Included as part of the PRECAUTIONS section.
Hypocalcemia and Mineral Metabolism
BONIVA Injection may cause a decrease in serum calcium
values. Treat hypocalcemia, hypovitaminosis D, and other disturbances of bone
and mineral metabolism before starting BONIVA Injection therapy.
Adequate intake of calcium and vitamin D is important in
all patients. It is recommended that patients receive supplemental calcium and
vitamin D if dietary intake is inadequate.
Cases of anaphylaxis, including fatal events, have been
reported in patients treated with BONIVA Injection.
Appropriate medical support and monitoring measures
should be readily available when BONIVA Injection is administered. If
anaphylactic or other severe hypersensitivity/allergic reactions occur,
immediately discontinue the injection and initiate appropriate treatment.
Treatment with intravenous bisphosphonates has been
associated with renal toxicity manifested as deterioration in renal function
and acute renal failure. Although 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, acute renal failure has been reported postmarketing. Do
not administer BONIVA Injection to patients with severe renal impairment
(creatinine clearance less than 30 mL/min).
Obtain serum creatinine prior to each BONIVA Injection.
After BONIVA Injection, assess renal function, as clinically appropriate, in
patients with concomitant diseases or taking medications that have the
potential for adverse effects on the kidney. BONIVA Injection should be
withheld in patients with renal deterioration.
Tissue Damage Related to Inappropriate Drug
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.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in
patients treated with bisphosphonates, including BONIVA Injection. Most cases
have been in cancer patients treated with intravenous bisphosphonates
undergoing dental procedures. Some cases have occurred in patients with
postmenopausal osteoporosis treated with either oral or intravenous
bisphosphonates. A routine oral examination should be performed by the
prescriber prior to initiation of bisphosphonate treatment. Consider a dental
examination with appropriate preventive dentistry prior to treatment with
bisphosphonates in patients with a history of concomitant risk factors (e.g.,
cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene,
pre-existing dental disease or infection, anemia, coagulopathy).
While on treatment, patients with concomitant risk
factors should avoid invasive dental procedures if possible. For patients who
develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the
condition. For patients requiring dental procedures, there are no data
available to suggest whether discontinuation of bisphosphonate treatment
reduces the risk of ONJ. The clinical judgment of the treating physician should
guide the management plan of each patient based on individual benefit/risk
assessment [see ADVERSE REACTIONS].
Severe and occasionally incapacitating bone, joint,
and/or muscle pain has been reported in patients taking BONIVA and other
bisphosphonates [see ADVERSE REACTIONS]. The time to onset of symptoms
varied from one day to several months after starting the drug. Most patients
had relief of symptoms after stopping the bisphosphonate. A subset of patients
had recurrence of symptoms when rechallenged with the same drug or another
bisphosphonate. Discontinue BONIVA if severe symptoms develop.
Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Atypical, low-energy, or low-trauma fractures of the
femoral shaft have been reported in bisphosphonate-treated patients. These
fractures can occur anywhere in the femoral shaft from just below the lesser
trochanter to above the supracondylar flare and are transverse or short oblique
in orientation without evidence of comminution. Causality has not been
established as these fractures also occur in osteoporotic patients who have not
been treated with bisphosphonates.
Atypical femur fractures most commonly occur with minimal
or no trauma to the affected area. They may be bilateral and many patients
report prodromal pain in the affected area, usually presenting as dull, aching
thigh pain, weeks to months before a complete fracture occurs. A number of
reports note that patients were also receiving treatment with glucocorticoids (e.g.,
prednisone) at the time of fracture.
Any patient with a history of bisphosphonate exposure who
presents with thigh or groin pain should be suspected of having an atypical
fracture and should be evaluated to rule out an incomplete femur fracture. Patients
presenting with an atypical fracture should also be assessed for symptoms and
signs of fracture in the contralateral limb. Interruption of bisphosphonate
therapy should be considered, pending a risk/benefit assessment, on an
Patient Counseling Information
“See FDA-approved patient
labeling (Medication Guide)”
Inform patients that BONIVA
Injection must be administered intravenously by a health care professional.
Patients should be instructed to read the Medication
Guide carefully before BONIVA is administered and to reread it each time the
prescription is renewed because it contains important information the patient
should know about BONIVA.
Inform patients that BONIVA Injection is administered
once every 3 months. If the dose is missed, the 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 more frequently than once every 3 months.
Inform patients that they should take supplemental
calcium and vitamin D if their dietary intake is inadequate [see WARNINGS
Inform patients BONIVA injection should not be
administered to patients with creatinine clearance less than 30 mL/min. A serum
creatinine should be measured prior to each dose [see WARNINGS AND
Inform patients that the most common side effects of
BONIVA include arthralgia, back pain, hypertension, and abdominal pain.
Flu-like symptoms (acute phase reaction) may occur within 3 days following
infusion, and usually subside within 24-48 hours without specific therapy.
Inform patients that there have been reports of
persistent pain and/or a non-healing sore of the mouth or jaw, primarily in
patients treated with bisphosphonates for other illnesses. If they experience
these symptoms, they should inform their physician or dentist.
Inform patients that severe bone, joint, and/or muscle
pain have been reported in patients taking bisphosphonates, including BONIVA.
Patients should report severe symptoms if they develop.
