Ibandronate
Introduction
Synthetic
bisphosphonate; bone resorption inhibitor.
Uses
for Ibandronate
Osteoporosis
Prevention
of osteoporosis in postmenopausal women. Risk factors for postmenopausal
osteoporosis and related fractures include early menopause, advanced age, low
bone mineral density (BMD), low body mass index (BMI), previous fracture or
family history of fracture/osteoporosis, excessive alcohol intake, smoking,
inadequate physical activity, low calcium and vitamin D intake, certain drugs
(e.g., glucocorticoids), and medical conditions or diseases (e.g., rheumatoid
arthritis, diabetes mellitus, Cushing syndrome, hyperparathyroidism).
Treatment
of osteoporosis in postmenopausal women.
In
addition to adequate intake of calcium/vitamin D and other lifestyle
modifications (e.g., exercise, avoidance of excessive alcohol and tobacco use),
experts recommend that pharmacologic therapy for osteoporosis be considered in
postmenopausal women with previous hip or vertebral fractures or low BMD;
pharmacologic therapy also may be considered in postmenopausal women with low
bone mass, although there is less evidence supporting overall fracture risk
reduction in such patients.
Use
of a drug with proven efficacy in reducing fracture risk is recommended;
bisphosphonates (e.g., alendronate, risedronate, zoledronic acid, ibandronate)
are recommended as one of several first-line drugs.
Individualize
choice of therapy based on potential benefits (with respect to fracture risk
reduction) and adverse effects of therapy, patient preferences, comorbidities,
and risk factors.
Glucocorticoid-induced
Osteoporosis
Also
has been used in the management of glucocorticoid-induced osteoporosis†.
American
College of Rheumatology (ACR) recommends optimizing calcium and vitamin D
intake and lifestyle modifications (e.g., diet, smoking cessation,
weight-bearing or resistance-training exercise) in all patients receiving
long-term glucocorticoid therapy; in addition, pharmacologic therapy with an
oral bisphosphonate is recommended in patients who are considered to be at moderate-to-high
risk of fracture. Oral bisphosphonates generally are preferred because of their
demonstrated antifracture benefits, safety, and low cost.
Ibandronate
Dosage and Administration
General
Correct
hypocalcemia and other disturbances of bone and mineral metabolism prior to
initiation of therapy.
Provide
supplemental calcium and vitamin D if dietary intake is inadequate.
Administration
Oral
Administration
Administer
orally with a full glass (180–240 mL) of plain water ≥60 minutes prior to the
first food, beverage (other than plain water), or other orally administered
drug or supplement (including vitamins, antacids, and calcium) of the day. (See
Food under Pharmacokinetics.)
Avoid
lying down for ≥60 minutes following administration.
Do
not to suck or chew tablets; potential for oropharyngeal ulceration. (See Upper
GI Effects under Cautions.)
If
a morning daily oral dose is missed, do not take missed dose later that same
day. Resume the regular schedule the next day.
When
administered monthly, take tablets in the morning on the same day each month.
If a monthly dose is missed and the next scheduled dose is more than 7 days
away, take the missed dose the next morning after it is remembered and resume
the regular schedule. If the next scheduled dose is 1–7 days away, maintain the
regular schedule; do not take more than one 150-mg tablet within the same week.
IV
Administration
Administer
by IV injection once every 3 months by a health-care professional.
Injection
must only be administered IV. Safety and efficacy of IV injection administered
by other routes not established.
Because
of the risk of anaphylaxis or other severe hypersensitivity reactions,
appropriate medical support should be readily available during IV
administration. (See Hypersensitivity under Cautions.)
If
a dose is missed, reschedule administration with a health-care professional as
soon as possible. Schedule subsequent injections at 3-month intervals; should
not be administered more often than once every 3 months.
Administration
Risks
Take
care to avoid intra-arterial or paravenous injection as such administration
could result in tissue damage.
Rate
of Administration
Administer
IV over a period of 15–30 seconds.
Dosage
Available
as ibandronate sodium (as the monosodium monohydrate); dosage expressed in
terms of ibandronate.
Adults
Osteoporosis
Prevention
in Postmenopausal Women
Oral
150
mg once monthly.
Osteoporosis
Treatment
in Postmenopausal Women
Oral
150
mg once monthly.
