治疗转移性骨癌新药Zometa

    美国食品及药物管理局FDA最近批准，瑞士Novartis AG生产的注射药Zometa可以用于治疗因多种癌症转移而致的骨癌，包括前列腺癌、乳癌、肺癌和其它实质性癌症，并且还可以用于多发性骨髓瘤的辅助治疗。去年八月这种属名为zoledronic acid的药物就已经获准用于治疗肿瘤诱发的高钙血症TIH，这种血钙含量的异常升高通常会导致骨癌。FDA是根据三项国际临床实验结果而做出上述批准的，这些研究全面评估了该药用于治疗3,000多例各种癌症患者的疗效，结果证实它确实能够有效缓解这些与骨骼有关的恶性肿瘤症状。但专家们也警告说，由于Zometa属于二磷酸盐类化合物，其副作用可能会包括某些肾功能异常如衰竭和贫血等，因而肾病患者在接受治疗前需要进行肾功能测试以确保安全。

Zometa 英文说明书
Zometa vial
Description
Each vial contains zoledronic acid monohydrate 4.264 mg corresponding to zoledronic acid 4 mg on an anhydrous basis. It also contains mannitol USP 220 mg and sodium citrate USP 24 mg as other excipients.
Zoledronic acid is 1-Hydroxy-2-imidazol-1-yl-phosphonoethyl phosphoric acid monohydrate. It is a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Its molecular formula is C5H10N2O7P2-H2O and its molecular mass is 290.1 g/mole.
Zoledronic acid is highly soluble in 0.1 N sodium hydroxide solution, sparingly soluble in water and 0.1 N hydrochloric acid, and practically insoluble in organic solvents. The pH of a 0.7% solution of zoledronic acid in water is approximately 2.
Actions
Pharmacology: General: The principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone.
Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.
Pharmacodynamics: Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of Zometa are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion.
Hypercalcemia of Malignancy: Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease. Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy.
Patients who have hypercalcemia of malignancy can generally be divided into 2 groups according to the pathophysiologic mechanism involved: Humoral hypercalcemia and hypercalcemia due to tumor invasion of bone. In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors, eg parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous cell malignancies of the lung or head and neck or in genitourinary tumors, eg renal cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma.
Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for differences in albumin levels (corrected serum calcium, CSC) is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation (see Dosage & Administration).
Clinical Trials in Hypercalcemia of Malignancy: Two identical multicenter, randomized, double-blind, double-dummy studies of Zometa 4 mg given as a 5-min IV infusion or pamidronate 90 mg given as a 2-hr IV infusion were conducted in 185 patients with hypercalcemia of malignancy (HCM).
Note: Administration of Zometa 4 mg given as a 5-min IV infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-min IV infusion. Zometa should be administered by IV infusion over no less than 15 min. (See Warnings and Dosage & Administration.)
The treatment groups in the clinical studies were generally well balanced with regards to age, sex, race and tumor types. The mean age of the study population was 59 years; 81% were Caucasian, 15% were Black and 4% were of other races. Sixty percent of the patients were male. The most common tumor types were lung, breast, head and neck, and renal.
In these studies, HCM was defined as a corrected serum calcium (CSC) concentration of ³12 mg/dL (3 mmol/L). The primary efficacy variable was the proportion of patients having a complete response, defined as the lowering of the CSC to £10.8 mg/dL (2.7 mmol/L) within 10 days after drug infusion.
To assess the effects of Zometa versus those of pamidronate, the 2 multicenter HCM studies were combined in a pre-planned analysis. The results of the primary analysis revealed that the proportion of patients that had normalization of corrected serum calcium by Day 10 were 88% and 70% for Zometa 4 mg and pamidronate 90 mg, respectively (p=0.002). In these studies, no additional benefit was seen for Zometa 8 mg over Zometa 4 mg; however, the risk of renal toxicity of Zometa 8 mg was significantly greater than that seen with Zometa 4 mg.
Secondary efficacy variables from the pooled HCM studies included the proportion of patients who had normalization of corrected serum calcium (CSC) by Day 4; the proportion of patients who had normalization of CSC by Day 7; time to relapse the HCM; and duration of complete response. Time to relapse of HCM was defined as the duration (in days) of normalization of serum calcium from study drug infusion until the last CSC value <11.6 mg/dL (<2.9 mmol/L). Patients who did not have a complete response were assigned a time to relapse of 0 days. Duration of complete response was defined as the duration (in days) from the occurrence of a complete response until the last CSC £10.8 mg/dL (2.7 mmol/L). The results of these secondary analyses for Zometa 4 mg and pamidronate 90 mg are shown in Table 1. (See Table 1.)
