`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ZOMETA safely and effectively. See full prescribing information for
`ZOMETA.
`ZOMETA® (zoledronic acid) Injection
`Ready-to-Use Solution for Intravenous Infusion (For Single Use)
`Concentrate for Intravenous Infusion
`Initial U.S. Approval: 2001
`----------------------------RECENT MAJOR CHANGES--------------------------
`Warnings and Precautions, Hypocalcemia (5.10)
`
`09/2013
`----------------------------INDICATIONS AND USAGE---------------------------
`Zometa is a bisphosphonate indicated for the treatment of:
`• Hypercalcemia of malignancy. (1.1)
`• 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. (1.2)
`Important limitation of use: The safety and efficacy of Zometa has not been
`established for use in hyperparathyroidism or nontumor-related
`hypercalcemia. (1.3)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`Hypercalcemia of malignancy (2.1)
`• 4 mg as a single-use intravenous infusion over no less than 15 minutes.
`• 4 mg as retreatment after a minimum of 7 days.
`Multiple myeloma and bone metastasis from solid tumors. (2.2)
`• 4 mg as a single-use intravenous infusion over no less than 15 minutes
`every 3-4 weeks for patients with creatinine clearance of greater than
`60 mL/min.
`• Reduce the dose for patients with renal impairment.
`• Coadminister oral calcium supplements of 500 mg and a multiple vitamin
`containing 400 international units of Vitamin D daily.
`Administer through a separate vented infusion line and do not allow to come
`in contact with any calcium or divalent cation-containing solutions. (2.3)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`4 mg/100 mL single-use ready-to-use bottle (3)
`4 mg/5 mL single-use vial of concentrate (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`Hypersensitivity to any component of Zometa (4)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`• Patients being treated with Zometa should not be treated with Reclast®.
`(5.1)
`
`
`
`2
`
`3
`4
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Hypercalcemia of Malignancy
`1.2 Multiple Myeloma and Bone Metastases of Solid Tumors
`1.3
`Important Limitation of Use
`DOSAGE AND ADMINISTRATION
`2.1 Hypercalcemia of Malignancy
`2.2 Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors
`2.3
`Preparation of Solution
`2.4 Method of Administration
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1 Hypersensitivity to Zoledronic Acid or Any Components of
`Zometa
`5 WARNINGS AND PRECAUTIONS
`5.1 Drugs with Same Active Ingredient or in the Same Drug Class
`5.2 Hydration and Electrolyte Monitoring
`5.3 Renal Impairment
`5.4 Osteonecrosis of the Jaw
`5.5 Musculoskeletal Pain
`5.6 Atypical Subtrochanteric and Diaphyseal Femoral Fractures
`5.7
`Patients with Asthma
`5.8 Hepatic Impairment
`5.9 Use in Pregnancy
`5.10 Hypocalcemia
`ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`
`6
`
`
`
`Reference ID: 3488314
`
`• Adequately rehydrate patients with hypercalcemia of malignancy prior to
`administration of Zometa and monitor electrolytes during treatment. (5.2)
`• Renal toxicity may be greater in patients with renal impairment. Do not use
`doses greater than 4 mg. Treatment in patients with severe renal
`impairment is not recommended. Monitor serum creatinine before each
`dose. (5.3)
`• Osteonecrosis of the jaw has been reported. Preventive dental exams should
`be performed before starting Zometa. Avoid invasive dental procedures.
`(5.4)
`• Severe incapacitating bone, joint, and/or muscle pain may occur.
`Discontinue Zometa if severe symptoms occur. (5.5)
`• Zometa can cause fetal harm. Women of childbearing potential should be
`advised of the potential hazard to the fetus and to avoid becoming pregnant.
`(5.9, 8.1)
`• Atypical subtrochanteric and diaphyseal femoral fractures have been
`reported in patients receiving bisphosphonate therapy. These fractures may
`occur after minimal or no trauma. Evaluate patients with thigh or groin pain
`to rule out a femoral fracture. Consider drug discontinuation in patients
`suspected to have an atypical femur fracture. (5.6)
`• Hypocalcemia: Correct before initiating Zometa. Adequately supplement
`patients with calcium and vitamin D (5.10)
`-------------------------------ADVERSE REACTIONS------------------------------
`The most common adverse events (greater than 25%) were nausea, fatigue,
`anemia, bone pain, constipation, fever, vomiting, and dyspnea (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch.
`-------------------------------DRUG INTERACTIONS------------------------------
`• Aminoglycosides: May have an additive effect to lower serum calcium for
`prolonged periods. (7.1)
`• Loop diuretics: Concomitant use with Zometa may increase risk of
`hypocalcemia. (7.2)
`• Nephrotoxic drugs: Use with caution. (7.3)
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`• Nursing Mothers: It is not known whether Zometa is excreted in human
`milk. (8.3)
`• Pediatric Use: Not indicated for use in pediatric patients. (8.4)
`• Geriatric Use: Special care to monitor renal function. (8.5)
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`Revised: 4/2014
`
`8
`
`7
`
`Postmarketing Experience
`6.2
`DRUG INTERACTIONS
`7.1 Aminoglycosides
`7.2
`Loop Diuretics
`7.3 Nephrotoxic Drugs
`7.4
`Thalidomide
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Hypercalcemia of Malignancy
`14.2 Clinical Trials in Multiple Myeloma and Bone Metastases of
`Solid Tumors
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`* Sections or subsections omitted from the full prescribing information are not
`listed
`
`00001
`
`Grun. Exh. 1014
`PGR for U.S. Patent No. 9,539,268
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`1.1 Hypercalcemia of Malignancy
`Zometa 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 [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8
`(4.0 g/dL - patient albumin [g/dL]).
`1.2 Multiple Myeloma and Bone Metastases of Solid Tumors
`Zometa 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 Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or
`with other nontumor-related conditions have not been established.
`
`DOSAGE AND ADMINISTRATION
`2
`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 Zometa in hypercalcemia of malignancy (albumin-corrected serum
`calcium greater than or equal to 12 mg/dL [3.0 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 Zometa should have serum creatinine
`assessed prior to each treatment.
`Dose adjustments of Zometa 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 µmol/L or
`less than 4.5 mg/dL).
`Patients should be adequately rehydrated prior to administration of Zometa [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 Zometa. 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 Zometa 4 mg may be considered if serum calcium does not return to normal or remain normal
`after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full
`response to the initial dose. Renal function must be carefully monitored in all patients receiving Zometa and
`serum creatinine must be assessed prior to retreatment with Zometa [see Warnings and Precautions (5.2)].
`2.2 Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors
`The recommended dose of Zometa 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.
`
`
`
`Reference ID: 3488314
`
`00002
`
`

