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warnings and cautions
5 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) 5.1 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 Pregnancy 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 apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while on zoledronic acid injection therapy [ see Use in Specific Populations ( 8.1 ) ]. 5.7 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 ) ]. 5.8 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 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 Heritage Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Paget's Disease of Bone In the Paget's disease trials, two 6-month, double-blind, comparative, multinational studies of 349 men and women aged greater than 30 years with moderate to severe disease and with confirmed Paget's disease of bone, 177 patients were exposed to zoledronic acid injection and 172 patients exposed to risedronate. Zoledronic acid injection was administered once as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. Risedronate was given as an oral daily dose of 30 mg for 2 months. The incidence of serious adverse events was 5.1% in the zoledronic acid injection group and 6.4% in the risedronate group. The percentage of patients who withdrew from the study due to adverse events was 1.7% and 1.2% for the zoledronic acid injection and risedronate groups, respectively. Adverse reactions occurring in at least 2% of the Paget's patients receiving zoledronic acid injection (single 5 mg intravenous infusion) or risedronate (30 mg oral daily dose for 2 months) over a 6-month study period are listed by system organ class in Table 4. Table 4. Adverse Reactions Reported in at Least 2% of Paget's Patients Receiving Zoledronic Acid Injection (Single 5 mg intravenous Infusion) or Risedronate (Oral 30 mg Daily for 2 Months) Over a 6-Month Follow-Up Period System Organ Class 5 mg IV Zoledronic acid injection % (N = 177) 30 mg/day x 2 Months risedronate %( N = 172) Infections and Infestations Influenza 7 5 Metabolism and Nutrition Disorders Hypocalcemia 3 1 Anorexia 2 2 Nervous System Disorders Headache 11 10 Dizziness 9 4 Lethargy 5 1 Paresthesia 2 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 5 1 Gastrointestinal Disorders Nausea 9 6 Diarrhea 6 6 Constipation 6 5 Dyspepsia 5 4 Abdominal Distension 2 1 Abdominal Pain 2 2 Vomiting 2 2 Abdominal Pain Upper 1 2 Skin and Subcutaneous Tissue Disorders Rash 3 2 Musculoskeletal, Connective Tissue and Bone Disorders Arthralgia 9 11 Bone Pain 9 5 Myalgia 7 4 Back Pain 4 7 Musculoskeletal Stiffness 2 1 General Disorders and Administrative Site Conditions Influenza-like Illness 11 6 Pyrexia 9 2 Fatigue 8 4 Rigors 8 1 Pain 5 4 Peripheral Edema 3 1 Asthenia 2 1 Laboratory Findings In the Paget's disease trials, early, transient decreases in serum calcium and phosphate levels were observed. Approximately 21% of patients had serum calcium levels less than 8.4 mg/dL 9 to 11 days following zoledronic acid injection administration. Renal Impairment In clinical trials in Paget's disease there were no cases of renal deterioration following a single 5 mg 15-minute infusion [s ee Warnings and Precautions ( 5.3 ) ]. Acute Phase Reaction The signs and symptoms of acute phase reaction (influenza-like illness, pyrexia, myalgia, arthralgia, and bone pain) were reported in 25% of patients in the zoledronic acid injection-treated group compared to 8% in the risedronate-treated group. Symptoms usually occur within the first 3 days following zoledronic acid injection administration. The majority of these symptoms resolved within 4 days of onset. Osteonecrosis of the Jaw Osteonecrosis of the jaw has been reported with zoledronic acid [ see Warnings and Precautions ( 5.4 ) ]. 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: Acute Phase Reactions Fever, headache, flu-like symptoms, nausea, vomiting, diarrhea, arthralgia, and myalgia. Symptoms may be significant and lead to dehydration. Acute Renal Failure Acute renal failure requiring hospitalization and/or dialysis or with a fatal outcome have been rarely reported. Increased serum creatinine was reported in patients with 1) underlying renal disease, 2) dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic therapy, or 3) other risk factors such as advanced age, or concomitant nephrotoxic drugs in the post-infusion period. Transient rise in serum creatinine can be correctable with intravenous fluids. Allergic Reactions Allergic reactions with intravenous zoledronic acid including anaphylactic reaction/shock, urticaria, angioedema, Stevens- Johnson syndrome, toxic epidermal necrolysis, and bronchoconstriction have been reported. Asthma Exacerbations Asthma exacerbations have been reported. Hypocalcemia Hypocalcemia has been reported. Hypophosphatemia Hypophosphatemia has been reported. Osteonecrosis of the Jaw Osteonecrosis of the jaw has been reported. Osteonecrosis of other bones Cases of osteonecrosis of other bones (including femur, hip, knee, ankle, wrist and humerus) have been reported; causality has not been determined in the population treated with zoledronic acid injection. Ocular Adverse Events Cases of the following events have been reported: conjunctivitis, iritis, iridocyclitis, uveitis, episcleritis, scleritis and orbital inflammation/edema. Other Hypotension in patients with underlying risk factors has been reported.