Zoledronic acid injection is a bisphosphonate indicated for:
Treatment and prevention of postmenopausal osteoporosis (1.1, 1.2)
Treatment to increase bone mass in men with osteoporosis (1.3)
Treatment and prevention of glucocorticoid-induced osteoporosis (1.4)
Treatment of Paget’s disease of bone in men and women (1.5) Limitations of Use Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use (1.6)
1.1Treatment of Osteoporosis in Postmenopausal Women
Zoledronic acid injection is indicated for treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, diagnosed by bone mineral density (BMD) or prevalent vertebral fracture, zoledronic acid injection reduces the incidence of fractures (hip, vertebral and non-vertebral osteoporosis-related fractures). In patients at high risk of fracture, defined as a recent low-trauma hip fracture, zoledronic acid injection reduces the incidence of new clinical fractures [ see Clinical Studies (14.1) ].
1.2Prevention of Osteoporosis in Postmenopausal Women
Zoledronic acid injection is indicated for prevention of osteoporosis in postmenopausal women [ see Clinical Studies (14.2) ].
1.3Osteoporosis in Men
Zoledronic acid injection is indicated for treatment to increase bone mass in men with osteoporosis [ see Clinical Studies (14.3) ].
1.4Glucocorticoid-Induced Osteoporosis
Zoledronic acid injection is indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who are expected to remain on glucocorticoids for at least 12 months [ see Clinical Studies (14.4) ].
1.5Paget's Disease of Bone
Zoledronic acid injection is indicated for treatment of Paget's disease of bone in men and women. Treatment is indicated in patients with Paget’s disease of bone with elevations in serum alkaline phosphatase of two times or higher than the upper limit of the age-specific normal reference range, or those who are symptomatic, or those at risk for complications from their disease [ see Clinical Studies (14.5) ].
The safety and effectiveness of zoledronic acid injection for the treatment of osteoporosis is based on clinical data of three years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.
Contraindications
Zoledronic acid injection is contraindicated in patients with the following conditions:
Hypocalcemia [ see Warnings and Precautions (5.2) ]
Creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment due to an increased risk of renal failure [ see Warnings and Precautions (5.3) ].
Known hypersensitivity to zoledronic acid or any components of zoledronic acid injection. Hypersensitivity reactions including urticaria, angioedema, and anaphylactic reaction/shock have been reported [ see Post- Marketing Experience (6.2) ]. Hypocalcemia (4) Patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment (4, 5.3) Hypersensitivity to any component of zoledronic acid injection (4, 6.2)
Warnings and precautions
Products Containing Same Active Ingredient: Patients receiving Zometa should not receive zoledronic acid injection (5.1) Hypocalcemia may worsen during treatment . Patients must be adequately supplemented with calcium and vitamin D (5.2) Renal Impairment: A single dose should not exceed 5 mg and the duration of infusion should be no less than 15 minutes. Renal toxicity may be greater in patients with underlying renal impairment or with other risk factors, including advanced age or dehydration.
Monitor creatinine clearance before each dose (2.7, 5.3) Osteonecrosis of the Jaw (ONJ) has been reported. All patients should have a routine oral exam by the prescriber prior to treatment (5.4) Atypical Femur Fractures have been reported. Patients with thigh or groin pain should be evaluated to rule out a femoral fracture (5.5) Pregnancy: Zoledronic acid injection can cause fetal harm. Women of childbearing potential should be advised (5.6, 8.1) Severe Bone, Joint, and Muscle Pain may occur.
Withhold future doses of zoledronic acid injection if severe symptoms occur (5.7)
5.1Drug Products with Same Active Ingredient
Zoledronic acid injection contains the same active ingredient found in Zometa, used for oncology indications, and a patient being treated with Zometa should not be treated with zoledronic acid injection.