`

`
`Upon treatment initiation, the recommended Zometa 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/min
`Baseline Creatinine Clearance (mL/min)
`Zometa Recommended Dose*
`greater than 60
`4 mg
`50–60
`3.5 mg
`40–49
`3.3 mg
`30–39
`3 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 Zometa dose and treatment should be
`withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:
`
`For patients with normal baseline creatinine, increase of 0.5 mg/dL
`
`For patients with abnormal baseline creatinine, increase of 1.0 mg/dL
`In the clinical studies, Zometa treatment was resumed only when the creatinine returned to within 10% of the
`baseline value. Zometa 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.
`
`Preparation of Solution
`2.3
`Zometa 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/100 mL Single-Use Ready-to-Use Bottle
`Bottles of Zometa ready-to-use solution for infusion contain overfill allowing for the administration of 100 mL
`of solution (equivalent to 4 mg zoledronic acid). This solution is ready-to-use and may be administered directly
`to the patient without further preparation. For single use only.
`To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the
`specified volume of the Zometa solution from the bottle (see Table 2) and replace with an equal volume of
`sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. Administer the newly-prepared dose-
`adjusted solution to the patient by infusion. Follow proper aseptic technique. Properly discard previously
`withdrawn volume of ready-to-use solution - do not store or reuse.
`
`Table 2: Preparation of Reduced Doses–Zometa Ready-to-Use Bottle
`Remove and discard the
`Replace with the following volume of
`Dose (mg)
`following Zometa ready-to-use
`sterile 0.9% Sodium Chloride, USP
`solution (mL)
`or 5% Dextrose Injection, USP (mL)
`3.5
`12.0
`12.0
`3.3
`18.0
`18.0
`3.0
`25.0
`25.0
`If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be
`refrigerated at 2°C–8°C (36°F–46°F). The refrigerated solution should then be equilibrated to room temperature
`
`
`Reference ID: 3488314
`
`00003
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`

