Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1307
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Boniva (Injection, Solution)
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The recommended dose of BONIVA Injection for the
treatment of postmenopausal osteoporosis is 3 mg every 3 months (see INDICATIONS
AND USAGE) administered over a period of 15 to
30 seconds. No cases of acute renal failure
were observed in controlled clinical trials in which intravenous BONIVA
was administered as a 15- to 30-second bolus. The risk of serious
renal toxicity with other intravenous bisphosphonates appears to be
inversely related to the rate of drug administration . BONIVA Injection must be administered
by a health care professional. BONIVA Injection
must only be administered intravenously . Care must
be taken not to administer BONIVA Injection intra-arterially or paravenously
as this could lead to tissue damage. Do not
administer BONIVA Injection by any other route of administration.
The safety and efficacy of BONIVA Injection following non-intravenous
routes of administration have not been established. Administer BONIVA Injection using the enclosed needle. Prefilled
syringes are for single use only. Discard unused portion. BONIVA Injection must not be mixed with calcium-containing
solutions or other intravenously administered drugs. Parenteral drug products should be inspected visually for particulate
matter and discoloration before administration, and not used if particulate
matter is visible or product is discolored. Prefilled syringes with
particulate matter or discoloration should not be used. If the dose is missed, BONIVA Injection should be administered
as soon as it can be rescheduled. Thereafter, injections should be
scheduled every 3 months from the date of the last injection. Do not
administer BONIVA Injection (3 mg) more frequently than once every
3 months. Patients must receive supplemental
calcium and vitamin D .<br/>Patients with Hepatic Impairment: No dose adjustment is necessary (see CLINICAL PHARMACOLOGY:
Special Populations).<br/>Patients with Renal Impairment: No dose adjustment is necessary for patients with
mild or moderate renal impairment where creatinine clearance is equal
to or greater than 30 mL/min. BONIVA Injection
should not be administered to patients with severe renal impairment,
ie, patients with serum creatinine>200��mol/L (2.3 mg/dL) or
creatinine clearance (measured or estimated)<30 mL/min (see CLINICAL PHARMACOLOGY:
Special Populations).<br/>Geriatric Patients: No dosage adjustment is necessary in the elderly
(see PRECAUTIONS:
Geriatric Use).
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BONIVA (ibandronate sodium) is a nitrogen-containing
bisphosphonate that inhibits osteoclast-mediated bone resorption.
The chemical name for ibandronate sodium is 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid,
monosodium salt, monohydrate with the molecular formula CHNOPNa���HO
and a molecular weight of 359.24. Ibandronate sodium is a white- to
off-white powder. It is freely soluble in water and practically insoluble
in organic solvents. Ibandronate sodium has the following structural
formula: BONIVA Injection is intended for intravenous
administration only. BONIVA Injection is available as a sterile, clear,
colorless, ready-to-use solution in a prefilled syringe that delivers
3.375 mg of ibandronate monosodium salt monohydrate in 3 mL of solution,
equivalent to a dose of 3 mg ibandronate free acid. Inactive ingredients
include sodium chloride, glacial acetic acid, sodium acetate and water.
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Mechanism of Action: The action of ibandronate on bone tissue is based
on its affinity for hydroxyapatite, which is part of the mineral matrix
of bone. Ibandronate inhibits osteoclast activity and reduces bone
resorption and turnover. In postmenopausal women, it reduces the elevated
rate of bone turnover, leading to, on average, a net gain in bone
mass.<br/>Pharmacokinetics:<br/>Distribution: Area under the serum ibandronate concentrations versus
time curve increases in a dose-proportional manner after administration
of 2 mg to 6 mg by intravenous injection. After administration, ibandronate
either rapidly binds to bone or is excreted into urine. In humans,
the apparent terminal volume of distribution is at least 90 L, and
the amount of dose removed from the circulation into thebone is estimated
to be 40% to 50% of the circulating dose. In vitro protein binding
in human serum was approximately 86% over an ibandronate concentration
range of 20 to 2000 ng/mL (approximate range of maximum serum ibandronate
concentrations upon intravenous bolus administration) in one study.<br/>Metabolism: There is no evidence that ibandronate is metabolized
in humans. Ibandronate does not inhibit human P450 1A2, 2A6, 2C9,
2C19, 2D6, 2E1, and 3A4 isozymes in vitro.<br/>Elimination: The portion of ibandronate that is not removed from
the circulation via bone absorption is eliminated unchanged by the
kidney (approximately 50% to 60% of the administered intravenous dose). The plasma elimination of ibandronate is multiphasic.
