DESCRIPTION:
DRONATE OS tablets contain 250 MG of etidronate disodium, the
disodium salt of (1-hydroxyethylidene) diphosphonic acid, for oral
administration. This compound, also known as EHDP, regulates bone metabolism. It
is a white powder, highly soluble in water, with a molecular weight of 250 .
INACTIVE INGREDIENTS: Each tablet contains magnesium stearate, microcrystalline
cellulose, and starch.
ACTIONS/CLINICAL PHARMACOLOGY:
DRONATE OS acts primarily on bone. It can inhibit the formation, growth, and
dissolution of hydroxyapatite crystals and their amorphous precursors by
chemisorption to calcium phosphate surfaces. Inhibition of crystal resorption
occurs at lower doses than are required to inhibit crystal growth. Both effects
increase as the dose increases.
DRONATE OS is not metabolized. The amount of drug absorbed after an oral dose is
approximately 3%. In normal subjects, plasma half-life (t1/2) of etidronate,
based on non-compartmental pharmacokinetics is 1 to 6 hours. Within 24 hours,
approximately half the absorbed dose is excreted in urine; the remainder is
distributed to bone compartments from which it is slowly eliminated. Animal
studies have yielded bone clearance estimates up to 165 days. In humans, the
residence time on bone may vary due to such factors as specific metabolic
condition and bone type. Unabsorbed drug is excreted intact in the feces.
Preclinical studies indicate etidronate disodium does not cross the blood-brain
barrier.
DRONATE OS therapy does not adversely affect serum levels of parathyroid hormone
or calcium.
PAGET'S DISEASE: Paget's disease of bone (osteitis deformans) is an idiopathic,
progressive disease characterized by abnormal and accelerated bone metabolism in
one or more bones. Signs and symptoms may include bone pain and
vascular disorders, and increased serum alkaline phosphatase and/or urinary
hydroxyproline levels. Bone fractures are common in patients with Paget's
disease.
DRONATE OS slows accelerated bone turnover (resorption and accretion) in pagetic
lesions and, to a lesser extent, in normal bone. This has been demonstrated
histologically, scintigraphically, biochemically, and through calcium kinetic
and balance studies. Reduced bone turnover is often accompanied by symptomatic
improvement, including reduced bone pain. Also, the incidence of pagetic
fractures may be reduced, and elevated cardiac output and other vascular
disorders may be improved by DRONATE OS therapy.
HETEROTOPIC OSSIFICATION: Heterotopic ossification, also referred to as
myositis ossificans (circumscripta, progressiva or traumatica), ectopic
calcification, periarticular ossification, or paraosteoarthropathy, is
characterized by metaplastic osteogenesis. It usually presents with signs of
localized inflammation or pain, elevated skin temperature, and redness. When
tissues near joints are involved, functional loss may also be present.
Heterotopic ossification may occur for no known reason as in myositis ossificans
progressiva or may follow a wide variety of surgical, occupational, and sports
trauma (eg, hip arthroplasty, spinal cord injury, head injury, burns, and severe
thigh bruises). Heterotopic ossification has also been observed in non-
traumatic conditions (eg, infections of the central nervous system, peripheral
neuropathy, tetanus, biliary cirrhosis, Peyronie's disease, as well as in
association with a variety of benign and malignant neoplasms).
Clinical trials have demonstrated the efficacy of DRONATE OS in heterotopic
ossification following total hip replacement, or due to spinal cord injury.
--Heterotopic Ossification Complicating Total Hip Replacement typically
develops radiographically 3 to 8 weeks postoperatively in the pericapsular area
of the affected hip joint. The overall incidence is about 50%; about one-third
of these cases are clinically significant.
--Heterotopic Ossification Due To Spinal Cord Injury typically develops
radiographically 1 to 4 months after injury. It occurs below the level of
injury, usually at major joints. The overall incidence is about 40%; about one-
half of these cases are clinically significant.
DRONATE OS chemisorbs to calcium hydroxyapatite crystals and their amorphous
precursors, blocking the aggregation, growth, and mineralization of these
crystals. This is thought to be the mechanism by which DRONATE OS prevents or
retards heterotopic ossification. There is no evidence DRONATE OS affects mature
heterotopic bone.