`

`
`prior to administration. The total time between dilution, storage in the refrigerator, and end of administration
`must not exceed 24 hours.
`4 mg/5 mL Single-Use Vial
`Vials of Zometa 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 Zometa concentrate from the vial for the dose required (see Table 3).
`
`Table 3: Preparation of Reduced Doses–Zometa Concentrate
`Remove and Use
`Dose (mg)
`Zometa Volume (mL)
`4.4
`4.1
`3.8
`
`3.5
`3.3
`3.0
`
`The 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°C–8°C (36°F–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 Zometa 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 postmarketing 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 Zometa dose.
`
`DOSAGE FORMS AND STRENGTHS
`3
`4 mg/100 mL single-use ready-to-use bottle
`4 mg/5 mL single-use vial of concentrate
`
`CONTRAINDICATIONS
`4
`4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa
`Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic
`reaction/shock have been reported [see Adverse Reactions (6.2)].
`
`WARNINGS AND PRECAUTIONS
`5
`Drugs with Same Active Ingredient or in the Same Drug Class
`5.1
`Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with
`Zometa should not be treated with Reclast or other bisphosphonates.
`
`
`Reference ID: 3488314
`
`00004
`
`

`

`
`5.2 Hydration and Electrolyte Monitoring
`Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa.
`Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in
`combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other
`nephrotoxic drugs.
`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
`Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may
`be necessary.
`5.3
`Renal Impairment
`Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse
`reactions, may be greater in patients with impaired renal function. 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 Zometa and other bisphosphonates are
`risk factors for subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as
`dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible.
`Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be
`considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum
`creatinine greater than 400 µmol/L or greater than 4.5 mg/dL were excluded.
`Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the
`clinical studies, patients with serum creatinine greater than 265 µmol/L or greater than 3.0 mg/dL were
`excluded and there were only 8 of 564 patients treated with Zometa 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 Zometa. Many of these patients were also receiving chemotherapy and
`corticosteroids which may be risk factors for ONJ. Postmarketing 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 postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been
`reported in patients taking bisphosphonates, including Zometa. 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)].
`
`
`
`Reference ID: 3488314
`
`00005
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`

`

`
`Atypical Subtrochanteric and Diaphyseal Femoral Fractures
`5.6
`Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving
`bisphosphonate therapy, including Zometa. 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 Zometa
`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 Zometa, 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 Zometa to treat hypercalcemia of malignancy in patients with
`hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely
`use Zometa in these patients.
`Use in Pregnancy
`5.9
`Bisphosphonates, such as Zometa, 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.
`Zometa 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
`postimplantation 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)].
`
`5.10 Hypocalcemia
`Hypocalcemia has been reported in patients treated with Zometa. 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. Hypocalcemia must be corrected before initiating Zometa.
`Adequately supplement patients with calcium and vitamin D.
`
`ADVERSE REACTIONS
`6
`Clinical Studies Experience
`6.1
`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.
`
`
`
`Reference ID: 3488314
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`00006
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`