Its renal clearance and distribution into bone accounts for a rapid
and early decline in plasma concentrations, reaching 10% of Cwithin 3 or 8 hours after intravenous or oral administration,
respectively. This is followed by a slower clearance phase as ibandronate
redistributes back into the blood from bone. The observed apparent
terminal half-life for ibandronate is generally dependent on the dose
studied and on assay sensitivity. The observed apparent terminal half-life
for intravenous 2 and 4 mg ibandronate after 2 hours of infusion ranges
from 4.6 to 15.3 hours and 5 to 25.5 hours, respectively. Following intravenous administration, total clearance
of ibandronate is low, with average values in the range 84 to 160
mL/min. Renal clearance (about 60 mL/min in healthy postmenopausal
women) accounts for 50% to 60% of total clearance and is related to
creatinine clearance. The difference between the apparent total and
renal clearances likely reflects bone uptake of the drug.<br/>Special Populations:<br/>Pediatrics: The pharmacokinetics of ibandronate has not been
studied in patients<18 years of age.<br/>Gender: The pharmacokinetics of ibandronate is similar in
both men and women.<br/>Geriatric: Since ibandronate is not known to be metabolized,
the only difference in ibandronate elimination for geriatric patients
versus younger patients is expected to relate to progressive age-related
changes in renal function (see Special Populations: Renal Impairment).<br/>Race: Pharmacokinetic differences due to race have not
been studied.<br/>Renal Impairment: Renal clearance of ibandronate in patients with various
degrees of renal impairment is linearly related to creatinine clearance
(CLcr). Following a single dose of 0.5 mg ibandronate
by intravenous administration, patients with CLcr 40 to 70 mL/min
had 55% higher exposure (AUC) than the exposure
observed in subjects with CLcr>90 mL/min. Patients with CLcr<30
mL/min had more than a two-fold increase in exposure compared to the
exposure for healthy subjects (see DOSAGE AND ADMINISTRATION: Patients with
Renal Impairment).<br/>Hepatic Impairment: No studies have been performed to assess the pharmacokinetics
of ibandronate in patients with hepatic impairment since ibandronate
is not metabolized in the human liver.<br/>Drug Interactions: Ibandronate does not undergo hepatic metabolism and
does not inhibit the hepatic cytochrome P450 system. Ibandronate is
eliminated by renal excretion. Based on a rat study, the ibandronate
secretory pathway does not appear to include known acidic or basic
transport systems involved in the excretion of other drugs.<br/>Melphalan/Prednisolone: A pharmacokinetic interaction study in multiple myeloma
patients demonstrated that intravenous melphalan (10 mg/m) and oral prednisolone (60 mg/m) did not interact with
6 mg ibandronate upon intravenous coadministration. Ibandronate did
not interact with melphalan or prednisolone.<br/>Tamoxifen: A pharmacokinetic interaction study in healthy postmenopausal
women demonstrated that there was no interaction between oral 30 mg
tamoxifen and intravenous 2 mg ibandronate.<br/>Pharmacodynamics: Osteoporosis is characterized by decreased bone mass
and increased fracture risk, most commonly at the spine, hip, and
wrist. The diagnosis can be confirmed by a finding of low bone mass,
evidence of fracture on x-ray, a history of osteoporotic fracture,
or height loss or kyphosis indicative of vertebral fracture. While
osteoporosis occurs in both men and women, it is most common among
women following menopause. In healthy humans, bone formation and resorption
are closely linked; old bone is resorbed and replaced by newly formed
bone. In postmenopausal osteoporosis, bone resorption exceeds bone
formation, leading to bone loss and increased risk of fracture. After
menopause, the risk of fractures of the spine and hip increases; approximately
40% of 50-year-old women will experience an osteoporosis-related fracture
during their remaining lifetimes. In studies
of postmenopausal women, BONIVA Injection at doses of 0.5 mg to 3
mg produced biochemical changes indicative of inhibition of bone resorption,
including decreases of biochemical markers of bone collagen degradation
(cross-linked C-telopeptide of Type I collagen [CTX]). Changes in
markers of bone formation (osteocalcin) were observed later than changes
in resorption markers, as expected, due to the coupled nature of bone
resorption and formation. Year 1 results from
an efficacy and safety study comparing BONIVA Injection 3 mg every
3 months and BONIVA 2.5 mg daily oral tablet demonstrated that both
dosing regimens significantly suppressed serum CTX levels at Months
3, 6, and 12. The median pre-dose or trough serum CTX levels in the
ITT population reached a nadir of 57% (BONIVA Injection) and 62% (BONIVA
2.5 mg tablets) below baseline values by Month 6, and remained stable
at Month 12 of treatment.<br/>Clinical Studies:<br/>Daily Oral Tablets: The effectiveness and safety of BONIVA daily oral