INDICATIONS AND USAGE:
DRONATE OS is indicated for the treatment of symptomatic Paget's disease of bone
and in the prevention and treatment of heterotopic ossification following total
hip replacement or due to spinal cord injury. DRONATE OS is not approved for the
treatment of osteoporosis.
PAGET'S DISEASE: DRONATE OS is indicated for the treatment of symptomatic Paget's
disease of bone. DRONATE OS therapy usually arrests or significantly impedes the
disease process as evidenced by:
-- Symptomatic relief, including decreased pain and/or increased mobility
(experienced by 3 out of 5 patients).
-- Reductions in serum alkaline phosphatase and urinary hydroxy-proline levels
(30% or more in 4 out of 5 patients).
-- Histomorphometry showing reduced numbers of osteoclasts and osteoblasts, and
more lamellar bone formation.
-- Bone scans showing reduced radionuclide uptake at pagetic lesions.
In addition, reductions in pagetically elevated cardiac output and skin
temperature have been observed in some patients.
In many patients, the disease process will be suppressed for a period of at
least 1 year following cessation of therapy. The upper limit of this period has
not been determined.
The effects of the DRONATE OS treatment in patients with asymptomatic Paget's
disease have not been studied. However, DRONATE OS treatment of such patients may
be warranted if extensive involvement threatens irreversible neurologic damage,
major joints, or major weight-bearing bones.
HETEROTOPIC OSSIFICATION: DRONATE OS is indicated in the prevention and
treatment of heterotopic ossification following total hip replacement or due to
spinal cord injury.
DRONATE OS reduces the incidence of clinically important heterotopic bone by about
two-thirds. Among those patients who form heterotopic bone, DRONATE OS retards the
progression of immature lesions and reduces the severity by at least half.
Follow-up data (at least 9 months posttherapy) suggest these benefits persist.
In Total Hip Replacement Patients, DRONATE OS does not promote loosening of the
prosthesis or impede trochanteric reattachment.
In Spinal Cord Injury Patients, DRONATE OS does not inhibit fracture healing or
stabilization of the spine.
CONTRAINDICATIONS:
DRONATE OS tablets are contraindicated in patients with known hypersensitivity to
etidronate disodium or in patients with clinically overt osteomalacia.
WARNINGS:
PAGET'S DISEASE: In Paget's patients the response to therapy may be of slow
onset and continue for months after DRONATE OS therapy is discontinued. Dosage
should not be increased prematurely. A 90-day drug-free interval should be
provided between courses of therapy.
HETEROTOPIC OSSIFICATION: No specific warnings.
PRECAUTIONS:
GENERAL: Patients should maintain an adequate nutritional status, particularly
an adequate intake of calcium and vitamin D.
Therapy has been withheld from some patients with enterocolitis since diarrhea
may be experienced, particularly at higher doses.
DRONATE OS is not metabolized and is excreted intact via the kidney.
Hyperphosphatemia may occur at doses of 10 to 20 mg/kg/day, apparently as a
result of drug-related increases in tubular reabsorption of phosphate. Serum
phosphate levels generally return to normal 2 to 4 weeks posttherapy. There is
no experience to specifically guide treatment in patients with impaired renal
function. DRONATE OS dosage should be reduced when reductions in glomerular
filtration rates are present. Patients with renal impairment should be closely
monitored. In approximately 10% of patients in clinical trials of DRONATE OS(R)
I.V. INFUSION (etidronate disodium) for hypercalcemia of malignancy, occasional,
mild-to-moderate abnormalities in renal function (increases of >0.5 mg/dl serum
creatinine) were observed during or immediately after treatment.
DRONATE OS suppresses bone turnover, and may retard mineralization of osteoid laid
down during the bone accretion process. These effects are dose and time
dependent. Osteoid, which may accumulate noticeably at doses of 10 to 20
mg/kg/day, mineralizes normally posttherapy. In patients with fractures,
especially of long bones, it may be advisable to delay or interrupt treatment
until callus is evident.
