Aclasta 5mg/100mL

The interaction of zoledronic acid with herbal medications or supplements has not been studied.

Specific drug-lifestyle interaction studies have not been conducted with zoledronic acid.

The interaction of zoledronic acid has not been studied with regards to food.

No data suggest that zoledronic acid interferes with laboratory tests.

ACLASTA is not metabolized in humans. Zoledronic acid is eliminated by renal excretion.

ACLASTA must not be allowed to come in contact with any calcium- or other divalent cations-containing solutions, and it should be administered as a single dose through a separate vented infusion line.

Zoledronic acid is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min). No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min. Patients must be appropriately hydrated prior to administration of ACLASTA, and this is especially important for patients receiving diuretic therapy (see Warnings and Precautions).

Specific re-treatment data are not available. After one treatment with ACLASTA in Paget’s disease an extended remission period of up to 19 months was observed in 98% (143/146) of patients.

It is strongly advised that patients receive adequate calcium and vitamin D supplementation especially in the days before and following ACLASTA administration (see Warnings and Precautions). All patients should be counseled regarding the importance of calcium and vitamin D supplementation in maintaining serum calcium levels, and on the symptoms of hypocalcemia. The recommended daily vitamin D supplement should be determined by the treating physician based on the patient's individual needs. In the postmenopausal osteoporosis trial (HORIZON-PFT), patients received 1000 to 1500 mg of elemental calcium plus 400 to 1200 IU of vitamin D supplements per day.

Treatment of postmenopausal osteoporosis

The recommended dose is a once yearly single intravenous infusion of ACLASTA.

ACLASTA (5 mg in 100 mL ready to infuse solution) is administered intravenously via a vented infusion line.

Patients should be advised to be appropriately hydrated before the administration of ACLASTA.

The infusion time must not be less than 15 minutes (see Warnings and Precautions) and the infusion rate should be constant. ACLASTA should only be given by intravenous infusion. The total volume of the ACLASTA solution should be infused. ACLASTA must never be given as a bolus injection.

About 25% of patients experienced transient post-dose symptoms within the first 3 days of their ACLASTA infusion (see Adverse Reactions). Symptomatic management can be considered on an individual basis. No anaphylactic reactions have been observed in the clinical trials but good medical practice dictates caution (see Contraindications).

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

The following adverse reactions have been identified during the post approval use of this drug: hypocalcaemia, arthralgia, myalgia, flu-like symptoms, fever and headache. Hypersensitivity reactions including rare cases of bronchoconstriction, urticaria and angioedema, and very rare cases of anaphylactic reactions/shock have also been reported.

Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid. In the postmenopausal osteoporosis trial, 9 (0.2%) patients treated with ACLASTA and 1 (<0.1%) patient treated with placebo developed iritis/uveitis/episcleritis. Of the ocular conditions known to be related to bisphosphonate use, one case of iritis in a zoledronic acid-treated patient was reported in the HORIZON-RFT trial. In the male osteoporosis trial, two cases of conjunctivitis and one case of eye pain were reported in zoledronic acid-treated patients. In addition, one case of iritis was reported in the alendronate group. One case of conjunctivitis in a zoledronic acid-treated patient was reported in the glucocorticoid-induced osteoporosis trial.

In the postmenopausal osteoporosis trial (HORIZON-PFT), mild, transient, asymptomatic decrease in calcium levels, have been observed with ACLASTA primarily after the first dose. Approximately 0.2% of patients had notable declines of serum calcium levels (less than 1.87 mmol/L) following ACLASTA administration. No symptomatic cases of hypocalcaemia were observed. In this trial, patients received supplemental daily doses of elemental calcium (1000 to 1500 mg) and vitamin D (400 to 1200 IU).

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Confirmed increases in serum creatinine from baseline (>0.5% mg/dL) were observed in 9 (2.2%) zoledronic acid-treated patients compared to 3 (0.7%) risedronate-treated patients. Adjudicated laboratory changes in renal function and renal adverse events over the one year trial are described in Table 11.

In the postmenopausal osteoporosis trial, local reactions at the infusion site such as itching, redness and/or pain have been reported in 0.7% of patients following the administration of ACLASTA and 0.5% of patients following the administration of placebo. In the male osteoporosis trial, the event rate was 2.6% in the zoledronic acid treatment group and 1.4% in the alendronate treatment group. In the glucocorticoid-induced osteoporosis trial, no local reactions were reported.

While not observed in clinical trials with ACLASTA there have been previous reports of bronchoconstriction in ASA-sensitive patients receiving bisphosphonates.