Clinical Trials in Multiple Myeloma and Bone Metastases of Solid Tumors: Table 2 describes 3 randomized Zometa trials in patients with multiple myeloma and bone metastases of solid tumors. These include a pamidronate-controlled study in breast cancer and multiple myeloma, a placebo-controlled study in a prostate cancer and a placebo-controlled study in other solid tumors. The prostate cancer study required documentation of previous bone metastases and 3 consecutive rising PSAs while on hormonal therapy. The other placebo-controlled solid tumor study included patients with bone metastases from malignancies other than breast cancer and prostate cancer, listed in Table 3. (See Tables 2 and 3.)
The planned duration of therapy was 12 months for multiple myeloma and breast cancer, 15 months for prostate cancer and 9 months for other solid tumors.
The studies were amended twice because of renal toxicity. The Zometa infusion duration was increased from 5-15 min. After all patients had been accrued, but while dosing and follow-up continued, patients in the 8-mg Zometa treatment arm were switched to 4 mg. Patients who were randomized to the Zometa 8-mg group are not included in these analyses.
Each study evaluated skeletal-related events (SREs), defined as any of the following: Pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Change in antineoplastic therapy due to increased pain was a SRE in the prostate cancer study only. Planned analyses included the proportion of patients with a SRE during the study (the primary endpoint) and time to first SRE. Results for the 2 Zometa placebo-controlled studies are given in Table 4. (See Table 4.)
In the breast cancer and myeloma trial, efficacy was determined by a non-inferiority analysis comparing Zometa to pamidronate 90 mg for the proportion of patients with a SRE. This analysis required an estimation of pamidronate efficacy. Historical data from 1128 patients in 3 pamidronate placebo-controlled trials demonstrated that pamidronate decreased the proportion of patients with a SRE by 13.1% (95% Cl=73%, 18.9%). Results of the comparison of treatment with Zometa compared to pamidronate are given in Table 5. (See Table 5.)
Pharmacokinetics: Single or multiple (every 28 days) 5- or 15-min infusions of 2, 4, 8 or 16 mg Zometa were given to 64 patients with cancer and bone metastases. 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 Cmax 24 hrs post-infusion with population half-lives of t½a 24 hrs and t½b 1.87 hrs 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 a terminal elimination half-life t½g of 146 hrs. The area under the plasma concentration versus time curve (AUC0-24 hr) of zoledronic acid was dose proportional from 2-16 mg. The accumulation of zoledronic acid measured over 3 cycles was low, with mean AUC0-24 hrs ratios for cycles 2 and 3 versus 1 of 1.13 ± 0.3 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 22% and was independent of the concentration of zoledronic acid.
Metabolism: Zoledronic acid does not inhibit human P-450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, <3% of the administered IV 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. Following an IV 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.
Excretion: In 64 patients with cancer and bone metastases on average (±SD) 39±16% of the administered zoledronic acid dose was recovered in the urine within 24 hrs, with only trace amount of drug found in urine post-day 2. The cumulative percent of drug excreted in the urine over 0-24 hrs was independent of dose. The balance of drug not recovered in urine over 0-24 hrs, 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 hr renal clearance of zoledronic acid was 3.7±2 L/hr.
Zoledronic acid clearance was independent of dose but dependent upon the patient’s creatinine clearance. In a study in patients with cancer and bone metastases, increasing the infusion time of a 4-mg dose of zoledronic acid from 5 min (n=5) to 15 min (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion ( 403±118 ng/mL vs 264±86 ng/mL) and a 10% increase in the total AUC (378±116 ng·hr/mL vs 420±218 ng·hr/mL). The difference between the AUC means was not statistically significant.
Special Populations: Pharmacokinetic data in patients with hypercalcemia are not available.
Pediatrics: Pharmacokinetic data in pediatric patients are not available.
Geriatrics: The pharmacokinetics of zoledronic acid were not affected by age in patients with cancer and bone metastases who ranged in age 38-84 years.
Race: The pharmacokinetics of zoledronic acid were not affected by race in patients with cancer and bone metastases.
Hepatic Insufficiency: No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid.
Renal Insufficiency: The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately impaired renal function. Compared to patients with normal renal function (N=37), patients with mild renal impairment (N=15) showed an average increase in plasma AUC of 15%, whereas patients with moderate renal impairment (N=11) showed an average increase in plasma AUC of 43%.
