Indications and Usage for Zoledronic Acid IV
Hypercalcemia of Malignancy
Zoledronic acid injection is
indicated for the treatment of hypercalcemia of malignancy defined as an
albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3 mmol/L]
using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL - patient albumin
[g/dL]).
Multiple Myeloma and Bone
Metastases of Solid Tumors
Zoledronic acid injection is
indicated for the treatment of patients with multiple myeloma and patients with
documented bone metastases from solid tumors, in conjunction with standard
antineoplastic therapy. Prostate cancer should have progressed after treatment
with at least one hormonal therapy.
Limitations
of Use
The safety and efficacy of
zoledronic acid in the treatment of hypercalcemia associated with
hyperparathyroidism or with other nontumor-related conditions have not been
established.
Zoledronic Acid IV Dosage and Administration
Parenteral drug products
should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
Hypercalcemia of Malignancy
The maximum recommended dose
of zoledronic acid in hypercalcemia of malignancy (albumin-corrected serum
calcium greater than or equal to 12 mg/dL [3 mmol/L]) is 4 mg. The 4-mg dose
must be given as a single-dose intravenous infusion over no
less than 15 minutes. Patients who receive zoledronic acid injection
should have serum creatinine assessed prior to each treatment.
Dose adjustments of zoledronic
acid injection are not necessary in treating patients for hypercalcemia of
malignancy presenting with mild-to-moderate renal impairment prior to
initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5
mg/dL).
Patients should be adequately
rehydrated prior to administration of zoledronic acid injection [see Warnings and Precautions (5.2)].
Consideration should be given
to the severity of, as well as the symptoms of, tumor-induced hypercalcemia
when considering use of zoledronic acid. Vigorous saline hydration, an integral
part of hypercalcemia therapy, should be initiated promptly and an attempt
should be made to restore the urine output to about 2 L/day throughout
treatment. Mild or asymptomatic hypercalcemia may be treated with conservative
measures (i.e., saline hydration, with or without loop diuretics). Patients
should be hydrated adequately throughout the treatment, but overhydration,
especially in those patients who have cardiac failure, must be avoided.
Diuretic therapy should not be employed prior to correction of hypovolemia.
Retreatment with zoledronic
acid injection 4 mg may be considered if serum calcium does not return to
normal or remain normal after initial treatment. It is recommended that a
minimum of 7 days elapse before retreatment, to allow for full response to the
initial dose. Renal function must be carefully monitored in all patients
receiving zoledronic acid injection and serum creatinine must be assessed prior
to retreatment with zoledronic acid injection [see
Warnings and Precautions (5.2)].
Multiple Myeloma and Bone
Metastases of Solid Tumors
The recommended dose of
zoledronic acid in patients with multiple myeloma and metastatic bone lesions
from solid tumors for patients with creatinine clearance (CrCl) greater than 60
mL/min is 4 mg infused over no less than 15 minutes every
3 to 4 weeks. The optimal duration of therapy is not known.
Upon treatment initiation, the
recommended zoledronic acid doses for patients with reduced renal function
(mild and moderate renal impairment) are listed in Table 1. These doses are
calculated to achieve the same area under the curve (AUC) as that achieved in
patients with creatinine clearance of 75 mL/min. CrCl is calculated using the
Cockcroft-Gault formula [see Warnings and
Precautions (5.2)].
Table 1: Reduced Doses for Patients with
Baseline CrCl Less than or Equal to 60 mL/min
|
|
*Doses calculated assuming target AUC of
0.66(mg•hr/L) (CrCl=75 mL/min)
|
|
Baseline Creatinine Clearance (mL/min)
|
Zoledronic Acid Recommended Dose*
|
|
greater than 60
|
4 mg
|
|
50-60
|
3.5 mg
|
|
40-49
|
3.3 mg
|
|
30-39
|
3 mg
|
During treatment, serum
creatinine should be measured before each zoledronic acid dose and treatment
should be withheld for renal deterioration. In the clinical studies, renal
deterioration was defined as follows:
For patients with normal baseline creatinine, increase of 0.5 mg/dL
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL
In the clinical studies,
zoledronic acid treatment was resumed only when the creatinine returned to
within 10% of the baseline value. Zoledronic acid injection should be reinitiated
at the same dose as that prior to treatment interruption.
Patients should also be
administered an oral calcium supplement of 500 mg and a multiple vitamin
containing 400 international units of vitamin D daily.
Preparation of Solution
Zoledronic acid must not be
mixed with calcium or other divalent cation-containing infusion solutions, such
as Lactated Ringer's solution, and should be administered as a single
intravenous solution in a line separate from all other drugs.
4 mg
per100 mL Single-Dose Ready-to-Use Vial
Vials of zoledronic acid
injection ready-to-use solution for infusion contain overfill allowing for the
administration of 100 mL of solution (equivalent to 4 mg zoledronic acid). This
solution is ready-to-use and may be administered directly to the patient
without further preparation. For single dose only.
To prepare reduced doses for
patients with baseline CrCl less than or equal to 60 mL/min, withdraw the
specified volume of the zoledronic acid solution from the vial (see Table 2)
and replace with an equal volume of sterile 0.9% Sodium Chloride, USP, or 5%
Dextrose Injection, USP. Administer the newly-prepared dose adjusted solution
to the patient by infusion. Follow proper aseptic technique. Properly discard
previously withdrawn volume of ready-to-use solution - do not store or reuse.
Table 2: Preparation of Reduced
Doses–Zoledronic Acid Injection Ready-to-Use vial
|
|
Remove and discard the following
zoledronic acid ready-to-use solution (mL)
|
Replace with the following volume of
sterile 0.9% Sodium Chloride, USP or 5% Dextrose Injection, USP (mL)
|
Dose (mg)
|
|
12.0
|
12.0
|
3.5 mg
|
|
18.0
|
18.0
|
3.3 mg
|
|
25.0
|
25.0
|
3 mg
|
If not used immediately after
dilution with infusion media, for microbiological integrity, the solution
should be refrigerated at 2°C–8°C (36°F–46°F). The refrigerated solution should
then be equilibrated to room temperature prior to administration. The total
time between dilution, storage in the refrigerator, and end of administration
must not exceed 24 hours.
Method of Administration
Due to the risk of clinically
significant deterioration in renal function, which may progress to renal
failure, single doses of zoledronic acid injection should not exceed 4 mg and
the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in
postmarketing experience, renal deterioration, progression to renal failure and
dialysis, have occurred in patients, including those treated with the approved
dose of 4 mg infused over 15 minutes. There have been instances of this
occurring after the initial zoledronic acid injection dose.
Dosage Forms and Strengths
4 mg per100 mL single-dose
ready-to-use vial
Contraindications
Hypersensitivity
to Zoledronic Acid or Any Components of Zoledronic Acid Injection
Hypersensitivity reactions
including rare cases of urticaria and angioedema, and very rare cases of
anaphylactic reaction/shock have been reported [see
Adverse Reactions (6.2)].
Warnings and PrecautionsDrugs with Same Active
Ingredient or in the Same Drug Class
Zoledronic acid injection
contains the same active ingredient as found in Reclast® (zoledronic acid).
Patients being treated with zoledronic acid 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 zoledronic
acid injection. Loop diuretics should not be used until the patient is
adequately rehydrated and should be used with caution in combination with
zoledronic acid in order to avoid hypocalcemia. Zoledronic acid injection
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 zoledronic acid injection. If hypocalcemia,
hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may
be necessary.
