Caltine (Synthetic Calcitonin Salmon)

CALTINE®

Ferring

Synthetic Calcitonin Salmon (Salcatonin)

Paget’s Disease Therapy – Hypercalcemia Treatment

Action And Clinical Pharmacology: Salmon calcitonin participates in the regulation of the homeostasis of calcium by acting primarily on the bone, in Paget’s disease presumably by an initial blocking effect on accelerated bone resorption. The rate of bone turnover appears to be decreased.

The pharmacologic activity of salmon calcitonin is the same as that of the endogenously produced hormone, but salmon calcitonin is substantially more potent on a weight basis and has a longer duration of action. Calcitonin acts predominantly on bone to depress bone resorption, but also has direct effects on the kidneys and the gastrointestinal tract. As a result of the inhibition of release of calcium from bone, and the stimulation of urinary calcium excretion, calcitonin tends to lower blood calcium.

Following parenteral administration, the hypocalcemic effect of calcitonin is apparent in about 15 minutes, peaks at approximately 4 hours, and lasts for 8 to 24 hours.

The lowering of serum calcium with calcitonin can, under certain conditions, be as much as 3 to 4 mg%. Chronic administration of calcitonin results in a parallel diminution of 2 parameters of bone turnover, namely, serum alkaline phosphatase levels, and total hydroxyproline excretion in the urine. The extent to which calcitonin can inhibit bone resorption depends on the existing rate of bone resorption (the higher the rate of bone resorption, the more evident the inhibition of bone resorption following calcitonin administration). Thus, these biochemical effects are more prominent in patients with generalized Paget’s disease, or hypercalcemia than in healthy adults, who have a relatively low rate of bone resorption.

Paget’s disease is characterized by a mixed picture of bone resorption, increased vascularity, high bone turnover and irregular bone formation. One or more bones may be affected, and an increased alkaline phosphatase is often found on a routine laboratory screen. Clinical features can include bone pain, deformities, nerve and blood vessel compression, increased cardiac output, spontaneous fractures and osteogenic sarcoma. Immobilization of patients with Paget’s disease may lead to hypercalcemia, hypercalciuria, and renal calculus formation.

Salmon calcitonin has been shown to be effective in relieving bone pain in 60 to 80% of patients with Paget’s disease. A similar proportion show a parallel diminution of alkaline phosphatase levels in the serum (reflecting increased bone formation), and of total hydroxyproline excretion in the urine (reflecting breakdown of collagen-containing bone matrix) in the same proportions (average 50%). Significant pain relief is usually evident within 2 months after initiation of therapy, with the maximum relief being obtained within 6 to 12 months.

The biochemical changes produced by calcitonin have been shown to correlate with changes toward more normal bone, as evidenced by radiologic assessments showing slowing or even regression of resorption fronts in pagetic lesions, the observation of rapid healing of pathological fractures during treatment with the prevention of immobilization hypercalcemia, and the decreased fracture rate during therapy.

In Paget’s disease, orthopedic surgery is associated with complications due to softness of bone and/or excessive bleeding in about 50% of cases. In patients pretreated with calcitonin prior to surgery, no complications were found.

Other symptoms of Paget’s disease that may show a beneficial effect with calcitonin treatment are high output cardiac failure, and symptoms due to, or mimicking neurologic compression.

In most patients with hypercalcemia treated with calcitonin, the hypocalcemic response was partial, with the serum calcium decreasing from a dangerously high level to a more tolerable or mildly hypercalcemic range. Often, there was an accompanying clinical improvement, allowing resumption of eating and further improvement, and, where applicable, the institution of definitive treatment for the underlying disease. In patients with multiple myeloma, a stable normocalcemia was achieved in all those with mild hypercalcemia, and about half of those with severe hypercalcemia. Prolonged normocalcemia after cessation of calcitonin therapy has been reported.

Indications And Clinical Uses: Paget’s Disease of Bone: For the management of symptomatic Paget’s disease of bone (osteitis deformans).

