Medication Guide App

Calcitonin (Systemic)

This monograph includes information on the following:

1) Calcitonin-Human  
2) Calcitonin-Salmon

VA CLASSIFICATION
Primary: HS304

Commonly used brand name(s): Calcimar2; Cibacalcin1; Miacalcin2.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Bone resorption inhibitor—

osteoporosis therapy adjunct—

antihypercalcemic therapy adjunct—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Paget's disease of bone (treatment)—Calcitonin-salmon and calcitonin-human are indicated in the treatment of moderate to severe symptomatic Paget's disease (osteitis deformans), characterized by abnormal and accelerated bone metabolism in one or more bones. Signs and symptoms may include bone pain, deformity, and/or fractures; increased concentrations of serum alkaline phosphatase and/or urinary hydroxyproline; neurologic disorders associated with skull lesions and spinal deformities; and elevated cardiac output and other vascular disorders associated with increased vascularity of bones. Calcitonin-human may be effective for {13} treatment of patients who have developed resistance to calcitonin-salmon. {01} {02} {04} {07}

Osteoporosis, postmenopausal (treatment adjunct)—Calcitonin-salmon1 is indicated [and calcitonin-human is used] for the treatment of osteoporosis in postmenopausal women in conjunction with an adequate intake of calcium (1.5 grams of elemental calcium per day) and vitamin D (400 IU per day) to aid in the prevention of {10} the progressive loss of bone mass. An adequate diet is also essential. {01} {02} {05} {06} {25} {27}
—Although calcitonin may increase bone mass or {09} {25} help slow the loss of bone mass in some patients, questions still remain as to whether treatment with calcitonin will actually decrease the incidence of compression fractures in postmenopausal women with osteoporosis.

Hypercalcemia (treatment adjunct)—Calcitonin-salmon is indicated [and calcitonin-human is used] with intravenous saline and other appropriate hypocalcemic agents in the treatment of hypercalcemic emergencies. Calcitonin has been shown to effectively lower serum calcium concentrations in patients with carcinoma, multiple myeloma, or, to a lesser degree, primary {10} hyperparathyroidism. {02} Calcitonin-salmon may be added to existing therapeutic regimens for the treatment of hypercalcemia, such as intravenous fluids, furosemide, oral phosphates, or adrenocorticoids. {01} {02}

[Osteoporosis, secondary (treatment adjunct)]1—Calcitonin-human and calcitonin-salmon are used in conjunction with an adequate intake of calcium and vitamin D {28} for the treatment of osteoporosis secondary to hormonal disturbances, drug therapy, immobilization, {01} and other causes. Calcitonin therapy is initiated when treatment of the underlying etiology is not feasible. {20} {21} {22} {23} {24} {26}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Calcitonin-human: 3527.20
    Calcitonin-salmon: 3431.88

Mechanism of action/Effect:

Paget's disease—Calcitonin reduces the rate of bone turnover, possibly by an initial blocking of bone resorption, resulting in decreases in serum alkaline phosphatase (reflecting decreased bone formation) and decreases in urinary hydroxyproline excretion {20} (reflecting decreased bone resorption, i.e., breakdown of collagen). {01} {03}

Osteoporosis or

Hypercalcemia—Calcitonin lowers serum calcium concentration primarily by a direct inhibition of bone resorption. The number and/or function of osteoclasts is reduced and a decrease in osteocytic resorption may also be involved. {01} These effects may be mediated in part by a drug-induced increase in cyclic adenosine monophosphate concentration in bone cells and subsequent alteration of calcium and/or phosphate transport across the plasma membrane of the osteoclast.


Other actions/effects:

Calcitonin also has a direct effect on the kidneys, increasing the excretion of calcium, phosphate, and sodium by inhibiting their tubular reabsorption. {01} These effects are also mediated in part by cyclic adenosine monophosphate. However, in some patients, calcitonin-induced inhibition of bone resorption has a greater effect on calcium excretion than does the drug's direct renal action, so that urinary calcium is decreased rather than increased. {01}

Short-term administration of calcitonin results in decreases in the volume and acidity of gastric juice, and in trypsin and amylase content and volume of pancreatic juice. {01}


Duration of effect

Calcitonin-salmon—Hypercalcemia: 6 to 8 hours. {02}

Biotransformation:

Calcitonin is rapidly metabolized, primarily in the kidneys but also in blood and peripheral tissues. {01}

Half-life:

Calcitonin-human—60 minutes, after a single dose. {04}

Calcitonin-salmon—70 to 90 minutes, after a single dose. {12}

Onset of therapeutic action

Calcitonin-human and calcitonin-salmon— {20}Maximum reductions of serum alkaline phosphatase and urinary hydroxyproline excretion in Paget's disease {08} may take 6 to 24 months of continuous treatment. {04}