tablets were demonstrated in a randomized, double-blind, placebo-controlled,
multinational study (Treatment Study) of 2946 women aged 55 to 80
years, who were on average 21 years postmenopause, who had lumbar
spine bone mineral density (BMD) 2 to 5 SD below the premenopausal
mean (T-score) in at least one vertebra [L1-L4], and who had one to
four prevalent vertebral fractures. BONIVA was evaluated at oral doses
of 2.5 mg daily and 20 mg intermittently. The main outcome measure
was the occurrence of new radiographically diagnosed, vertebral fractures
after 3 years of treatment. The diagnosis of an incident vertebral
fracture was based on both qualitative diagnosis by the radiologist
and quantitative morphometric criterion. The morphometric criterion
required the dual occurrence of two events: a relative height ratio
or relative height reduction in a vertebral body of at least 20%,
together with at least a 4 mm absolute decrease in height. All women
received 400 IU vitamin D and 500 mg calcium supplementation per day.<br/>Quarterly IV Injection: The effectiveness and safety of BONIVA Injection
3 mg once every 3 months were demonstrated in a randomized, double-blind,
multinational, noninferiority study (DIVA Study) in 1358 women with
postmenopausal osteoporosis (L2-L4 lumbar spine BMD, T score below
-2.5 SD at baseline). The control group received BONIVA 2.5 mg daily
oral tablets. The primary efficacy parameter was the relative change
from baseline to 1 year of treatment in lumbar spine BMD, which was
compared between the intravenous injection and the daily oral treatment
groups. All patients received 400 IU vitamin D and 500 mg calcium
supplementation per day.<br/>Effect on Vertebral Fracture: BONIVA 2.5 mg daily oral tablet significantly reduced
the incidence of new vertebral and of new and worsening vertebral
fractures (Daily Oral Tablet���Treatment Study). Over the course of the 3-year study,
the risk for vertebral fracture was 9.6% in the placebo-treated women
and 4.7% in the women treated with BONIVA 2.5 mg daily oral tablet
(p<0.001) (see Table 1). In an unapproved regimen, intermittent
oral administration of 20 mg BONIVA, involving a 9- to 10-week drug-free
interval, produced a statistically significant reduction (50%) in
the incidence of new vertebral fractures, similar to that seen with
the daily oral 2.5 mg regimen.<br/>Effect on Nonvertebral Fractures: There was a similar number of nonvertebral osteoporotic
fractures at 3 years reported in women treated with BONIVA 2.5 mg
daily oral tablet [9.1%, (95% CI: 7.1%, 11.1%)] and placebo [8.2%,
(95% CI: 6.3%, 10.2%)]. The two treatment groups were also similar
with regard to the number of fractures reported at the individual
non-vertebral sites: pelvis, femur, wrist, forearm, rib, and hip (Daily Oral Tablet - Treatment Study).<br/>Effect on Bone Mineral Density
(BMD):<br/>Bone Histology: The effects of BONIVA 2.5 mg daily oral tablet on
bone histology were evaluated in iliac crest biopsies from 16 women
after 22 months of treatment and 20 women after 34 months of treatment.
The histological analysis of bone biopsies showed bone of normal quality
and no indication of osteomalacia or a mineralization defect. The histological analysis of bone biopsies after 22 months
of treatment with 3 mg intravenous ibandronate every 3 months (n=30)
or 23 months of treatment with 2 mg intravenous ibandronate every
2 months (n=27) in women with postmenopausal osteoporosis showed bone
of normal quality and no indication of a mineralization defect.<br/>Animal Pharmacology: Animal studies have shown that ibandronate is an
inhibitor of osteoclast-mediated bone resorption. In the Schenk assay
in growing rats, ibandronate inhibited bone resorption and increased
bone volume, based on histologic examination of the tibial metaphyses.
There was no evidence of impaired mineralization at the highest dose
of 5 mg/kg/day (subcutaneously), which is 1000 times the lowest antiresorptive
dose of 0.005 mg/kg/day in this model, and 5000 times the optimal
antiresorptive dose of 0.001 mg/kg/day in the aged ovariectomized
rat. This indicates that BONIVA Injection administered at a therapeutic
dose is unlikely to induce osteomalacia. Long-term
daily or intermittent administration of ibandronate to ovariectomized
rats or monkeys was associated with suppression of bone turnover and
increases in bone mass. Vertebral BMD, trabecular density, and biomechanical
strength were increased dose-dependently in rats and monkeys, at doses
up to 8 to 4 times the human intravenous dose of 3 mg every 3 months,
based on cumulative dose normalized for body surface area (mg/m) and AUC comparison, respectively. Ibandronate maintained
the positive correlation between bone mass and strength at the ulna
and femoral neck. New bone formed in the presence of ibandronate had
normal histologic structure and did not show mineralization defects.
