Calcimar

CALCIMAR®

Rhône-Poulenc Rorer

Calcitonin Salmon

Paget’s Disease Therapy – Hypercalcemia Treatment

Action And Clinical Pharmacology: Calcitonin is a group of polypeptide hormones secreted by the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. It is of physiological importance in the regulation of calcium metabolism in certain animal species, and may also have physiological importance in certain extra skeletal systems (e.g., gastrointestinal and renal function).

Only small amounts of the drug are absorbed after administration by buccal, oral, topical (to the skin) or inhalation routes, and no practical use of these non parenteral routes has been made thus far. The drug is given s.c. or i.m.

Calcitonin, particularly the salmon form, is extremely potent. As little as 1 nanogram given s.c. to young rats lowers the serum calcium by 1 to 2 mg%.

Calcitonin is rapidly absorbed from i.m. and s.c. sites into the blood, although absorption is slowed by the use of a gelatin vehicle. Its half-life in the circulation, like that of other peptide hormones, is measured in minutes rather than hours. Salmon calcitonin, however, has a relatively longer half life than does porcine or human calcitonin. Immediately after introduction into the circulation calcitonin is present in the free form. Later it is largely protein bound, but this does not appear to interfere with either its biological or immunological activity.

Salmon calcitonin participates in the regulation of the homeostasis of calcium by acting primarily on the bone. In Paget’s disease, it is presumed to directly inhibit the accelerated bone resorption which characterizes the disease.

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 pre treatment levels with continued therapy.

Short-term calcitonin 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.

Indications And Clinical Uses: Treatment of symptomatic Paget’s disease of the bone. 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 also may be added to existing therapeutic regimens for hypercalcemia such as i.v. fluids and furosemide, oral phosphate or corticosteroids, or other agents. Calcitonin may be used in patients with azotemia and those with limited cardiac reserve in whom i.v. fluids may be contraindicated.

Contra-Indications: Known hypersensitivity to salmon calcitonin.

Manufacturers’ Warnings In Clinical States: Pregnancy: Reproduction studies in animals have revealed decreases in fetal birth weight. Data in humans are not available. Use of salmon calcitonin in women who are or may become pregnant requires that the potential benefit to the patient outweighs the possibility of risk to the fetus.

Lactation: Salmon calcitonin has been shown to inhibit lactation in animals and should not be administered to nursing mothers.

Children: The safety of the use of salmon calcitonin in children has not been established.

Precautions: Skin testing should be considered prior to treatment of patients with suspected sensitivity to calcitonin. The following procedure is suggested: Prepare a dilution of 10 IU/mL by withdrawing 0.05 mL of the reconstituted product 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.

Because calcitonin is protein in nature, the possibility of a systemic allergic reaction must be considered. Administration of calcitonin salmon has been reported in a few cases to cause serious allergic-type reactions (e.g. bronchospasms, swelling of the tongue or throat, and anaphylactic shock), and in one case, death due 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.

Calcitonin administration could possibly 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.

Coarse granular casts and casts containing renal tubular epithelial cells were reported in young adult volunteers at bed rest who were given salmon calcitonin to study its effect on immobilization 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, however, patients on chronic therapy should have periodic examinations of urine sediment.

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

There are no known interactions with other drugs.

Adverse Reactions: Nausea with or without vomiting has been noted in about 10% of patients treated. It is most evident when treatment is first initiated and tends to decrease or disappear with continued administration. Local inflammatory reactions at the injection site have been reported in about 10% of patients. Facial flushing occurs in about 2% of patients. Administration of calcitonin salmon has been reported in a few cases to cause serious allergic-type reactions (e.g. bronchospasms, swelling of the tongue or throat, and anaphylactic shock), and in one case, death due to anaphylaxis (see Precautions). Other systemic effects include anorexia, a metallic taste and tingling of the hands. These effects usually occur early in the treatment and tend to diminish with continued therapy.

Evidence of systemic allergic reactions is minimal and no anaphylactic reaction has been reported. In approximately one half the patients tested after 6 months or more of treatment, indications of circulating antibodies to calcitonin were obtained. In most of the patients the level of antibodies was not high enough to interfere with the effect of exogenous calcitonin. In a few patients, resistance to calcitonin was attributed to high levels of antibodies. Secondary hyperparathyroidism as a result of the transient hypocalcemia following calcitonin administration did not develop in patients with Paget’s disease.

Symptoms And Treatment Of Overdose: Symptoms: Calcitonin administration can lead to antibody development. This is minimal when the hormone is injected in the absence of an adjuvant or when it is not complexed with a larger protein. Gelatin and acetate buffer solutions have been shown to have little or no adjuvant like action in comparison to Freund’s adjuvant.

The antibodies which develop when calcitonin is administered repeatedly with Freund’s adjuvant are measurable in the circulation by radio-immunoassay techniques. In no instance has any systemic allergic or anaphylactic effect been reported in animal studies with calcitonin, in spite of the known development of circulating antibodies.

Treatment: There is no specific antidote; however, additional symptoms other than those discussed under Adverse Effects have not been observed and no corrective action need be taken other than to discontinue treatment temporarily and maintain the patient under observation. Supportive treatment may be indicated.

Dosage And Administration: Paget’s Disease: The recommended adult starting dose is 100 IU/day administered s.c. or i.m. Monitor drug effect by periodic measurement of serum alkaline phosphatase and 24 hour urinary hydroxyproline (if available) and evaluation 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 1 year.

In many patients, doses of 50 IU/day or alternate days 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, explore the possibility of antibody formation. Although specialized tests for antibody titre 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 Calcimar 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 will not be effective.

Assess patient compliance in the event of relapse. In patients who relapse, whether because of antibodies or for unexplained reasons, a dosage increase beyond 100 IU/day does not usually appear to elicit an improved response.

Hypercalcemia: The recommended starting dose of calcitonin in hypercalcemia is 4 IU/kg every 12 hours by s.c. or i.m. injection. If the response to this dose is not satisfactory after 1 or 2 days, the dose may be increased to 8 IU/kg every 12 hours. If the response remains unsatisfactory after 2 more days, the dose may be further increased to a maximum of 8 IU/kg every 6 hours.

If the volume to be injected exceeds 2 mL, i.m. injection is preferable and multiple sites of injection should be used.

In clinical trials, Calcimar 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 Calcimar therapy. The decrease in calcium occurs about 2 hours after the first injection and lasts for about 6 to 8 hours. Calcimar given every 12 hours maintained a calcium lowering effect for about 5 to 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%.

The use of Calcimar Solution in the management of hypercalcemia should be limited to patients under close supervision in hospitals.

Availability And Storage: Each mL of sterile solution contains: calcitonin salmon 200 IU. Nonmedicinal ingredients: acetic acid, phenol, sodium acetate, sodium chloride, sodium hydroxide and water for injection. Vials of 2 mL. Store refrigerated (2 to 8°C). Stable for 2 weeks at room temperature.

CALCIMAR® Rhône-Poulenc Rorer Calcitonin Salmon Paget’s Disease Therapy – Hypercalcemia Treatment

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Paget’s Disease

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