Inform patients that atypical femur fractures in patients
on bisphosphonate therapy have been reported. Patients should report new thigh
or groin pain and undergo evaluation to rule out a femoral fracture.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study, doses of 3, 7, or 15
mg/kg/day were administered by oral gavage to Wistar rats (systemic exposures
in males and females up to 3 and 1 times, respectively, human exposure). There
were no significant drug-related tumor findings in male or female rats. In a
78-week carcinogenicity study, doses of 5, 20, or 40 mg/kg/day were
administered by oral gavage to NMRI mice (exposures in males and females up to
96 and 14 times, respectively, human exposure). There were no significant
drug-related tumor findings in male or female mice. In a 90-week
carcinogenicity study, doses of 5, 20, or 80 mg/kg/day were administered in the
drinking water to NMRI mice. A dose-related increased incidence of adrenal
subcapsular adenoma/carcinoma was observed in female mice, which was
statistically significant at 80 mg/kg/day (32 to 51 times human exposure). The
relevance of these findings to humans is unknown.
Exposure multiples comparing human and rodent doses were
calculated using human exposure at the recommended intravenous dose of 3 mg
every 3 months, based on cumulative AUC comparison.
There was no evidence for a mutagenic or clastogenic
potential of ibandronate in the following assays: in vitro bacterial
mutagenesis assay in Salmonella typhimurium and Escherichia coli (Ames test),
mammalian cell mutagenesis assay in Chinese hamster V79 cells, and chromosomal
aberration test in human peripheral lymphocytes, each with and without
metabolic activation. Ibandronate was not genotoxic in the in vivo mouse
micronucleus tests for chromosomal damage.
Impairment of Fertility
In female rats treated from 14 days prior to mating
through gestation, decreases in fertility, corpora lutea and implantation
sites, and increased preimplantation loss were observed at an intravenous dose
of 1.2 mg/kg/day (117 times human exposure). In male rats treated for 28 days
prior to mating, a decrease in sperm production and altered sperm morphology
were observed at intravenous doses greater than or equal to 0.3 mg/kg/day
(greater than or equal to 40 times human exposure).
Exposure multiples comparing human and rat doses were
calculated using human exposure at the recommended intravenous dose of 3 mg
every 3 months, based on cumulative AUC comparison.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies in
pregnant women. BONIVA should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Bisphosphonates are incorporated into the bone matrix,
from where they are gradually released over periods of weeks to years. The
extent of bisphosphonate incorporation into adult bone, and hence, the amount
available for release back into the systemic circulation, is directly related
to the total dose and duration of bisphosphonate use. Although there are no
data on fetal risk in humans, bisphosphonates do cause fetal harm in animals,
and animal data suggest that uptake of bisphosphonates into fetal bone is
greater than into maternal bone. Therefore, there is a theoretical risk of
fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant
after completing a course of bisphosphonate therapy. The impact of variables
such as time between cessation of bisphosphonate therapy to conception, the
particular bisphosphonate used, and the route of administration (intravenous
versus oral) on this risk has not been established.
In pregnant rats given intravenous doses greater than or
equal to 2 times human exposure from Day 17 postcoitum until Day 20
post-partum, ibandronate treatment resulted in dystocia, maternal mortality,
and early postnatal pup loss in all dose groups. Reduced body weight at birth
was observed at greater than or equal to 4 times the human exposure. Pups
exhibited abnormal odontogeny that decreased food consumption and body weight gain
at greater than or equal to 18 times human exposure. Periparturient mortality
has also been observed with other bisphosphonates and appears to be a class
effect related to inhibition of skeletal calcium mobilization resulting in
hypocalcemia and dystocia.
Exposure of pregnant rats during the period of
organogenesis resulted in an increased fetal incidence of RPU (renal pelvis
ureter) syndrome at an intravenous dose greater than or equal to 47 times human
exposure. In this spontaneous delivery study, dystocia was counteracted by
perinatal calcium supplementation. In rat studies with intravenous dosing
during gestation, fetal weight and pup growth were reduced at doses greater
than or equal to 5 times human exposure.
In pregnant rabbits given intravenous doses during the
period of organogenesis, maternal mortality, reduced maternal body weight gain,
decreased litter size due to increased resorption rate, and decreased fetal
weight were observed at 19 times the recommended human intravenous dose.
Exposure multiples for the rat studies were calculated
using human exposure at the recommended intravenous dose of 3 mg every 3 months
and were based on cumulative area under the time-concentration (AUC)
comparison. Exposure multiples for the rabbit study were calculated for the
recommended human intravenous dose of 3 mg every 3 months and were based on
cumulative dose/[body surface area] comparison. Doses in pregnant animals were
0.05, 0.1, 0.15, 0.3, 0.5 or 1 mg/kg/day in rats, and 0.03, 0.07, or 0.2
mg/kg/day in rabbits.
It is not known whether BONIVA is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
BONIVA Injection is administered to a nursing woman. In lactating rats treated
with intravenous doses of 0.08 mg/kg, ibandronate was present in breast milk at
concentrations of 8.1 to 0.4 ng/mL from 2 to 24 hours after dose
administration. Concentrations in milk averaged 1.5 times plasma
Safety and effectiveness of BONIVA in pediatric patients
have not been established.
Of the patients receiving BONIVA Injection 3 mg every 3
months for 1 year, 51% were over 65 years of age. No overall differences in
effectiveness or safety were observed between these patients and younger
patients, but greater sensitivity in some older individuals cannot be ruled
BONIVA Injection should not be administered to patients
with severe renal impairment (creatinine clearance less than 30 mL/min) [see WARNINGS