Limited pharmacokinetic data are available for Zometa in patients with severe renal impairment (creatinine clearance <30 mL/min). Based on population PK/PD modeling, the risk of renal deterioration appears to increase with AUC, which is doubled at a creatinine clearance of 10 mL/min.
Creatinine clearance is calculated by the Cockcroft-Gault formula . Zometa systemic clearance in individual patients can be calculated from the population clearance of Zometa, Cl (L/hr)=6.5(ClCr/90)0.4. These formulae can be used to predict the Zometa AUC in patients. Cl = Dose/AUC. The average AUC in patients with normal renal function was 0.42 mg·hr/L (%CV 33) following a 4-mg dose of Zometa. However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed. (See Warnings.)
Indications
Hypercalcemia of Malignancy: Treatment of hypercalcemia of malignancy.
Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (ie, saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established.
Multiple Myeloma and Bone Metastases of Solid Tumors: Treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least 1 hormonal therapy.
Dosage
Hypercalcemia of Malignancy: Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zometa. Vigorous saline hydration alone may be sufficient to treat mild asymptomatic hypercalcemia. The maximum recommended dose of Zometa in hypercalcemia of malignancy (albumin-corrected serum calcium* ³12 mg/dL <3 mmol/L>) is 4 mg. The 4-mg dose must be given as a single-dose IV infusion over no less than 15 min. Patients should be adequately rehydrated prior to administration of Zometa. (See Warnings and Precautions.)
Re-treatment with Zometa 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before re-treatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zometa and possible deterioration in renal function must be assessed prior to re-treatment with Zometa. (See Warnings and Precautions.)
*Albumin-corrected serum calcium (CCa, mg/dL)= Ca + 0.8 (mid-range albumin-measured albumin in mg/dL).
Multiple Myeloma and Metastatic Bone Lesions from Solid Tumors: Recommended Dose: 4 mg infused over 15 min every 3 or 4 weeks. Duration of treatment in the clinical studies was 15 months for prostate cancer, 12 months for breast cancer and multiple myeloma, and 9 months for other solid tumors. Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 iu of vitamin D daily.
Serum creatinine should be measured before each Zometa dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:
For patients with normal baseline creatinine, increase of 0.5 mg/dL.
For patients with abnormal baseline creatinine, increase of 1 mg/dL.
In the clinical studies, Zometa treatment was resumed only when the creatinine returned to within 10% of the baseline value.
Preparation of Solution: Zometa is reconstituted by adding 5 mL of Sterile Water for Injection USP to each vial. The resulting solution allows for withdrawal of 4 mg of zoledronic acid. The drug must be completely dissolved before the solution is withdrawn.
The maximum recommended 4-mg dose must be further diluted in 100 mL of sterile 0.9% Sodium Chloride USP or 5% Dextrose Injection USP. The dose must be given as a single IV infusion over no less than 15 min.
If not used immediately after reconstitution, for microbiological integrity, the solution should be refrigerated at 36-46°F (2-8°C). The total time between reconstitution, dilution, storage in the refrigerator, and end of administration must not exceed 24 hrs.
Zometa must not be mixed with calcium-containing infusion solutions eg, Lactated Ringer’s solution, and should be administered as a single IV solution in a line separate from all other drugs.
Method of Administration: Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zometa should not exceed 4 mg and the duration of infusion should be no less than 15 min. (see Warnings.)
There must be strict adherence to the IV administration recommendations for Zometa in order to decrease the risk of deterioration in renal function.
Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Overdosage
There is no experience of acute overdose with Zometa. Two patients received Zometa 32 mg over 5 min in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus and magnesium should be corrected by IV administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.
In controlled clinical trials, administration of Zometa 4 mg as an IV infusion over 5 min has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-min IV infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-min IV infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy. Single doses of Zometa should not exceed 4 mg and the duration of the IV infusion should be no less than 15 min. (See Warnings.)
Contraindication
Patients with clinically significant hypersensitivity to zoledronic acid or other bisphosphonates, or any of the excipients of Zometa.
Warning
Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zometa should not exceed 4 mg and the duration of infusion should be no less than 15 min.
Because safety and pharmacokinetic data are limited in patients with severe renal impairment:
Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine >3 mg/dL were excluded; Zometa treatment in patients with hypercalcemia of malignancy should be considered only after evaluating the risks and benefits of treatment. In clinical studies, patients with serum creatinine >400 micromole/L or >4.5 mg/dL were excluded.
