ZOLEDRONIC ACID injection, solution, concentrate

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

ZOLEDRONIC ACID (UNII: 6XC1PAD3KF) (ZOLEDRONIC ACID ANHYDROUS - UNII:70HZ18PH24)

Available from:

Hospira, Inc.

INN (International Name):

ZOLEDRONIC ACID

Composition:

ZOLEDRONIC ACID ANHYDROUS 4 mg in 5 mL

Administration route:

INTRAVENOUS

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

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 [3.0 mmol/L] using the formula: cCa in mg/dL = Ca in mg/dL + 0.8 (4.0 g/dL - patient albumin [g/dL]). 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 injection in the treatment of hypercalcemia associated with hyperparathyroidism or with other non–tumor-related conditions have not been established. 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)]. Risk Summary Based on findings from animal studies and its mechanism of action, zoledronic acid can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of zoledronic acid to pregnant rats during organogenesis resulted in fetal malformations and embryo-fetal lethality at maternal exposures that were ≥ 2.4 times the human clinical exposure based on AUC (see ). 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. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies. Data Animal Data 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 at 0.1 mg/kg/day (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. Risk Summary After administration of zoledronic acid, it is not known whether zoledronic acid is present in human milk, or whether it affects milk production or the breastfed child. Zoledronic acid binds to bone long term and may be released over periods of weeks to years. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during and after zoledronic acid treatment. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiation of zoledronic acid. Contraception Females Zoledronic acid can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] . Zoledronic acid binds to bone long term and may be released over periods of weeks to years. Advise females of reproductive potential to use effective contraception during and after zoledronic acid treatment. Infertility Females Based on animal studies, zoledronic acid may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)] . Zoledronic acid 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. 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.

Product summary:

4 mg/5 mL (0.8 mg/mL) single-dose vial for dilution prior to intravenous infusion NDC 0409-4215-01 4 mg/5 mL Carton of 1 single-dose plastic Vial (0.8mg/mL) Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature]. Discard unused portion.

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

ZOLEDRONIC ACID- ZOLEDRONIC ACID INJECTION, SOLUTION, CONCENTRATE
HOSPIRA, INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
ZOLEDRONIC ACID
INJECTION SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
ZOLEDRONIC ACID
INJECTION.
ZOLEDRONIC ACID INJECTION, FOR INTRAVENOUS INFUSION
INITIAL U.S. APPROVAL: 2001
RECENT MAJOR CHANGES
Warnings and Precautions, Embryo-Fetal Toxicity (5.10)
12/2018
INDICATIONS AND USAGE
Zoledronic acid injection is a bisphosphonate indicated for the
treatment of:
•
•
Limitations of Use: The safety and efficacy of zoledronic acid
injection has not been established for use in
hyperparathyroidism or non-tumor-related hypercalcemia.
DOSAGE AND ADMINISTRATION
Hypercalcemia of malignancy. (2.1)
•
•
Multiple myeloma and bone metastasis from solid tumors. (2.2)
•
•
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Administer through a separate vented infusion line and do not allow to
come in contact with any calcium or
divalent cation-containing solutions. (2.3)
DOSAGE FORMS AND STRENGTHS
Injection: 4 mg/5 mL (0.8 mg/mL) single-dose vial for dilution prior
to intravenous infusion. (3)
CONTRAINDICATIONS
Hypersensitivity to any component of zoledronic acid injection. (4)
WARNINGS AND PRECAUTIONS
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•
•
•
•
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Hypercalcemia of malignancy. (1.1)
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. (1.2)
4 mg as a single-use intravenous infusion over no less than 15
minutes.
4 mg as retreatment after a minimum of 7 days.
4 mg as a single-use intravenous infusion over no less than 15 minutes
every 3–4 weeks for patients
with creatinine clearance of greater than 60 mL/min.
Reduce the dose for patients with renal impairment.
Coadminister oral calcium supplements of 500 mg and a multiple vitamin
containing 400 international
units of vitamin D daily.
Patients being t