituitary adenomas that do not produce hormones, probably through the perturbation of physiologic processes involved in the evolution of this commonly occurring endocrine lesion in the rat. Although administration of Calcitonin (salmon) reduces the latency period of the development of non-functional proliferative lesions in rats, it did not induce the hyperplastic/neoplastic process. Calcitonin (salmon) was tested for mutagenicity using Salmonella typhimurium (5 strains) and Escherichia coli (2 strains), with and without rat liver metabolic activation, and found to be non- mutagenic. The drug was also not mutagenic in a chromosome aberration test in mammalian V79 cells of the Chinese Hamster in vitro. Laboratory Tests: Urine sediment abnormalities have not been reported in ambulatory volunteers treated with Miacalcin (calcitonin- salmon) Nasal Spray. Coarse granular 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 evidence of renal abnormality and the urine sediment became normal after calcitonin was stopped. Periodic examinations of urine sediment should be considered. Pregnancy, Teratogenic Effects, Pregnancy Category C: Calcitonin (salmon) has been shown to cause a decrease in fetal birth weights in rabbits when given by injection in doses 8-33 times the parenteral dose and 70-278 times the intranasal dose recommended for human use based on body surface area. Since calcitonin does not cross the placental barrier, this finding may be due to metabolic effects on the pregnant animal. There are no adequate and well controlled studies in pregnant women with Calcitonin (salmon). Calcitonin (salmon) nasal spray is not indicated for use in pregnancy. Nursing Mothers: It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be undertaken while a patient is on this drug since many drugs are excreted in human milk. Calcitonin has been shown to inhibit lactation in animals. Geriatric Use: Clinical trials using Miacalcin (calcitonin- salmon) Nasal Spray have included post-menopausal patients 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. Pediatric Use There are no data to support
the use of Calcitonin (salmon) nasal
spray in children. 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
in these disorders is very limited.
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