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The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.
1.1 Hypercalcemia Of Malignancy
Zoledronic acid injection is indicated for the treatment of hypercalcemia of malignancy defined as an albumin‑corrected calcium (cCa) of greater than or equal to 12 mg/dL [3 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4 g/dL - patient albumin (g/dL)).
1.2 Multiple Myeloma And Bone Metastases Of Solid Tumors
Zoledronic acid injection is indicated for the 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 one hormonal therapy.
1.3 Important Limitation Of Use
The safety and efficacy of zoledronic acid injection in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions have not been established.
2 Dosage And Administration
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
2.1 Hypercalcemia Of Malignancy
The maximum recommended dose of zoledronic acid in hypercalcemia of malignancy (albumin‑corrected serum calcium greater than or equal to 12 mg/dL [3 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid should have serum creatinine assessed prior to each treatment. Dose adjustments of zoledronic acid are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 mcmol/L or less than 4.5 mg/dL). Patients should be adequately rehydrated prior to administration of zoledronic acid [see Warnings and Precautions (5.2)]. Consideration should be given to the severity of, as well as the symptoms of, tumor‑induced hypercalcemia when considering use of zoledronic acid. 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 (i.e., 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. Retreatment with zoledronic acid 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 retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid and serum creatinine must be assessed prior to retreatment with zoledronic acid [see Warnings and Precautions (5.2)].
2.2 Multiple Myeloma And Metastatic Bone Lesions Of Solid Tumors
The recommended dose of zoledronic acid in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known. Upon treatment initiation, the recommended zoledronic acid doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].Table 1: Reduced Doses for Patients with Baseline CrCl Less than or Equal to 60 mL/minBaseline Creatinine Clearance (mL/min) Zoledronic Acid Injection Recommended Dose* greater than 6050 to 6040 to 4930 to 394 mg3.5 mg3.3 mg3 mg * Doses calculated assuming target AUC of 0.66 (mg•hr/L) (CrCl = 75 mL/min)During treatment, serum creatinine should be measured before each zoledronic acid 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, zoledronic acid treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid should be reinitiated at the same dose as that prior to treatment interruption. Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily.
2.3 Preparation Of Solution
Zoledronic acid must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs. 4 mg/5 mL Single-Dose VialVials of zoledronic acid concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid concentrate from the vial for the dose required (see Table 3).Table 3: Preparation of Reduced Doses - Zoledronic Acid Injection ConcentrateRemove and Use Zoledronic Acid Injection Volume (mL) Dose (mg)220.127.116.11.53.33The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2° to 8°C (36° to 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.
2.4 Method Of Administration
Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in post marketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid dose.
3 Dosage Forms And Strengths
4 mg/5 mL single-dose vial of concentrate
Hypersensitivity to Zoledronic Acid or Any Components of Zoledronic Acid InjectionHypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2)].
5.1 Drugs With Same Active Ingredient Or In The Same Drug Class
Zoledronic acid contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with zoledronic acid should not be treated with Reclast or other bisphosphonates.
5.2 Hydration And Electrolyte Monitoring
Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of zoledronic acid. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with zoledronic acid in order to avoid hypocalcemia. Zoledronic acid should be used with caution with other nephrotoxic drugs. Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with zoledronic acid. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short‑term supplemental therapy may be necessary.
5.3 Renal Impairment
Zoledronic acid 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. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1)]. Preexisting renal insufficiency and multiple cycles of zoledronic acid and other bisphosphonates are risk factors for subsequent renal deterioration with zoledronic acid. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. Zoledronic acid treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. [see Dosage and Administration (2.1)]. In the clinical studies, patients with serum creatinine greater than 400 mcmol/L or greater than 4.5 mg/dL were excluded. Zoledronic acid treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine greater than 265 mcmol/L or greater than 3 mg/dL were excluded and there were only 8 of 564 patients treated with zoledronic acid 4 mg by 15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance less than 30 mL/min [see Clinical Pharmacology (12.3)].
5.4 Osteonecrosis Of The Jaw
Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. The risk of ONJ may increase with duration of exposure to bisphosphonates. Post marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients 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. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)].
5.5 Musculoskeletal Pain
In post marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been 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. Discontinue use 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)].
5.6 Atypical Subtrochanteric And Diaphyseal Femoral Fractures
Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including zoledronic acid. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of zoledronic acid therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.
5.7 Patients With Asthma
While not observed in clinical trials with zoledronic acid, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates.
5.8 Hepatic Impairment
Only limited clinical data are available for use of zoledronic acid 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 zoledronic acid in these patients.
5.9 Use In Pregnancy
Bisphosphonates, such as zoledronic acid, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Zoledronic acid may cause fetal harm when administered to a pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre- and post‑implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
Hypocalcemia has been reported in patients treated with zoledronic acid. Cardiac arrhythmias and neurologic adverse events (seizures, tetany, and numbness) have been reported secondary to cases of severe hypocalcemia. In some instances, hypocalcemia may be life-threatening. Caution is advised when zoledronic acid is administered with drugs known to cause hypocalcemia, as severe hypocalcemia may develop, [see Drug Interactions (7)]. Serum calcium should be measured and hypocalcemia must be corrected before initiating zoledronic acid. Adequately supplement patients with calcium and vitamin D.