Renal Impairment
Zoledronic acid 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 (6.1)]. Pre-existing renal
insufficiency and multiple cycles of zoledronic acid injection and other
bisphosphonates are risk factors for subsequent renal deterioration with
zoledronic acid. Factors predisposing to renal deterioration, such as
dehydration or the use of other nephrotoxic drugs, should be identified and
managed, if possible.
Zoledronic acid injection
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 (2.1)]. In the clinical studies,
patients with serum creatinine greater than 400 μmol/L or greater than 4.5
mg/dL were excluded.
Zoledronic acid injection
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 zoledronic acid 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 (12.3)].
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ)
has been reported predominantly in cancer patients treated with intravenous
bisphosphonates, including zoledronic acid. 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 with bisphosphonates.
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 Reactions (6.2)].
Musculoskeletal Pain
In postmarketing experience,
severe and occasionally incapacitating bone, joint, and/or muscle pain has been
reported in patients taking bisphosphonates, including zoledronic acid. 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 (6.2)].
Atypical Subtrochanteric and
Diaphyseal Femoral Fractures
Atypical subtrochanteric and
diaphyseal femoral fractures have been reported in patients receiving
bisphosphonate therapy, including zoledronic acid. 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 zoledronic acid injection 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 zoledronic acid, there have been reports of bronchoconstriction in
aspirin sensitive patients receiving bisphosphonates.
Hepatic Impairment
Only limited clinical data are
available for use of zoledronic acid 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 zoledronic acid in these
patients.
Use in Pregnancy
Bisphosphonates, such as
zoledronic acid, 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 therapy.
Zoledronic acid 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 post implantation 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 (8.1)].
Hypocalcemia
Hypocalcemia has been reported
in patients treated with zoledronic acid. 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 zoledronic acid is administered with
drugs known to cause hypocalcemia, as severe hypocalcemia may develop, [see Drug Interactions (7)]. Serum calcium should be
measured and hypocalcemia must be corrected before initiating zoledronic acid
injection. Adequately supplement patients with calcium and vitamin D.
Adverse ReactionsClinical Trials Experience
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
practice.
Hypercalcemia
of Malignancy
The safety of zoledronic acid
was studied in 185 patients with hypercalcemia of malignancy (HCM) who received
either zoledronic acid 4 mg given as a 5-minute intravenous infusion (n=86) or
pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The
population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung,
head and neck, and renal cancer as the most common forms of malignancy. NOTE:
pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative
safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to
the same dose given as a 24-hour intravenous infusion has not been adequately
studied in controlled clinical trials.
Renal
Toxicity
Administration of zoledronic
acid 4 mg given as a 5-minute intravenous infusion has been shown to result in
an increased risk of renal toxicity, as measured by increases in serum
creatinine, which can progress to renal failure. The incidence of renal
toxicity and renal failure has been shown to be reduced when zoledronic acid 4
mg is given as a 15-minute intravenous infusion. Zoledronic acid should be
administered by intravenous infusion over no less than 15 minutes [see Warnings and Precautions (5.3), Dosage and Administration (2.4)].
The most frequently observed
adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table
4).
Table 4 provides adverse
events that were reported by 10% or more of the 189 patients treated with
zoledronic acid 4 mg or pamidronate 90 mg from the two HCM trials. Adverse
events are listed regardless of presumed causality to study drug.
Table 4: Percentage of Patients with
Adverse Events greater than or equal to10% Reported in Hypercalcemia of
Malignancy Clinical Trials by Body System
|
|
|
Zoledronic Acid
4 mg
n (%)
|
Pamidronate
90 mg
n (%)
|
|
Patients Studied
|
|
|
Total No. of
Patients Studied
|
86
|
(100)
|
103
|
(100)
|
|
Total No. of
Patients with any AE
|
81
|
(94)
|
95
|
(92)
|
|
Body as a Whole
|
|
|
Fever
|
38
|
(44)
|
34
|
(33)
|
|
Progression of
Cancer
|
14
|
(16)
|
21
|
(20)
|
|
Cardiovascular
|
|
|
Hypotension
|
9
|
(11)
|
2
|
(2)
|
|
Digestive
|
|
|
Nausea
|
25
|
(29)
|
28
|
(27)
|
|
Constipation
|
23
|
(27)
|
13
|
(13)
|
|
Diarrhea
|
15
|
(17)
|
17
|
(17)
|
|
Abdominal Pain
|
14
|
(16)
|
13
|
(13)
|
|
Vomiting
|
12
|
(14)
|
17
|
(17)
|
|
Anorexia
|
8
|
(9)
|
14
|
(14)
|
|
Hemic and Lymphatic System
|
|
|
Anemia
|
19
|
(22)
|
18
|
(18)
|
|
Infections
|
|
|
Moniliasis
|
10
|
(12)
|
4
|
(4)
|
|
Laboratory Abnormalities
|
|
|
Hypophosphatemia
|
11
|
(13)
|
2
|
(2)
|
|
Hypokalemia
|
10
|
(12)
|
16
|
(16)
|
|
Hypomagnesemia
|
9
|
(11)
|
5
|
(5)
|
|
Musculoskeletal
|
|
|
Skeletal Pain
|
10
|
(12)
|
10
|
(10)
|
|
Nervous
|
|
|
Insomnia
|
13
|
(15)
|
10
|
(10)
|
|
Anxiety
|
12
|
(14)
|
8
|
(8)
|
|
Confusion
|
11
|
(13)
|
13
|
(13)
|
|
Agitation
|
11
|
(13)
|
8
|
(8)
|
|
Respiratory
|
|
|
Dyspnea
|
19
|
(22)
|
20
|
(19)
|
|
Coughing
|
10
|
(12)
|
12
|
(12)
|
|
Urogenital
|
|
|
Urinary Tract
Infection
|
12
|
(14)
|
15
|
(15)
|
The following adverse events
from the two controlled multicenter HCM trials (n=189) were reported by a
greater percentage of patients treated with zoledronic acid 4 mg than with
pamidronate 90 mg and occurred with a frequency of greater than or equal to 5%
but less than 10%. Adverse events are listed regardless of presumed causality
to study drug: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia,
thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia,
dehydration, arthralgias, headache and somnolence. Rare cases of rash,
pruritus, and chest pain have been reported following treatment with zoledronic
acid.
Acute
Phase Reaction
Within three days after
zoledronic acid administration, an acute phase reaction has been reported in
patients, with symptoms including pyrexia, fatigue, bone pain and/or
arthralgias, myalgias, chills, and influenza-like illness. These symptoms
usually resolve within a few days. Pyrexia has been the most commonly
associated symptom, occurring in 44% of patients.
Mineral
and Electrolyte Abnormalities
Electrolyte abnormalities,
most commonly hypocalcemia, hypophosphatemia, and hypomagnesemia, can occur
with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum
creatinine, serum calcium, serum phosphorus, and serum magnesium observed in
two clinical trials of zoledronic acid in patients with HCM are shown in Table
5 and 6.
