Included as part of the PRECAUTIONS section.
Drugs With Same Active Ingredient Or In The Same Drug
Zometa contains the same active ingredient as found in
Reclast® (zoledronic acid). Patients being treated with Zometa should not be
treated with Reclast or other bisphosphonates.
Hydration And Electrolyte Monitoring
Patients with hypercalcemia of malignancy must be
adequately rehydrated prior to administration of Zometa. Loop diuretics should
not be used until the patient is adequately rehydrated and should be used with
caution in combination with Zometa in order to avoid hypocalcemia. Zometa
should be used with caution with other nephrotoxic drugs.
Standard hypercalcemia-related metabolic parameters, such
as serum levels of calcium, phosphate, and magnesium, as well as serum
creatinine, should be carefully monitored following initiation of therapy with
Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term
supplemental therapy may be necessary.
Zometa is excreted intact primarily via the kidney, and
the risk of adverse reactions, in particular renal adverse reactions, may be
greater in patients with impaired renal function. Safety and pharmacokinetic
data are limited in patients with severe renal impairment and the risk of renal
deterioration is increased [see ADVERSE REACTIONS]. Preexisting renal
insufficiency and multiple cycles of Zometa and other bisphosphonates are risk
factors for subsequent renal deterioration with Zometa. Factors predisposing to
renal deterioration, such as dehydration or the use of other nephrotoxic drugs,
should be identified and managed, if possible.
Zometa treatment in patients with hypercalcemia of
malignancy with severe renal impairment should be considered only after
evaluating the risks and benefits of treatment [see DOSAGE AND
ADMINISTRATION]. In the clinical studies, patients with serum creatinine
greater than 400 μmol/L or greater than 4.5 mg/dL were excluded.
Zometa treatment is not recommended in patients with bone
metastases with severe renal impairment. In the clinical studies, patients with
serum creatinine greater than 265 μmol/L or greater than 3.0 mg/dL were
excluded and there were only 8 of 564 patients treated with Zometa 4 mg by
15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited
pharmacokinetic data exists in patients with creatinine clearance less than 30
mL/min [see CLINICAL PHARMACOLOGY].
Osteonecrosis Of The Jaw
Osteonecrosis of the jaw (ONJ) has been reported
predominantly in cancer patients treated with intravenous bisphosphonates,
including Zometa. Many of these patients were also receiving chemotherapy and
corticosteroids which may be risk factors for ONJ. The risk of ONJ may increase
with duration of exposure to bisphosphonates.
Postmarketing experience and the literature suggest a
greater frequency of reports of ONJ based on tumor type (advanced breast
cancer, multiple myeloma), and dental status (dental extraction, periodontal
disease, local trauma including poorly fitting dentures). Many reports of ONJ
involved patients with signs of local infection including osteomyelitis.
Cancer patients should maintain good oral hygiene and
should have a dental examination with preventive dentistry prior to treatment
While on treatment, these patients 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.
Clinical judgment of the treating physician should guide the management plan of
each patient based on individual benefit/risk assessment [see ADVERSE
In postmarketing experience, severe and occasionally
incapacitating bone, joint, and/or muscle pain has been reported in patients
taking bisphosphonates, including Zometa. The time to onset of symptoms varied
from one day to several months after starting the drug. Discontinue use if
severe symptoms develop. Most patients had relief of symptoms after stopping. A
subset had recurrence of symptoms when rechallenged with the same drug or
another bisphosphonate [see ADVERSE REACTIONS].
Atypical Subtrochanteric And Diaphyseal Femoral Fractures
Atypical subtrochanteric and diaphyseal femoral fractures
have been reported in patients receiving bisphosphonate therapy, including
Zometa. These fractures can occur anywhere in the femoral shaft from just below
the lesser trochanter to just above the supracondylar flare and are transverse
or short oblique in orientation without evidence of comminution. These
fractures occur after minimal or no trauma. Patients may experience thigh or
groin pain weeks to months before presenting with a completed femoral fracture.
