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ZOLEDRONIC ACID INJECTION - PREMIXED SOLUTION FOR INTRAVENOUS INFUSION (FOR SINGLE DOSE) (zoledronic acid for injection - PREMIXED SOLUTION FOR INTRAVENOUS INFUSION (FOR SINGLE DOSE)) Adverse Reactions

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hypercalcemia of Malignancy

The 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 33–84 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 Toxicity

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 Injection should be administered by intravenous infusion over no less than 15 minutes [see Warnings and Precautions (5.3), Dosage and Administration (2.4)].

Common Adverse Events

The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3).

Table 3 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 3: Percentage of Patients with Adverse Events greater than or equal to 10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System
Zoledronic Acid
4 mg
n (%)
Pamidronate
90 mg
n (%)
Patients Studied
Total No. of Patients Studied86(100)103(100)
Total No. of Patients with any AE81(94)95(92)
Body as a Whole
Fever38(44)34(33)
Progression of Cancer14(16)21(20)
Cardiovascular
Hypotension9(11)2(2)
Digestive
Nausea25(29)28(27)
Constipation23(27)13(13)
Diarrhea15(17)17(17)
Abdominal Pain14(16)13(13)
Vomiting12(14)17(17)
Anorexia8(9)14(14)
Hemic and Lymphatic System
Anemia19(22)18(18)
Infections
Moniliasis10(12)4(4)
Laboratory Abnormalities
Hypophosphatemia11(13)2(2)
Hypokalemia10(12)16(16)
Hypomagnesemia9(11)5(5)
Musculoskeletal
Skeletal Pain10(12)10(10)
Nervous
Insomnia13(15)10(10)
Anxiety12(14)8(8)
Confusion11(13)13(13)
Agitation11(13)8(8)
Respiratory
Dyspnea19(22)20(19)
Coughing10(12)12(12)
Urogenital
Urinary Tract Infection12(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 Reaction

Within 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 Abnormalities

Electrolyte 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 4 and 5.

Table 4: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM
Grade 3
Zoledronic Acid
4 mg
Pamidronate
90 mg
Laboratory Parametern/N(%)n/N(%)
Serum Creatinine*2/86(2%)3/100(3%)
Hypocalcemia1/86(1%)2/100(2%)
Hypophosphatemia36/70(51%)27/81(33%)
Hypomagnesemia§0/710/84
Table 5: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM
Grade 4
Zoledronic Acid
4 mg
Pamidronate
90 mg
Laboratory Parametern/N(%)n/N(%)
*
Grade 3 (greater than 3× Upper Limit of Normal); Grade 4 (greater than 6× Upper Limit of Normal)
Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)
Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)
§
Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L)
Serum Creatinine*0/861/100(1%)
Hypocalcemia0/860/100
Hypophosphatemia1/70(1%)4/81(5%)
Hypomagnesemia§0/711/84(1%)

Injection Site Reactions

Local 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 24–48 hours.

Ocular Adverse Events

Ocular 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 postmarketing use [see Adverse Reactions (6.2)].

Multiple Myeloma and Bone Metastases of Solid Tumors

The 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 4.0 months for other solid tumors.

Table 6 describes adverse events that were reported by 10% or more of patients. Adverse events are listed regardless of presumed causality to study drug.

