Zoledronic Acid IV

Paget's Disease of Bone

Zoledronic acid 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)].

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.

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. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended for these patients [see Contraindications (4)].

Hypocalcemia following zoledronic acid 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), Adverse Reactions (6.1), Information for Patients (17)].

Renal Impairment

A single dose of zoledronic acid should not exceed 5 mg and the duration of infusion should be no less than 15 minutes [see Dosage and Administration (2.1)].

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 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 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. Zoledronic acid 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)].

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)].

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. 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.

Pregnancy

ZOLEDRONIC ACID SHOULD NOT BE USED DURING PREGNANCY. Zoledronic acid may cause fetal harm when administered to a pregnant woman. 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 on zoledronic acid therapy [see Use in Specific Populations (8.1)].

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. The time to onset of symptoms varied from one day to several months after starting the drug. Consider withholding future zoledronic acid 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)].

Patients with Asthma

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

Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.6)].

ZOLEDRONIC ACID 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.

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/m2 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/m2 comparison). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia [see Nonclinical Toxicology (13.3)].

Nursing Mothers

It is not known whether zoledronic acid is excreted in human milk. Because many drugs are excreted in human milk, and because zoledronic acid binds to bone long-term, zoledronic acid should not be administered to a nursing woman.

Pediatric Use

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 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 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 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.

Geriatric Use

Of the patients receiving zoledronic acid 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.

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

Renal Impairment

Zoledronic acid 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)].

Hepatic Impairment

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

Clinical experience with acute overdosage of zoledronic acid solution for intravenous infusion is limited. Patients who have received doses higher than those recommended should be carefully monitored. Overdosage may cause clinically significant renal impairment, 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.

Single doses of zoledronic acid should not exceed 5 mg and the duration of the intravenous infusion should be no less than 15 minutes [see Dosage and Administration (2)].

Treatment of Paget's Disease of Bone

Zoledronic acid 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 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 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-treated patients achieved a therapeutic response as compared with 74% (127/171) of patients treated with risedronate. Most zoledronic acid patients achieved a therapeutic response by the Day 63 visit. In addition, at 6 months, 89% (156/176) of zoledronic acid-treated patients achieved normalization of SAP levels, compared to 58% (99/171) of patients treated with risedronate (p<0.0001) (see Figure 1).

The therapeutic response to zoledronic acid 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-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 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 (98%) relative to risedronate (86%). In patients with symptomatic pain at screening, therapeutic response rates were 94% and 70% for zoledronic acid and risedronate respectively. For patients without pain at screening, therapeutic response rates were 100% and 82% for zoledronic acid and risedronate respectively.

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

Zoledronic Acid Injection (ZOE-le-DRON-ik AS-id)

Read the Medication Guide that comes with Zoledronic Acid Injection before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about Zoledronic Acid Injection.

What is the most important information I should know about Zoledronic Acid Injection?

You should not receive Zoledronic Acid Injection if you are already receiving Zometa. Both Zoledronic Acid Injection and Zometa contain zoledronic acid.

Zoledronic Acid Injection can cause serious side effects including:

1. Low calcium levels in your blood (hypocalcemia) 2. Severe kidney problems 3. Severe jaw bone problems (osteonecrosis) 4. Bone, joint or muscle pain 5. Unusual thigh bone fractures

1.   Low calcium levels in your blood (hypocalcemia).

Zoledronic Acid Injection may lower the calcium levels in your blood. If you have low blood calcium before you start taking Zoledronic Acid Injection, it may get worse during treatment. Your low blood calcium must be treated before you take Zoledronic Acid Injection. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:

• Spasms, twitches, or cramps in your muscles • Numbness or tingling in your fingers, toes, or around your mouth

Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood, while you take Zoledronic Acid Injection. Take calcium and Vitamin D as your doctor tells you to.

2.   Severe kidney problems.

Severe kidney problems may happen when you take Zoledronic Acid Injection. Severe kidney problems may lead to hospitalization or kidney dialysis and can be life-threatening. Your risk of kidney problems is higher if you:

• already have kidney problems • take a diuretic or "water pill" • do not have enough water in your body (dehydrated) before or after you receive Zoledronic Acid Injection • are of advanced age since the risk increases as you get older • take any medicines known to harm your kidneys

You should drink at least 2 glasses of fluid within a few hours before receiving Zoledronic Acid Injections to reduce the risk of kidney problems.