5.2Hypocalcemia and Mineral Metabolism
Pre-existing hypocalcemia and disturbances of mineral metabolism (e.g., hypoparathyroidism, thyroid surgery, parathyroid surgery; malabsorption syndromes, excision of small intestine) must be effectively treated before initiating therapy with zoledronic acid injection. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended for these patients [ see Contraindications (4) ]. Hypocalcemia following zoledronic acid injection administration is a significant risk in Paget’s disease.
All patients should be instructed about the symptoms of hypocalcemia and the importance of calcium and vitamin D supplementation in maintaining serum calcium levels [see Dosage and Administration (2.8), Adverse Reactions (6.1), Information for Patients (17) ]. All osteoporosis patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels [ see Dosage and Administration (2.8), Adverse Reactions (6.1), Information for Patients (17) ].
5.3Renal Impairment
A single dose of zoledronic acid injection should not exceed 5 mg and the duration of infusion should be no less than 15 minutes [ see Dosage and Administration (2) ]. Zoledronic acid injection is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment [ see Contraindications (4) ]. If history or physical signs suggest dehydration, zoledronic acid injection therapy should be withheld until normovolemic status has been achieved [ see Post-Marketing Experience (6.2) ].
Zoledronic acid injection should be used with caution in patients with chronic renal impairment. Acute renal impairment, including renal failure, has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal compromise, advanced age, concomitant nephrotoxic medications, concomitant diuretic therapy, or severe dehydration occurring before or after zoledronic acid injection administration.
Acute renal failure (ARF) has been observed in patients after a single administration. Rare reports of hospitalization and/or dialysis or fatal outcome occurred in patients with underlying moderate to severe renal impairment or with any of the risk factors described in this section [ see Post-Marketing Experience (6.2) ]. Renal impairment may lead to increased exposure of concomitant medications and/or their metabolites that are primarily renally excreted [ see Drug Interactions (7.4) ].
Creatinine clearance should be calculated based on actual body weight using Cockcroft-Gault formula before each zoledronic acid injection dose. Transient increase in serum creatinine may be greater in patients with impaired renal function; interim monitoring of creatinine clearance should be performed in at-risk patients. Elderly patients and those receiving diuretic therapy are at increased risk of acute renal failure.
These patients should have their fluid status assessed and be appropriately hydrated prior to administration of zoledronic acid injection. Zoledronic acid injection should be used with caution with other nephrotoxic drugs [ see Drug Interactions (7.3) ]. Consider monitoring creatinine clearance in patients at-risk for ARF who are taking concomitant medications that are primarily excreted by the kidney [ see Drug Interactions (7.4) ].
5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates, including zoledronic acid. Most cases have been in cancer patients treated with intravenous bisphosphonates undergoing dental procedures. Some cases have occurred in patients with postmenopausal osteoporosis treated with either oral or intravenous bisphosphonates. A routine oral examination should be performed by the prescriber prior to initiation of bisphosphonate treatment.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with a history of concomitant risk factors (e.g., cancer, chemotherapy, angiogenesis inhibitors, radiotherapy, corticosteroids, poor oral hygiene, pre-existing dental disease or infection, anemia, coagulopathy). The risk of ONJ may increase with duration of exposure to bisphosphonates. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ.
While on treatment, patients with concomitant risk factors 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. The clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.1)].
5.5Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture.
Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.
5.6Pregnancy
ZOLEDRONIC ACID INJECTION SHOULD NOT BE USED DURING PREGNANCY . Zoledronic acid injection may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking this drug, the patient should be ap
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Interactions
No in vivo drug interaction studies have been performed for zoledronic acid injection. In vitro and ex vivo studies showed low affinity of zoledronic acid for the cellular components of human blood. In vitro mean zoledronic acid protein binding in human plasma ranged from 28% at 200 ng/mL to 53% at 50 ng/mL. In vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug.
Aminoglycosides: May lower serum calcium for prolonged periods (7.1) Loop diuretics: May increase risk of hypocalcemia (7.2) Nephrotoxic drugs: Use with caution (7.3) Drugs primarily excreted by the kidney: Exposure may be increased with renal impairment. Monitor serum creatinine in patients at risk (7.4)
7.1Aminoglycosides
Caution is advised when bisphosphonates, including zoledronic acid, are administered with aminoglycosides, 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.