Table 5: Grade 3 Laboratory Abnormalities
for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in
Two Clinical Trials in Patients with HCM
|
|
|
Laboratory Parameter
|
Grade 3
|
|
|
Zoledronic Acid 4 mg
|
Pamidronate 90 mg
|
|
|
n/N
|
(%)
|
n/N
|
(%)
|
|
|
Serum Creatinine1
|
2/86
|
(2%)
|
3/100
|
(3%)
|
|
|
Hypocalcemia2
|
1/86
|
(1%)
|
2/100
|
(2%)
|
|
|
Hypophosphatemia3
|
36/70
|
(51%)
|
27/81
|
(33%)
|
|
|
Hypomagnesemia4
|
0/71
|
-
|
0/84
|
-
|
|
Table 6: Grade 4 Laboratory Abnormalities
for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in
Two Clinical Trials in Patients with HCM
|
|
|
1 Grade 3 (greater than 3x Upper Limit
of Normal); Grade 4 (greater than 6x Upper Limit of Normal)
|
|
|
2 Grade 3 (less than 7 mg/dL); Grade 4
(less than 6 mg/dL)
|
|
|
3 Grade 3 (less than 2 mg/dL); Grade 4
(less than 1 mg/dL)
|
|
|
4 Grade 3 (less than 0.8 mEq/L); Grade
4 (less than 0.5 mEq/L)
|
|
|
Laboratory Parameter
|
Grade 4
|
|
|
Zoledronic Acid 4 mg
|
Pamidronate 90 mg
|
|
|
n/N
|
(%)
|
n/N
|
(%)
|
|
|
Serum Creatinine1
|
0/86
|
-
|
1/100
|
(1%)
|
|
|
Hypocalcemia2
|
0/86
|
-
|
0/100
|
-
|
|
|
Hypophosphatemia3
|
1/70
|
(1%)
|
4/81
|
(5%)
|
|
|
Hypomagnesemia4
|
0/71
|
-
|
1/84
|
(1%)
|
|
Injection
Site Reactions
Local reactions at the
infusion site, such as redness or swelling, were observed infrequently. In most
cases, no specific treatment is required and the symptoms subside after 24-48
hours.
Ocular
Adverse Events
Ocular inflammation such as
uveitis and scleritis can occur with bisphosphonate use, including zoledronic
acid. No cases of iritis, scleritis, or uveitis were reported during these
clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)].
Multiple
Myeloma and Bone Metastases of Solid Tumors
The safety analysis includes
patients treated in the core and extension phases of the trials. The analysis
includes the 2042 patients treated with zoledronic acid 4 mg, pamidronate 90
mg, or placebo in the three controlled multicenter bone metastases trials,
including 969 patients completing the efficacy phase of the trial, and 619
patients that continued in the safety extension phase. Only 347 patients
completed the extension phases and were followed for 2 years (or 21 months for
the other solid tumor patients). The median duration of exposure for safety
analysis for zoledronic acid 4 mg (core plus extension phases) was 12.8 months
for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and
4.0 months for other solid tumors.
Table 7 describes adverse
events that were reported by 10% or more of patients. Adverse events are listed
regardless of presumed causality to study drug.
Table 7: Percentage of Patients with
Adverse Events greater than or equal to10% Reported in Three Bone Metastases
Clinical Trials by Body System
|
|
|
Zoledronic Acid 4 mg
n (%)
|
Pamidronate
90 mg
n (%)
|
Placebo
n (%)
|
|
Patients Studied
|
|
|
|
|
Total No. of
Patients
|
1031
|
(100)
|
556
|
(100)
|
455
|
(100)
|
|
Total No. of
Patients with any AE
|
1015
|
(98)
|
548
|
(99)
|
445
|
(98)
|
|
Blood and Lymphatic
|
|
|
|
|
Anemia
|
344
|
(33)
|
175
|
(32)
|
128
|
(28)
|
|
Neutropenia
|
124
|
(12)
|
83
|
(15)
|
35
|
(8)
|
|
Thrombocytopenia
|
102
|
(10)
|
53
|
(10)
|
20
|
(4)
|
|
Gastrointestinal
|
|
|
|
|
Nausea
|
476
|
(46)
|
266
|
(48)
|
171
|
(38)
|
|
Vomiting
|
333
|
(32)
|
183
|
(33)
|
122
|
(27)
|
|
Constipation
|
320
|
(31)
|
162
|
(29)
|
174
|
(38)
|
|
Diarrhea
|
249
|
(24)
|
162
|
(29)
|
83
|
(18)
|
|
Abdominal Pain
|
143
|
(14)
|
81
|
(15)
|
48
|
(11)
|
|
Dyspepsia
|
105
|
(10)
|
74
|
(13)
|
31
|
(7)
|
|
Stomatitis
|
86
|
(8)
|
65
|
(12)
|
14
|
(3)
|
|
Sore Throat
|
82
|
(8)
|
61
|
(11)
|
17
|
(4)
|
|
General Disorders and Administration Site
|
|
|
|
Fatigue
|
398
|
(39)
|
240
|
(43)
|
130
|
(29)
|
|
Pyrexia
|
328
|
(32)
|
172
|
(31)
|
89
|
(20)
|
|
Weakness
|
252
|
(24)
|
108
|
(19)
|
114
|
(25)
|
|
Edema Lower Limb
|
215
|
(21)
|
126
|
(23)
|
84
|
(19)
|
|
Rigors
|
112
|
(11)
|
62
|
(11)
|
28
|
(6)
|
|
Infections
|
|
|
|
|
Urinary Tract
Infection
|
124
|
(12)
|
50
|
(9)
|
41
|
(9)
|
|
Upper
Respiratory Tract Infection
|
101
|
(10)
|
82
|
(15)
|
30
|
(7)
|
|
Metabolism
|
|
|
|
|
Anorexia
|
231
|
(22)
|
81
|
(15)
|
105
|
(23)
|
|
Weight Decreased
|
164
|
(16)
|
50
|
(9)
|
61
|
(13)
|
|
Dehydration
|
145
|
(14)
|
60
|
(11)
|
59
|
(13)
|
|
Appetite
Decreased
|
130
|
(13)
|
48
|
(9)
|
45
|
(10)
|
|
Musculoskeletal
|
|
|
|
|
Bone Pain
|
569
|
(55)
|
316
|
(57)
|
284
|
(62)
|
|
Myalgia
|
239
|
(23)
|
143
|
(26)
|
74
|
(16)
|
|
Arthralgia
|
216
|
(21)
|
131
|
(24)
|
73
|
(16)
|
|
Back Pain
|
156
|
(15)
|
106
|
(19)
|
40
|
(9)
|
|
Pain in Limb
|
143
|
(14)
|
84
|
(15)
|
52
|
(11)
|
|
Neoplasms
|
|
|
|
|
Malignant
Neoplasm Aggravated
|
205
|
(20)
|
97
|
(17)
|
89
|
(20)
|
|
Nervous
|
|
|
|
|
Headache
|
191
|
(19)
|
149
|
(27)
|
50
|
(11)
|
|
Dizziness
(excluding vertigo)
|
180
|
(18)
|
91
|
(16)
|
58
|
(13)
|
|
Insomnia
|
166
|
(16)
|
111
|
(20)
|
73
|
(16)
|
|
Paresthesia
|
149
|
(15)
|
85
|
(15)
|
35
|
(8)
|
|
Hypoesthesia
|
127
|
(12)
|
65
|
(12)
|
43
|
(10)
|
|
Psychiatric
|
|
|
|
|
Depression
|
146
|
(14)
|
95
|
(17)
|
49
|
(11)
|
|
Anxiety
|
112
|
(11)
|
73
|
(13)
|
37
|
(8)
|
|
Confusion
|
74
|
(7)
|
39
|
(7)
|
47
|
(10)
|
|
Respiratory
|
|
|
|
|
Dyspnea
|
282
|
(27)
|
155
|
(28)
|
107
|
(24)
|
|
Cough
|
224
|
(22)
|
129
|
(23)
|
65
|
(14)
|
|
Skin
|
|
|
|
|
Alopecia
|
125
|
(12)
|
80
|
(14)
|
36
|
(8)
|
|
Dermatitis
|
114
|
(11)
|
74
|
(13)
|
38
|
(8)
|
Grade 3 and Grade 4 laboratory
abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum
magnesium observed in three clinical trials of zoledronic acid in patients with
bone metastases are shown in Tables 8 and 9.