6.1 Clinical Studies 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.Hypercalcemia of MalignancyThe safety of zoledronic acid was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either zoledronic acid 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33 to 84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials. Renal ToxicityAdministration of zoledronic acid 4 mg given as a 5-minute intravenous 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 zoledronic acid 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid should be administered by intravenous infusion over no less than 15 minutes [see Warnings and Precautions (5.3) and Dosage and Administration (2.4)]. The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 4).Table 4 provides adverse events that were reported by 10% or more of the 189 patients treated with zoledronic acid 4 mg or pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug.Table 4: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System Zoledronic Acid Injection4 mgn (%) Pamidronate90 mgn (%)Patients Studied Total No. of Patients Studied Total No. of Patients with any AE8681(100)(94)10395(100)(92) Body as a Whole Fever Progression of Cancer3814(44)(16) 3421(33)(20)Cardiovascular Hypotension 9(11) 2(2)Digestive Nausea Constipation Diarrhea Abdominal Pain Vomitting Anorexia25231514128(29)(27)(17)(16)(14)(9) 281317131714(27)(13)(17)(13)(17)(14)Hemic and Lymphatic System Anemia 19(22)18 (18) Infections Moniliasis 10(12)4 (4)Laboratory Abnormalities Hypophosphatemia Hypokalemia Hypomagnesemia11109(13)(12)(11)2165(2)(16)(5)Musculoskeletal Skeletal Pain10(12)10(10)Nervous Insomnia Anxiety Confusion Agitation13121111(15)(14)(13)(13)108138(10)(8)(13)(8)Respiratory Dyspnea Coughing1910(22)(12) 2012(19)(12)Urogenital Urinary Tract Infection 12(14)15(15)The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with zoledronic acid 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment with zoledronic acid. Acute Phase ReactionWithin three days after zoledronic acid administration, an acute phase reaction has been reported in patients, with symptoms including pyrexia, fatigue, bone pain and/or arthralgias, myalgias, chills, and influenza-like illness. These symptoms usually resolve within a few days. Pyrexia has been the most commonly associated symptom, occurring in 44% of patients.Mineral and Electrolyte AbnormalitiesElectrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of zoledronic acid in patients with HCM are shown in Table 5 and 6.Table 5: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCMGrade 3 Laboratory Parameter Zoledronic Acid Injection4 mgPamidronate90 mg n/N (%) n/N (%)Serum Creatinine 1Hypocalcemia 2Hypophosphatemia 3Hypomagnesemia 42/861/8636/700/71 (2%)(1%)(51%)—3/1002/10027/810/84 (3%)(2%)(33%)—Table 6: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 4 Laboratory Parameter Zoledronic Acid Injection4 mg Pamidronate90 mg n/N(%) n/N (%)Serum Creatinine 1Hypocalcemia 2Hypophosphatemia 3Hypomagnesemia 40/860/861/700/71——(1%)— 1/1000/1004/811/84 (1%)—(5%)(1%)1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal)2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)4 Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L)Injection Site ReactionsLocal reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24 to 48 hours. Ocular Adverse EventsOcular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including zoledronic acid. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in post-marketing use [see Adverse Reactions (6.2)]. Multiple Myeloma and Bone Metastases of Solid TumorsThe safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2042 patients treated with zoledronic acid 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for zoledronic acid 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4 months for other solid tumors. Table 7 describes adverse events that were reported by 10% or more of patients. Adverse events are listed regardless of presumed causality to study drug.Table 7: Percentage of Patients with Adverse Events ≥ 10% Reported in Three Bone Metastases Clinical Trials by Body System Zoledronic Acid Injection4 mgPamidronate90 mgPlacebo n(%)n(%)n(%)Patients Studied Total No. of Patients Total No. of Patients with any AE10311015(100)(98)556548(100)(99)455445(100)(98)Blood and Lymphatic Anemia Neutropenia Thrombocytopenia344124102(33)(12)(10)1758353(32)(15)(10)1283520(28)(8)(4)Gastrointestinal Nausea Vomiting Constipation Diarrhea Abdominal Pain Dyspepsia Stomatitis Sore Throat4763333202491431058682(46)(32)(31)(24)(14)(10)(8)(8)26618316216281746561(48)(33)(29)(29)(15)(13)(12)(11)1711221748348311417(38)(27)(38)(18)(11)(7)(3)(4)General Disorders and Administration Site Fatigue Pyrexia Weakness Edema Lower Limb Rigors398328252215112(39)(32)(24)(21)(11)24017210812662(43)(31)(19)(23)(11)130891148428(29)(20)(25)(19)(6)Infections Urinary Tract InfectionUpper Respiratory Tract Infection124101(12)(10)5082(9)(15)4130(9)(7)Metabolism AnorexiaWeight DecreasedDehydrationAppetite Decreased231164145130(22)(16)(14)(13)81506048(15)(9)(11)(9)105615945(23)(13)(13)(10)Musculoskeletal Bone PainMyalgiaArthralgiaBack PainPain in Limb569239216156143(55)(23)(21)(15)(14) 31614313110684(57)(26)(24)(19)(15)28474734052(62)(16)(16)(9)(11)Neoplasms Malignant Neoplasm Aggravated 205 (20) 97 (17) 89 (20)Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia191180166149127(19)(18)(16)(15)(12)149911118565(27)(16)(20)(15)(12)5058733543(11)(13)(16)(8)(10)Psychiatric Depression Anxiety Confusion14611274(14)(11)(7)957339(17)(13)(7) 493747(11)(8)(10)Respiratory Dyspnea Cough282224(27)(22)155129(28)(23)10765(24)(14)Skin AlopeciaDermatitis125114(12)(11)8074(14)(13)3638(8)(8)Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of zoledronic acid in patients with bone metastases are shown in Tables 8 and 9.Table 8: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone MetastasesGrade 3Laboratory ParameterZoledronic Acid Injection4 mgPamidronate 90 mgPlacebo n/N(%)n/N(%) n/N(%) Serum Creatinine1*Hypocalcemia2Hypophosphatemia3Hypermagnesemia4Hypomagnesemia57/5296/973115/97319/9711/971(1%)(<1%)(12%)(2%)(<1%)4/2684/53638/5372/5350/535(2%)(<1%)(7%)(<1%)—4/2410/41514/4158/4151/415(2%)—(3%)(2%)(<1%)1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal)* Serum creatinine data for all patients randomized after the 15-minute infusion amendment2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)4 Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L)5 Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)Table 9: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 4Laboratory ParameterZoledronic Acid Injection4 mgPamidronate 90 mgPlacebo n/N(%)n/N(%) n/N(%) Serum Creatinine1*Hypocalcemia2Hypophosphatemia3Hypermagnesemia4Hypomagnesemia52/5297/9735/9730/9712/971(<1%)(<1%)(<1%)—(<1%)1/2683/5360/5370/5351/535(<1%)(<1%)——(<1%)0/2412/4151/4152/4150/415—(<1%)(<1%)(<1%)—1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal)* Serum creatinine data for all patients randomized after the 15-minute infusion amendment2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)4 Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L)5 Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)Among the less frequently occurring adverse events (less than 15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (zoledronic acid 4 mg and pamidronate groups) compared to the placebo group. Less common adverse events reported more often with zoledronic acid 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the zoledronic acid 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the zoledronic acid 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear. Renal