Time to peak effect:

Cacitonin-salmon—Hypercalcemia: 2 hours. {02}

Elimination:
    Renal; very small amounts are excreted unchanged.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients who are allergic to proteins may be allergic to calcitonin, since calcitonin is a protein. Its use is not recommended in patients with suspected sensitivity {03} who show a positive response to skin testing prior to initiating therapy. {01} Since calcitonin-salmon is a foreign protein, it may induce antibodies with continued use. In short-term treatment (2 years or less), antibody titers appear in 30 to 60% of treated patients, but only 5 to 15% become resistant to treatment as a result. {08} Long-term treatment may be possible in patients who are not limited by antibody formation. {12} Because synthetic human calcitonin is identical to naturally occurring human calcitonin, antibody formation is rare, allowing longer term {15}treatment that is not limited by antibody-mediated resistance. {04}

Carcinogenicity

No long-term studies have been done to evaluate carcinogenic potential of calcitonin. {01} The incidence of osteogenic sarcoma is increased in Paget's disease with or without treatment {15}. Pagetic lesions, with or without therapy, should be carefully evaluated to distinguish them from osteogenic sarcoma, since such lesions may show marked progression on x-ray, with possible loss of periosteal margins. Calcitonin does not appear to slow the progression of such sarcomas. {08}

Pregnancy/Reproduction

Pregnancy—
No adequate and well-controlled studies in humans have been done. However, calcitonin does not cross the placenta.

In animal studies, calcitonin has been shown to decrease fetal birth weight, when given in doses 14 to 56 times the dose recommended for human use, possibly due to metabolic effects on the pregnant animal {01} {04}.

FDA Pregnancy Category C. {01} {04}

Breast-feeding

Calcitonin is distributed into breast milk. {12} However, problems in humans have not been documented. In animal studies, calcitonin has been shown to inhibit lactation. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of calcitonin have not been performed in the pediatric population.


Geriatrics


Appropriate studies on the relationship of age to the effects of calcitonin have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date. {15} {16}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Calcium-containing preparations or
Vitamin D, including calcifediol and calcitriol    (in the treatment of hypercalcemia, concurrent use may antagonize the effect of calcitonin; in the treatment of other conditions, calcium-containing preparations may be given 4 hours after calcitonin {29})

{03}
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Allergy to proteins (or history of) or
» Sensitivity to calcitonin    (possibility of systemic allergic reaction, especially in patients with a history of severe allergy, even with a negative skin test reaction to calcitonin, {03} because of the protein nature of calcitonin; allergic reaction is more likely with calcitonin-salmon {01} {28})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Alkaline phosphatase concentrations, serum and{01}{04}
Urinary hydroxyproline concentrations (24-hour){01}{04}    (determinations recommended at periodic intervals during therapy with calcitonin-salmon in Paget's disease of bone; during therapy with calcitonin-human, biochemical determinations are recommended prior to initiation, and once {20} during the first three months, and at approximately 3- to 6-month intervals during chronic treatment of Paget's bone disease to determine effectiveness and dosage of calcitonin {04}; most clinicians prefer to measure serum alkaline phosphatase for routine use because urinary hydroxyproline concentrations are cumbersome to measure and expensive {28})


Calcium concentrations, serum    (determinations required at periodic intervals during therapy for hypercalcemia)


Skin testing for allergic reaction    (recommended prior to treatment for patients with suspected hypersensitivity to calcitonin or patients with a history of florid allergy to foreign proteins {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Allergic reactions, specifically{01}
skin rash
and urticaria (hives)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Flushing, redness, or tingling of face, ears, hands, or feet {01}{04}{18}
    
gastrointestinal effects, specifically{18}
diarrhea{04}
loss of appetite{04}
nausea or vomiting{01}{04}
and stomach pain
    
redness, soreness, or swelling at injection site {04}

Incidence less frequent
    
Increased frequency of urination {04}

Incidence rare {04}
    
Chills
    
dizziness
    
headache
    
pressure in chest
    
stuffy nose
    
tenderness or tingling of hands or feet
    
trouble in breathing
    
weakness





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Calcitonin (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergies (history of) or sensitivity to calcitonin or other proteins





Breast-feeding—Distributed into breast milk; lactation inhibited in animal studies

Proper use of this medication
Proper administration: Using aseptic technique; subcutaneous injection preferred for self-administration {03}

Importance of using reconstituted solution of calcitonin-human within 6 hours

Importance of inspecting solution for particles or discoloration before administering

» Proper dosing
Missed dose: If dosage schedule is:

Two doses a day—Taking missed dose, if remembered within 2 hours, and continuing on schedule; if remembered later, skipping missed dose, not doubling doses, and continuing on schedule