In the postmenopausal osteoporosis trial, 3 cases (2 zoledronic acid, 1 placebo patient) were confirmed to be cases of delayed union of fracture, one of which occurred in a patient with fracture that pre-existed at baseline. 7 cases of avascular necrosis (zoledronic acid=4, placebo=3) were reported (6 cases occurred in the hip region and 1 case was in the knee region). In the HORIZON-RFT trial, 3 (0.3%) patients had confirmed events of delayed union/nonunion in the zoledronic acid group (2 incident hip and 1 humerus) and 3 (0.3%) patients had confirmed events in the placebo group (1 incident hip, 1 contralateral hip, and 1 shoulder). Six (0.6%) patients in the zoledronic acid group and 3 (0.3%) patients in the placebo group had confirmed events of avascular necrosis, all of which involved the hip. In the glucocorticoid-induced osteoporosis trial, 5 cases of avascular necrosis (zoledronic acid=2 and risedronate=3) were reported.

In the postmenopausal osteoporosis trial (HORIZON-PFT) in 7736 patients, symptoms consistent with ONJ occurred in one patient treated with ACLASTA and one patients treated with placebo. Both cases resolved after appropriate treatment. ONJ has not been observed in the HORIZON-RFT, the male osteoporosis, the glucocorticoid-induced osteoporosis, or the Paget’s disease trials with ACLASTA.

In the Paget’s disease trials, early, transient decreases in serum calcium and phosphate levels, that were usually asymptomatic, have been observed. Approximately 21% of subjects had serum calcium levels <2.1 mmol/L (<8.4 mg/dL) 9-11 days following ACLASTA infusion. In the Paget’s disease trials, symptomatic hypocalcemia was observed in approximately 1% of patients, all of which resolved.

In the HORIZON-RFT, the male osteoporosis, or the glucocorticoid induced-osteoporosis trials, there were no patients who had treatment emergent serum calcium levels below 1.87 mmol/L.

There was a transient increase in serum creatinine from baseline (>0.5 mg/dL) observed 9-11 days post-infusion in 7 (4.6%) zoledronic acid-treated patients versus 1 (0.7%) alendronate-treated patient which subsequently decreased to baseline or near baseline levels. Adjudicated changes in renal function and renal adverse events over the two year trial are described in Table 9 and Table 10 (see Adverse Reactions).

Most Frequent Adverse Reactions Occurring in at Least 5% of Paget’s Patients in any Group Receiving ACLASTA (single 5 mg i.v. infusion) or Risedronate (oral 30 mg daily for 2 months) by Time of Occurrence

Safety and efficacy in children and growing adolescents have not been established. ACLASTA should not be given to this patient population.

No overall differences in safety and efficacy were observed according to age (see Warnings and Precautions, Special Populations).

Renal function should be assessed and serum creatinine should be measured before every treatment with ACLASTA (e.g., as part of their annual examination).

Serum calcium levels and vitamin D levels should be assessed for all patients before treatment with ACLASTA (e.g., as part of their annual examination). The recommended daily vitamin D supplement should be determined by the treating physician based on the patient's individual needs.

In post-marketing experience with multiple dose regimen bisphosphonates, including ACLASTA, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients. The time to onset of symptoms varied from one day to several months after starting the drug. A subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

The 5 mg single dose of ACLASTA (zoledronic acid 5 mg/100 mL) should be infused in no less than 15 minutes.

While not observed in clinical trials with ACLASTA, there have been reports of bronchoconstriction in ASA (acetylsalicylic acid) sensitive patients receiving bisphosphonates. ACLASTA must be used with caution in ASA-sensitive patients.

Zoledronic acid, has been associated with renal dysfunction manifested as deterioration in renal function (i.e., increased serum creatinine), and in rare cases, acute renal failure. Renal deterioration, progression to renal failure (some with fatal outcome) and dialysis have been reported very rarely in oncology patients (e.g., those with hypercalcemia of malignancy and/or pre-existing renal disease), after the initial dose or a single dose of zoledronic acid (4 mg dose, every 3-4 weeks) (see Adverse Reactions).

ACLASTA should not be used during pregnancy as zoledronic acid may cause fetal harm when administered to a pregnant woman. In reproductive studies in the pregnant rat, subcutaneous doses equivalent to 2.0 or 4.5 times the human systemic exposure (an i.v. dose of 5 mg based on an AUC comparison) resulted in pre- and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral and external malformations.

There are no studies in pregnant women using zoledronic acid. 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.