Optimal
duration of treatment not established. Safety and efficacy based on data over 3
years. Reevaluate need for continued therapy periodically in all patients
receiving bisphosphonates. Consider discontinuance of bisphosphonate therapy
after 3–5 years in patients at low risk of fracture. Evaluate fracture risk
periodically in patients who discontinue therapy.
IV
3
mg once every 3 months.
Optimal
duration of treatment not established. Safety and efficacy of IV ibandronate
based on data supporting fracture reduction over 1 year of treatment.
Reevaluate need for continued therapy periodically in all patients receiving
bisphosphonates. Consider discontinuance of bisphosphonate therapy after 3–5
years in patients at low risk of fracture. Evaluate fracture risk periodically
in patients who discontinue therapy.
Special
Populations
Renal
Impairment
Oral
or IV
Dosage
adjustments not necessary in patients with mild to moderate renal impairment
(Clcr ≥30 mL/minute); use not recommended in patients with severe renal
impairment (Clcr <30 mL/minute).
Detailed Ibandronate
dosage information
Cautions
for Ibandronate
Contraindications
Oral:
Esophageal abnormalities that delay esophageal emptying (e.g., stricture,
achalasia).
Oral
and IV: Uncorrected hypocalcemia.
Oral
and IV: Known hypersensitivity to ibandronate or any ingredient in the
formulation.
Oral:
Inability to stand or sit upright for ≥60 minutes.
Warnings/Precautions
Upper
GI Effects
Possible
severe adverse esophageal effects (e.g., esophagitis, esophageal ulcers,
erosions, strictures, perforation). (See Oral Administration under Dosage and
Administration.) Monitor for any manifestations and discontinue if dysphagia,
odynophagia, new or worsening heartburn, or retrosternal pain occurs.
Use
with caution in patients with active upper GI disease (e.g., Barrett’s
esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis,
ulcers). Gastric and duodenal ulcers (some severe and with complications)
reported during postmarketing experience.
Route
of Administration
Injection
must be administered IV by a health-care professional; do not administer by
non-IV (e.g., intra-arterial) routes. (See Administration Risks under Dosage
and Administration.)
Metabolic
Effects
Correct
hypocalcemia, hypovitaminosis D, and other disturbances of bone and mineral
metabolism before initiating therapy.
If
daily intake inadequate, administer supplemental calcium and vitamin D.
Osteonecrosis
of the Jaw
Osteonecrosis
and osteomyelitis of the jaw reported in patients receiving bisphosphonates.
Most cases associated with tooth extraction and/or local infection with delayed
healing. Known risk factors include cancer, concomitant therapies (e.g.,
chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and
comorbid disorders (e.g., periodontal and/or other preexisting dental disease,
anemia, coagulopathy, infection, ill-fitting dentures). Risk also may be
increased with increased duration of bisphosphonate use.
If
osteonecrosis of the jaw develops, consult an oral surgeon for treatment.
Dental surgery may exacerbate condition.
In
patients requiring dental procedures, discontinuance of therapy prior to
procedure may reduce the risk of osteonecrosis of the jaw. Base management of
patients requiring dental treatment on an individual assessment of risks and
benefits.
Musculoskeletal
Pain
Severe
and occasionally incapacitating bone, joint, and/or muscle pain reported
infrequently with bisphosphonate therapy. Time to onset varied from 1 day to
years (mean onset about 3 months) after treatment initiation. If severe
symptoms occur, consider discontinuing drug. Such pain generally improves
following discontinuance, but may recur upon subsequent rechallenge with the
same drug or another bisphosphonate.
Atypical
Fracture of the Femur
Atypical
(subtrochanteric or diaphyseal) femur fractures reported rarely with long-term
use (>3 years) of bisphosphonates, mostly in patients receiving these drugs
for osteoporosis. Often occurs with minimal or no trauma, and may be bilateral.
Causality not established; atypical fractures also occur in osteoporotic
patients not receiving bisphosphonates. Risk may be increased with concomitant
use of glucocorticoid, estrogen, and proton-pump inhibitor therapy.
Evaluate
patients who present with new thigh or groin pain for possibility of an
atypical femoral fracture; include assessment of the contralateral limb.
Consider interruption of bisphosphonate therapy in patients with manifestations
of possible femoral fracture; weigh risks versus benefits of continued
treatment. Discontinue if a femoral shaft fracture is confirmed.