ToxicityIn the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (less than 1.4 mg/dL) or an increase of 1 mg/dL for patients with an abnormal baseline creatinine (greater than or equal to 1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving zoledronic acid 4 mg over 15 minutes in these trials (see Table 10).Table 10: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine*Patient Population/Baseline Creatinine Multiple Myeloma and Breast CancerZoledronic Acid Injection4 mgPamidronate90 mg n/N (%)n/N (%)NormalAbnormalTotal27/2462/2629/272(11%)(8%)(11%) 23/2462/2225/268 (9%)(9%)(9%)Solid TumorsZoledronic Acid Injection4 mgPlacebo n/N (%) n/N (%)NormalAbnormalTotal17/1541/1118/165 (11%)(9%)(11%)10/1431/2011/163(7%)(5%)(7%)Prostate Cancer Zoledronic Acid Injection4 mgPlacebo n/N (%) n/N (%)NormalAbnormalTotal12/824/1016/92 (15%)(40%)(17%) 8/682/1010/78(12%)(20%)(13%) * Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of zoledronic acid to 15 minutes.The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving zoledronic acid (4 mg over 15 minutes), placebo, or pamidronate. In the trials and in post marketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial zoledronic acid dose.
6.2 Post Marketing Experience
The following adverse reactions have been reported during post-approval use of zoledronic acid. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Osteonecrosis of the JawCases of osteonecrosis (primarily involving the jaw but also of other anatomical sites including hip, femur and external auditory canal)have been reported predominantly in cancer patients treated with intravenous bisphosphonates including zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Caution is advised when zoledronic acid is administered with anti-angiogenic drugs as an increased incidence of ONJ has been observed with concomitant use of these drugs. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings and Precautions (5.4)]. Acute Phase ReactionWithin three days after zoledronic acid administration, an acute phase reaction has been reported, with symptoms including pyrexia, fatigue, bone pain and/or arthralgias, myalgias, chills, influenza-like illness and arthritis with subsequent joint swelling; these symptoms usually resolve within three days of onset, but resolution could take up to 7 to 14 days. However, some of these symptoms have been reported to persist for a longer duration.Musculoskeletal PainSevere and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings and Precautions (5.5)]. Atypical Subtrochanteric and Diaphyseal Femoral FracturesAtypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including zoledronic acid [see Warnings and Precautions (5.6)]. Ocular Adverse EventsCases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during post marketing use. In some cases, symptoms resolved with topical steroids. Hypersensitivity ReactionsThere have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported. Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported.Additional adverse reactions reported in post marketing use include:CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; uveitis; Gastrointestinal: dry mouth; Skin: Increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchospasms, interstitial lung disease (ILD) with positive re-challenge; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities: hyperkalemia, hypernatremia, hypocalcemia (cardiac arrhythmias and neurologic adverse events including seizures, tetany, and numbness have been reported due to severe hypocalcemia).
7 Drug Interactions
In vitro studies indicate that the plasma protein binding of zoledronic acid is low, with the unbound fraction ranging from 60 to 77%. In vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug.
7.1 Aminoglycosides And Calcitonin
Caution is advised when bisphosphonates are administered with aminoglycosides or calcitonin, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in zoledronic acid clinical trials.
7.2 Loop Diuretics
Caution should also be exercised when zoledronic acid is used in combination with loop diuretics due to an increased risk of hypocalcemia.
7.3 Nephrotoxic Drugs
Caution is indicated when zoledronic acid is used with other potentially nephrotoxic drugs.
No dose adjustment for zoledronic acid 4 mg is needed when co-administered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, zoledronic acid 4 mg given as a 15-minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1 to 14 and 200 mg once daily on days 15 to 28). Co‑administration of thalidomide with zoledronic acid did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance.
Pregnancy Category D [see Warnings and Precautions (5.9)] There are no adequate and well-controlled studies of zoledronic acid in pregnant women. Zoledronic acid may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as zoledronic acid, are incorporated into the bone matrix and 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, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. If this drug is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be apprised of the potential hazard to the fetus. In female rats given subcutaneous 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 (≥ 0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥ 0.07 times the human systemic exposure following an intravenous 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 subcutaneous 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 intravenous 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 low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous 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 subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous 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 ≥0.05 times the human intravenous 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.
8.3 Nursing Mothers
It is not known whether zoledronic acid is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from zoledronic acid, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Zoledronic acid binds to bone long term and may be released over weeks to years.
8.4 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 to 17 years, 55% male, 84% Caucasian, with a mean lumbar spine bone mineral density (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 hypercalcemia of malignancy or bone metastases. 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 3 days after the first infusion and became less common with repeat dosing. 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 to 8 years and 6 in the age group of 9 to 17 years) infused with 0.05 mg/kg dose over 30 min. 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.
8.5 Geriatric Use
Clinical studies of zoledronic acid in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving zoledronic acid as compared to younger patients. Controlled clinical studies of zoledronic acid in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 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.
Clinical experience with acute overdosage of zoledronic acid is limited. Two patients received zoledronic acid 32 mg over 5 minutes 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 intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100 U/L, each value unknown). The outcome of this case is not known. In controlled clinical trials, administration of zoledronic acid 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, zoledronic acid 8 mg has been shown to be associated with an increased risk of renal toxicity compared to zoledronic acid 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage and Administration (2.4)].