The combined osteoporosis trials (HORIZON-PFT and HORIZON-RFT) included 4,761 ACLASTA-treated patients who were at least 65 years of age, while 2083 patients were at least 75 years old. No overall differences in safety and efficacy were observed according to age.

The osteoporosis study in men included 59 (38.3%) ACLASTA-treated patients who were at least 65 years of age, while 24 (15.6%) patients were at least 75 years old. No overall differences in safety and efficacy were observed according to age.

The glucocorticoid-induced osteoporosis trial included 116 (27.9%) ACLASTA-treated patients who were at least 65 years of age, while 29 (7.0%) patients were at least 75 years old. No overall differences in safety and efficacy were observed according to age.

Phase 3 studies of ACLASTA in the treatment of Paget’s disease of bone included 132 (75.5%) ACLASTA-treated patients who were at least 65 years of age, while 68 (37.4%) ACLASTA-treated patients were at least 75 years old. No overall differences in efficacy or safety were observed between these patients and younger patients.

ACLASTA contains the same active ingredient that is found in ZOMETA (zoledronic acid). Patients being treated with ZOMETA should not be treated with ACLASTA.

Patients being treated with ACLASTA should not be treated with other bisphosphonates concomitantly.

Osteonecrosis of the jaw (ONJ) has been reported rarely in the treatment of postmenopausal osteoporosis with zoledronic acid as well as with other oral and intravenous bisphosphonates. The condition currently termed Osteonecrosis of the jaw has unknown etiology and pathogenesis, and may or may not originate in the bone. ONJ has been reported in patients with cancer receiving treatment regimens that include bisphosphonates such as zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with invasive dental procedures, such as root canal or dental extraction. Many had signs of local infection including osteomyelitis. A causal relationship between bisphosphonate use and ONJ has not been established.

A routine dental examination with appropriate preventive dentistry should be performed prior to treatment with bisphosphonates, such as ACLASTA, in patients with possible risk factors (e.g., cancer, chemotherapy, head and neck radiotherapy, corticosteroids, poor oral hygiene). While receiving treatment, these patients should avoid invasive dental procedures, if possible, but should continue with regular dental cleaning and oral hygiene. For patients requiring oral surgery, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. In patients who develop ONJ while on bisphosphonate therapy, surgery at the affected area may exacerbate the condition. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

ACLASTA is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) due to lack of adequate clinical experience in this population (see Dosage and Administration). It is recommended that all patients have their serum creatinine measured before treatment with ACLASTA (e.g., as part of their annual examination).

The safety and effectiveness of ACLASTA in pediatric patients have not been established.

Physicians should instruct their patients to read the Patient Information before starting therapy with ACLASTA (zoledronic acid 5 mg/100 mL).

• ACLASTA is given as one single infusion into a vein by a nurse or a doctor, and the infusion time must not be less than 15 minutes. Before being given ACLASTA patients should tell their doctor if they have kidney problems and what medications they are taking.

  
  

• ACLASTA should not be given if the patient is taking ZOMETA, which contains the same active ingredient as in ACLASTA.

  
  

• ACLASTA should not be given if the patient is pregnant or plans to become pregnant, or if they are breast-feeding (see Contraindications and Warnings and Precautions).

  
  

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

  
  

• It is strongly advised that patients receive adequate calcium and vitamin D supplementation in order to maintain normal blood calcium levels. Supplementation of both calcium and vitamin D is especially important in the days before and following ACLASTA administration. The recommended daily vitamin D supplement should be determined by the treating physician based on the patient's individual needs.

  
  

• On the day of infusion, it is recommended that patients eat and drink normally, which includes drinking at least 2 glasses of fluids (500 mL or 2 cups) such as water, before and after the administration of ACLASTA.

  
  

• Patients should also be aware of the most common side effects. Patients may experience one or more side effects that could include: fever and chills; muscle, bone or joint pain; nausea; fatigue; and headache. Most of these side effects are mild to moderate and occur within 3 days after taking ACLASTA. They usually go away within 3 days after they start, but may last for up to 7-14 days. The incidence of post-dose symptoms occurring within the first 3 days after administration of ACLASTA, can be reduced with the administration of acetaminophen or ibuprofen shortly following ACLASTA administration.

  
  

• Some patients experienced hypocalcemia. Hypocalcemia is usually asymptomatic, but symptoms may include numbness or tingling sensations, especially in the area around the mouth, muscle cramps or muscle spasms. Patients should consult their physician immediately if they develop these symptoms of hypocalcemia after ACLASTA treatment (see Adverse Reactions).