7.2Loop Diuretics
Caution should also be exercised when zoledronic acid injection is used in combination with loop diuretics due to an increased risk of hypocalcemia.
7.3Nephrotoxic Drugs
Caution is indicated when zoledronic acid injection is used with other potentially nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs.
7.4Drugs Primarily Excreted by the Kidney
Renal impairment has been observed following the administration of zoledronic acid in patients with pre-existing renal compromise or other risk factors [ see Warnings and Precautions (5.3) ]. In patients with renal impairment, the exposure to concomitant medications that are primarily renally excreted (e.g., digoxin) may increase. Consider monitoring serum creatinine in patients at risk for renal impairment who are taking concomitant medications that are primarily excreted by the kidney.
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Category
D [ see Warnings and Precautions (5.6) ]. ZOLEDRONIC ACID INJECTION SHOULD NOT BE USED DURING PREGNANCY . If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving zoledronic acid injection. Bisphosphonates are incorporated into the bone matrix, from where they 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 space, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. In female rats given daily subcutaneous doses of zoledronic acid beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased at approximately greater than or equal to 0.3 times the anticipated human systemic exposure following a 5 mg intravenous dose (based on an AUC comparison).
Adverse maternal effects were observed in all dose groups at greater than or equal to 0.1 times the human systemic exposure following a 5 mg intravenous dose (based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality was considered 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 daily subcutaneous dose of zoledronic acid during gestation, adverse fetal effects were observed at about 2 and 4 times human systemic exposure following a 5 mg intravenous dose (based on an AUC comparison). These adverse effects included increases in pre- and post-implantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. In pregnant rabbits given daily subcutaneous doses of zoledronic acid during gestation at doses less than or equal to 0.4 times the anticipated human systemic exposure following a 5 mg intravenous dose (based on a mg/m 2 comparison) no adverse fetal effects were observed.
Maternal mortality and abortion occurred in all treatment groups (at doses greater than or equal to 0.04 times the human 5 mg intravenous dose, based on a mg/m 2 comparison). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia [ see Nonclinical Toxicology (13.3) ].
Adverse reactions
The most common adverse reactions (greater than 10%) were pyrexia, myalgia, headache, arthralgia, pain in extremity (6.1). Other important adverse reactions were flu-like illness, nausea, vomiting, diarrhea (6.2), and eye inflammation (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Studies 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. Treatment of Osteoporosis in Postmenopausal Women The safety of zoledronic acid injection in the treatment of postmenopausal osteoporosis was assessed in Study 1, a large, randomized, double-blind, placebo-controlled, multinational study of 7736 postmenopausal women aged 65 to 89 years with osteoporosis, diagnosed by bone mineral density or the presence of a prevalent vertebral fracture.
The duration of the trial was three years with 3862 patients exposed to zoledronic acid injection and 3852 patients exposed to placebo administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes, for a total of three doses. All women received 1000 to 1500 mg of elemental calcium plus 400 to 1200 international units of vitamin D supplementation per day. The incidence of all-cause mortality was similar between groups: 3.4% in the zoledronic acid injection group and 2.9% in the placebo group.
The incidence of serious adverse events was 29.2% in the zoledronic acid injection group and 30.1% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.4% and 4.8% for the zoledronic acid injection and placebo groups, respectively. The safety of zoledronic acid injection in the treatment of osteoporosis patients with a recent (within 90 days) low-trauma hip fracture was assessed in Study 2, a randomized, double-blind, placebo-controlled, multinational endpoint-driven study of 2127 men and women aged 50 to 95 years; 1065 patients were randomized to zoledronic acid injection and 1062 patients were randomized to placebo.