Table 8: Grade 3 Laboratory Abnormalities
for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in
Three Clinical Trials in Patients with Bone Metastases
|
|
1 Grade 3 (greater than 3x Upper Limit
of Normal); Grade 4 (greater than 6x Upper Limit of Normal)
|
|
* Serum creatinine data for all patients
randomized after the 15-minute infusion amendment
|
|
2 Grade 3 (less than 7 mg/dL); Grade 4
(less than 6 mg/dL)
|
|
3 Grade 3 (less than 2 mg/dL); Grade 4
(less than 1 mg/dL)
|
|
4 Grade 3 (greater than 3 mEq/L);
Grade 4 (greater than 8 mEq/L)
|
|
5 Grade 3 (less than 0.9 mEq/L); Grade
4 (less than 0.7 mEq/L)
|
|
Laboratory Parameter
|
Grade 3
|
|
Zoledronic Acid
4 mg
|
Pamidronate
90 mg
|
Placebo
|
|
n/N
|
(%)
|
n/N
|
(%)
|
n/N
|
(%)
|
|
Serum Creatinine1
|
7/529
|
(1%)
|
4/268
|
(2%)
|
4/241
|
(2%)
|
|
Hypocalcemia2
|
6/973
|
(<1%)
|
4/536
|
(<1%)
|
0/415
|
-
|
|
Hypophosphatemia3
|
115/973
|
(12%)
|
38/537
|
(7%)
|
14/415
|
(3%)
|
|
Hypermagnesemia4
|
19/971
|
(2%)
|
2/535
|
(<1%)
|
8/415
|
(2%)
|
|
Hypomagnesemia5
|
1/971
|
(<1%)
|
0/535
|
-
|
1/415
|
(<1%)
|
Table 9: Grade 4 Laboratory Abnormalities
for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in
Three Clinical Trials in Patients with Bone Metastases
|
|
1 Grade 3 (greater than 3x Upper Limit
of Normal); Grade 4 (greater than 6x Upper Limit of Normal)
|
|
* Serum creatinine data for all patients
randomized after the 15-minute infusion amendment
|
|
2 Grade 3 (less than 7 mg/dL); Grade 4
(less than 6 mg/dL)
|
|
3 Grade 3 (less than 2 mg/dL); Grade 4
(less than 1 mg/dL)
|
|
4 Grade 3 (greater than 3 mEq/L);
Grade 4 (greater than 8 mEq/L)
|
|
5 Grade 3 (less than 0.9 mEq/L); Grade
4 (less than 0.7 mEq/L)
|
|
Laboratory Parameter
|
Grade 4
|
|
Zoledronic Acid
4 mg
|
Pamidronate
90 mg
|
Placebo
|
|
n/N
|
(%)
|
n/N
|
(%)
|
n/N
|
(%)
|
|
Serum Creatinine1
|
2/529
|
(<1%)
|
1/268
|
(<1%)
|
0/241
|
-
|
|
Hypocalcemia2
|
7/973
|
(<1%)
|
3/536
|
(<1%)
|
2/415
|
(<1%)
|
|
Hypophosphatemia3
|
5/973
|
(<1%)
|
0/537
|
-
|
1/415
|
(<1%)
|
|
Hypermagnesemia4
|
0/971
|
-
|
0/535
|
-
|
2/415
|
(<1%)
|
|
Hypomagnesemia5
|
2/971
|
(<1%)
|
1/535
|
(<1%)
|
0/415
|
-
|
Among the less frequently
occurring adverse events (less than 15% of patients), rigors, hypokalemia,
influenza-like illness, and hypocalcemia showed a trend for more events with
bisphosphonate administration (zoledronic acid 4 mg and pamidronate groups) compared
to the placebo group.
Less common adverse events
reported more often with zoledronic acid 4 mg than pamidronate included
decreased weight, which was reported in 16% of patients in the zoledronic acid
4 mg group compared with 9% in the pamidronate group. Decreased appetite was
reported in slightly more patients in the zoledronic acid 4 mg group (13%)
compared with the pamidronate (9%) and placebo (10%) groups, but the clinical
significance of these small differences is not clear.
Renal
Toxicity
In the bone metastases trials,
renal deterioration was defined as an increase of 0.5 mg/dL for patients with
normal baseline creatinine (less than 1.4 mg/dL) or an increase of 1.0 mg/dL
for patients with an abnormal baseline creatinine (greater than or equal to1.4
mg/dL). The following are data on the incidence of renal deterioration in
patients receiving zoledronic acid 4 mg over 15 minutes in these trials (see
Table 10).
Table 10: Percentage of Patients with
Treatment-Emergent Renal Function Deterioration by Baseline Serum Creatinine*
|
|
*Table includes only patients who were
randomized to the trial after a protocol amendment that lengthened the
infusion duration of zoledronic acid to 15 minutes.
|
|
Patient Population/Baseline Creatinine
|
|
Multiple Myeloma and Breast Cancer
|
Zoledronic Acid 4 mg
|
Pamidronate 90 mg
|
|
|
n/N
|
(%)
|
n/N
|
(%)
|
|
Normal
|
27/246
|
(11%)
|
23/246
|
(9%)
|
|
Abnormal
|
2/26
|
(8%)
|
2/22
|
(9%)
|
|
Total
|
29/272
|
(11%)
|
25/268
|
(9%)
|
|
Solid Tumors
|
Zoledronic Acid 4 mg
|
Placebo
|
|
|
n/N
|
(%)
|
n/N
|
(%)
|
|
Normal
|
17/154
|
(11%)
|
10/143
|
(7%)
|
|
Abnormal
|
1/11
|
(9%)
|
1/20
|
(5%)
|
|
Total
|
18/165
|
(11%)
|
11/163
|
(7%)
|
|
Prostate Cancer
|
Zoledronic Acid 4 mg
|
Placebo
|
|
|
n/N
|
(%)
|
n/N
|
(%)
|
|
Normal
|
12/82
|
(15%)
|
8/68
|
(12%)
|
|
Abnormal
|
4/10
|
(40%)
|
2/10
|
(20%)
|
|
Total
|
16/92
|
(17%)
|
10/78
|
(13%)
|
The risk of deterioration in
renal function appeared to be related to time on study, whether patients were
receiving zoledronic acid (4 mg over 15 minutes), placebo, or pamidronate.
