Zometa

Generic Name: zoledronic acid

Dosage Form: injection, solution, concentrate
FULL PRESCRIBING INFORMATION

Indications and Usage for Zometa

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)).

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.

Important Limitation of Use

The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established.

Zometa Dosage and Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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)].

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 greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3-4 weeks. The optimal duration of therapy is not known.

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 AUC as that achieved in patients with creatinine clearance of 75 mL/min. Creatinine clearance (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 IU of Vitamin D daily.

Preparation of Solution

 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 following Zometa ready-to-use solution (mL)	Replace with the following volume of sterile 0.9% Sodium Chloride, USP or 5% Dextrose Injection, USP (mL)	Dose (mg)
12.0	12.0	3.5
18.0	18.0	3.3
25.0	25.0	3.0

 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 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  Zometa Volume (mL)	Dose (mg)
4.4	3.5
4.1	3.3
3.8	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.

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 (5.2)]. 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

4 mg/100 mL single-use ready-to-use bottle

4 mg/5 mL single-use vial of concentrate

Contraindications

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

Drugs with Same Active Ingredient or in the Same Drug Class 

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.

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.

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)].

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)].

Musculoskeletal Pain

In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes 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)].

Patients with Asthma

While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates.

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

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 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)].

Adverse Reactions

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 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) and Dosage And Administration (2)].

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		Pamidronate
	4 mg		90 mg
	n (%)		n (%)
Patients Studied
Total No. of Patients Studied	86	(100)	103	(100)
Total No. of Patients with any AE	81	(94)	95	(92)
Body as a Whole
Fever	38	(44)	34	(33)
Progression of Cancer	14	(16)	21	(20)
Cardiovascular
Hypotension	9	(11)	2	(2)
Digestive
Nausea	25	(29)	28	(27)
Constipation	23	(27)	13	(13)
Diarrhea	15	(17)	17	(17)
Abdominal Pain	14	(16)	13	(13)
Vomiting	12	(14)	17	(17)
Anorexia	8	(9)	14	(14)
Hemic and Lymphatic System
Anemia	19	(22)	18	(18)
Infections
Moniliasis	10	(12)	4	(4)
Laboratory Abnormalities
Hypophosphatemia	11	(13)	2	(2)
Hypokalemia	10	(12)	16	(16)
Hypomagnesemia	9	(11)	5	(5)
Musculoskeletal
Skeletal Pain	10	(12)	10	(10)
Nervous
Insomnia	13	(15)	10	(10)
Anxiety	12	(14)	8	(8)
Confusion	11	(13)	13	(13)
Agitation	11	(13)	8	(8)
Respiratory
Dyspnea	19	(22)	20	(19)
Coughing	10	(12)	12	(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 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-like Events

Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias.

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	Zometa		Pamidronate
	4 mg		90 mg
	n/N	(%)	n/N	(%)
Serum Creatinine1	2/86	(2%)	3/100	(3%)
Hypocalcemia2	1/86	(1%)	2/100	(2%)
Hypophosphatemia3	36/70	(51%)	27/81	(33%)
Hypomagnesemia4	0/71	—	0/84	—

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	Zometa		Pamidronate
	4 mg		90 mg
	n/N	(%)	n/N	(%)
Serum Creatinine1	0/86	—	1/100	(1%)
Hypocalcemia2	0/86	—	0/100	—
Hypophosphatemia3	1/70	(1%)	4/81	(5%)
Hypomagnesemia4	0/71	—	1/84	(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 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 2,042 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		Pamidronate		Placebo
	4 mg		90 mg
	n (%)		n (%)		n (%)
Patients Studied
Total No. of Patients	1031	(100)	556	(100)	455	(100)
Total No. of Patients with any AE	1015	(98)	548	(99)	445	(98)
Blood and Lymphatic
Anemia	344	(33)	175	(32)	128	(28)
Neutropenia	124	(12)	83	(15)	35	(8)
Thrombocytopenia	102	(10)	53	(10)	20	(4)
Gastrointestinal
Nausea	476	(46)	266	(48)	171	(38)
Vomiting	333	(32)	183	(33)	122	(27)
Constipation	320	(31)	162	(29)	174	(38)
Diarrhea	249	(24)	162	(29)	83	(18)
Abdominal Pain	143	(14)	81	(15)	48	(11)
Dyspepsia	105	(10)	74	(13)	31	(7)
Stomatitis	86	(8)	65	(12)	14	(3)
Sore Throat	82	(8)	61	(11)	17	(4)
General Disorders and Administration Site
Fatigue	398	(39)	240	(43)	130	(29)
Pyrexia	328	(32)