Zoledronic acid injection was administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. The study continued until at least 211 patients had a confirmed clinical fracture in the study population who were followed for an average of approximately 2 years on study drug. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 international units orally or IM) was given to patients and they were started on 1000 to 1500 mg of elemental calcium plus 800 to 1200 international units of vitamin D supplementation per day for at least 14 days prior to the study drug infusions.
The incidence of all-cause mortality was 9.6% in the zoledronic acid injection group and 13.3% in the placebo group. The incidence of serious adverse events was 38.3% in the zoledronic acid injection group and 41.3% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.3% and 4.7% for the zoledronic acid injection and placebo groups, respectively. Adverse reactions reported in at least 2% of patients with osteoporosis and more frequently in the zoledronic acid injection-treated patients than placebo-treated patients in either osteoporosis trial are shown below in Table 1.
Table 1. Adverse Reactions Occurring in greater than or equal to 2.0% of Patients with Osteoporosis and More Frequently than in Placebo-Treated Patients System Organ Class Study 1 Study 2 5 mg IV zoledronic acid injection once per year % (N=3862) Placebo once per year % (N=3852) 5 mg IV zoledronic acid injection once per year % (N=1054) Placebo once per year % (N=1057) Blood and the Lymphatic System Disorders Anemia 4.4 3.6 5.3
5.2 Metabolism and Nutrition Disorders Dehydration 0.6 0.6 2.5
2.3 Anorexia 2.0 1.1 1.0
1.0 Nervous System Disorders Headache 12.4 8.1 3.9
2.5 Dizziness 7.6 6.7 2.0
4.0 Ear and Labyrinth Disorders Vertigo 4.3 4.0 1.3
with intravenous bisphosphonates, including zoledronic acid, has been associated with renal impairment manifested as deterioration in renal function (i.e., increased serum creatinine) and in rare cases, acute renal failure. In the clinical trial for postmenopausal osteoporosis, patients with baseline creatinine clearance less than 30 mL/min (based on actual body weight), urine dipstick greater than or equal to 2+ protein or increase in serum creatinine of greater than 0.5 mg/dL during the screening visits were excluded.
The change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the zoledronic acid injection and placebo treatment groups over 3 years, including patients with creatinine clearance between 30 to 60 mL/min at baseline. Overall, there was a transient increase in serum creatinine observed within 10 days of dosing in 1.8% of zoledronic acid injection-treated patients versus 0.8% of placebo-treated patients which resolved without specific therapy [ see Warnings and Precautions (5.3) ].
Acute Phase Reaction The signs and symptoms of acute phase reaction occurred in Study 1 following zoledronic acid injection infusion including fever (18%), myalgia (9%), flu-like symptoms (8%), headache (7%), and arthralgia (7%). The majority of these symptoms occurred within the first 3 days following the dose of zoledronic acid injection and usually resolved within 3 days of onset but resolution could take up to 7 to 14 days.
In Study 2, patients without a contraindication to acetaminophen were provided with a standard oral dose at the time of the IV infusion and instructed to use additional acetaminophen at home for the next 72 hours as needed. Zoledronic acid injection was associated with fewer signs and symptoms of a transient acute phase reaction in this trial: fever (7%) and arthralgia (3%). The incidence of these symptoms decreased with subsequent doses of zoledronic acid injection.
Laboratory Findings In Study 1, in women with postmenopausal osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels (less than 7.5 mg/dL) following zoledronic acid injection administration. No symptomatic cases of hypocalcemia were observed. In Study 2, following pre-treatment with vitamin D, no patients had treatment emergent serum calcium levels below 7.5 mg/dL. Injection Site Reactions In the osteoporosis trials, local reactions at the infusion site such as itching, redness and/or pain have been reported in 0% to 0.7% of patients following the administration of zoledronic acid injection and 0% to 0.5% of patients following administration of placebo.
Osteonecrosis of the Jaw In the postmenopausal osteopo
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Composition
Active ingredients
ZOLEDRONIC ACID EQ 5MG BASE/100ML
Strengths and forms
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