1.5 Paget'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)].

2.1 Important Administration Instructions

Zoledronic Acid Injection must be administered as an intravenous infusion over no less than 15 minutes.

• Patients must be appropriately hydrated prior to administration of Zoledronic Acid Injection [see Warnings and Precautions (5.3)].
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
• Intravenous infusion should be followed by a 10 mL normal saline flush of the intravenous line.
• Administration of acetaminophen following Zoledronic Acid Injection administration may reduce the incidence of acute-phase reaction symptoms.

Caution: After removing the overwrap check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard container as sterility may be compromised. Use only if solution is clear and the container is undamaged.

Preparation for Administration:

1. Close flow control clamp of administration set.
2. Remove cover from port at bottom of container.
3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.
4. Suspend container from hanger.
5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Zoledronic Acid Injection.
6. Open flow control clamp to expel air from set. Close clamp.
7. Regulate rate of administration with flow control clamp.

2.6 Treatment of Paget's Disease of Bone

The recommended dose is a 5 mg infusion. The infusion time must not be less than 15 minutes given over a constant infusion rate.

2.7 Laboratory Testing and Oral Examination Prior to Administration

• Prior to administration of each dose of Zoledronic Acid Injection, obtain a serum creatinine and creatinine clearance should be calculated based on actual body weight using Cockcroft-Gault formula before each Zoledronic Acid Injection dose. Zoledronic Acid Injection is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment. A 5 mg dose of Zoledronic Acid Injection administered intravenously is recommended for patients with creatinine clearance greater than or equal to 35 mL/min. There are no safety or efficacy data to support the adjustment of the Zoledronic Acid Injection dose based on baseline renal function. Therefore, no dose adjustment is required in patients with CrCl greater than or equal to 35 mL/min [see Contraindications (4), Warnings and Precautions (5.3)].
• A routine oral examination should be performed by the prescriber prior to initiation of Zoledronic Acid Injection treatment [see Warnings and Precautions (5.4)].

2.8 Calcium and Vitamin D Supplementation

• Instruct patients being treated for Paget's disease of bone on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels, and on the symptoms of hypocalcemia. All patients should take 1500 mg elemental calcium daily in divided doses (750 mg two times a day, or 500 mg three times a day) and 800 international units vitamin D daily, particularly in the 2 weeks following Zoledronic Acid Injection administration [see Warnings and Precautions (5.2)].

2.9 Method of Administration

The Zoledronic Acid Injection infusion time must not be less than 15 minutes given over a constant infusion rate.

The intravenous infusion should be followed by a 10 mL normal saline flush of the intravenous line.

Zoledronic Acid Injection solution for infusion must not be allowed to come in contact with any calcium or other divalent cation-containing solutions, and should be administered as a single intravenous solution through a separate infusion line.

If refrigerated, allow the refrigerated solution to reach room temperature before administration. After opening, the solution is stable for 24 hours at 2°C to 8°C (36°F to 46°F) [see How Supplied/Storage and Handling (16)].

5.1 Drug 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.

5.2 Hypocalcemia 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), Patient Counseling Information (17)].

5.3 Renal 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 Adverse Reactions (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 Adverse Reactions (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. 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)].

5.5 Atypical 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.

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.

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.

5.6 Musculoskeletal Pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Zoledronic Acid Injection. The time to onset of symptoms varied from one day to several months after starting the drug. Consider withholding future Zoledronic Acid Injection treatment 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)].

5.7 Patients with Asthma

While not observed in clinical trials with Zoledronic Acid Injection, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates. Use Zoledronic Acid Injection with caution in aspirin-sensitive patients.

6.1 Clinical 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.

6.2 Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during post approval use of Zoledronic Acid Injection:

7.1 Aminoglycosides

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.

7.2 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.

7.3 Nephrotoxic Drugs

Caution is indicated when Zoledronic Acid Injection is used with other potentially nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs.

7.4 Drugs 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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 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 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 use in children did not raise any new safety findings beyond those previously seen in adults treated for Paget's disease of bone including osteonecrosis of the jaw (ONJ) and renal impairment. 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 three days after the first infusion and became less common with repeat dosing. No cases of ONJ or renal impairment were observed in this study. Because of long-term retention in bone, Zoledronic Acid 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 minutes. 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.

8.5 Geriatric Use

Of the patients receiving Zoledronic Acid Injection in the Paget's disease studies, 132 patients were 65 years of age or over, while 68 patients were at least 75 years of age.

Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.