Table 6: Percentage of Patients with Adverse Events greater than or equal to 10% Reported in Three Bone Metastases Clinical Trials by Body System
Zoledronic Acid
4 mg
n (%)
Pamidronate
90 mg
n (%)
Placebo
n (%)
Patients Studied
Total No. of Patients 1031(100)556(100)455(100)
Total No. of Patients with any AE1015(98)548(99)445(98)
Blood and Lymphatic
Anemia344(33)175(32)128(28)
Neutropenia124(12)83(15)35(8)
Thrombocytopenia102(10)53(10)20(4)
Gastrointestinal
Nausea476(46)266(48)171(38)
Vomiting333(32)183(33)122(27)
Constipation320(31)162(29)174(38)
Diarrhea249(24)162(29)83(18)
Abdominal Pain143(14)81(15)48(11)
Dyspepsia105(10)74(13)31(7)
Stomatitis86(8)65(12)14(3)
Sore Throat82(8)61(11)17(4)
General Disorders and Administration Site
Fatigue398(39)240(43)130(29)
Pyrexia328(32)172(31)89(20)
Weakness252(24)108(19)114(25)
Edema Lower Limb215(21)126(23)84(19)
Rigors112(11)62(11)28(6)
Infections
Urinary Tract Infection124(12)50(9)41(9)
Upper Respiratory Tract Infection101(10)82(15)30(7)
Metabolism
Anorexia231(22)81(15)105(23)
Weight Decreased164(16)50(9)61(13)
Dehydration145(14)60(11)59(13)
Appetite Decreased130(13)48(9)45(10)
Musculoskeletal
Bone Pain569(55)316(57)284(62)
Myalgia239(23)143(26)74(16)
Arthralgia216(21)131(24)73(16)
Back Pain156(15)106(19)40(9)
Pain in Limb143(14)84(15)52(11)
Neoplasms
Malignant Neoplasm Aggravated205(20)97(17)89(20)
Nervous
Headache191(19)149(27)50(11)
Dizziness (excluding vertigo)180(18)91(16)58(13)
Insomnia166(16)111(20)73(16)
Paresthesia149(15)85(15)35(8)
Hypoesthesia127(12)65(12)43(10)
Psychiatric
Depression146(14)95(17)49(11)
Anxiety112(11)73(13)37(8)
Confusion74(7)39(7)47(10)
Respiratory
Dyspnea282(27)155(28)107(24)
Cough224(22)129(23)65(14)
Skin
Alopecia125(12)80(14)36(8)
Dermatitis114(11)74(13)38(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 7 and 8.

Table 7: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases
Grade 3
Zoledronic Acid
4 mg
Pamidronate
90 mg
Placebo
Laboratory Parametern/N(%)n/N(%)n/N(%)
*
Grade 3 (greater than 3× Upper Limit of Normal); Grade 4 (greater than 6× Upper Limit of Normal)
Serum creatinine data for all patients randomized after the 15-minute infusion amendment
Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)
§
Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)
Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L)
#
Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)
Serum Creatinine*7/529(1%)4/268(2%)4/241(2%)
Hypocalcemia6/973(<1%)4/536(<1%)0/415
Hypophosphatemia§115/973(12%)38/537(7%)14/415(3%)
Hypermagnesemia19/971(2%)2/535(<1%)8/415(2%)
Hypomagnesemia#1/971(<1%)0/5351/415(<1%)
Table 8: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases
Grade 4
Zoledronic Acid
4 mg
Pamidronate
90 mg
Placebo
Laboratory Parametern/N(%)n/N(%)n/N(%)
*
Grade 3 (greater than 3× Upper Limit of Normal); Grade 4 (greater than 6× Upper Limit of Normal)
Serum creatinine data for all patients randomized after the 15-minute infusion amendment
Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)
§
Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)
Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L)
#
Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)
Serum Creatinine*2/529(<1%)1/268(<1%)0/241
Hypocalcemia7/973(<1%)3/536(<1%)2/415(<1%)
Hypophosphatemia§5/973(<1%)0/5371/415(<1%)
Hypermagnesemia0/9710/5352/415(<1%)
Hypomagnesemia#2/971(<1%)1/535(<1%)0/415

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 Toxicity

In 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 1.0 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 9).

Table 9: Percentage of Patients with Treatment-Emergent Renal Function Deterioration by Baseline Serum Creatinine*
Patient Population/Baseline Creatinine
*
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.
Zoledronic Acid 4 mgPamidronate 90 mg
Multiple Myeloma and Breast Cancern/N(%)n/N(%)
Normal27/246(11%)23/246(9%)
Abnormal2/26(8%)2/22(9%)
Total29/272(11%)25/268(9%)
Zoledronic Acid 4 mgPlacebo
Solid Tumorsn/N(%)n/N(%)
Normal17/154(11%)10/143(7%)
Abnormal1/11(9%)1/20(5%)
Total18/165(11%)11/163(7%)
Zoledronic Acid 4 mgPlacebo
Prostate Cancern/N(%)n/N(%)
Normal12/82(15%)8/68(12%)
Abnormal4/10(40%)2/10(20%)
Total16/92(17%)10/78(13%)

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 postmarketing 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 Postmarketing Experience

The following adverse reactions have been reported during postapproval 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 Jaw

Cases 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 Reaction

Within 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 Pain

Severe 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 Fractures

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including zoledronic acid [see Warnings and Precautions (5.6)].

Ocular Adverse Events

Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Hypersensitivity Reactions

There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have been reported. Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported.

Additional adverse reactions reported in postmarketing 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 rechallenge; Renal: hematuria, proteinuria, acquired Fanconi syndrome; 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).

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