Zoledronic acid injection contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula is:Zoledronic acid is a white crystalline powder. Its molecular formula is C5H10N2O7P2 • H2O and its molar mass is 290.1 g/mol. Zoledronic acid is highly soluble in 0.1N sodium hydroxide solution, sparingly soluble in water and 0.1N hydrochloric acid, and practically insoluble in organic solvents. The pH of a 0.7% solution of zoledronic acid in water is approximately 2. Zoledronic acid injection is available in 5 mL vials as a sterile liquid concentrate solution for intravenous infusion. Each 5 mL concentrate vial contains 4.264 mg zoledronic acid monohydrate, equivalent to 4 mg zoledronic acid on an anhydrous basis, 220 mg of Mannitol, USP, Water for Injection, USP, and 24 mg of Sodium Citrate, USP. Inactive Ingredients: Mannitol, USP, as bulking agent, Water for Injection, and Sodium Citrate, USP, as buffering agent.
12.1 Mechanism Of Action
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.
Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of zoledronic acid are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion. 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 two 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 such as 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 such as 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 and Administration (2.1)].
Pharmacokinetic data in patients with hypercalcemia are not available.DistributionSingle or multiple (q 28 days) 5-minute or 15-minute infusions of 2, 4, 8 or 16 mg zoledronic acid were given to 64 patients with cancer and bone metastases. The postinfusion 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 less than 1% of Cmax 24 hours postinfusion with population half‑lives of t1/2α 0.24 hours and t1/2β 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 postinfusion, and a terminal elimination half-life t1/2γ of 146 hours. The area under the plasma concentration versus time curve (AUC0 to 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 AUC0 to 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, with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/mL to 5000 ng/mL. In vitro, the plasma protein binding is low, with the unbound fraction ranging from 60% at 2 ng/mL to 77% at 2000 ng/mL of zoledronic acid.MetabolismZoledronic acid does not inhibit human P450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, less than 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. 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. ExcretionIn 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 hours, with only trace amounts of drug found in urine post-Day 2. The cumulative percent of drug excreted in the urine over 0 to 24 hours was independent of dose. The balance of drug not recovered in urine over 0 to 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 to 24 hour renal clearance of zoledronic acid was 3.7 ± 2 L/h. 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 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion ([mean ± SD] 403 ± 118 ng/mL versus 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng × h/mL versus 420 ± 218 ng × h/mL). The difference between the AUC means was not statistically significant. Special PopulationsPediatricsZoledronic acid is not indicated for use in children [see Use in Specific Populations, Pediatric Use (8.4)]. GeriatricsThe pharmacokinetics of zoledronic acid were not affected by age in patients with cancer and bone metastases who ranged in age from 38 years to 84 years. RacePopulation pharmacokinetic analyses did not indicate any differences in pharmacokinetics among Japanese and North American (Caucasian and African American) patients with cancer and bone metastases. Hepatic InsufficiencyNo clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid. Renal InsufficiencyThe 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 zoledronic acid in patients with severe renal impairment (creatinine clearance less than 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:Zoledronic acid systemic clearance in individual patients can be calculated from the population clearance of zoledronic acid, CL (L/h)=6.5(CrCl/90)0.4. These formulae can be used to predict the zoledronic acid AUC in patients, where CL = Dose/AUC0-∞. The average AUC0 to 24 in patients with normal renal function was 0.42 mg•h/L and the calculated AUC0-∞ for a patient with creatinine clearance of 75 mL/min was 0.66 mg•h/L following a 4-mg dose of zoledronic acid. However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed [see Warnings and Precautions (5.3)].
13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were 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 ≥ 0.002 times a human intravenous 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 intravenous dose of 4 mg, based on a comparison of relative body surface areas). 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. Female rats were given subcutaneous 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 intravenous 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 intravenous dose of 4 mg, based on an AUC comparison) and high-dose group included an increase in preimplantation losses and a decrease in the number of implantations and live fetuses.
14.1 Hypercalcemia Of Malignancy
Two identical multicenter, randomized, double-blind, double-dummy studies of zoledronic acid 4 mg given as a 5-minute intravenous infusion or pamidronate 90 mg given as a 2-hour intravenous infusion were conducted in 185 patients with hypercalcemia of malignancy (HCM). NOTE: Administration of zoledronic acid 4 mg given as a 5-minute intravenous 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 zoledronic acid 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid should be administered by intravenous infusion over no less than 15 minutes [see Warnings and Precautions (5.1 and 5.2) and Dosage and Administration (2.4)]. 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. 60% 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 greater than or equal to 12 mg/dL (3.00 mmol/L). The primary efficacy variable was the proportion of patients having a complete response, defined as the lowering of the CSC to less than or equal to 10.8 mg/dL (2.70 mmol/L) within 10 days after drug infusion. To assess the effects of zoledronic acid versus those of pamidronate, the two multicenter HCM studies were combined in a preplanned 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 zoledronic acid 4 mg and pamidronate 90 mg, respectively (P=0.002) (see Figure 1). In these studies, no additional benefit was seen for zoledronic acid 8 mg over zoledronic acid 4 mg; however, the risk of renal toxicity of zoledronic acid 8 mg was significantly greater than that seen with zoledronic acid 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 of 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 less than 11.6 mg/dL (less than 2.90 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 (2.70 mmol/L). The results of these secondary analyses for zoledronic acid 4 mg and pamidronate 90 mg are shown in Table 11.Table 11: Secondary Efficacy Variables in Pooled HCM Studies Zoledronic Acid Injection4 mg Pamidronate90 mgComplete Response NResponse Rate NResponse Rate By Day 4By Day 7868645.3%82.6%*999933.3%63.6%Duration of ResponseN Median Duration(Days) NMedian Duration(Days) Time to RelapseDuration of Complete Response 867630*3299691718 * P less than 0.05 versus pamidronate 90 mg.