8.6 Renal Impairment

Zoledronic Acid Injection is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment. There are no safety or efficacy data to support the adjustment of the Zoledronic Acid Injection dose based on baseline renal function. Therefore, no dosage adjustment is required in patients with a creatinine clearance of greater than or equal to 35 mL/min [see Warnings and Precautions (5.3), Clinical Pharmacology (12.3)]. Risk of acute renal failure may increase with underlying renal disease and dehydration secondary to fever, sepsis, gastrointestinal losses, diuretic therapy, advanced age, etc. [see Adverse Reactions (6.2)].

8.7 Hepatic Impairment

Zoledronic Acid Injection is not metabolized in the liver. No clinical data are available for use of Zoledronic Acid Injection in patients with hepatic impairment.

12.1 Mechanism of Action

Zoledronic Acid Injection is a bisphosphonate and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.

The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intravenously administered zoledronic acid rapidly partitions to bone and localizes preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity to bone mineral.

12.3 Pharmacokinetics

Pharmacokinetic data in patients with Paget's disease of bone are not available.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily oral doses of zoledronic acid of 0.1, 0.5, or 2 mg/kg/day for 2 years. There was an increased incidence of Harderian gland adenomas in males and females in all treatment groups (starting at doses equivalent to 0.002 times the human 5 mg intravenous dose, based on body surface area, mg/m2). Rats were given daily oral doses of zoledronic acid of 0.1, 0.5, or 2 mg/kg/day for 2 years. No increased incidence of tumors was observed at any dose (up to to 0.1 times the human intravenous dose of 5 mg, based on body surface area, mg/m2).

Mutagenesis: 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.

Impairment of Fertility: Female rats were given daily subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg beginning 15 days before mating and continuing through gestation. Inhibition of ovulation and a decrease in the number of pregnant rats were observed at 0.1 mg/kg/day (equivalent to the human 5 mg intravenous dose, based on AUC). An increase in preimplantation loss and a decrease in the number of implantations and live fetuses were observed at 0.03 and 1 mg/kg/day (0.3 to 1 times the human 5 mg human intravenous dose).

13.2 Animal Pharmacology

Bone Safety Studies: Zoledronic acid is a potent inhibitor of osteoclastic bone resorption. In the ovariectomized rat, single IV doses of zoledronic acid of 4 to 500 mcg/kg (0.1 to 3.5 times the human 5 mg intravenous dose, based on body surface area, mg/m2) suppressed bone turnover and protected against trabecular bone loss, cortical thinning and the reduction in vertebral and femoral bone strength in a dose-dependent manner. At a dose equivalent to human exposure at the 5 mg intravenous dose, the effect persisted for 8 months, which corresponds to approximately 8 remodeling cycles or 3 years in humans.

In ovariectomized rats and monkeys, weekly treatment with zoledronic acid dose-dependently suppressed bone turnover and prevented the decrease in cancellous and cortical BMD and bone strength, at yearly cumulative doses up to 3.5 times the human 5 mg intravenous dose, based on body surface area, mg/m2. Bone tissue was normal and there was no evidence of a mineralization defect, no accumulation of osteoid, and no woven bone.

14.5 Treatment of Paget's Disease of Bone

Zoledronic Acid Injection was studied in male and female patients with moderate to severe Paget's disease of bone, defined as serum alkaline phosphatase level at least twice the upper limit of the age-specific normal reference range at the time of study entry. Diagnosis was confirmed by radiographic evidence.

The efficacy of one infusion of 5 mg Zoledronic Acid Injection vs. oral daily doses of 30 mg risedronate for 2 months was demonstrated in two identically designed 6-month randomized, double-blind trials. The mean age of patients in the two trials was 70. Ninety-three percent (93%) of patients were Caucasian. Therapeutic response was defined as either normalization of serum alkaline phosphatase (SAP) or a reduction of at least 75% from baseline in total SAP excess at the end of 6 months. SAP excess was defined as the difference between the measured level and midpoint of normal range.

In both trials Zoledronic Acid Injection demonstrated a superior and more rapid therapeutic response compared with risedronate and returned more patients to normal levels of bone turnover, as evidenced by biochemical markers of formation (SAP, serum N-terminal propeptide of type I collagen [P1NP]) and resorption (serum CTx 1 [cross-linked C-telopeptides of type I collagen] and urine α-CTx).

The 6-month combined data from both trials showed that 96% (169/176) of Zoledronic Acid Injection-treated patients achieved a therapeutic response as compared with 74% (127/171) of patients treated with risedronate. Most Zoledronic Acid Injection patients achieved a therapeutic response by the Day 63 visit. In addition, at 6 months, 89% (156/176) of Zoledronic Acid Injection-treated patients achieved normalization of SAP levels, compared to 58% (99/171) of patients treated with risedronate (p<0.0001) (see Figure 1).