`

`
`Hypercalcemia of Malignancy
`The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received
`either Zometa 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 Zometa 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 Zometa 4 mg is
`given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less
`than 15 minutes [see Warnings and Precautions (5.3), 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 Zometa
`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
`Zometa
`4 mg
`n (%)
`
`Pamidronate
`90 mg
`n (%)
`
`
`
`
`Patients Studied
`Total No. of Patients Studied
`Total No. of Patients with any AE
`Body as a Whole
`Fever
`Progression of Cancer
`Cardiovascular
`Hypotension
`Digestive
`Nausea
`Constipation
`Diarrhea
`Abdominal Pain
`Vomiting
`Anorexia
`Hemic and Lymphatic System
`Anemia
`Infections
`Moniliasis
`Laboratory Abnormalities
`Hypophosphatemia
`Hypokalemia
`
`
`
`Reference ID: 3488314
`
`
`86
`81
`
`38
`14
`
`9
`
`25
`23
`15
`14
`12
`8
`
`19
`
`10
`
`11
`10
`
`
`(100)
`(94)
`
`(44)
`(16)
`
`(11)
`
`(29)
`(27)
`(17)
`(16)
`(14)
`(9)
`
`(22)
`
`(12)
`
`(13)
`(12)
`
`
`103
`95
`
`34
`21
`
`2
`
`28
`13
`17
`13
`17
`14
`
`18
`
`4
`
`2
`16
`
`
`(100)
`(92)
`
`(33)
`(20)
`
`(2)
`
`(27)
`(13)
`(17)
`(13)
`(17)
`(14)
`
`(18)
`
`(4)
`
`(2)
`(16)
`
`00007
`
`

`

`
`
`Hypomagnesemia
`Musculoskeletal
`Skeletal Pain
`Nervous
`Insomnia
`Anxiety
`Confusion
`Agitation
`Respiratory
`Dyspnea
`Coughing
`Urogenital
`Urinary Tract Infection
`
`9
`
`10
`
`13
`12
`11
`11
`
`19
`10
`
`12
`
`(11)
`
`(12)
`
`(15)
`(14)
`(13)
`(13)
`
`(22)
`(12)
`
`(14)
`
`5
`
`10
`
`10
`8
`13
`8
`
`20
`12
`
`15
`
`(5)
`
`(10)
`
`(10)
`(8)
`(13)
`(8)
`
`(19)
`(12)
`
`(15)
`
`The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a
`greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a
`frequency of 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 Zometa.
`Acute Phase Reaction
`Within three days after Zometa 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 Zometa 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 HCM
`Grade 3
`
`
`Laboratory Parameter
`
`
`Serum Creatinine1
`Hypocalcemia2
`Hypophosphatemia3
`Hypomagnesemia4
`
`Zometa
`4 mg
`
`n/N
`2/86
`1/86
`36/70
`0/71
`
`(%)
`(2%)
`(1%)
`(51%)
`—
`
`Pamidronate
`90 mg
`
`n/N
`3/100
`2/100
`27/81
`0/84
`
`(%)
`(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
`
`Zometa
`
`Pamidronate
`
`
`Laboratory Parameter
`
`
`Reference ID: 3488314
`
`00008
`
`