Fractures are often bilateral; therefore the contralateral femur should be
examined in bisphosphonate-treated patients who have sustained a femoral shaft
fracture. Poor healing of these fractures has also been reported. A number of
case reports noted that patients were also receiving treatment with
glucocorticoids (such as prednisone or dexamethasone) at the time of fracture.
Causality with bisphosphonate therapy has not been established.
Any patient with a history of bisphosphonate exposure who
presents with thigh or groin pain in the absence of trauma should be suspected
of having an atypical fracture and should be evaluated. Discontinuation of
Zometa therapy in patients suspected to have an atypical femur fracture should
be considered pending evaluation of the patient, based on an individual benefit
risk assessment. It is unknown whether the risk of atypical femur fracture
continues after stopping therapy.
Patients With Asthma
While not observed in clinical trials with Zometa, there
have been reports of bronchoconstriction in aspirin-sensitive patients
Only limited clinical data are available for use of
Zometa to treat hypercalcemia of malignancy in patients with hepatic
insufficiency, and these data are not adequate to provide guidance on dosage
selection or how to safely use Zometa in these patients.
Use In Pregnancy
Bisphosphonates, such as Zometa, are incorporated into
the bone matrix, from where they are gradually released over periods of weeks
to years. There may be a risk of fetal harm (e.g., skeletal and other
abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate
Zometa may cause fetal harm when administered to a
pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses
equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre-and
postimplantation losses, decreases in viable fetuses and fetal skeletal,
visceral, and external malformations. There are no adequate and well controlled
studies in pregnant women. If this drug is used during pregnancy, or if the
patient becomes pregnant while taking this drug, the patient should be apprised
of the potential hazard to a fetus [see Use in Specific Populations].
Hypocalcemia has been reported in patients treated with
Zometa. Cardiac arrhythmias and neurologic adverse events (seizures, tetany,
and numbness) have been reported secondary to cases of severe hypocalcemia. In
some instances, hypocalcemia may be life-threatening. Caution is advised when
Zometa is administered with drugs known to cause hypocalcemia, as severe
hypocalcemia may develop, [see DRUG INTERACTIONS]. Serum calcium should be measured and hypocalcemia must be
corrected before initiating Zometa. Adequately supplement patients with calcium
and vitamin D.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Standard lifetime carcinogenicity bioassays were
conducted in mice and rats. Mice were given oral doses of zoledronic acid of
0.1, 0.5, or 2.0 mg/kg/day. There was an increased incidence of Harderian gland
adenomas in males and females in all treatment groups (at doses ≥ 0.002 times
a human intravenous dose of 4 mg, based on a comparison of relative body
surface areas). Rats were given oral doses of zoledronic acid of 0.1, 0.5, or 2.0
mg/kg/day. No increased incidence of tumors was observed (at doses ≤ 0.2
times the human intravenous dose of 4 mg, based on a comparison of relative
body surface areas).
Zoledronic acid was not genotoxic in the Ames bacterial
mutagenicity assay, in the Chinese hamster ovary cell assay, or in the Chinese
hamster gene mutation assay, with or without metabolic activation. Zoledronic
acid was not genotoxic in the in vivo rat micronucleus assay.
Female rats were given subcutaneous doses of zoledronic
acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and
continuing through gestation. Effects observed in the high-dose group (with
systemic exposure of 1.2 times the human systemic exposure following an
intravenous dose of 4 mg, based on AUC comparison) included inhibition of
ovulation and a decrease in the number of pregnant rats. Effects observed in
both the mid-dose group (with systemic exposure of 0.2 times the human systemic
exposure following an intravenous dose of 4 mg, based on an AUC comparison) and
high-dose group included an increase in preimplantation losses and a decrease
in the number of implantations and live fetuses.
Use In Specific Populations
Pregnancy Category D [see WARNINGS AND
There are no adequate and well-controlled studies of
Zometa in pregnant women. Zometa may cause fetal harm when administered to a
pregnant woman. Bisphosphonates, such as Zometa, are incorporated into the bone
matrix and 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. If this drug is used during pregnancy or
if the patient becomes pregnant while taking or after taking this drug, the
patient should be apprised of the potential hazard to the fetus.
