WARNINGS AND PRECAUTIONS
5.1 Drug Products with Same Active Ingredient
Reclast contains the same active ingredient found in Zometa, used for oncology indications, and a patient being treated with Zometa should not be treated with Reclast.
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 Reclast. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended for these patients [ see Contraindications (4) ].
Hypocalcemia following Reclast 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 (17.1) ].
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), Adverse Reactions (6.1), Information for Patients (17.1) ].
5.3 Renal Impairment
A single dose of Reclast should not exceed 5 mg and the duration of infusion should be no less than 15 minutes [ see Dosage and Administration (2.1) ] .
Reclast should not be used in patients with severe renal impairment (creatinine clearance <35 mL/min) due to lack of adequate clinical experience in this population [ see Adverse Reactions (6.1)].
Renal impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal compromise or other risk factors including concomitant nephrotoxic medications, concomitant diuretic therapy, or severe dehydration occurring before or after Reclast administration. Renal impairment has been observed in patients after a single administration. Rare reports of hospitalization and/or dialysis occurred in patients with underlying moderate to severe renal impairment [ see Post-Marketing Experience (6.2) ]. Renal impairment may lead to increased exposure of concomitant medications that are primarily renally excreted [ see Drug Interactions (7.4) ].
Serum creatinine should be measured before each Reclast dose. Transient increase in serum creatinine may be greater in patients with impaired renal function; consider interim monitoring of serum creatinine in at-risk patients. Patients, especially those receiving diuretic therapy, should be appropriately hydrated prior to administration of Reclast. Reclast should be used with caution with other nephrotoxic drugs [ see Drug Interactions (7.3) ]. Consider monitoring serum creatinine in patients at risk for renal impairment 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, radiotherapy, corticosteroids, poor oral hygiene, pre-existing dental disease or infection, anemia, coagulopathy).
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) ].
RECLAST SHOULD NOT BE USED DURING PREGNANCY. Reclast 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 Reclast therapy [ see Use in Specific Populations (8.1) ].
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 Reclast. The time to onset of symptoms varied from one day to several months after starting the drug. Consider withholding future Reclast 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 Reclast, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates. Use Reclast with caution in aspirin-sensitive patients.
USE IN SPECIFIC POPULATIONS
Pregnancy Category D [ see Warnings and Precautions (5.5) ].
RECLAST 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 Reclast.
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 ≥ 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 ≥ 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 ≤ 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 ≥ 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. [ S ee NONCLINICAL TOXICOLOGY (13. 3 ) ].
It is not known whether Reclast is excreted in human milk. Because many drugs are excreted in human milk, and because Reclast binds to bone long-term, Reclast should not be administered to a nursing woman.
Reclast 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 and treatment of osteoporosis 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, Reclast 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.
The combined osteoporosis trials included 4761 Reclast-treated patients who were at least 65 years of age, while 2083 patients were at least 75 years old. No overall differences in efficacy or safety were observed between patients under 75 years of age with those at least 75 years of age, except that the acute phase reactions occurred less frequently in the older patients.
Of the patients receiving Reclast in the osteoporosis study in men and Paget’s disease studies, 83 and 132 patients, respectively were 65 years of age or over, while 24 and 68 patients, respectively 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.
8.6 Renal Impairment
Reclast should not be used in patients with severe renal impairment (creatinine clearance <35 mL/min) due to lack of adequate clinical experience in this population. No dosage adjustment is required in patients with a creatinine clearance of ≥ 35 mL/min [ see Warnings and Precautions (5.3), Clinical Pharmacology (12.3) ]. Risk of renal impairment may increase with underlying renal disease and dehydration secondary to fever, gastrointestinal losses, diuretic therapy, etc. [s ee Post -M arketing Experience (6.2) ].
8.7 Hepatic Impairment
Reclast is not metabolized in the liver. No clinical data are available for use of Reclast in patients with hepatic impairment.