zoledronic acid

7.1 Aminoglycosides

7.2 Loop Diuretics

7.3 Nephrotoxic Drugs

Caution is indicated when zoledronic acid is used with other potentially nephrotoxic drugs.

7.4 Thalidomide

No dose adjustment for zoledronic acid for 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 to 14 and 200 mg once daily on days 15 to 28). Coadministration of thalidomide with zoledronic acid for injection did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precaution (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 for injection, 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.

8.3 Nursing Mothers

8.4 Pediatric Use

Zoledronic acid for 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 to 17 years, 55% male, 84% Caucasian, with a mean lumbar spine 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 for injection 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 for injection 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 to 8 years and 6 in the age group of 9 to 17 years) infused with 0.05 mg/kg dose over 30 min.

Mean C_max 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.

8.5 Geriatric Use

10 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 100U/L, each value unknown). The outcome of this case is not known.

11 DESCRIPTION

Zoledronic acid for injection is available in vials as a sterile powder for reconstitution for intravenous infusion. Each vial contains 4.264 mg of zoledronic acid monohydrate, corresponding to 4 mg zoledronic acid on an anhydrous basis.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 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.

12.3 Pharmacokinetics

Distribution

Single or multiple (q 28 days) 5-minute or 15-minute infusions of 2 mg, 4 mg, 8 mg 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 C_max 24 hours postinfusion with population half-lives of t_1/2α 0.24 hours and t_1/2β 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 (AUC_0-24h) of zoledronic acid was dose proportional from 2 to 16 mg. The accumulation of zoledronic acid measured over three cycles was low, with mean AUC_0-24h ratios for cycles 2 and 3 versus 1 of 1.13 ± 0.3 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 (± s.d.) 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 to 24 hours was independent of dose. The balance of drug not recovered in urine over 0 to 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 to 24 hour renal clearance of zoledronic acid was 3.7 ± 2 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 for injection is not indicated for use in children [see Pediatric Use (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:

13 NONCLINICAL TOXICOLOGY

13.1 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 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 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.

14 CLINICAL STUDIES

14.1 Hypercalcemia 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, 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 mg/dL (3 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 (2.7 mmol/L) within 10 days after drug infusion.

Table 11: Secondary Efficacy Variables in Pooled HCM Studies

	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%P less than 0.05 versus pamidronate 90 mg.	99	63.6%
Duration of Response	N	Median Duration (Days)	N	Median Duration (Days)
Time to Relapse	86	30P less than 0.05 versus pamidronate 90 mg.	99	17
Duration of Complete Response	76	32	69	18

14.2 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.

Table 12: Overview of Efficacy Population for Phase III Studies

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 8Patients who were randomized to the 8 mg zoledronic acid group are not included in any of the analyses in this package insert. mg Q3 and 4 weeks	Pamidronate 90 mg Q3 and 4 weeks	12 months (13 months)
Metastatic prostate cancer	643	4 and 8Patients who were randomized to the 8 mg zoledronic acid group are not included in any of the analyses in this package insert. mg Q3 weeks	Placebo	10.5 months (15 months)
Metastatic solid tumor other than breast or prostate cancer	773	4 and 8Patients who were randomized to the 8 mg zoledronic acid group are not included in any of the analyses in this package insert. mg Q3 weeks	Placebo	3.8 months (9 months)

Table 13: Zoledronic Acid Compared to Placebo in Patients with Bone Metastases from Prostate Cancer or Other Solid Tumors

	I. Analysis of Proportion of Patients with a SRESRE=Skeletal-Related Event				II. Analysis of Time to the First SRE
Study	Study Arm & Patient Number	Proportion	DifferenceDifference for the proportion of patients with a SRE of zoledronic acid 4 mg versus placebo. & 95% CI	P-value	Median (Days)	Hazard RatioHazard ratio for the first occurrence of a SRE of zoledronic acid 4 mg versus placebo. & 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

Table 14: Zoledronic Acid Compared to Pamidronate in Patients with Multiple Myeloma or Bone Metastases from Breast Cancer

	I. Analysis of Proportion of Patients with a SRESRE = Skeletal-Related Event				II. Analysis of Time to the First SRE
Study	Study Arm & Patient Number	Proportion	DifferenceDifference for the proportion of patients with a SRE of zoledronic acid 4 mg versus pamidronate 90 mg. & 95% CI	P-value	Median (Days)	Hazard RatioHazard ratio for the first occurrence of a SRE of zoledronic acid 4 mg versus pamidronate 90 mg.& 95% CI	P-value
Multiple Myeloma & 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

16 HOW SUPPLIED/STORAGE AND HANDLING

DRUG PRODUCT

White to off white lyophilized cake in 5 mL colorless tubular glass vial with grey rubber stopper sealed with golden brown flip-off aluminum seal.

Each vial contains 4.264 mg zoledronic acid monohydrate, corresponding to 4 mg zoledronic acid on an anhydrous basis, 220 mg of mannitol, USP, and 24 mg of sodium citrate dihydrate, USP. (NDC 47335-962-40)

DILUENT

Clear colorless liquid filled in 5 mL clear One Point Cut (OPC) glass ampule with white dot.

Each ampule contains 5 mL of Sterile Water for Injection, USP. (NDC 47335-247-40)

The carton contains 1 vial of drug product & 1 ampule of sterile diluent. (NDC 47335-962-41)

17 PATIENT COUNSELING INFORMATION

• Patients should be instructed to tell their doctor if they have kidney problems before being given zoledronic acid for injection.
• Patients should be informed of the importance of getting their blood tests (serum creatinine) during the course of their zoledronic acid for injection therapy.
• Zoledronic acid for injection should not be given if the patient is pregnant or plans to become pregnant, or if she is breast-feeding.
• Patients should be advised to have a dental examination prior to treatment with zoledronic acid for injection and should avoid invasive dental procedures during treatment.
• Patients should be informed of the importance of good dental hygiene and routine dental care.
• Patients with multiple myeloma and bone metastasis of solid tumors should be advised to take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.
• Patients should be advised to report any thigh, hip or groin pain. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.
• Patients should be aware of the most common side effects including: anemia, nausea, vomiting, constipation, diarrhea, fatigue, fever, weakness, lower limb edema, anorexia, decreased weight, bone pain, myalgia, arthralgia, back pain, malignant neoplasm aggravated, headache, dizziness, insomnia, paresthesia, dyspnea, cough, and abdominal pain.
• There have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates, including zoledronic acid. Before being given zoledronic acid, patients should tell their doctor if they are aspirin-sensitive.

PRINCIPAL DISPLAY PANEL-Carton Label

• 1 Single dose vial of Zoledronic Acid for Injection
• 1 Ampule of Sterile Water for Injection