In female rats given subcutaneous doses of zoledronic
acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and
continuing through gestation, the number of stillbirths was increased and
survival of neonates was decreased in the mid-and high-dose groups ( ≥ 0.2
times the human systemic exposure following an intravenous dose of 4 mg, based
on an AUC comparison). Adverse maternal effects were observed in all dose
groups (with a systemic exposure of ≥ 0.07 times the human systemic exposure
following an intravenous dose of 4 mg, based on an AUC comparison) and included
dystocia and periparturient mortality in pregnant rats allowed to deliver.
Maternal mortality may have been related to drug-induced inhibition of skeletal
calcium mobilization, resulting in periparturient hypocalcemia. This appears to
be a bisphosphonate-class effect.
In pregnant rats given a subcutaneous dose of zoledronic
acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were
observed in the mid-and high-dose groups (with systemic exposures of 2.4 and 4.8
times, respectively, the human systemic exposure following an intravenous dose
of 4 mg, based on an AUC comparison). These adverse effects included increases
in pre-and postimplantation losses, decreases in viable fetuses, and fetal
skeletal, visceral, and external malformations. Fetal skeletal effects observed
in the high-dose group included unossified or incompletely ossified bones,
thickened, curved, or shortened bones, wavy ribs, and shortened jaw. Other adverse
fetal effects observed in the high-dose group included reduced lens,
rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung
lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also
observed in the low-dose group (with systemic exposure of 1.2 times the human
systemic exposure following an intravenous dose of 4 mg, based on an AUC
comparison). Signs of maternal toxicity were observed in the high-dose group
and included reduced body weights and food consumption, indicating that maximal
exposure levels were achieved in this study.
In pregnant rabbits given subcutaneous doses of
zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation ( ≤ 0.5
times the human intravenous dose of 4 mg, based on a comparison of relative
body surface areas), no adverse fetal effects were observed. Maternal mortality
and abortion occurred in all treatment groups (at doses ≥ 0.05 times the
human intravenous dose of 4 mg, based on a comparison of relative body surface areas).
Adverse maternal effects were associated with, and may have been caused by,
It is not known whether zoledronic acid is excreted in
human milk. Because many drugs are excreted in human milk, and because of the
potential for serious adverse reactions in nursing infants from Zometa, a
decision should be made to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother. Zoledronic acid binds
to bone long term and may be released over weeks to years.
Zometa is not indicated for use in children.
The safety and effectiveness of zoledronic acid was
studied in a one-year, active-controlled trial of 152 pediatric subjects (74
receiving zoledronic acid). The enrolled population was subjects with severe
osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean
lumbar spine bone mineral density (BMD) of 0.431 gm/cm², which is
2.7 standard deviations below the mean for age-matched controls (BMD Z-score of
-2.7). At one year, increases in BMD were observed in the zoledronic acid
treatment group. However, changes in BMD in individual patients with severe
osteogenesis imperfecta did not necessarily correlate with the risk for
fracture or the incidence or severity of chronic bone pain. The adverse events
observed with Zometa use in children did not raise any new safety findings
beyond those previously seen in adults treated for hypercalcemia of malignancy
or bone metastases. However, adverse reactions seen more commonly in pediatric
patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and
headache (22%). These reactions, excluding arthralgia, occurred most frequently
within 3 days after the first infusion and became less common with repeat
dosing. Because of long-term retention in bone, Zometa should only be used in
children if the potential benefit outweighs the potential risk.
Plasma zoledronic acid concentration data was obtained
from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8
years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over
30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng•h/mL, respectively.
The plasma concentration time profile of zoledronic acid in pediatric patients
represent a multi-exponential decline, as observed in adult cancer patients at
an approximately equivalent mg/kg dose.
Clinical studies of Zometa in hypercalcemia of malignancy
included 34 patients who were 65 years of age or older. No significant
differences in response rate or adverse reactions were seen in geriatric
patients receiving Zometa as compared to younger patients. Controlled clinical
studies of Zometa in the treatment of multiple myeloma and bone metastases of
solid tumors in patients over age 65 revealed similar efficacy and safety in
older and younger patients. Because decreased renal function occurs more
commonly in the elderly, special care should be taken to monitor renal function.