CALCITONIN
DESCRIPTION:
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.
CALSYNAR (calcitonin-salmon) Injection, Synthetic is a synthetic polypeptide
of 32 amino acids in the same linear sequence that is found in calcitonin of
salmon origin.
The activity of CALSYNAR (calcitonin-salmon) 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 for Biological Standards and Control, Holly Hill, London.
ACTIONS/CLINICAL PHARMACOLOGY:
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' 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.
INDICATIONS AND USAGE:
CALSYNAR (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.
Paget's Disease--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--CALSYNAR (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--CALSYNAR (calcitonin-salmon) Injection,
Synthetic is indicated for the treatment of postmenopausal osteoporosis in
conjunction with adequate calcium and vitamin D intake to prevent the
progressive loss of bone mass. No evidence currently exists to indicate whether
or not CALSYNAR (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 CALSYNAR (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 CALSYNAR (calcitonin-
salmon).
CONTRAINDICATIONS:
Clinical allergy to synthetic calcitonin-salmon.
WARNINGS:
ALLERGIC REACTIONS
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.
For patients with suspected sensitivity to calcitonin, skin testing should be
considered prior to treatment utilizing a dilute, sterile solution of
CALSYNAR (calcitonin-salmon) Injection, Synthetic. Physicians may wish to
refer patients who require skin testing to an allergist. A detailed skin testing
protocol is available from the Medical Services Department of Sandoz
Pharmaceuticals Corporation.
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.
PRECAUTIONS:
1. 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.
2. 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.
3. INSTRUCTIONS FOR THE PATIENT
Careful instruction in sterile injection technique should be given to the
patient, and to other persons who may administer CALSYNAR (calcitonin-
salmon) Injection, Synthetic.
4. 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 I.U./kg/day and in Fisher 344 rats given 80 I.U./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.
5. PREGNANCY: TERATOGENIC EFFECTS
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 on the pregnant animal. There are no adequate and well-
controlled studies in pregnant women. CALSYNAR (calcitonin-salmon)
Injection, Synthetic should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
6. 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.
7. 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 is no adequate data to support the use of
CALSYNAR (calcitonin-salmon) Injection, Synthetic in children.
ADVERSE REACTIONS:
GASTROINTESTINAL SYSTEM
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
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).
OVERDOSAGE:
A dose of 1000 I.U. subcutaneously may produce nausea and vomiting as the only
adverse effects. Doses of 32 units per kg per day for 1-2 days demonstrate no
other adverse effects.
Data on chronic high dose administration are insufficient to judge toxicity.
DOSAGE AND ADMINISTRATION:
Paget's Disease--The recommended starting dose of calcitonin-salmon in Paget's
disease is 100 I.U. (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 I.U. (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 I.U. per day does not usually appear to
elicit an improved response.
Hypercalcemia--The recommended starting dose of CALSYNAR (calcitonin-salmon)
Injection, Synthetic in hypercalcemia is 4 I.U./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 I.U./kg every
12 hours. If the response remains unsatisfactory after two more days, the dose
may be further increased to a maximum of 8 I.U./kg every 6 hours.
Postmenopausal Osteoporosis--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 I.U. (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. Patients should also receive supplemental calcium such
as calcium carbonate 1.5 g daily and an adequate vitamin D intake (400 units
daily). An adequate diet is also essential.
If the volume of CALSYNAR (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.
************************************************************************