Hypercalcemia: For the early treatment of hypercalcemic emergencies (eg. hypercalcemic patients with carcinoma – with or without metastases, multiple myeloma or primary hyperparathyroidism), along with other appropriate agents, in cases where a rapid reduction in serum calcium concentration is required, until more specific treatment of the underlying disorder is instituted. The drug may also be added to the existing therapeutic regimens for the treatment of hypercalcemia, such as i.v. fluids and furosemide, oral phosphates, corticosteroids or other agents.

Salmon calcitonin may be used in patients with azotemia and those with limited cardiac reserve in whom i.v. fluids may be contraindicated.

Contra-Indications: Hypersensitivity to salmon calcitonin.

Manufacturers’ Warnings In Clinical States: Administration of salmon calcitonin has been associated with serious allergic type reactions, such as bronchospasm, swelling of the tongue or throat, tachycardia, hypotension, collapse and anaphylactic shock and in 1 case death due to anaphylaxis (see Precautions).

Children: There are no adequate safety and efficacy data supporting the use of calcitonin in children. The relationship between juvenile Paget’s disease to Paget’s disease in adults has not been established and salmon calcitonin has been used only rarely in children.

Pregnancy: Salmon calcitonin has been shown to decrease fetal birth weights in rabbits when given in doses 14 to 56 times the human therapeutic doses. It is not known whether salmon calcitonin can cause fetal harm when administered to pregnant women. Therefore the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Lactation: Salmon calcitonin inhibits lactation in animals, and the drug should therefore not be administered to nursing mothers.

Precautions: The possibility of a systemic allergic reaction should be borne in mind, and appropriate measures of treatment of a hypersensitivity reaction should be readily available. Skin testing should be considered prior to initiating salmon calcitonin therapy and the drug should not be given to patients with a positive skin test. The following procedure is suggested for the skin test:

Prepare a dilution of 10 IU/mL by withdrawing 1/10 mL (0.1 mL) in a tuberculin syringe and filling it to 1 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.

The possibility of hypocalcemic tetany following salmon calcitonin administration should be considered, and calcium injection should be readily available, particularly during administration of the first several doses of salmon calcitonin.

Patients receiving salmon calcitonin for long periods should have periodic examinations of urine sediment as coarse granular casts and casts containing renal tubular epithelial cells were reported in some volunteers in a study of the effect of calcitonin salmon on immobilization osteoporosis.

Radiographic evidence of marked progressive pagetic lesions, possibly with some loss of definition of periosteal margins, must be evaluated carefully to rule out the possibility of osteogenic sarcoma since the frequency of this tumor is increased in patients with Paget’s disease of bone.

Careful instructions in sterile injection technique should be given to the patient, and to other persons who may administer salmon calcitonin.

Adverse Reactions: Adverse effects with salmon calcitonin are usually mild, although, in about 10% of patients adverse effects may be severe enough to require discontinuance of the drug.

Adverse effects of salmon calcitonin most frequently involve the gastrointestinal tract. Nausea, with or without vomiting, is the most common adverse effect (incidence of about 20 to 40%), but it usually disappears with continued use. Other less common adverse effects on the gastrointestinal tract include: anorexia, diarrhea, epigastric pain, abdominal pain and an unusual taste.

Three cases of hypertension have been reported following the use of salmon calcitonin.

Flushing of face, ears, hands, and feet may occur (incidence of 10 to 35%), usually within minutes after salmon calcitonin injection, but this effect is usually well tolerated. Tenderness and/or tingling of the palms and soles has also been reported.

A local inflammatory reaction may occur at the site of injection: swelling, pain, erythema, urticaria have been occasionally reported (incidence of about 10%). A few cases of generalized urticaria have been reported with both salmon and human forms of calcitonin.

During the first few days of the drug administration, some patients may experience diuresis and increased urinary sodium excretion but this usually returns to the baseline levels within 5 to 7 days. Urinary frequency may occur during this time.

Antibodies to salmon calcitonin have been reported in 30 to 50% of patients after 2 to 18 months of therapy, but in no instance have these elevated antibody titers been associated with any systemic allergic or anaphylactic effect, and only rarely have antibodies been associated with the development of clinical resistance to calcitonin.