In the trials and in
postmarketing experience, renal deterioration, progression to renal failure,
and dialysis have occurred in patients with normal and abnormal baseline renal
function, including patients treated with 4 mg infused over a 15-minute period.
There have been instances of this occurring after the initial zoledronic acid
dose.
Postmarketing Experience
The following adverse
reactions have been reported during postapproval use of zoledronic acid.
Because these reports are from a population of uncertain size and are subject
to confounding factors, it is not possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
Osteonecrosis
of the Jaw
Cases of osteonecrosis
(primarily involving the jaw but also of other anatomical sites including hip,
femur and external auditory canal) have been reported predominantly in cancer
patients treated with intravenous bisphosphonates including zoledronic acid.
Many of these patients were also receiving chemotherapy and corticosteroids
which may be a risk factor for ONJ. Caution is advised when zoledronic acid is
administered with antiangiogenic drugs as an increased incidence of ONJ has
been observed with concomitant use of these drugs. Data suggests a greater
frequency of reports of ONJ in certain cancers, such as advanced breast cancer
and multiple myeloma. The majority of the reported cases are in cancer patients
following invasive dental procedures, such as tooth extraction. It is therefore
prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings and Precautions (5.4)].
Acute
Phase Reaction
Within three days after zoledronic
acid administration, an acute phase reaction has been reported, with symptoms
including pyrexia, fatigue, bone pain and/or arthralgias, myalgias, chills,
influenza-like illness and arthritis with subsequent joint swelling; these
symptoms usually resolve within three days of onset, but resolution could
takeup to 7 to 14 days. However, some of these symptoms have been reported to
persist for a longer duration.
Musculoskeletal
Pain
Severe and occasionally
incapacitating bone, joint, and/or muscle pain has been reported with
bisphosphonate use [see Warnings and Precautions (5.5)].
Atypical
Subtrochanteric and Diaphyseal Femoral Fractures
Atypical subtrochanteric and
diaphyseal femoral fractures have been reported with bisphosphonate therapy,
including zoledronic acid [see Warnings and
Precautions (5.6)].
Ocular
Adverse Events
Cases of uveitis, scleritis, episcleritis,
conjunctivitis, iritis, and orbital inflammation including orbital edema have
been reported during postmarketing use. In some cases, symptoms resolved with
topical steroids.
Hypersensitivity
Reactions
There have been rare reports
of allergic reaction with intravenous zoledronic acid including angioedema and
bronchoconstriction. Very rare cases of anaphylactic reaction/shock have been
reported. Cases of Stevens- Johnson syndrome and toxic epidermal necrolysis
have also been reported.
Additional adverse reactions
reported in postmarketing use include:
CNS: taste disturbance,
hyperesthesia, tremor; Special Senses: blurred
vision; uveitis; Gastrointestinal:dry
mouth; Skin: Increased
sweating; Musculoskeletal: muscle
cramps; Cardiovascular: hypertension,
bradycardia, hypotension (associated with syncope or circulatory collapse
primarily in patients with underlying risk factors); Respiratory: bronchospasms,
interstitial lung disease (ILD) with positive rechallenge; Renal: hematuria, proteinuria,
acquired Fanconi syndrome; General Disorders and
Administration Site: weight increase, influenza-like
illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30
days; Laboratory Abnormalities: hyperkalemia,
hypernatremia, hypocalcemia (cardiac arrhythmias and neurologic adverse events
including seizures, tetany, and numbness have been reported due to severe
hypocalcemia).
Drug Interactions
In vitro studies indicate
that the plasma protein binding of zoledronic acid is low, with the unbound
fraction ranging from 60%–77%. In vitro studies
also indicate that zoledronic acid does not inhibit microsomal CYP450
enzymes. In vivo studies showed
that zoledronic acid is not metabolized, and is excreted into the urine as the
intact drug.
Aminoglycosides and Calcitonin
Caution is advised when
bisphosphonates are administered with aminoglycosides or calcitonin, since
these agents may have an additive effect to lower serum calcium level for
prolonged periods. This effect has not been reported in zoledronic acid
clinical trials.
Loop Diuretics
Caution should also be
exercised when zoledronic acid injection is used in combination with loop
diuretics due to an increased risk of hypocalcemia.
Nephrotoxic Drugs
Caution is indicated when
zoledronic acid injection is used with other potentially nephrotoxic drugs.
Thalidomide
No dose adjustment for
zoledronic acid injection 4 mg is needed when coadministered with thalidomide.
In a pharmacokinetic study of 24 patients with multiple myeloma, zoledronic acid
4 mg given as a 15-minute infusion was administered either alone or with
thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days
15-28). Coadministration of thalidomide with zoledronic acid did not
significantly change the pharmacokinetics of zoledronic acid or creatinine
clearance.
USE IN SPECIFIC POPULATIONSPregnancy
Pregnancy
Category D [see
Warnings and Precautions (5.9)]
There are no adequate and
well-controlled studies of zoledronic acid in pregnant women. zoledronic acid
may cause fetal harm when administered to a pregnant woman. Bisphosphonates,
such as zoledronic acid, 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 (greater than or equal to 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 greater than or equal to 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 (less than or equal to 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 greater than or equal to 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, drug-induced
hypocalcemia.
Nursing Mothers
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 zoledronic acid, 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.
Pediatric Use
Zoledronic acid injection 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 zoledronic acid 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, zoledronic acid 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.
Geriatric Use
Clinical studies of zoledronic
acid 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 zoledronic acid as compared to
younger patients. Controlled clinical studies of zoledronic acid 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.
Overdosage
Clinical experience with acute
overdosage of zoledronic acid is limited. Two patients received zoledronic acid
32 mg over 5 minutes in clinical trials. Neither patient experienced any
clinical or laboratory toxicity. Overdosage may cause clinically significant
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.
In an open-label study of
zoledronic acid 4 mg in breast cancer patients, a female patient received a
single 48-mg dose of zoledronic acid in error. Two days after the overdose, the
patient experienced a single episode of hyperthermia (38°C), which resolved
after treatment. All other evaluations were normal, and the patient was discharged
seven days after the overdose.
A patient with non-Hodgkin's
lymphoma received zoledronic acid 4 mg daily on four successive days for a
total dose of 16 mg. The patient developed paresthesia and abnormal liver
function tests with increased GGT (nearly 100 U/L, each value unknown). The
outcome of this case is not known.
In controlled clinical trials,
administration of zoledronic acid 4 mg as an intravenous infusion over 5
minutes has been shown to increase the risk of renal toxicity compared to the
same dose administered as a 15-minute intravenous infusion. In controlled
clinical trials, zoledronic acid 8 mg has been shown to be associated with an
increased risk of renal toxicity compared to zoledronic acid 4 mg, even when
given as a 15-minute intravenous infusion, and was not associated with added
benefit in patients with hypercalcemia of malignancy [see
Dosage and Administration (2.4)].
Zoledronic Acid IV Description
Zoledronic acid injection
contains zoledronic acid, a bisphosphonic acid which is an inhibitor of
osteoclastic bone resorption. Zoledronic acid is designated chemically as
(1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its
structural formula is:
Zoledronic acid is a white
crystalline powder. Its molecular formula is C5H10N2O7P2•H2O and its molar mass is
290.1g/mol. Zoledronic acid is highly soluble in 0.1N sodium hydroxide
solution, sparingly soluble in water and 0.1N hydrochloric acid, and
practically insoluble in organic solvents. The pH of a 0.7% solution of
zoledronic acid in water is approximately 2.0.