Atrial
Fibrillation
Although
data are conflicting, possible increased risk of atrial fibrillation with use
of bisphosphonates. FDA analysis of data from long-term (6 months to 3 years)
controlled trials identified a higher rate of atrial fibrillation in patients
receiving bisphosphonates (alendronate, ibandronate, risedronate, or zoledronic
acid) versus placebo; however, only a few events reported in each study. FDA is
continuing to monitor this safety concern.
Potential
Risk of Esophageal Cancer
Some
evidence (from postmarketing experience and observational studies) suggests a
possible association between use of oral bisphosphonates and an increased risk
of esophageal cancer. However, because of conflicting data, additional study
needed to confirm such findings.
FDA
states that benefits of oral bisphosphonates continue to outweigh their
potential risks in patients with osteoporosis; it is important to consider that
esophageal cancer is rare, especially in women.
Avoidance
of oral bisphosphonates in patients with Barrett’s esophagus, a known precursor
to esophageal adenocarcinoma, has been recommended.
Renal
Effects
Possible
renal toxicity (e.g., deterioration of renal function and, rarely, renal
failure) with bisphosphonates. Risk may be greater in patients with coexisting
conditions associated with renal impairment, concomitant therapy with other
nephrotoxic drugs, preexisting renal disease, dehydration, dosage, infusion
volume and rate, and multiple cycles of treatment. Assess renal function in
such patients.
Use
not recommended in patients with severe renal impairment (Clcr <30
mL/minute).
Measure
Scr prior to each IV dose. Withhold treatment if deterioration of renal
function occurs.
Sensitivity
Reactions
Hypersensitivity
Hypersensitivity
reactions, including fatal anaphylaxis in patients who received ibandronate
injection, reported. (See Contraindications under Cautions and see IV
Administration under Dosage and Administration.)
Specific
Populations
Pregnancy
No
data in pregnant women to inform any drug-associated risks. In reproductive
animal studies, maternal and fetal toxicity (including postimplantation loss,
developmental anomalies, and deaths) observed.
Lactation
Distributed
into milk in rats; not known whether distributed into human milk. Also not
known whether the drug has any effects on the nursing infant or milk
production.
Pediatric
Use
Safety
and efficacy not established in children. Not indicated for use in children.
Geriatric
Use
No
substantial differences in safety and efficacy relative to younger adults, but
increased sensitivity cannot be ruled out. Consider age-related decreases in
renal function.
Renal
Impairment
Use
not recommended in patients with severe renal impairment (CLcr <30
mL/minute).
Common
Adverse Effects
Oral:
Back pain, dyspepsia, pain in the extremities, diarrhea, headache, myalgia.
IV:
Arthralgia, back pain, abdominal pain.
Interactions
for Ibandronate
Does
not induce or inhibit CYP isoenzymes (i.e., CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1,
or 3A4) and is not metabolized.
Antacids
or Mineral Supplements Containing Divalent Cations
Pharmacokinetic
interaction (decreased absorption of ibandronate) when tablets are used
concomitantly with antacids or mineral supplements containing divalent cations
(e.g., aluminum, calcium, magnesium, iron). Administer tablets ≥60 minutes
prior to such drugs or supplements.
Drugs
Affecting Hepatic Microsomal Enzymes
Pharmacokinetic
interactions unlikely.
Drugs
Excreted through Renal Tubular Transport
Based
on limited data in animals, not excreted through renal tubular transport.
Pharmacokinetic interaction unlikely.
Nephrotoxic
Agents
Potential
pharmacologic interaction (increased risk of renal toxicity). Assess patients
taking concomitant nephrotoxic agents. (See Renal Effects under Cautions.)
Specific
Drugs and Tests
|
Drug
|
Interaction
|
Comments
|
|
Bone-imaging
agents
|
Potential
to interfere with use of bone-imaging agents
|
|
|
Histamine
H2-receptor antagonists
|
Increased
oral bioavailability of ibandronate
No
evidence of increased adverse upper GI effects
|
Not
considered clinically important
|
|
Melphalan
|
Pharmacokinetic
interaction unlikely with IV ibandronate
|
|
|
NSAIAs
|
No
evidence of increased adverse upper GI effects
|
Use
concomitantly with caution
|
|
Prednisolone
|
Pharmacokinetic
interaction unlikely with IV ibandronate
|
|
|
Tamoxifen
|
Pharmacokinetic
interaction unlikely with IV ibandronate
|
|
Absolute
(compared with IV administration) oral bioavailability about 0.6%.
Onset
Reduction
in bone turnover evident within 1–3 months of treatment initiation; maximal
effects observed at 6 months.