14.2 Clinical Trials In Multiple Myeloma And Bone Metastases Of Solid Tumors
Table 12 describes an overview of the efficacy population in three randomized zoledronic acid trials in patients with multiple myeloma and bone metastases of solid tumors. These trials included a pamidronate-controlled study in breast cancer and multiple myeloma, a placebo-controlled study in 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, including NSCLC, renal cell cancer, small cell lung cancer, colorectal cancer, bladder cancer, GI/genitourinary cancer, head and neck cancer, and others. These trials were comprised of a core phase and an extension phase. In the solid tumor, breast cancer and multiple myeloma trials, only the core phase was evaluated for efficacy as a high percentage of patients did not choose to participate in the extension phase. In the prostate cancer trials, both the core and extension phases were evaluated for efficacy showing the zoledronic acid effect during the first 15 months was maintained without decrement or improvement for another 9 months. The design of these clinical trials does not permit assessment of whether more than one-year administration of zoledronic acid is beneficial. The optimal duration of zoledronic acid administration is not known. The studies were amended twice because of renal toxicity. The zoledronic acid infusion duration was increased from 5 minutes to 15 minutes. After all patients had been accrued, but while dosing and follow-up continued, patients in the 8 mg zoledronic acid treatment arm were switched to 4 mg due to toxicity. Patients who were randomized to the zoledronic acid 8 mg group are not included in these analyses.Table 12: Overview of Efficacy Population for Phase III StudiesPatient Population No. of Patients Zoledronic AcidInjection DoseControl Median Duration(Planned Duration)Zoledronic Acid Injection4 mgMultiple myeloma or metastatic breast cancer1,648 4 and 8* mgQ3-4 weeks Pamidronate 90 mgQ3-4 weeks 12 months(13 months) Metastatic prostate cancer643 4 and 8* mgQ3 weeksPlacebo 10.5 months(15 months) Metastatic solid tumor other than breast or prostate cancer773 4 and 8* mg Q3 weeks Placebo 3.8 months(9 months) * Patients who were randomized to the 8 mg zoledronic acid group are not included in any of the analyses in this package insert.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 and time to the first SRE. Results for the two zoledronic acid placebo-controlled studies are given in Table 13.Table 13: Zoledronic Acid Injection Compared to Placebo in Patients with Bone Metastases from Prostate Cancer or Other Solid Tumors I. Analysis of Proportion of Patients with a SRE1 II. Analysis of Time to the First SREStudyStudy Arm & Patient NumberProportionDifference2 & 95% CIP-valueMedian (Days)Hazard Ratio3 & 95% CIP-valueProstate CancerZoledronic AcidInjection 4 mg(n=214)Placebo(n=208)33%44%-11%(-20%, -1%)0.02 Not Reached3210.67(0.49, 0.91) 0.011Solid TumorsZoledronic AcidInjection 4 mg(n=257)Placebo(n=250)38%44%-7%(-15%, 2%) 0.13230163 0.73(0.55, 0.96) 0.0231 SRE = Skeletal-Related Event2 Difference for the proportion of patients with a SRE of zoledronic acid 4 mg versus placebo.3 Hazard ratio for the first occurrence of a SRE of zoledronic acid 4 mg versus placebo.In the breast cancer and myeloma trial, efficacy was determined by a noninferiority analysis comparing zoledronic acid to pamidronate 90 mg for the proportion of patients with a SRE. This analysis required an estimation of pamidronate efficacy. Historical data from 1,128 patients in three pamidronate placebo-controlled trials demonstrated that pamidronate decreased the proportion of patients with a SRE by 13.1% (95% CI = 7.3%, 18.9%). Results of the comparison of treatment with zoledronic acid compared to pamidronate are given in Table 14.Table 14: Zoledronic Acid Injection Compared to Pamidronate in Patients with Multiple Myeloma or Bone Metastases from Breast Cancer I. Analysis of Proportion of Patients with a SRE1 II. Analysis of Time to the First SREStudy Study Arm &Patient Number Proportion Difference2& 95% Cl P-valueMedian(Days) Hazard Ratio3 & 95% ClP-value Multiple Myeloma& Breast CancerZoledronic Acid Injection 4 mg(n=561)Pamidronate(n=555)44%46%-2%(-7.9%, 3.7%) 0.463733630.92(0.77,109) 0.321 SRE = Skeletal-Related Event2 Difference for the proportion of patients with a SRE of zoledronic acid injection 4 mg versus pamidronate 90 mg.3 Hazard ratio for the first occurrence of a SRE of zoledronic acid injection 4 mg versus pamidronate 90 mg.
16 How Supplied/Storage And Handling
Zoledronic acid injection, 4 mg/5 mL single-dose vial of concentrateCarton of 1 vial………………..NDC 0143-9642-01Store at 25°C (77°F); excursions permitted to 15º to 30°C (59º to 86°F) [see USP Controlled Room Temperature].
17 Patient Counseling Information
- Patients should be instructed to tell their doctor if they have kidney problems before being given zoledronic acid. Patients should be informed of the importance of getting their blood tests (serum creatinine) during the course of their zoledronic acid therapy.
- Zoledronic acid should not be given if the patient is pregnant or plans to become pregnant, or if she is breast feeding. Patients should be advised to have a dental examination prior to treatment with zoledronic acid and should avoid invasive dental procedures during treatment. Patients should be informed of the importance of good dental hygiene, routine dental care and regular dental check-ups.Patients should be advised to immediately tell their doctor about any oral symptoms such as loosening of a tooth, pain, swelling, or non-healing of sores or discharge during treatment with zoledronic acid.Patients with multiple myeloma and bone metastasis of solid tumors should be advised to take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily. Patients should be advised to report any thigh, hip or groin pain. It is unknown whether the risk of atypical femur fracture continues after stopping therapy. Patients should be aware of the most common side effects including: anemia, nausea, vomiting, constipation, diarrhea, fatigue, fever, weakness, lower limb edema, anorexia, decreased weight, bone pain, myalgia, arthralgia, back pain, malignant neoplasm aggravated, headache, dizziness, insomnia, paresthesia, dyspnea, cough, and abdominal pain. There have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates, including zoledronic acid. Before being given zoledronic acid, patients should tell their doctor if they are aspirin-sensitive. Reclast® is a registered trademark of Novartis Pharmaceutical Corporation.Manufactured by: HIKMA FARMACÊUTICA (PORTUGAL), S.A.Estrada do Rio da Mó, 8, 8A e 8B – Fervença – 2705-906 Terrugem SNT, PORTUGALDistributed by: WEST-WARD PHARMACEUTICALS CORP.Eatontown, NJ 07724 USARevised: September 2016PIN307-WES/5
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Robotic-assisted surgery is a continuously developing field because robots have demonstrated clear benefits in operating rooms. Until now, vast majority of robots used in surgery had serial structures. This paper presents the kinematic modelling of a 5-degree of freedom hybrid parallel architecture in two slightly different variants. The kinematics of this structure is determined, and following the analysis of singularities, the best variant is chosen. The robot workspace is computed and finally the experimental model and some simulation results are presented.