One case of symptoms of hypocalcemic tetany accompanying administration of human calcitonin has been reported (paresthesia, increased irritability). These symptoms disappeared on administration of calcium salts.

Administration of salmon calcitonin has been associated with serious allergic type reactions, such as bronchospasm, swelling of the tongue or throat, tachycardia, hypotension, collapse and anaphylactic shock and in 1 case death due to anaphylaxis.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In general, no corrective action needs to be taken, other than to discontinue treatment temporarily and maintain the patient under observation. Supportive treatment may be indicated. Provisions for parenteral calcium administration should be available during the first several administrations of calcitonin in case of hypocalcemic tetany.

Dosage And Administration: Dosage is expressed in terms of IU (International Units). An International Unit for salmon calcitonin is defined as the activity contained in 0.02525 mg of the International Reference Preparation of Calcitonin, Salmon for Bioassay.

Paget’s Disease: The recommended adult dosage in Paget’s disease of bone is 100 IU (1 mL) daily administered s.c. or i.m. The effect of the drug should be monitored by determinations of serum alkaline phosphatase and urinary hydroxyproline excretion before initiating salmon calcitonin therapy and every 3 to 6 months during chronic therapy. Decreases in these parameters are usually seen within the first few months of therapy, as is relief of bone pain.

Adjustments in dosage should be guided by clinical and radiologic response and by changes in biochemical parameters. When clinical or biochemical improvement occurs, the patient can often be maintained at a dose of 50 IU/day or at 50 to 100 IU 3 times/week. A dose of 100 IU/day should be continued in more severe cases. Benefits of long-term calcitonin therapy generally persist for weeks or months after drug withdrawal, usually followed by return to the pretreatment status.

The possibility of substantial antibody formation should be investigated. Although specialized tests for antibody titer are not widely available, the following test will detect titers that interfere with the action of calcitonin.

After overnight fasting, a sample of the patient’s blood is taken for determination of serum calcium and 100 IU of salmon calcitonin are injected i.m. The patient is then permitted to eat his usual breakfast. At 3 and 6 hours post-injection, additional blood samples are drawn. The serum calcium values are then compared. A decrease of 0.5 mg% or more from fasting level at 3 and 6 hours is usually seen in the responsive patient. Decreases of 0.3 mg% or less constitute an inadequate response to calcitonin in the patient with active Paget’s disease. If the hypocalcemic action of calcitonin is lost, further therapy with salmon calcitonin will not be effective. In these cases, patient compliance should also be assessed in the event of relapse.

Hypercalcemia: For the management of hypercalcemia, the recommended initial dosage is 4 IU/kg every 12 hours by s.c. or i.m. injection. If the response to this dosage is not satisfactory after 1 to 2 days, dosage may be increased up to 8 IU/kg every 12 hours. If there is no satisfactory improvement after another 2 days, dosage may be increased to a maximum of 8 IU/kg every 6 hours.

Administration: Calcitonin salmon may be administered s.c. or i.m. Prior to initiation of salmon calcitonin therapy, a skin test using calcitonin salmon should be performed (see Precautions). When the injection volume exceeds 2 mL, the i.m. route is preferable and multiple sites of injection should be used. The s.c. route of administration is preferred for self-administration. Patients and/or other individuals who are administering calcitonin salmon should be carefully instructed about proper techniques including aseptic precautions. Because treatment with salmon calcitonin is usually prolonged, injection sites should be alternated.

Availability And Storage: Each mL contains: salcatonin (B.P.) 100 IU, sodium acetate 0.489 mg, sodium chloride 0.067 mg, acetic acid and sodium hydroxide to adjust toxicity and pH. pH: 3.9 to 4.5. Prescored glass ampuls of either 100 IU (1 mL) or 50 IU (0.5 mL). Store at refrigerator temperature (2 to 8°C).

CALTINE® Ferring Synthetic Calcitonin Salmon (Salcatonin) Paget’s Disease Therapy – Hypercalcemia Treatment

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Paget’s Disease

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