`

`4 mg
`
`
`
`
`(%)
`n/N
`Serum Creatinine1
`—
`0/86
`Hypocalcemia2
`—
`0/86
`Hypophosphatemia3
`(1%)
`1/70
`Hypomagnesemia4
`—
`0/71
`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)
`
`90 mg
`
`n/N
`1/100
`0/100
`4/81
`1/84
`
`(%)
`(1%)
`—
`(5%)
`(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 Zometa. 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 Zometa 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 Zometa 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 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
`Zometa
`4 mg
`n (%)
`
`Pamidronate
`90 mg
`n (%)
`
`Placebo
`
`n (%)
`
`
`455
`445
`
`128
`35
`20
`
`171
`122
`174
`83
`48
`
`
`(100)
`(98)
`
`(28)
`(8)
`(4)
`
`(38)
`(27)
`(38)
`(18)
`(11)
`
`
`
`
`Patients Studied
`Total No. of Patients
`Total No. of Patients with any AE
`Blood and Lymphatic
`Anemia
`Neutropenia
`Thrombocytopenia
`Gastrointestinal
`Nausea
`Vomiting
`Constipation
`Diarrhea
`Abdominal Pain
`
`
`
`Reference ID: 3488314
`
`
`1031
`1015
`
`344
`124
`102
`
`476
`333
`320
`249
`143
`
`
`(100)
`(98)
`
`(33)
`(12)
`(10)
`
`(46)
`(32)
`(31)
`(24)
`(14)
`
`
`556
`548
`
`175
`83
`53
`
`266
`183
`162
`162
`81
`
`
`(100)
`(99)
`
`(32)
`(15)
`(10)
`
`(48)
`(33)
`(29)
`(29)
`(15)
`
`00009
`
`

`

`
`Dyspepsia
`Stomatitis
`Sore Throat
`General Disorders and Administration Site
`Fatigue
`Pyrexia
`Weakness
`Edema Lower Limb
`Rigors
`Infections
`Urinary Tract Infection
`Upper Respiratory Tract Infection
`Metabolism
`Anorexia
`Weight Decreased
`Dehydration
`Appetite Decreased
`Musculoskeletal
`Bone Pain
`Myalgia
`Arthralgia
`Back Pain
`Pain in Limb
`Neoplasms
`Malignant Neoplasm Aggravated
`Nervous
`Headache
`Dizziness (excluding vertigo)
`Insomnia
`Paresthesia
`Hypoesthesia
`Psychiatric
`Depression
`Anxiety
`Confusion
`Respiratory
`Dyspnea
`Cough
`Skin
`Alopecia
`Dermatitis
`
`105
`86
`82
`
`398
`328
`252
`215
`112
`
`124
`101
`
`231
`164
`145
`130
`
`569
`239
`216
`156
`143
`
`205
`
`191
`180
`166
`149
`127
`
`146
`112
`74
`
`282
`224
`
`125
`114
`
`(10)
`(8)
`(8)
`
`(39)
`(32)
`(24)
`(21)
`(11)
`
`(12)
`(10)
`
`(22)
`(16)
`(14)
`(13)
`
`(55)
`(23)
`(21)
`(15)
`(14)
`
`(20)
`
`(19)
`(18)
`(16)
`(15)
`(12)
`
`(14)
`(11)
`(7)
`
`(27)
`(22)
`
`(12)
`(11)
`
`74
`65
`61
`
`240
`172
`108
`126
`62
`
`50
`82
`
`81
`50
`60
`48
`
`316
`143
`131
`106
`84
`
`97
`
`149
`91
`111
`85
`65
`
`95
`73
`39
`
`155
`129
`
`80
`74
`
`(13)
`(12)
`(11)
`
`(43)
`(31)
`(19)
`(23)
`(11)
`
`(9)
`(15)
`
`(15)
`(9)
`(11)
`(9)
`
`(57)
`(26)
`(24)
`(19)
`(15)
`
`(17)
`
`(27)
`(16)
`(20)
`(15)
`(12)
`
`(17)
`(13)
`(7)
`
`(28)
`(23)
`
`(14)
`(13)
`
`31
`14
`17
`
`130
`89
`114
`84
`28
`
`41
`30
`
`105
`61
`59
`45
`
`284
`74
`73
`40
`52
`
`89
`
`50
`58
`73
`35
`43
`
`49
`37
`47
`
`107
`65
`
`36
`38
`
`(7)
`(3)
`(4)
`
`(29)
`(20)
`(25)
`(19)
`(6)
`
`(9)
`(7)
`
`(23)
`(13)
`(13)
`(10)
`
`(62)
`(16)
`(16)
`(9)
`(11)
`
`(20)
`
`(11)
`(13)
`(