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|Screencap from Machinima's youtube video|
FRAK! FRAK! FRAK! Was that a frakkin' classic cylon raider I just saw!
Battlestar Galatica: Blood & Chrome would not air on television. The first of ten segments of the web series will air on November 9th on the Machinima Prime YouTube channel. All of the episodes will air together, on the Syfy channel, in early 2013, and a DVD release will follow.
Check out the trailer!

domain: entertainment


Dates: January 26-29, 2014
Tutorial day: January 26, 2014
Location: London, UK
Chairs: Karlheinz Brandenburg and Mark Sandler
Registration for the conference is now closed.
Thank you for your paper, poster and demo submissions and your participation.
Registration fee includes gala dinner, tutorial day and BBC technical tour.
The detailed technical programme is now available here.
Papers and proceedings are available from the AES E-library.
The conference is sponsored by Native Instruments, iZotope Inc., Adobe Systems and CoSound.
Full paper submission is now closed. Thank you for your contributions.
Early registration deadline is
January 2, 2014.
Late breaking demo/poster deadline for accepted authors is
January 6, 2014.
Please remember that demo papers can be proposed
until October 15.
Authors can now update full papers until
Friday, September 27, 2013.
Two tutorials and a new invited speaker confirmed.
Paper deadline extended:
September 25, 2013 September 15, 2013
Paper submission site is open: www.aes.org/53rd_authors
Late-breaking demo/poster proposal deadline: October 15, 2013.
Semantic Audio is concerned with content-based management of digital audio recordings. The rapid evolution of digital audio technologies, e.g. audio data compression and streaming, the availability of large audio libraries online and offline, and recent developments in content-based audio retrieval have significantly changed the way digital audio is created, processed, and consumed. New audio content can be produced at lower cost, while also large audio archives at libraries or record labels are opening to the public. Thus the sheer amount of available audio data grows more and more each day.
Semantic analysis of audio resulting in high-level metadata descriptors such as musical chords and tempo, or the identification of speakers facilitate content-based management of audio recordings. Aside from audio retrieval and recommendation technologies, the semantics of audio signals are also becoming increasingly important, for instance, in object-based audio coding, as well as intelligent audio editing, and processing. Recent product releases already demonstrate this to a great extent, however, more innovative functionalities relying on semantic audio analysis and management are imminent. These functionalities may utilise, for instance, (informed) audio source separation, speaker segmentation and identification, structural music segmentation, or social and Semantic Web technologies, including ontologies and linked open data.
This conference will give a broad overview of the state of the art and address many of the new scientific disciplines involved in this still-emerging field. Our purpose is to continue fostering this line of interdisciplinary research. This is reflected by the wide variety of invited speakers presenting at the conference.
Download the Official Call for Contributions PDF (J. Audio Eng. Soc., Vol. 61, No. 6, 2013 June)
SoundSoftware.ac.uk is sponsoring a Prize for Reproducible Research in the field of Semantic Audio published at the conference and supports our tutorial day.
Our technical tour is organised in collaboration with BBC R&D.
The conference is sponsored by Native Instruments.
The conference is sponsored by iZotope Inc.
The conference is sponsored by Adobe Systems.
The conference is sponsored by the Danish strategic research project CoSound.


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Beat rush game for android description: Take your characters across hard levels moving to the rhythm of music.
To make your character jump you need to touch the screen with your finger.
Test your reflexes and feeling of the rhythm completing engrossing levels of this dynamic android game.
Catch the rhythm and touch the screen.
Help the character jump over sharp thorns in time overcome streams of lava and other deadly dangers waiting for you on your way.
Apply a jetpack skateboard and other power ups.
Be ready for the gravity change.
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domain: game


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News: Ask Not For Whom The Cellphone Rings
Sounds like an episode from Six Feet Under: the family of a deceased motorcyclist are suing a funeral firm after the dead man’s cell phone started ringing – from inside the coffin.
A Belgian newspaper, Gazet van Antwerpen, is reporting that the night before the funeral the family gathered at the undertakers for a final private farewell when they heard ringing from within the sealed coffin. Several distressed members of the family had to leave the funeral home whilst staff rushed to remove the cell phone.
The family is now suing, according to Cellular News, claiming that the undertakers were negligent in preparing their relative for burial.