One dose a day—Taking as soon as possible unless remembered the next day; then skipping missed dose and continuing on schedule, but not doubling doses

One dose every other day—Taking as soon as possible if on scheduled day; taking if remembered on alternate day, but skipping the following day and restarting schedule

One dose three times a week (Monday-Wednesday-Friday)—Taking missed dose the next day; setting each injection back a day and resuming regular schedule the following week

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during therapy

Possible need for calcium and vitamin D restriction, including calcifediol and calcitriol, in patients with hypercalcemia


Side/adverse effects
Signs of potential side effects, especially allergic reaction


General Dosing Information

For use in Paget's disease of bone
Clinical or biochemical improvement (decreased serum alkaline phosphatase) usually occurs within the first few months of therapy if calcitonin is effective. A longer period of therapy, often more than a year, may be required for maximum improvement.

Dosage adjustments depend on clinical and radiologic evidence, changes in serum alkaline phosphatase and urinary hydroxyproline excretion, and severity of nausea or flushing. {04}

Bedtime administration may help to reduce the severity of nausea or flushing. Reduction in dosage may also be helpful. {04}

After at least 6 months of treatment for Paget's disease, {04} if symptoms have been relieved, therapy may be reduced for 6 months, monitoring biochemical and clinical responses, before being discontinued. {20} Since biochemical indexes will relapse after cessation of treatment, they cannot be relied on to indicate a need for restarting therapy. {04}

CALCITONIN-HUMAN

Summary of Differences
Cross-sensitivity and/or related problems: May be used for longer term {15} treatment with less antibody formation or protein hypersensitivity than calcitonin-salmon. {17}


Additional Dosing Information
See also General Dosing Information.

More severe cases of Paget's disease of bone (evidence of weak bones with osteolytic lesions) may require doses of up to 1 mg a day, given in divided doses. {04}


Parenteral Dosage Forms

CALCITONIN-HUMAN FOR INJECTION

Usual adult dose
Paget's disease of bone
Subcutaneous, initially 500 mcg (0.5 mg) a day, the dosage being reduced for some patients to 500 mcg (0.5 mg) two or three times a week, or 250 mcg (0.25 mg) a day.

Note: To diminish side effects, some clinicians recommend starting with a low dose and gradually increasing dosage over 2 weeks. {20}



Usual pediatric dose
Dosage has not been established.

Size(s) usually available:
U.S.—


500 mcg (0.5 mg) (Rx) [Cibacalcin]

Canada—
Not commercially available.

Packaging and storage:
Store at a temperature not exceeding 25 °C (77 °F), unless otherwise specified by manufacturer. Protect from light. Do not refrigerate.

Preparation of dosage form:
To reconstitute, push the barrel of the double-chambered syringe into the vial as far as possible, and press upward on the plunger to release the water into the dry powder. Shake gently to mix. Withdraw the reconstituted medication back into the syringe and inject.

Stability:
The reconstituted solution should be used within 6 hours. {04}

Additional information:
One chamber of the dual syringe contains 0.5 mg of calcitonin-human for injection and mannitol (20 mg) {14} in sterile, lyophilized form. The other chamber contains mannitol (30 mg) in 1 mL of water for injection.


CALCITONIN-SALMON

Summary of Differences
Cross-sensitivity and/or related problems: Risk of protein hypersensitivity and antibody-mediated resistance greater than with calcitonin-human.


Additional Dosing Information
See also General Dosing Information.

This medicine is for intramuscular or subcutaneous injection. The subcutaneous route of administration is usually preferred for patient self-administration. {01}

If the volume to be injected exceeds 2 mL, the intramuscular route of administration is usually preferred and multiple sites of injection should be used to minimize local inflammatory reactions. {02}

Skin testing should be considered prior to treatment of patients with suspected sensitivity to calcitonin-salmon. The manufacturer's recommendation for preparing the solution for skin testing is as follows:
   • Prepare a dilution of 10 IU per mL by withdrawing 0.05 mL into a tuberculin syringe (an insulin syringe with no ``dead space'' {11} may be preferred for a more accurate dilution {11}).
   • Fill to 1 mL with 0.9% sodium chloride injection. Mix well. {01}
   • Discard 0.9 mL and inject 0.1 mL intracutaneously on the inner forearm. {01}
   • Observe injection site 15 minutes after injection. {01}
   • A positive response is considered to be the appearance of a more than mild erythema or wheal. {01}
In any patient who has an acceptable initial response but later relapses, either clinically or biochemically, there is the possibility of antibody formation. Testing the patient for high antibody titer by an appropriate specialized test or by critical clinical evaluation {02} should be considered. Alternatively, a trial of therapy with calcitonin-human may be considered. {20} Patient compliance should also be assessed in the event of relapse.