Bisphosphonates, including Zometa, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. In clinical trials, the risk for renal function deterioration (defined as an increase in serum creatinine) was significantly increased in patients who received Zometa over 5 min compared to patients who received the same dose over 15 min. In addition, the risk for renal function deterioration and renal failure was significantly increased in patients who received Zometa 8 mg, even when given over 15 min. While this risk is reduced with the Zometa 4-mg dose administered over 15 min, deterioration in renal function can still occur. Risk factors for this deterioration include elevated baseline creatinine and multiple cycles of treatment with the bisphosphonate.
Patients who receive Zometa should have serum creatinine assessed prior to each treatment. Patients treated with Zometa for bone metastases should have the dose withheld if renal function has deteriorated. (See Dosage & Administration.) Patients with hypercalcemia of malignancy with evidence of deterioration in renal function should be appropriately evaluated as to whether the potential benefit of continued treatment with Zometa outweighs the possible risk.
Pregnancy: Zometa should not be used during pregnancy. Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in the pregnant rat, SC doses equivalent to 2.4 or 4.8 times the human systemic exposure (an IV dose of 4 mg based on an AUC comparison) resulted in pre- and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral and external malformations (see Use in pregnancy under Precautions).
There are no studies in pregnant women using Zometa. 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.
Precautions
General: Standard hypercalcemia-related metabolic parameters, eg serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary.
Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs.
Renal Insufficiency: Limited clinical data are available regarding use of Zometa in patients with renal impairment. Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Serum creatinine should be monitored in all patients treated with Zometa prior to each dose.
Studies of Zometa in the treatment of hypercalcemia of malignancy excluded patients with serum creatinine ³400 micromole/L or ³4.5 mg/dL. Bone metastases trials excluded patients with serum creatinine >265 micromole/L or >3 mg/dL. No clinical or pharmacokinetics data are available to guide dose selection or to provide guidance on how to safely use Zometa in patients with severe renal impairment. For hypercalcemia of malignancy, Zometa should be used in patients with severe renal impairment only if the expected clinical benefits outweigh the risk of renal failure and after considering other available treatment options. (See Warnings.) Dose adjustments of Zometa are not necessary in treating patients for hypercalcemia presenting with mild to moderate renal impairment prior to initiation of therapy (serum creatinine <400 micromole/L or <4.5 mg/dL). For bone metastases, the use of Zometa in patients with severe renal impairment is not recommended. In studies of patients with bone metastases, patients with a serum creatinine >3 mg/dL were excluded.
Patients receiving Zometa for hypercalcemia of malignancy with evidence of deterioration in renal function with Zometa treatment should be appropriately evaluated and consideration should be given as to whether the potential benefit of continued treatment with Zometa outweighs the possible risk. In patients receiving Zometa for bone metastases, who show evidence of deterioration in renal function should be withheld until renal function returns to baseline. (See Warnings and Dosage & Administration.)
Hepatic Insufficiency: Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients.
Patients with Asthma: While not observed in clinical trials with Zometa, administration of other biphosphonates has been associated with bronchoconstriction in aspirin-sensitive asthmatic patients. Zometa should be used with caution in patients with aspirin-sensitive asthma.
Laboratory Tests: Serum creatinine should be monitored prior to each dose of Zometa. Serum calcium, electrolytes, phosphate, magnesium and hematocrit/hemoglobin should also be monitored regularly. (See Warnings, Dosage & Administration and Adverse Reactions.)
Carcinogenicity: Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice given oral doses of zoledronic acid of 0.1, 0.5 or 2 mg/kg/day. There was an increased incidence of Harderian gland adenomas in males and females in all treatment groups (at doses ³0.002 times a human IV dose of 4 mg, based on a comparison of relative body surface areas). Rats were given oral doses of zoledronic acid of 0.1, 0.5 or 2 mg/kg/day. No increased incidence of tumors was observed (at doses £0.2 times the human IV dose of 4 mg, based on a comparison of relative body surface areas).
Mutagenicity: 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 SC doses of zoledronic acid of 0.01, 0.03 or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation. Effects observed in the high-dose group (with systemic exposure of 1.2 times the human systemic exposure following an IV dose of 4 mg, based on AUC comparison) included inhibition of ovulation and a decrease in the number of pregnant rats. Effects observed in both the mid-dose group (with systemic exposure of 0.2 times the human systemic exposure following an IV dose of 4 mg, based on an AUC comparison) and high-dose group increase in pre-implantation losses and a decrease in the number of implantations and live fetuses.