3.   Severe jaw bone problems (osteonecrosis).

Severe jaw bone problems may happen when you take Zoledronic Acid Injection. Your doctor should examine your mouth before you start Zoledronic Acid Injection. Your doctor may tell you to see your dentist before you start Zoledronic Acid Injection. It is important for you to practice good mouth care during treatment with Zoledronic Acid Injection.

4.   Unusual thigh bone fractures.

Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture may include new or unusual pain in your hip, groin, or thigh.

5.   Possible harm to your unborn baby.

Zoledronic Acid Injection should not be used if you are pregnant. Tell your doctor right away if you are pregnant or plan to become pregnant. Zoledronic Acid Injection may harm your unborn baby.

6.   Bone, joint, or muscle pain.

Some people who take bisphosphonates develop severe bone, joint, or muscle pain.

Call your doctor right away if you have any of these side effects.

What is Zoledronic Acid Injection?

Zoledronic Acid Injection is a prescription medicine used to:

• Treat certain men and women who have Paget's disease of the bone.

Zoledronic Acid Injection is not for use in children.

Who should not take Zoledronic Acid Injection?

Do not take Zoledronic Acid Injection if you:

• Have low levels of calcium in your blood • Have kidney problems • Are allergic to zoledronic acid or any of its ingredients. A list of ingredients is at the end of this leaflet.

What should I tell my doctor before taking Zoledronic Acid Injection?

Before you start Zoledronic Acid Injection, be sure to talk to your doctor if you:

• Have low blood calcium. • Have kidney problems. • Had parathyroid or thyroid surgery (glands in your neck). • Have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome) or have had parts of your intestine removed. • Have asthma (wheezing) from taking aspirin. • Plan to have dental surgery or teeth removed. • Are pregnant or plan to become pregnant. Zoledronic acid may harm your unborn baby. Zoledronic Acid Injection should not be used if you are pregnant. • Are breast-feeding or plan to breast-feed. It is not known if zoledronic acid passes into your milk and may harm your baby.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Certain medicines may affect how Zoledronic Acid Injection works.

Especially tell your doctor if you are taking:

• An antibiotic. Certain antibiotics called aminoglycosides may increase the effect of Zoledronic Acid Injection in lowering your blood calcium for a long period of time. • A diuretic or "water pill". • Non-steroidal anti-inflammatory medicines (NSAIDS).

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine.

How will I receive Zoledronic Acid Injection?

• Your doctor will tell you how often you will receive Zoledronic Acid Injection. • Zoledronic Acid Injection is given by infusion into your vein (intravenously). Your infusion should last at least 15 minutes. • Before you receive Zoledronic Acid Injection, drink at least 2 glasses of fluid (such as water) within a few hours as directed by your doctor. • You may eat before your treatment with Zoledronic Acid Injection. • If you miss a dose of Zoledronic Acid Injection, call your doctor or healthcare provider to schedule your next dose.

What are the possible side effects of Zoledronic Acid Injection?

Zoledronic Acid Injection may cause serious side effects.

• See "What is the most important information I should know about Zoledronic Acid Injection?"

The most common side effects of Zoledronic Acid Injection include:

• Fever • Pain in your bones, joints or muscles • Pain in your arms and legs • Headache • Flu-like illness (fever, chills, bone, joint, or muscle pain, fatigue) • Nausea • Vomiting • Diarrhea

Talk to your doctor about things you can do to help decrease some of these side effects that might happen with a zoledronic acid infusion.

You may get allergic reactions, such as hives, swelling of your face, lips, tongue, or throat.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Zoledronic Acid Injection. For more information ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about safe and effective use of Zoledronic Acid Injection.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. This Medication Guide summarizes the most important information about Zoledronic Acid Injection. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Zoledronic Acid Injection that is written for health professionals.

For more information, go to: www.hospira.com or call 1-800-615-0187.

What are the ingredients in Zoledronic Acid Injection?

Active ingredient: zoledronic acid monohydrate

Inactive ingredients: mannitol and sodium citrate

 

1/2017

 

 

Manufactured by:
Laboratorios Grifols, SA
Barcelona, Spain

Manufactured for:
Hospira Inc.
Lake Forest, Illinois 60045 USA

Product of Spain

This Medication Guide has been approved by the U.S. Food and Drug Administration.
Zometa® is a registered trademark of Novartis Pharmaceutical Corporation.

LAB-0929-1.0