  
  

• Redness, swelling and or pain at the infusion site may occur. Redness, itching, or pain to the eyes may occur.

  
  

• There have been some reports of persistent pain and/or a non-healing sore of the mouth or jaw, if you experience these symptoms tell your doctor or dentist.

It is not known whether ACLASTA is excreted in human milk. Because many drugs are excreted in human milk, it should not be administered to a nursing woman.

Overall incidence of atrial fibrillation in the 3-year postmenopausal osteoporosis trial (HORIZON-PFT) using ACLASTA (zoledronic acid) 5 mg dose yearly, was 2.5% (96 out of 3862) and 1.9% (75 out of 3852) in patients receiving zoledronic acid and placebo, respectively. The rate of atrial fibrillation serious adverse events was 1.3% (51 out of 3862) and 0.6% (22 out of 3852) in patients receiving zoledronic acid and placebo, respectively. The overall incidence of atrial fibrillation in the 2-year male osteoporosis trial was 3.3 % (5 out of 153) for zoledronic acid-treated patients compared to 2% (3 out of 148) for alendronate-treated patients. The rate of atrial fibrillation serious adverse events was 0% for zoledronic acid-treated patients compared to 0.7% (1/148) for alendronate-treated patients. The overall incidence of atrial fibrillation in the 1-year glucocorticoid induced-osteoporosis trial was 0.7 % (3 out of 416) for zoledronic acid-treated patients compared to 0.0% (0 out of 417) for risedronate-treated patients. The rate of atrial fibrillation serious adverse events was 0% for zoledronic acid-treated patients and 0% for risedronate-treated patients. This increased incidence of atrial fibrillation was not observed in clinical trials conducted in Paget’s disease or in the HORIZON-RFT trial in post-hip fracture patients. The mechanism behind the increased incidence of atrial fibrillation is unknown.

Single or multiple (q 28 days) 5-minute or 15-minute infusions of 2, 4, 8 or 16 mg zoledronic acid were given to 64 cancer patients. The post-infusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process showing a rapid decrease from peak concentrations at end-of-infusion to <1% of C_max 24 hours post infusion with population half-lives of t_1/2α 0.24 hours and t_1/2β 1.87 hours for the early disposition phases of the drug. The terminal elimination phase of zoledronic acid was prolonged, with very low concentrations in plasma between days 2 and 28 post infusion, and an estimated terminal elimination half-life t_1/2γ of 146 hours. The area under the plasma concentration versus time curve (AUC_0-24h) of zoledronic acid was dose proportional from 2 to 16 mg. The accumulation of zoledronic acid measured over three cycles was low, with mean AUC_0-24h ratios for cycles 2 and 3 versus 1 of 1.13±0.30 and 1.16±0.36, respectively.

In vitro and ex vivo studies showed low affinity of zoledronic acid for the cellular components of human blood. Binding to human plasma proteins was approximately 43-55% at 50 ng/mL, a concentration of zoledronic acid within the range observed after 15 minute infusion of the 5 mg dose. It was only slightly less (about 43%) at 500 ng/mL a concentration of zoledronic acid greater than the expected C_max. Therefore, interactions resulting from displacement of highly protein-bound drugs are unlikely.

Pharmacokinetic data in patients with postmenopausal osteoporosis, osteoporosis and Paget's disease of bone are not available.

Dynamic bone histomorphometry was evaluated in 93 postmenopausal patients with osteoporosis after being treated with 3 annual doses of ACLASTA. These results showed bone of normal quality with no evidence of impaired bone remodeling and no evidence of mineralization defects. Microcomputed tomography analysis demonstrated preservation of trabecular bone architecture in patients treated with ACLASTA compared to placebo. In summary, the bone biopsies and biomarkers indicate ongoing bone remodeling with qualitatively normal bone.

In the osteoporosis treatment trial, the effect of ACLASTA treatment on markers of bone resorption (serum beta-C-telopeptides (b-CTx)) and bone formation (bone specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type I collagen (P1NP)) was evaluated in patients (subsets ranging from 517 to 1246 patients) at periodic intervals. Treatment with a 5 mg annual dose of ACLASTA reduces bone turnover markers to the pre-menopausal range with an approximate 55% reduction in b-CTx, a 29% reduction in BSAP and a 52 % reduction in P1NP over 36 months. There was no progressive reduction of bone turnover markers with repeated annual dosing.

ACLASTA treatment rapidly reduced the rate of bone turnover from elevated postmenopausal levels with the nadir for resorption markers observed at 7 days, and for formation markers at 12 months. Thereafter bone markers stabilized within the pre-menopausal range. There was no progressive reduction of bone turnover markers with repeated annual dosing.