Figure 1. Therapeutic Response/Serum Alkaline Phosphatase (SAP) Normalization Over Time

The therapeutic response to Zoledronic Acid Injection was similar across demographic and disease-severity groups defined by gender, age, previous bisphosphonate use, and disease severity. At 6 months, the percentage of Zoledronic Acid Injection-treated patients who achieved therapeutic response was 97% and 95%, respectively, in each of the baseline disease severity subgroups (baseline SAP less than 3xULN, greater than or equal to 3xULN) compared to 75% and 74%, respectively, for the same disease severity subgroups of risedronate-treated patients.

In patients who had previously received treatment with oral bisphosphonates, therapeutic response rates were 96% and 55% for Zoledronic Acid Injection and risedronate, respectively. The comparatively low risedronate response was due to the low response rate (7/23, 30%) in patients previously treated with risedronate. In patients naïve to previous treatment, a greater therapeutic response was also observed with Zoledronic Acid Injection (98%) relative to risedronate (86%). In patients with symptomatic pain at screening, therapeutic response rates were 94% and 70% for Zoledronic Acid Injection and risedronate respectively. For patients without pain at screening, therapeutic response rates were 100% and 82% for Zoledronic Acid Injection and risedronate respectively.

Bone histology was evaluated in 7 patients with Paget's disease 6 months after being treated with Zoledronic Acid Injection 5 mg. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodeling and no evidence of mineralization defect.

Handling

After entering the IV administration port, the solution is stable for 24 hours at 2° to 8°C (36° to 46°F). If refrigerated, allow the refrigerated solution to reach room temperature before administration.

Storage Conditions

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.]

Single-use only. Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free, DEHP-free, PVC-free.

The container closure is not made with natural rubber latex.

Information for Patients

Patients should be made aware that Zoledronic Acid Injection contains the same active ingredient (zoledronic acid) found in Zometa®, and that patients being treated with Zometa should not be treated with Zoledronic Acid Injection.

Zoledronic Acid Injection is contraindicated in patients with creatinine clearance less than 35 mL/min [see Contraindications (4)].

Before being given Zoledronic Acid Injection, patients should tell their doctor if they have kidney problems and what medications they are taking.

Zoledronic Acid Injection should not be given if the patient is pregnant or plans to become pregnant, or if she is breast-feeding [see Warnings and Precautions (5.6)].

There have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates, including Zoledronic Acid Injection. Before being given Zoledronic Acid Injection, patients should tell their doctor if they are aspirin-sensitive.

If the patient had surgery to remove some or all of the parathyroid glands in their neck, or had sections of their intestine removed, or are unable to take calcium supplements they should tell their doctor.

Zoledronic Acid Injection is given as an infusion into a vein by a nurse or a doctor, and the infusion time must not be less than 15 minutes.

On the day of treatment the patient should eat and drink normally, which includes drinking at least 2 glasses of fluid such as water within a few hours prior to the infusion, as directed by their doctor, before receiving Zoledronic Acid Injection.

After getting Zoledronic Acid Injection it is strongly recommended patients with Paget's disease take calcium in divided doses (for example, 2 to 4 times a day) for a total of 1500 mg calcium a day to prevent low blood calcium levels. This is especially important for the two weeks after getting Zoledronic Acid Injection [see Warnings and Precautions (5.2)].

Patients should be aware of the most commonly associated side effects of therapy. Patients may experience one or more side effects that could include: fever, flu-like symptoms, myalgia, arthralgia, and headache. Most of these side effects occur within the first 3 days following the dose of Zoledronic Acid Injection. They usually resolve within 3 days of onset but may last for up to 7 to 14 days. Patients should consult their physician if they have questions or if these symptoms persist. The incidence of these symptoms decreased markedly with subsequent doses of Zoledronic Acid Injection.

Administration of acetaminophen following Zoledronic Acid Injection administration may reduce the incidence of these symptoms.

Physicians should inform their patients that there have been reports of persistent pain and/or a non-healing sore of the mouth or jaw, primarily in patients treated with bisphosphonates for other illnesses. During treatment with Zoledronic Acid Injection, patients should be instructed to maintain good oral hygiene and undergo routine dental check-ups. If they experience any oral symptoms, they should immediately report them to their physician or dentist.

Severe and occasionally incapacitating bone, joint, and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Zoledronic Acid Injection. Consider withholding future Zoledronic Acid Injection treatment if severe symptoms develop.

Atypical femur fractures in patients on bisphosphonate therapy have been reported; patients with thigh or groin pain should be evaluated to rule out a femoral fracture.

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Revised: August 2020