domain: news


- Products & Services
- Knowledge Base
"When we saw the effects of COVID-19 on the retail industry, we knew that we had an effective solution retail businesses can benefit from."
OTTAWA, ON, April 22, 2020 /24-7PressRelease/ -- Humdinner, a drive-thru technology company focused on the Quick-Serve Restaurant (QSR) and retail industries, today announced the launch of its world's first "No-Touch" multi-lane drive-thru system. Sold as a suite of solutions, customers can now safely place and pick up their orders at QSR's, grocery stores, pharmacies, and other retail locations without coming into physical contact with anyone or any shared surfaces.
In today's challenging pandemic, businesses have been searching for a solution to enable order pickup without risk to customers or employees. Although existing drive-thru services offer elements of social distancing safety, customers and employees often come within close contact, touch objects such as credit cards, bags, and other shared surfaces, and speak face-to-face at the payment and pickup windows.
Providing customers with a safe solution for product pickup, whether at QSR's or retail, enables local economies and businesses of all sizes to regain the ability to safely conduct business transactions without the risks associated during times of social distancing.
Humdinner utilizes patent-pending technology that enables customers to make and complete transactions without touching any common surfaces and pick up their orders without coming into physical contact or close proximity to any person. Humdinner was originally created to optimize QSR traffic-flow by providing multi-lane drive-thru systems. With the emergence of COVID-19, Humdinner identified that its systems can be deployed for use in retail, solving a major problem.
"We are excited that the Humdinner drive-thru system provides such an immediate and effective solution to a serious global problem," said Brett Gould, chief marketing officer at Humdinner. "We knew that 'fast food' restaurants would be able to multiply their drive-thru orders and that customers would be thrilled with not having to wait in long lines. But when we saw the effects of COVID-19 on the retail industry, we knew that we had an effective solution retail businesses can benefit from. The Humdinner platform provides a complete *no-touch* customer experience, while ensuring high-speed service, an optimized pickup process, and personalized customer service. Although Humdinner can work in conjunction with existing drive-thru menu and ordering systems, our end-to-end platform enables customers to place their orders, pay, and pickup without coming into contact with any person or shared surfaces."
In the QSR industry prior to COVID-19, most major restaurants attributed about 70% of their business to their drive-thru service. Since the shift from in-restaurant dining to drive-thru, average drive-thru order times have increased, resulting in longer lines and lost business.
"Every second counts when customers are sitting in a drive-thru. If customers arrive at a restaurant and see a long line, typically they will just keep driving to find another place with a shorter line," says Gould. "By providing a distributed drive-thru system, Humdinner improves the customer experience and allows locations to quickly serve more customers. We are delighted to deliver a drive-thru experience unlike anything you've ever encountered before. Now with the serious challenges of a global pandemic, we feel a social obligation to be provide our safe end-to-end no-touch solution for the QSR and retail industries."
Humdinner drive-thru systems are designed to deliver up to 500 lbs. of products, making it a viable solution for retail orders of all sizes. An optional safety system can include a bacteria and virus-killing UV-light to sanitize the surface that delivers products to the customers. "Adding the UV-light tunnel provides an additional level of safety for everyone," says Gould. "This ensures that customers and employees will not come in contact with a surface that could even be touched accidentally."
For more information about Humdinner, please visit https://humdinner.com
Humdinner provides QSR and retail businesses with an easy-to-use, fun and engaging multiple-lane drive-thru service that is 'no-touch' to provide safety and customer confidence in the post COVID-19 world. As the first true end-to-end multi-lane drive-thru system, companies can serve their customers with the most efficient, tailored customer experience. Humdinner offers this technology as a modular drive-thru system. Existing menu board-based ordering and online orders can be integrated in conjunction with Humdinner delivery lanes. When deployed with the Humdinner product ordering platform, customers can interact with an Artificial Intelligence-based ordering SmartBoard or opt for speaking with a live person. Humdinner - let's get flowing! For more information, please visit https://humdinner.com/.
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How To Estimate Your Moving Cost
Estimating Your Moving Cost
Relocation sometimes can turn out as a challenging experience, and it can take a toll on your physical, emotional, and financial muscle quite fast. Being in control of your moving cost involved in every step helps a lot when planning your household relocation cost. Among the initial stages and considerations that will determine the estimation of moving whether you will include a moving company or you will do it yourself. In most instances, though not always relocating with a professional moving company usually costs slightly more than doing it yourself.
Bring in the professionals
Involving a professional moving company may be a bit expensive. Still, when you consolidate the benefits accrued, you will be surprised by how efficient the whole process is and how they reduce your relocation stress.
While navigating through the entire moving and relocation process, if you fail to plan accordingly, it’s most likely that your budget may rise out of control. It’s critical to prepare all the costs and expenditures involved in your relocation to make a sound financial judgment. With a budget estimate on your moving cost, it will be easier to plan and better understand your moving expectation. It’s relatively easy to estimate the cost involved in relocation by considering the following factors on how to estimate your moving cost.
1. The total weight of all your items
One of the first considerations and determinant of relocation cost is the weight of your items getting relocated. This factor applies when you decide to move via a professional moving company or decide to do it yourself. A professional Pack And Ship Movers company will charge you differently when the items’ weight in question varies. Moving heavy objects costs a bit more than moving light items. When you are using weight as a standard rate of determining the cost of relocation, your items’ size does not matter compared to how much they weigh.
Similarly, you can separate and organize your heavy objects or household items to get transported as a unit rather than trying to combine everything in one whole big consignment. Your professional moving company will give you an estimate different from the other items. Your heavier items will attract a different rate compared to the delicate household items.
2. The size of your items intended to move
Naturally, we tend to accumulate stuff over time without even taking note. We realize how much we have got when it comes to relocation time. Most moving professional like Pack And Ship Movers’ transportation cost are based on your items size. Similarly, the time taken to offload and load your items gets determined by your item’s size. At the same time, huge items and more massive takes quite some time to rack during shipment. When combined, all these factors will determine the cost of moving your items to your new residence. More oversized loads will attract a higher rate of transportation compared to moving small items. When calculating how to estimate your moving cost consider the size of the load.
3. Packing services for your items
One of the most tiring and consuming task both emotionally and in time is shouldering the whole burden of packaging your entire load of items in preparedness for relocation. Such a job demands excellent interpersonal organization and planning skills, and strong stamina, especially if you have many things. Most relocating people involve professional Pack And Ship Movers services to organize, plan, and packing & more their belongings as a package on the moving cost.
Doing so reduces the stress involved in handling the item’s tiniest in their house and ensuring they fit back where they were previously. It may sound like an easy task, but it constitutes one of the most challenging tasks involved in transport. Hence, if you consider professional moving services during your relocation, be assured that the cost will get inflated by some hundreds of bucks on your final bill, hence an essential aspect in determining how to estimate your moving cost.
4. Cost of purchasing moving supplies
Another factor that determines estimating your moving cost includes items used to pack your entire load of things. This purchase of moving supplies includes packing paper, plastic bins, bubble wrap, and cardboard boxes. The above items are essential for packing and protecting your possession from damages that might occur during movement. Not unless you have an alternative way of moving your shipment load, the moving supplies will add an extra cost to your transport relocation budget.
You must factor in all the items you need in your budget earlier. It’s also essential not to forget things such as markers and tapes. The best way to get a tentative average cost of moving supplies is to create a list of all the items with the average cost per item and determine how much they affect your relocation budget. Boxes that form part of moving supplies will usually add extra weight to your moving price, and you will need to put the number of containers you have into consideration when it comes to how to estimate your moving costs.
5. Cost of transportation
Whether long-distance or barely a short distance, moving items will make up your relocation budget’s highest cost. There is no standard rate on which professional Pack And Ship Movers Estimates for carrying things. In most instances, short-distance transportation gets charged on an hourly basis. In this case, if your relocation transport took half an hour or even three quarters, you will get charged for the whole hour.
When it comes to long distance moving services costs, estimating moving costs usually varies and is dependent on several factors. One of these determining factors on your movement cost is the distance to be covered. You must do some due diligence and survey by collecting quotes from various transportation companies and comparing the prices.
Don’t be surprised to find out that most transportation companies usually have their independent formula when calculating Pack And Ship Movers service estimates. It should not shock you when you get denied the aces to this transportation company formula.
6. Your preferred dates of moving
One mistake you can make not be conscious that your preferred date of relocation may affect the quote you will get from transportation companies. For instance, if you happen to be relocating during a weekend, you will most likely get a different quote than when you decide to move during a typical weekday. Similarly, the time of the year you are moving will impact the cost of moving, and you need to factor it into your moving budget. Movement during spring and summer usually attract higher charges as they comprise the peak season. You will probably get a lower quote during winter as most people do not move during such a time.
Other factors that will significantly affect your moving cost include transporting items that demand careful handling. Things such as furniture and appliances attract a higher cost of transport compared to other items. Most of these items require full Service Moving Packages that get disconnected from their current state and get reconnected upon arriving at your new residence.
Also, transporting fragile items that may break will attract an extra fee. Things such as artwork, glass, or antiques require handling with extra caution, and in return, you will have to dig deeper. Finally, stairs will be another factor that will influence the pricing. If you happen to be moving to a residence with stairs and items will need to be moved along the stairway, additional charges get included.

domain: finance


Drake Milligan has dropped a surprise new song, “I Got A Problem.” The spirited track was penned by hit songwriters Jessi Alexander, Justin Wilson and Will Bundy. Drake will debut “I Got A Problem” on the performance stage of NBC’s America’s Got Talent on Wednesday, September 13.
Josh Turner has released his new Greatest Hits album. The 11-track collection includes the chart-topping singles “Why Don’t We Just Dance” and “Your Man.” Exclusive signed LPs and CDs are available now at shop.joshturner.com.
Jon Langston‘s debut album, Heart On Ice, has arrived. Out now via EMI Records Nashville, the 14-track record includes “I ain’t Country,” a rocking duet with Travis Denning.
Copyright © 2023, ABC Audio. All rights reserved.