Zoledronic acid injection is
available in 100 mL vial as a sterile liquid ready-to-use solution for
intravenous infusion.
·
Each 100 mL ready-to-use vial
contains 4.264 mg zoledronic acid monohydrate, corresponding to 4 mg zoledronic
acid on an anhydrous basis, 5100 mg of mannitol, USP, water for injection, and
24 mg of sodium citrate, USP.
Inactive
Ingredients: mannitol, USP, as
bulking agent, water for injection, and sodium citrate, USP, as buffering
agent.
Zoledronic Acid IV - Clinical Pharmacology
Mechanism of Action
The principal pharmacologic
action of zoledronic acid is inhibition of bone resorption. Although the
antiresorptive mechanism is not completely understood, several factors are
thought to contribute to this action. In vitro,
zoledronic acid inhibits osteoclastic activity and induces osteoclast
apoptosis. Zoledronic acid also blocks the osteoclastic resorption of
mineralized bone and cartilage through its binding to bone. Zoledronic acid
inhibits the increased osteoclastic activity and skeletal calcium release
induced by various stimulatory factors released by tumors.
Pharmacodynamics
Clinical studies in patients
with hypercalcemia of malignancy (HCM) showed that single-dose infusions of
zoledronic acid are associated with decreases in serum calcium and phosphorus
and increases in urinary calcium and phosphorus excretion.
Osteoclastic hyperactivity
resulting in excessive bone resorption is the underlying pathophysiologic
derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia)
and metastatic bone disease. Excessive release of calcium into the blood as
bone is resorbed results in polyuria and gastrointestinal disturbances, with
progressive dehydration and decreasing glomerular filtration rate. This, in
turn, results in increased renal resorption of calcium, setting up a cycle of
worsening systemic hypercalcemia. Reducing excessive bone resorption and
maintaining adequate fluid administration are, therefore, essential to the
management of hypercalcemia of malignancy.
Patients who have hypercalcemia
of malignancy can generally be divided into two groups according to the
pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia
due to tumor invasion of bone. In humoral hypercalcemia, osteoclasts are
activated and bone resorption is stimulated by factors such as parathyroid
hormone-related protein, which are elaborated by the tumor and circulate
systemically. Humoral hypercalcemia usually occurs in squamous cell
malignancies of the lung or head and neck or in genitourinary tumors such as
renal cell carcinoma or ovarian cancer. Skeletal metastases may be absent or
minimal in these patients.
Extensive invasion of bone by
tumor cells can also result in hypercalcemia due to local tumor products that
stimulate bone resorption by osteoclasts. Tumors commonly associated with
locally mediated hypercalcemia include breast cancer and multiple myeloma.
Total serum calcium levels in
patients who have hypercalcemia of malignancy may not reflect the severity of
hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally,
ionized calcium levels should be used to diagnose and follow hypercalcemic
conditions; however, these are not commonly or rapidly available in many
clinical situations. Therefore, adjustment of the total serum calcium value for
differences in albumin levels (corrected serum calcium, CSC) is often used in
place of measurement of ionized calcium; several nomograms are in use for this
type of calculation [see Dosage and Administration
(2.1)].
Pharmacokinetics
Pharmacokinetic data in
patients with hypercalcemia are not available.
Distribution
Single or multiple (every 28
days) 5-minute or 15-minute infusions of 2, 4, 8, or 16 mg zoledronic acid were
given to 64 patients with cancer and bone metastases. The postinfusion decline
of zoledronic acid concentrations in plasma was consistent with a triphasic
process showing a rapid decrease from peak concentrations at end of infusion to
less than 1% of Cmax 24 hours postinfusion with population half-lives of t1/2α 0.24 hours and t1/2β 1.87 hours for the early
disposition phases of the drug. The terminal elimination phase of zoledronic
acid was prolonged, with very low concentrations in plasma between Days 2 and
28 postinfusion, and a terminal elimination half-life t 1/2γ of 146 hours. The area
under the plasma concentration versus time curve (AUC0-24h) of zoledronic acid was dose
proportional from 2-16 mg. The accumulation of zoledronic acid measured over
three cycles was low, with mean AUC0-24hratios for cycles 2 and 3 versus 1 of 1.13 ± 0.30 and 1.16 ±
0.36, respectively.
In
vitro and ex
vivo studies showed low affinity of zoledronic acid for the
cellular components of human blood, with a mean blood to plasma concentration
ratio of 0.59 in a concentration range of 30 ng/mL to 5000 ng/mL. In vitro, the plasma protein binding is low,
with the unbound fraction ranging from 60% at 2 ng/mL to 77% at
2000 ng/mL of zoledronic acid.
Metabolism
Zoledronic acid does not
inhibit human P450 enzymes in vitro.
Zoledronic acid does not undergo biotransformation in
vivo. In animal studies, less than 3% of the administered
intravenous dose was found in the feces, with the balance either recovered in
the urine or taken up by bone, indicating that the drug is eliminated intact
via the kidney. Following an intravenous dose of 20 nCi 14C-zoledronic acid in a patient
with cancer and bone metastases, only a single radioactive species with
chromatographic properties identical to those of parent drug was recovered in
urine, which suggests that zoledronic acid is not metabolized.
Excretion
In 64 patients with cancer and
bone metastases, on average (± SD) 39 ± 16% of the administered zoledronic acid
dose was recovered in the urine within 24 hours, with only trace amounts of
drug found in urine post-Day 2. The cumulative percent of drug excreted in the
urine over 0-24 hours was independent of dose. The balance of drug not
recovered in urine over 0-24 hours, representing drug presumably bound to bone,
is slowly released back into the systemic circulation, giving rise to the
observed prolonged low plasma concentrations. The 0-24 hour renal clearance of
zoledronic acid was 3.7 ± 2.0 L/h.
Zoledronic acid clearance was
independent of dose but dependent upon the patient's creatinine clearance. In a
study in patients with cancer and bone metastases, increasing the infusion time
of a 4-mg dose of zoledronic acid from 5 minutes (n=5) to 15 minutes (n=7)
resulted in a 34% decrease in the zoledronic acid concentration at the end of
the infusion ([mean ± SD] 403 ± 118 ng/mL versus 264 ± 86 ng/mL) and a 10%
increase in the total AUC (378 ± 116 ng x h/mL versus 420 ± 218 ng x h/mL). The
difference between the AUC means was not statistically significant.
Special
Populations
Pediatrics
Zoledronic acid injection is
not indicated for use in children [see Use in
Specific Populations (8.4)].
Geriatrics
The pharmacokinetics of
zoledronic acid were not affected by age in patients with cancer and bone
metastases who ranged in age from 38 years to 84 years.
Race
Population pharmacokinetic
analyses did not indicate any differences in pharmacokinetics among Japanese
and North American (Caucasian and African American) patients with cancer and
bone metastases.
Hepatic
Insufficiency
No clinical studies were
conducted to evaluate the effect of hepatic impairment on the pharmacokinetics
of zoledronic acid.