In patients who have relapsed, a dosage increase above 100 IU per day does not appear to improve patient response. {02}


Parenteral Dosage Forms

CALCITONIN-SALMON INJECTION

Usual adult dose
Paget's disease of bone
Intramuscular or subcutaneous, initially 100 IU a day, the dosage being decreased to 50 IU once a day, once every other day, or three times a week, in patients without serious deformity or bone involvement. {01}

Hypercalcemia
Intramuscular or subcutaneous, initially 4 IU per kg of body weight every twelve hours, the dosage being increased, if necessary for a more satisfactory response, to 8 IU per kg of body weight every twelve hours, up to a maximum of 8 IU per kg of body weight every six hours. {01}

Postmenopausal osteoporosis1
Intramuscular or subcutaneous, 100 IU once a day, once every other day, or three times a week {03}.


Note: To diminish side effects, some clinicians recommend starting with a low dose and gradually increasing dosage over 2 weeks. {20}


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


200 IU per mL (Rx) [Calcimar] [Miacalcin]

Canada—


200 IU per mL (Rx) [Calcimar]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer. Do not freeze.

Auxiliary labeling:
   • Refrigerate.

Additional information:
May also contain 5 mg of phenol per mL, as a preservative.

The activity of calcitonin-salmon is stated in terms of International Units (IU), which are equal to Medical Research Council Units (MRC).



Revised: 06/27/1994



References
  1. Calcitonin-salmon product information (Miacalcin—Sandoz, U.S.) rec 12/91.
  1. Calcitonin-salmon product information (Calcimar—Rhone-Poulenc Rorer) 1992 Physicians Desk Reference.
  1. Panelist comment.
  1. Calcitonin-human product information (Cibacalcin—Ciba-Geigy, U.S.) rec 1991, rev 2/88.
  1. Palmieri G, Pitcock J, Brown P, Karas J, Roen L. Effect of calcitonin and vitamin D in osteoporosis. Calcif Tissue Int 1989; 45: 137-141.
  1. Gruber H, Ivey J, Baylink D, et al. Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism 1984; 33[4]: 295-303.
  1. Calcitonin-salmon product information (Calcimar—Rorer, Canada) 1991 CPS.
  1. Panelist comment, 1987 revision cycle.
  1. Panelist comment, 1991 revision cycle.
  1. Panelist comment, 1987 revision cycle.
  1. Panelist comment, 1987 revision cycle.
  1. Manufacturer comment, 1987 revision cycle.
  1. Manufacturer comment, 1987 revision cycle.
  1. Manufacturer comment, 1987 revision cycle.
  1. Panelist comment, 1988 revision cycle.
  1. Panelist comment, 1988 revision cycle.
  1. Altman R, Yudiskas B. Synthetic human calcitonin in refractory Paget's disease of bone. Arch Intern Med 1987; 147: 1305-1308.
  1. Gennan C, et al. Side-effects of synthetic salmon and human calcitonin. Lancet 3/12/83; pp 594-595.
  1. Panelist comment Calcitonin monograph, USP DI, 1990.
  1. Panelist comment, 1990 revision cycle.
  1. Maresca V. Human calcitonin in the management of osteoporosis: a multicentre study. J Int Med Res 1985; 13: 311.
  1. Rizzato G, et al. Bone protection with salmon calcitonin (sCT) in the long-term steroid therapy of chronic sarcoidosis. Sarcoidosis 1988; 5[2]: 99-103.
  1. Ringe J, Welzel D. Salmon calcitonin in the therapy of corticoid-induced osteoporosis. Eur J Clin Pharm 1987; 33: 35-39.
  1. Reid J. Pathogenesis and treatment of steroid osteopososis. Clin Endocrinol 1989; 30: 82-103.
  1. Gennari C, Chierichetti S, Bigazzi S, et al. Comparative effects on bone mineral content of calcium and calcium plus salmon calcitonin given in two different regimens in postmenopausal osteoporosis. Curr Ther Res 1985; 38[3]: 455-463.
  1. Luengo M, Picado C, Del Rio L, Guanabens N, Montserrat J, Setoain J. Treatment of steroid-induced osteopenia with calcitonin in corticosteroid-dependent asthma. Am Rev Resp Dis 1990; 142: 104-107.
  1. Civitelli R, Gonnelli S, Zacchei F, et al. Bone turnover in postmenopausal osteoporosis. J Clin Invest 1988; 82: 1268-1274.
  1. Panel consensus, 1991 revision cycle.
  1. Schapira D. Prevention and treatment of osteoporosis. Compreh Ther 1990; 10[3]: 27-33.
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