Food
Bioavailability
decreased by 90% when administered with a standard breakfast compared with
administration under fasting conditions. Bioavailability and effect on BMD
reduced when food and beverages taken <60 minutes following oral
administration.
Special
Populations
In
patients with renal impairment (Clcr 40–70 mL/minute), AUC is increased by
55% compared with that in patients with normal renal function (Clcr >90
mL/minute). Patients with severe renal impairment (Clcr <30 mL/minute)
had >2-fold increase in AUC compared with exposure for healthy individuals.
Distribution
Extent
Widely
distributed throughout the body and redistributed to bone. Subsequently, the
drug is released systemically via bone turnover. Not known whether distributed
into milk.
Plasma
Protein Binding
84–99.5%
at therapeutic drug concentrations.
Elimination
Metabolism
No
evidence of metabolism.
Elimination
Route
Excreted
in urine (50–60% of circulating dose) as unchanged drug and in feces
(unabsorbed drug).
Half-life
Apparent
oral terminal half-life is 37–157 hours; dose-dependent.
Apparent
IV terminal half-life is 4.6–25.5 hours; dose-dependent.
Special
Populations
Pharmacokinetic
differences based on race not evaluated. Pharmacokinetics not affected by
gender.
Pharmacokinetics
not evaluated in pediatric patients. Pharmacokinetics in patients with hepatic
impairment not studied as ibandronate is not metabolized in the liver.
Stability
Storage
Oral
Tablets
25°C
(may be exposed to 15–30°C).
Parenteral
Injection
25°C
(may be exposed to 15–30°C).
Compatibility
For
information on systemic interactions resulting from concomitant use, see
Interactions.
Parenteral
Do
not admix with calcium-containing solutions or other IV drugs.
Actions
Incorporates
into bone and selectively inhibits osteoclast-mediated bone resorption in a
dose-dependent manner.
Reduces
biochemical markers of bone resorption in patients with postmenopausal
osteoporosis.
Maintains
or increases BMD and increases bone mass in postmenopausal women.
Advice
to Patients
Importance
of providing patient with a copy of the manufacturer’s patient information.
Importance
of adhering to recommended life-style modifications (e.g., exercise, calcium
and vitamin D supplementation).
Importance
of correct oral administration (e.g., avoiding foods and beverages other than
plain water [including mineral water] prior to administration, not lying down
for ≥60 minutes following administration).
Importance
of not taking vitamins, calcium, or antacids ≤60 minutes of taking
oral ibandronate.
Necessity
of swallowing tablets whole, without chewing or sucking.
Importance
of reviewing how to resume therapy in the event of a missed dose.
Importance
of discontinuing oral ibandronate and informing clinician if symptoms of
esophageal disease (e.g., new or worsening dysphagia, difficulty or pain on
swallowing, retrosternal pain, heartburn) develop.
Importance
of informing a clinician if severe bone pain, joint pain, muscular pain, or jaw
problems develop.
Importance
of women informing clinicians if they are or plan to become pregnant or to plan
to breast-feed.
Importance
of informing clinicians of existing or contemplated concomitant therapy,
including prescription and OTC drugs (vitamins, supplements, antacids), as well
as any concomitant illnesses (e.g., preexisting dysphagia, esophageal
disorders, renal impairment).
Importance
of advising patients of other important precautionary information. (See
Cautions.)
Preparations
Excipients
in commercially available drug preparations may have clinically important
effects in some individuals; consult specific product labeling for details.
Please
refer to the ASHP Drug
Shortages Resource Center for information on shortages of one or more
of these preparations.
*
available from one or more manufacturer, distributor, and/or repackager by
generic (nonproprietary) name
|
Ibandronate
Sodium
|
|
Routes
|
Dosage
Forms
|
Strengths
|
Brand
Names
|
Manufacturer
|
|
Oral
|
Tablets,
film-coated
|
150
mg (of ibandronate)*
|
Boniva
|
Genentech
|
|
|
|
Ibandronate
Sodium Tablets
|
|
|
Injection,
for IV use only
|
1
mg (of ibandronate) per mL*
|
Boniva (available
in prefilled syringe with needle and swabs)
|
Genentech
|
|
|
|
Ibandronate
Sodium Injection
|
|
AHFS DI
Essentials™. © Copyright 2021, Selected Revisions March 12, 2018. American
Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900,
Bethesda, Maryland 20814.
† Use is not currently included in the
labeling approved by the US Food and Drug Administration.