PAGET'S DISEASE: In Paget's patients, treatment regimens exceeding the
recommended (see DOSAGE AND ADMINISTRATION) daily maximum dose of 20 mg/kg or
continuous administration of medication for periods greater than 6 months may be
associated with osteomalacia and an increased risk of fracture.
Long bones predominantly affected by lytic lesions, particularly in those
patients unresponsive to DRONATE OS therapy, may be especially prone to fracture.
Patients with predominantly lytic lesions should be monitored radiographically
and biochemically to permit termination of DRONATE OS in those patients
unresponsive to treatment.
DRUG INTERACTIONS: There have been isolated reports of patients experiencing
increases in their prothrombin times when etidronate was added to warfarin
therapy. The majority of these reports concerned variable elevations in
prothrombin times without clinically significant sequelae. Although the
relevance of these reports and any mechanism of coagulation alterations is
unclear, patients on warfarin should have their prothrombin time monitored.
CARCINOGENESIS: Long-term studies in rats have indicated that DRONATE OS is not
carcinogenic.
PREGNANCY: TERATOGENIC EFFECTS: Pregnancy Category C. In teratology and
developmental toxicity studies conducted in rats and rabbits treated with
dosages of up to 100 mg/kg (5 to 20 times the clinical dose), no adverse or
teratogenic effects have been observed in the offspring. Etidronate disodium has
been shown to cause skeletal abnormalities in rats when given at oral dose
levels of 300 mg/kg (15 to 60 times the human dose). Other effects on the
offspring (including decreased live births) are at dosages that cause
significant toxicity in the parent generation and are 25 to 200 times the human
dose. The skeletal effects are thought to be the result of the pharmacological
effects of the drug on bone.
There are no adequate and well-controlled studies in pregnant women, DRONATE OS
(etidronate disodium) 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.
Because many drugs are excreted in human milk, caution should be exercised when
DRONATE OS is administered to a nursing woman.
PEDIATRIC USE: Safety and effectiveness in pediatric patients have not been
established. Pediatric patients have been treated with DRONATE OS, at doses
recommended for adults, to prevent heterotopic ossifications or soft tissue
calcifications. A rachitic syndrome has been reported infrequently at doses of
10 mg/kg/day and more for prolonged periods approaching or exceeding a year. The
epiphyseal radiologic changes associated with retarded mineralization of new
osteoid and cartilage, and occasional symptoms reported, have been reversible
when medication is discontinued.
DRUG INTERACTIONS:
There have been isolated reports of patients experiencing increases in their
prothrombin times when etidronate was added to warfarin therapy. The majority of
these reports concerned variable elevations in prothrombin times without
clinically significant sequelae. Although the relevance of these reports and any
mechanism of coagulation alterations is unclear, patients on warfarin should
have their prothrombin time monitored.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
The incidence of gastrointestinal complaints (diarrhea, nausea) is the same for
DRONATE OS at 5 mg/kg/day as for placebo, about 1 patient in 15. At 10 to 20
mg/kg/day the incidence may increase to 2 or 3 in 10. These complaints are often
alleviated by dividing the total daily dose.
PAGET'S DISEASE: In Paget's patients, increased or recurrent bone pain at
pagetic sites, and/or the onset of pain at previously asymptomatic sites has
been reported. At 5 mg/kg/day about 1 patient in 10 (versus 1 in 15 in the
placebo group) report these phenomena. At higher doses the incidence rises to
about 2 in 10. When therapy continues, pain resolves in some patients but
persists in others.
HETEROTOPIC OSSIFICATION: No specific adverse reactions.
WORLDWIDE POSTMARKETING EXPERIENCE: The worldwide postmarketing experience for
etidronate disodium reflects its use in the following approved indications:
Paget's disease, heterotopic ossification, and hypercalcemia of malignancy. It
also reflects the use of etidronate disodium for osteoporosis where approved in
countries outside the US. Other adverse events that have been reported and were
thought to be possibly related to etidronate disodium include the following:
alopecia; arthropathies, including arthralgia and arthritis; bone fracture;
esophagitis; glossitis; hypersensitivity reactions, including angioedema,
follicular eruption, macular rash, maculopapular rash, pruritus, a single case
of Stevens-Johnson syndrome, and urticaria; osteomalacia; neuropsychiatric
events, including amnesia, confusion, depression, and hallucination; and
paresthesias.