Renal
Insufficiency
The pharmacokinetic studies
conducted in 64 cancer patients represented typical clinical populations with
normal to moderately impaired renal function. Compared to patients with normal
renal function (N=37), patients with mild renal impairment (N=15) showed an
average increase in plasma AUC of 15%, whereas patients with moderate renal
impairment (N=11) showed an average increase in plasma AUC of 43%. Limited
pharmacokinetic data are available for zoledronic acid in patients with severe
renal impairment (creatinine clearance less than 30 mL/min). Based on
population PK/PD modeling, the risk of renal deterioration appears to increase
with AUC, which is doubled at a creatinine clearance of 10 mL/min. Creatinine
clearance is calculated by the Cockcroft-Gault formula:
CrCl= [140-age (years)] x weight (kg) {x 0.85 for
female patients}
[72 x serum creatinine (mg/dL)]
Zoledronic acid systemic
clearance in individual patients can be calculated from the population
clearance of zoledronic acid, CL (L/h)=6.5(CrCl/90)0.4. These formulae can be used
to predict the zoledronic acid AUC in patients, where CL=Dose/AUC0-∞. The average AUC0-24 in patients with normal
renal function was 0.42 mg•h/L and the calculated AUC0-∞ for a patient with
creatinine clearance of 75 mL/min was 0.66 mg•h/L following a 4-mg dose of
zoledronic acid. However, efficacy and safety of adjusted dosing based on these
formulae have not been prospectively assessed [see
Warnings and Precautions (5.3)].
Nonclinical ToxicologyCarcinogenesis, 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 greater than or equal to 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 less than or equal to 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.
Clinical StudiesHypercalcemia of Malignancy
Two identical multicenter,
randomized, double-blind, double-dummy studies of zoledronic acid 4 mg given as
a 5-minute intravenous infusion or pamidronate 90 mg given as a 2-hour
intravenous infusion were conducted in 185 patients with hypercalcemia of
malignancy (HCM). NOTE: Administration of zoledronic acid 4 mg given as a
5-minute intravenous infusion has been shown to result in an increased risk of
renal toxicity, as measured by increases in serum creatinine, which can progress
to renal failure. The incidence of renal toxicity and renal failure has been
shown to be reduced when zoledronic acid 4 mg is given as a 15-minute
intravenous infusion. Zoledronic acid should be administered by intravenous
infusion over no less than 15 minutes [see Warnings
and Precautions (5.1 and 5.2) and Dosage and Administration (2.4)]. The treatment groups in the
clinical studies were generally well balanced with regards to age, sex, race,
and tumor types. The mean age of the study population was 59 years; 81% were
Caucasian, 15% were Black, and 4% were of other races. 60% of the patients were
male. The most common tumor types were lung, breast, head and neck, and renal.
In these studies, HCM was
defined as a corrected serum calcium (CSC) concentration of greater than or equal
to 12.0 mg/dL (3.00 mmol/L). The primary efficacy variable was the proportion
of patients having a complete response, defined as the lowering of the CSC to
less than or equal to 10.8 mg/dL (2.70 mmol/L) within 10 days after drug
infusion.
To assess the effects of
zoledronic acid versus those of pamidronate, the two multicenter HCM studies
were combined in a preplanned analysis. The results of the primary analysis
revealed that the proportion of patients that had normalization of corrected
serum calcium by Day 10 were 88% and 70% for zoledronic acid 4 mg and
pamidronate 90 mg, respectively (P=0.002) (see Figure 1). In these studies, no
additional benefit was seen for zoledronic acid 8 mg over zoledronic acid 4 mg;
however, the risk of renal toxicity of zoledronic acid 8 mg was significantly
greater than that seen with zoledronic acid 4 mg.
Secondary efficacy variables
from the pooled HCM studies included the proportion of patients who had
normalization of corrected serum calcium (CSC) by Day 4; the proportion of
patients who had normalization of CSC by Day 7; time to relapse of HCM; and
duration of complete response. Time to relapse of HCM was defined as the
duration (in days) of normalization of serum calcium from study drug infusion
until the last CSC value less than 11.6 mg/dL (less than 2.90 mmol/L). Patients
who did not have a complete response were assigned a time to relapse of 0 days.
Duration of complete response was defined as the duration (in days) from the
occurrence of a complete response until the last CSC less than or equal to 10.8
mg/dL (2.70 mmol/L). The results of these secondary analyses for zoledronic
acid 4 mg and pamidronate 90 mg are shown in Table 11.
Table 11: Secondary Efficacy Variables in
Pooled HCM Studies
|
|
* P less than 0.05 versus pamidronate 90
mg.
|
|
|
Zoledronic Acid 4 mg
|
Pamidronate 90 mg
|
|
Complete Response
|
N
|
Response Rate
|
N
|
Response Rate
|
|
By Day 4
|
86
|
45.3%
|
99
|
33.3%
|
|
By Day 7
|
86
|
82.6%*
|
99
|
63.6%
|
|
Duration of Response
|
N
|
Median Duration (Days)
|
N
|
Median Duration (Days)
|
|
Time to Relapse
|
86
|
30*
|
99
|
17
|
|
Duration of Complete Response
|
76
|
32
|
69
|
18
|
Clinical Trials in Multiple
Myeloma and Bone Metastases of Solid Tumors
Table 12 describes an overview
of the efficacy population in three randomized zoledronic acid trials in
patients with multiple myeloma and bone metastases of solid tumors. These
trials included a pamidronate-controlled study in breast cancer and multiple
myeloma, a placebo-controlled study in prostate cancer, and a
placebo-controlled study in other solid tumors. The prostate cancer study
required documentation of previous bone metastases and 3 consecutive rising
PSAs while on hormonal therapy. The other placebo-controlled solid tumor study
included patients with bone metastases from malignancies other than breast
cancer and prostate cancer, including NSCLC, renal cell cancer, small cell lung
cancer, colorectal cancer, bladder cancer, GI/genitourinary cancer, head and
neck cancer, and others. These trials were comprised of a core phase and an extension
phase. In the solid tumor, breast cancer and multiple myeloma trials, only the
core phase was evaluated for efficacy as a high percentage of patients did not
choose to participate in the extension phase. In the prostate cancer trials,
both the core and extension phases were evaluated for efficacy showing the
zoledronic acid effect during the first 15 months was maintained without
decrement or improvement for another 9 months. The design of these clinical
trials does not permit assessment of whether more than one-year administration
of zoledronic acid is beneficial. The optimal duration of zoledronic acid
administration is not known.
The studies were amended twice
because of renal toxicity. The zoledronic acid infusion duration was increased
from 5 minutes to 15 minutes. After all patients had been accrued, but while
dosing and follow-up continued, patients in the 8 mg zoledronic acid treatment
arm were switched to 4 mg due to toxicity. Patients who were randomized to the
zoledronic acid 8 mg group are not included in these analyses.
Table 12: Overview of Efficacy Population
for Phase III Studies
|
|
* Patients who were randomized to the 8 mg
zoledronic acid injection group are not included in any of the analyses in
this package insert.
|
|
Patient Population
|
No. of Patients
|
Zoledronic Acid Dose
|
Control
|
Median Duration (Planned Duration) Zoledronic Acid 4 mg
|
|
Multiple myeloma
or metastatic breast cancer
|
1,648
|
4 and 8* mg
Q3-4 weeks
|
Pamidronate 90
mg
Q3-4 weeks
|
12.0 months
(13 months)
|
|
Metastatic
prostate cancer
|
643
|
4 and 8* mg
Q3 weeks
|
Placebo
|
10.5 months
(15 months)
|
|
Metastatic solid
tumor other than breast or prostate cancer
|
773
|
4 and 8* mg
Q3 weeks
|
Placebo
|
3.8 months
(9 months)
|
Each study evaluated
skeletal-related events (SREs), defined as any of the following: pathologic
fracture, radiation therapy to bone, surgery to bone, or spinal cord
compression. Change in antineoplastic therapy due to increased pain was a SRE
in the prostate cancer study only. Planned analyses included the proportion of
patients with a SRE during the study and time to the first SRE. Results for the
two zoledronic acid placebo-controlled studies are given in Table 13.