text:
Soy Americano, y ahora vivo en las Filipinas. Vivo en Dumaguete.
Acerca de mí
I am a retired American man, single, looking for a home. I am very interested in Nha Trang as I want to live on the sea. I have lived in Sanya, Hainan, China for 6 years previously and 6months in Siem Reap, Cambodia. I have now moved to Nha Trang and like it very much. Great place for foreigners. Inexpensive to live here. Many western restaurants and bars. Beautiful beaches. Friendly people. It is more expensive than any other place in Asia but it is so nice to be able to speak english and shop in supermarkets and have large shopping malls. Still cheaper than USA. One month and so far so good.
Hablo English, some Chinese
fishing, reading, travel
Actividad del usuario en el foro
Ultimo mensaje: 2013-02-25 11:36:01

domain: geography


After a 20-year hiatus, the Land Rover Defender is returning to the US with a completely new design, the latest driver-assistance and safety tech, and an independent suspension setup. A 2.0-liter diesel four-cylinder engine is expected to sit under hood aided by a 48-volt mild-hybrid system, while gasoline variants will also be offered.
The off-roader will take design cues from the current crop of Land Rover and Range Rover products, married with subtle nods to the old car. The 2020 Defender will have a similar stature to the current Discovery while expect a relatively luxurious interior as it looks to cross swords with the Mercedes-Benz G-Class.
A series of Defender models are planned, including performance SVR, hardcore SVX and luxurious SVA variants.
The all-new Defender will be revealed sometime in 2019 and hit showrooms in 2020.


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Superstar Krishna and late Vijaya Nirmala was one of those strong couples who remained faithful to each other despite all the hurdles in life and seem to have loved every minute of their togetherness. They have lived in perfect harmony for 50 years. The couple has met on the sets of their film, Sakshi, in 1967. The film also marks as the directorial debut of ace filmmaker Bapu.
One of the famous songs from the film has been shot at the Meesala Krishnudu temple in Medak district. The temple is popularly known for couples getting married soon after visiting Lord Krishna idol here. Moreover, the song had lyrics 'Thali Kattu Vela..', which was so apt for the situation that Vijaya Nirmala and Krishna fell for each other at this place.
One funny incident has taken place while shooting this song when comedian Rajababu jokingly said 'Meerika Bharyabarthalu Ayipoyinatte' to the actors after telling them about the history of the powerful God there. Vijaya Nirmala has reportedly got furious over his words initially. Later, Krishna, who already had feelings on her, took the help of Chandramohan and conveyed his feelings to the actress. Thereafter, Krishna himself proposed to Vijaya Nirmala by saying, 'Manamiddaram Pelli Chesukundam'.
This is how the on-set chemistry blossomed into their real lives ever since 1969. This aww-inducing love story has now definitely left a void in Superstars life after Vijaya Nirmala's sudden demise. Hoping that God gives him all the strength in the world, this beautiful love will be a timeless treasure even for the future generations to come.


Kolkata, Jun 5 (PTI) Customs officials have seized 14 gold biscuits from a passenger who disembarked at Netaji Subhas Chandra Bose International Airport here.
The gold biscuits, weighing 16.31 gm, have a street value of 47.82 lakh approximately. They were seized from the passenger who alighted from a Jet Airways flight from Dhaka yesterday, a Customs official said today.
The man, who was apprehended yesterday, was produced at a Barrackpore court today. PTI COR MM PVI


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Hispanics and health care in the united states ii hispanics and chronic disease in the us by gretchen livingston, susan minushkin and d'vera cohn. Percentage of us children who have chronic health conditions on the rise diseases such as asthma and attention deficit hyperactivity disorder have increased at a disproportionate rate among children living in poverty, according to new research being presented at the pediatric academic societies. Medical research news and exclusive interviews medical research in the author's own words search main menu skip to primary content the nature of chronic diseases is that they require long-term management and usually cannot be cured. The challenges of chronic disease the cost of chronic diseases the traditional medical model of caring for people with chronic diseases which focuses more on the illness than on the patient we also remain committed to research and development work on evidence-based self-management. Chronic disease and the internet 93% of adults living with chronic disease ask a health professional for information or assistance in dealing with health or medical issues about pew research center pew research center is a nonpartisan fact tank that informs the public about the issues.
The chronic care model :: improving chronic illness care care coordination practice change patient-centered medical home global work evidence integrated delivery systems have taken a great interest in correcting the many deficiencies in current management of diseases such as diabetes. The center for managing chronic disease is dedicated to helping people control the effects of chronic illness by conducting research that develops new and better ways to support patients and their caregivers in disease management. The chronic kidney disease program supports basic, translational, and clinical research the program includes studies to improve diagnosis and understand the biological and functional adaptation to nephron loss the program also advances studies that identify and test possible therapeutic. The national kidney foundation participates in research that is helping advance knowledge about chronic kidney disease and the chronic kidney disease prognosis consortium research grant applications click kidney, and heart disease, this program is improving the health and awareness of. Landing page for chronic disease programs at the nj department of health.
Prevalence of chronic diseases in the population covered by medical schemes in south africa research and monitoring unit january 2015 chairperson: 333 chronic renal disease. Choose from any research paper topic on diseases 24 of aids - order a custom research paper on the causes of aids and you will receive the most up-to-date and relevant medical health research sjogren's syndrome - sjogren's syndrome research papers discuss the chronic. Nih recently established a research program that will target health disparities' role in chronic disease among certain minority and disadvantaged patient populations. Slideshow 10 diseases vaccines can prevent slideshow vitamins & minerals from a - zinc it's probably no surprise that chronic stress is connected with higher rates of depression and anxiety webmd does not provide medical advice. In collaboration with the global alliance for chronic diseases (gacd) 1, the japan agency for medical research and development (amed) implemented a joint international research call on mental health and, following an international joint peer review, selected two highly meritorious.
While the panel touched on various chronic diseases, mental health issues among youth, teens, and young adults were a key topic of discussion although universities, nonprofits, and other research organizations are studying mental health disorders. Chronic kidney disease learn about kidney failure symptoms, tests, diagnosis and treatment options, including medication, dialysis and kidney transplant.
Journal of medical internet research - international scientific journal for medical research, information and communication outcomes of interest included effect of mhealth on patient adherence to chronic diseases management, disease-specific clinical outcomes after intervention, and the. Comprehensive guides on hundreds of diseases and conditions from mayo clinic experts. The global alliance for chronic diseases (gacd) supports international and interdisciplinary collaborations in research, focusing on chronic non-communicable diseases the gacd places particular emphasis on research into cardiovascular diseases (mainly heart disease and stroke), type 2 diabetes. The center for chronic disease outcomes research, a va health services research and development (hsr&d) center of innovation (coin) operating under the direction of the office of research and development (ord), is an interdisciplinary community of professionals conducting methodologically.

domain: medical