In patients receiving etidronate disodium, there have been rare reports of
agranulocytosis, pancytopenia, and a report of leukopenia with recurrence on
rechallenge. In addition, there have been rare reports of exacerbation of
asthma. Exacerbation of existing peptic ulcer disease has been reported in a few
patients. In one patient, perforation also occurred.
OVERDOSAGE:
Clinical experience with acute DRONATE OS overdosage is extremely limited.
Decreases in serum calcium following substantial overdosage may be expected in
some patients. Signs and symptoms of hypocalcemia also may occur in some of
these patients. Some patients may develop vomiting. In one event, an 18-year-old
female who ingested an estimated single dose of 4000 to 6000mg (67 to 100 mg/kg)
of DRONATE OS was reported to be mildly hypocalcemic (7.52 mg/dl) and experienced
paresthesia of the fingers. Hypocalcemia resolved 6 hours after lavage and
treatment with intravenous calcium gluconate. A 92-year-old female who
accidentally received 1600mg of etidronate disodium per day for 3.5 days
experienced marked diarrhea and required treatment for electrolyte imbalance.
Orally administered etidronate disodium may cause hematologic abnormalities in
some patients (see ADVERSE REACTIONS).
Etidronate disodium suppresses bone turnover and may retard mineralization of
osteoid laid down during the bone accretion process. These effects are dose and
time dependent. Osteoid which may accumulate noticeably at doses of 10 to 20
mg/kg/day of chronic, continuous dosing mineralizes normally posttherapy.
Prolonged continuous treatment (chronic overdosage) has been reported to cause
nephrotic syndrome and fracture.
Gastric lavage may remove unabsorbed drug. Standard procedures for treating
hypocalcemia, including the administration of Ca++ intravenously, would be
expected to restore physiologic amounts of ionized calcium and relieve signs and
symptoms of hypocalcemia. Such treatment has been effective.
DOSAGE AND ADMINISTRATION:
DRONATE OS should be taken as a single, oral dose. However, should
gastrointestinal discomfort occur, the dose may be divided. To maximize
absorption, patients should avoid taking the following items within two hours of
dosing:
--Food, especially food high in calcium, such as milk or milk products.
--Vitamins with mineral supplements or antacids which are high in metals such
as calcium, iron, magnesium, or aluminum.
PAGET'S DISEASE: INITIAL TREATMENT REGIMENS: 5 to 10 mg/kg/day, not to exceed 6
months, or 11 to 20mg/kg/day, not to exceed 3 months.
The recommended initial dose is 5 mg/kg/day for a period not to exceed 6 months.
Doses above 10 mg/kg/day should be reserved for when 1) lower doses are
ineffective or 2) there is an overriding need to suppress rapid bone turnover
(especially when irreversible neurologic damage is possible) or reduce elevated
cardiac output. Doses in excess of 20 mg/kg/day are not recommended.
RETREATMENT GUIDELINES: Retreatment should be initiated only after 1) a
DRONATE OS-free period of at least 90 days and 2) there is biochemical,
symptomatic or other evidence of active disease process. It is advisable to
monitor patients every 3 to 6 months although some patients may go drug free for
extended periods. Retreatment regimens are the same as for initial treatment.
For most patients the original dose will be adequate for retreatment. If not,
consideration should be given to increasing the dose within the recommended
guidelines.
HETEROTOPIC OSSIFICATION: The following treatment regimens have been shown to be
effective:
--Total Hip Replacement Patients: 20 mg/kg/day for 1 month before and 3 months
after surgery (4 months total).
--Spinal Cord Injured Patients: 20 mg/kg/day for 2 weeks followed by 10
mg/kg/day for 10 weeks (12 weeks total). DRONATE OS therapy should begin as soon
as medically feasible following the injury, preferably prior to evidence of
heterotopic ossification.
Retreatment has not been studied.
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