Table 13: Zoledronic acid Compared to
Placebo in Patients with Bone Metastases from Prostate Cancer or Other Solid
Tumors
|
|
1SRE=Skeletal-Related Event
|
|
2Difference for the proportion of patients
with a SRE of zoledronic acid 4 mg versus placebo.
|
|
3Hazard ratio for the first occurrence of a
SRE of zoledronic acid 4 mg versus placebo.
|
|
I. Analysis of Proportion of Patients
with a SRE1
|
II. Analysis of Time to the First SRE
|
|
Study
|
Study Arm & Patient Number
|
Proportion
|
Difference2 & 95% CI
|
P-value
|
Median (Days)
|
Hazard Ratio3 & 95% CI
|
P-value
|
|
Prostate Cancer
|
Zoledronic acid 4 mg (n=214)
|
33%
|
-11%
(-20%, -1%)
|
0.02
|
Not Reached
|
0.67
(0.49, 0.91)
|
0.011
|
|
|
Placebo (n=208)
|
44%
|
321
|
|
Solid Tumors
|
Zoledronic acid 4 mg (n=257)
|
38%
|
-7% (-15%, 2%)
|
0.13
|
230
|
0.73
(0.55, 0.96)
|
0.023
|
|
|
Placebo (n=250)
|
44%
|
163
|
In the breast cancer and
myeloma trial, efficacy was determined by a noninferiority analysis comparing
zoledronic acid to pamidronate 90 mg for the proportion of patients with a SRE.
This analysis required an estimation of pamidronate efficacy. Historical data
from 1,128 patients in three pamidronate placebo-controlled trials demonstrated
that pamidronate decreased the proportion of patients with a SRE by 13.1% (95%
CI=7.3%, 18.9%). Results of the comparison of treatment with zoledronic acid
compared to pamidronate are given in Table 14.
Table 14: Zoledronic acid Compared to
Pamidronate in Patients with Multiple Myeloma or Bone Metastases from Breast
Cancer
|
|
1SRE=Skeletal-Related Event
|
|
2Difference for the proportion of patients
with a SRE of zoledronic acid4 mg versus pamidronate 90 mg.
|
|
3Hazard ratio for the first occurrence of a
SRE of zoledronic acid4 mg versus pamidronate 90 mg.
|
|
I. Analysis of Proportion of Patients
with a SRE1
|
II. Analysis of Time to the First SRE
|
|
Study
|
Study Arm & Patient Number
|
Proportion
|
Difference2& 95% CI
|
P-value
|
Median (Days)
|
Hazard Ratio3 & 95% CI
|
P-value
|
|
Multiple Myeloma and Breast Cancer
|
Zoledronic acid 4 mg (n=561)
|
44%
|
-2%
(-7.9%, 3.7%)
|
0.46
|
373
|
0.92
(0.77, 1.09)
|
0.32
|
|
Pamidronate (n=555)
|
46%
|
363
|
How Supplied/Storage and Handling
4 mg per 100 mL single-dose ready-to-use vial
Carton of 1
Vial
NDC 69097-399-44
Store at 25°C (77°F);
excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room
Temperature].
Patient Counseling Information
Drugs with Same Active Ingredient or in the Same Drug Class
·
Inform patients not to
take Reclast or other bisphosphonates during the course of their zoledronic
acid injection therapy [see Warnings and
Precautions (5.1)].
Renal
Impairment
·
Instruct patients to
tell their doctor if they have kidney problems before being given zoledronic
acid injection.
·
Inform patients of the
importance of getting their blood tests (serum creatinine) during the course of
their zoledronic acid injection therapy [see
Warnings and Precautions (5.3)].
Osteonecrosis
of the Jaw
·
Advise patients to have
a dental examination prior to treatment with zoledronic acid injection and to
avoid invasive dental procedures during treatment.
·
Inform patients of the
importance of good dental hygiene, routine dental care, and regular dental
check-ups.
·
Advise patients to
immediately tell their doctor about any oral symptoms such as loosening of a
tooth, pain,swelling, or non-healing of sores or discharge during treatment
with zoledronic acid injection [see Warnings and
Precautions (5.4)].
Musculoskeletal
Pain
·
Advise patients to
immediately tell their doctor about any severe bone, joint, and/or muscle
pain [see Warnings and Precautions (5.5)].
Atypical
subtrochanteric and diaphyseal femoral fracture
·
Advise patients to
report any thigh, hip, or groin pain. It is unknown whether the risk of
atypical femur fracture continues after stopping therapy [see Warnings and Precautions (5.6)].
Patients
with Asthma
·
There have been reports
of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates,
including zoledronic acid. Before being given zoledronic acid, instruct
patients to tell their doctor if they are aspirin-sensitive [see Warnings and Precautions (5.7)].
Embryo-Fetal
Toxicity
·
Zoledronic acid
injection should not be given if the patient is pregnant or plans to become
pregnant, or if she is breastfeeding [see Warnings
and Precautions (5.9)].
Hypocalcemia
·
Advise patients with
multiple myeloma and bone metastasis of solid tumors to take an oral calcium
supplement of 500 mg and a multiple vitamin containing 400 international units
of vitamin D daily [see Warnings and Precautions (5.10)].
Common
Adverse Reactions
·
Advise patients that
the most common side effects of zoledronic acid injection are nausea, fatigue,
anemia, bone pain, constipation, fever, vomiting, and dyspnea.
Manufactured
by:
Cipla Ltd.
Verna Goa, India
Manufactured
for:
Cipla USA, Inc.
1560 Sawgrass Corporate
Parkway,
Suite 130, Sunrise, FL 33323
Revised:
10/2017
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC
69097-399-44 Rx Only
Zoledronic acid injection
4 mg/ 100 mL
For Intravenous Infusion
Single Dose only
|
ZOLEDRONIC ACID zoledronic
acid injection
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:69097-399
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
ZOLEDRONIC ACID (ZOLEDRONIC ACID ANHYDROUS)
|
ZOLEDRONIC ACID
ANHYDROUS
|
4 mg
in 100 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
MANNITOL
|
5100 mg
in 100 mL
|
|
SODIUM CITRATE
|
24 mg
in 100 mL
|
|
WATER
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:69097-399-44
|
1 BOTTLE in 1
CARTON
|
|
|
1
|
|
100 mL in 1
BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
ANDA
|
ANDA210174
|
10/27/2017
|
|
|
|
Labeler - Cipla USA Inc. (078719707)
|
|
Registrant - Cipla USA Inc. (078719707)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Cipla Kurkumbh
|
|
917066446
|
API
MANUFACTURE(69097-399)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Cipla Ltd.- Goa
|
|
650072015
|
MANUFACTURE(69097-399)
|
Revised:
11/2017
Cipla USA Inc.