In 64 patients, on average 39±16% (±SD) of the administered zoledronic acid dose was recovered in the urine within 24 hours with only trace amounts of drug found in urine after 48 hours. The cumulative percentage of drug excreted in the urine over 0-24 hours was independent of dose. The balance of drug not recovered in urine over 0-24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0-24 hour renal clearance of zoledronic acid was 3.7±2.0 L/h (±SD).

Zoledronic acid clearance was independent of dose but dependent upon the patient’s creatinine clearance. In a study with patients, increasing the infusion time of a 4 mg dose of zoledronic acid from 5 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the zoledronic acid plasma concentration at the end of the infusion ([mean±SD] 403±118 ng/mL vs 264±86 ng/mL) and a 10% increase in the total AUC (378±116 ng×h/mL vs 420±218 ng×h/mL). The difference between the AUC means was not statistically significant.

Bone biopsy specimens were obtained at month 12 from 23 patients treated with either an annual dose of ACLASTA or daily oral risedronate (12 in the ACLASTA treatment group and 11 in the risedronate treatment group). All biopsies were adequate for qualitative histomorphometry assessment. Qualitative and quantitative assessments showed bone of normal architecture and quality without mineralization defects.

The pharmacokinetics of zoledronic acid were not affected by gender.

In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting bone formation, mineralization or mechanical properties of bone. Histomorphometric data from long-term rat and monkey studies showed the typical response of bone to an anti-resorptive agent with a dose-dependent reduction in osteoclastic activity and in activation frequency of new remodeling sites in both trabecular and haversian bone. Continuing bone remodeling was observed in bone samples from all animals treated with clinically relevant doses of zoledronic acid. There was no evidence of a mineralizing defect, no aberrant accumulation of osteoid, and no woven bone in treated animals.

Zoledronic acid is not metabolized in humans. It was found to have little or no capacity as a direct acting and/or irreversible metabolism-dependent inhibitor of P450 enzymes. Therefore, zoledronic acid is unlikely to reduce the metabolic clearance of substances which are metabolized via the cytochrome P450 enzyme systems. In animal studies, <3% of the administered intravenous dose was found in the feces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney.

Bone histology was evaluated in 7 patients with Paget’s disease 6 months after being treated with ACLASTA. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodeling and no evidence of mineralization defect. These results were consistent with biochemical marker evidence of normalization of bone turnover.

Pharmacokinetic data of zoledronic acid in pediatric patients are not available.

The pharmacokinetics of zoledronic acid were not affected by age in patients who ranged in age from 38 years to 84 years.

No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid. Zoledronic acid does not inhibit human P450 enzymes in vitro, shows no biotransformation, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid and no required dosage adjustment. Following an intravenous dose of 20 nCi 14C-zoledronic acid in a patient with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug was recovered in urine, which suggests that zoledronic acid is not metabolized.

ACLASTA belongs to the class of nitrogen containing bisphosphonates and acts primarily on bone in order to protect the bone against excessive and abnormal osteoclastic and osteoblastic activity. 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, as with other bisphosphonates, localizes preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase (FPP) which is critical for the regulation of a variety of cell processes important for osteoclast function, but this does not exclude other inhibitory mechanisms. In vitro assays have demonstrated that zoledronic acid has the highest potency to inhibit FPP synthase amongst available nitrogen containing bisphosphonates. This higher inhibition of FPP synthase correlated with a greater anti-resorptive potency as observed in vivo in rats. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity for the active site of farnesyl pyrophosphate (FPP) synthase and its strong binding affinity to bone mineral.

The pharmacokinetics of zoledronic acid were not affected by race.

The pharmacokinetic studies conducted in 64 patients represented typical clinical populations with normal to moderately impaired renal function. Compared to patients with normal renal function (creatinine clearance >80 mL/min, N=37), patients with mild renal impairment (creatinine clearance=50 to 80 mL/min, N=15) showed an average increase in plasma AUC of 15%, whereas patients with moderate renal impairment (creatinine clearance=30 to 50 mL/min, N=11) showed an average increase in plasma AUC of 43%. No dosage adjustment is required in patients with a creatinine clearance of ≥30 mL/min. Based on population PK/PD modeling, the risk of renal deterioration appears to increase with AUC, the risk is doubled at a creatinine clearance of 10 mL/min. Zoledronic acid is not recommended for patients with severe renal impairment (creatinine clearance <30 mL/min) due to lack of adequate clinical experience in this population (see Warnings and Precautions).