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One prefilled syringe of BONIVA Injection (ibandronate
sodium), 3 mg/3 mL single-use, clear glass prefilled syringe, in a
box with 1 needle and 2 alcohol swabs (NDC 0004-0188-09). Each syringe is a 5 mL (5 cc) volume syringe supplied
with a 23-gauge, 3/4 inch needle with wings, needle-stick protection
device, and 3-inch plastic tubing for attachment.<br/>Storage: Store at 25��C (77��F); excursions permitted
between 15��and 30��C (59��and 86��F) [see USP Controlled
Room Temperature].
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No cases of overdose were reported in premarketing
studies with BONIVA Injection. Intravenous overdosage may result in
hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant
reductions in serum levels of calcium, phosphorus, and magnesium should
be corrected by intravenous administration of calcium gluconate, potassium
or sodium phosphate, and magnesium sulfate, respectively. Dialysis would not be beneficial unless it is administered
within 2 hours following the overdose.
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ibandronate sodium
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Boniva (Injection, Solution)
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Daily Oral Tablet: Treatment with BONIVA 2.5 mg daily oral tablet was
studied in over 3900 patients in postmenopausal osteoporosis trials
of up to 3 years duration. The overall adverse event profile of BONIVA
2.5 mg once daily tablet in these studies was similar to that of placebo. Most adverse events were mild or moderate and did not
lead to discontinuation. The incidence of serious adverse events was
20% in the placebo group and 23% in the BONIVA 2.5 mg daily oral tablet
group. The percentage of patients who withdrew from treatment due
to adverse events was approximately 17% in both the BONIVA 2.5 mg
daily oral tablet group and the placebo group. Overall, and according
to body system, there was no difference between BONIVA daily oral
tablet and placebo, with adverse events of the digestive system being
the most common reason for withdrawal. Table 3 lists adverse events from the Treatment
and Prevention Studies reported in���2% of patients and in more
patients treated with BONIVA 2.5 mg daily oral tablet than patients
treated with placebo. Adverse events are shown without attribution
of causality.<br/>Quarterly IV Injection���DIVA Study: In a 1-year, double-blind, multicenter study comparing
BONIVA Injection administered intravenously as 3 mg every 3 months
to BONIVA 2.5 mg daily oral tablet in women with postmenopausal osteoporosis,
the overall safety and tolerability profiles of the two dosing regimens
were similar. The incidence of serious adverse events was 8.0% in
the BONIVA 2.5 mg daily group and 7.5% in the BONIVA Injection 3 mg
once every 3 months group. The percentage of patients who withdrew
from treatment due to adverse events was approximately 6.7% in the
BONIVA 2.5 mg daily group and 8.5% in the BONIVA Injection 3 mg every
3 months group. Table
4 lists the adverse events reported in>2% of patients
without attribution of causality.<br/>Acute Phase Reaction-like
Events: Symptoms consistent with acute phase reaction (APR)
have been reported with intravenous bisphosphonate use. The overall
incidence of patients with APR-like events was higher in the intravenous
treatment group (4% in the BONIVA 2.5 mg daily oral tablet group vs.
10% in the BONIVA Injection 3 mg once every 3 months group). These
incidence rates are based on reporting of any of 33 potential APR-like
symptoms within 3 days of an IV dose and for a duration of 7 days
or less. In most cases, no specific treatment was required and the
symptoms subsided within 24 to 48 hours.<br/>Injection Site Reactions: Local reactions at the injection site, such as redness
or swelling, were observed infrequently, but at a higher incidence
in patients treated with BONIVA Injection 3 mg every 3 months (<2%;
8/469) than in patients treated with placebo injections (<1%; 1/465).
In most cases, the reaction was of mild to moderate severity.<br/>Ocular Adverse Events: Bisphosphonates may be associated with ocular inflammation
such as uveitis and scleritis. In some cases, these events did not
resolve until the bisphosphonate was discontinued.<br/>Laboratory Test Findings: There were no clinically significant changes from
baseline values or shifts in any laboratory variable with oral ibandronate.
As expected with bisphosphonate treatment, a decrease in total alkaline
phosphatase levels was seen with 2.5 mg daily oral ibandronate compared
to placebo. There was no difference compared with placebo for laboratory
abnormalities indicative of hepatic or renal dysfunction, hypocalcemia,
or hypophosphatemia. There also was no evidence that BONIVA Injection
3 mg every 3 months induced clinically significant laboratory abnormalities
indicative of hepatic or renal dysfunction compared to BONIVA 2.5
mg daily oral tablet.
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BONIVA Injection is indicated for the treatment of
osteoporosis in postmenopausal women. In postmenopausal
women with osteoporosis, BONIVA increases BMD and reduces the incidence
of vertebral fractures . Osteoporosis may be confirmed by the presence or history
of osteoporotic fracture or by a finding of low bone mass (BMD more
than 2.0 standard deviations below the premenopausal mean [ie, T-score]).
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Boniva
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