Use in pregnancy: Pregnancy Category D: In female rats given SC doses of zoledronic acid of 0.01, 0.03 or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (³0.2 times the human systemic exposure following an IV dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups with a systemic exposure of ³0.07 times the human systemic exposure following an IV dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been 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 a SC dose of zoledronic acid of 0.1, 0.2 or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an IV dose of 4 mg, 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. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate and edema. Skeletal variations were also observed in the loux%oose group (with systemic exposure of 1.2 times the human systemic exposure following an IV dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study.
In pregnant rabbits given SC doses of zoledronic acid of 0.01, 0.03 or 0.1 mg/kg/day during gestation (£0.5 times the human IV dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ³0.05 times the human IV dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.
Use in lactation: It is not known whether Zometa is excreted in human milk. Because many drugs are excreted in human milk and because Zometa binds to bone long-term, Zometa should not be administered to a nursing woman.
Use in children: The safety and effectiveness of Zometa in pediatric patients have not been established. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk.
Use in the elderly: Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were ³65 years. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients >65 years revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.
Adverse Reactions
Hypercalcemia of Malignancy: Adverse reactions to Zometa are usually mild and transient and similar to those reported for other bisphosphonates. IV administration has been most commonly associated with fever. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, bone pain and/or arthralgias, and myalgias. Gastrointestinal reactions, eg nausea and vomiting have been reported following IV infusion of Zometa. Local reactions at the infusion site, eg redness or swelling, were also observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hrs. Rare cases of rash, pruritus and chest pain have been reported following treatment with Zometa.
As with other biphosphonates, cases of conjunctivitis and hypomagnesemia have been reported following treatment with Zometa. Grades 3 and 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus and serum magnesium observed in 2 clinical trials of Zometa in patients with HCM are shown in Table 6. (See Table 6.)
Table 7 provides adverse events that were reported by ³10% of the 189 patients treated with Zometa 4 mg or pamidronate 90 mg from the 2 controlled multicenter HCM trials. Adverse events are listed regardless of presumed causality to study drug. (See Table 7.)
The following adverse events from the 2 controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of ³5% but <10%. Adverse events are listed regardless of presumed causality to study drug.
Body as a Whole: Asthenia, chest pain, leg edema, mucositis, metastases.
Digestive System: Dysphagia.
Hemic and Lymphatic System: Granulocytopenia, thrombocytopenia, pancytopenia.
Infection: Non-specific infection.
Laboratory Abnormalities: Hypocalcemia.
Metabolic and Nutritional: Dehydration.
Musculoskeletal: Arthralgias.
Nervous System: Headache, somnolence.
Respiratory System: Pleural effusion.
Note: In the HCM clinical trials, pamidronate 90 mg was given as a 2-hr IV infusion. The relative safety of pamidronate 90 mg given as a 2-hr IV infusion compared to the same dose given as a 24-hr IV infusion has not been adequately studied in controlled clinical trials.
Multiple Myeloma and Bone Metastases of Solid Tumors: Table 8 provides adverse events that were reported by ³10% of the 2185 patients treated with Zometa 4 mg, pamidronate 90 mg or placebo from the 4 controlled multicenter bone metastases trials. Adverse events are listed regardless of presumed causality to study drug. (See Table 8.)
Grades 3 and 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus and serum magnesium observed in 4 clinical trials of Zometa in patients with bone metastases are shown in Tables 9 and 10. (See Tables 9 and 10.)
Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenza-like illness and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group.
Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 13% of patients in the Zometa 4 mg compared with 7.1% in the pamidronate group. The incidence of decreased weight, however, was similar for the placebo group (12.5%) and Zometa. Decreased appetite was reported in slightly more patients in the Zometa 4 mg (10.8%) compared with the pamidronate (7.3%) and placebo (8.6%) groups, but the clinical significance of these small differences is not clear.
Renal Toxicity: In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1 mg/dL for patients with an abnormal baseline creatinine (³1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 min in these trials. (See Table 11.)
The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 min), placebo or pamidronate.
Drug Interaction
In vitro studies indicate that zoledronic acid is approximately 56% bound to plasma proteins. In vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP-450 enzymes. In vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. However, no in vivo drug interaction studies have been performed.
Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This has not been reported in Zometa clinical trials. Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia. Caution is indicated when Zometa is used with other potentially nephrotoxic drugs.
In multiple myeloma patients, the risk of renal dysfunction may be increased when Zometa is used in combination with thalidomide.
Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).