GANITE

GANITE- gallium nitrate injection, solution, concentrate
Genta Incorporated

WARNING

Concurrent use of gallium nitrate with other potentially nephrotoxic drugs (e.g., aminoglycosides, amphotericin B) may increase the risk for developing severe renal insufficiency in patients with cancer-related hypercalcemia. If use of a potentially nephrotoxic drug is indicated during gallium nitrate therapy, gallium nitrate administration should be discontinued and it is recommended that hydration be continued for several days after administration of the potentially nephrotoxic drug. Serum creatinine and urine output should be closely monitored during and subsequent to this period. Ganite therapy should be discontinued if the serum creatinine level exceeds 2.5 mg/dL.

DESCRIPTION

Gallium nitrate injection is a clear, colorless, odorless, sterile solution of gallium nitrate, a hydrated nitrate salt of the group IIIa element, gallium. Gallium nitrate is formed by the reaction of elemental gallium with nitric acid, followed by crystallization of the drug from the solution. The stable, nonahydrate, Ga(N03 )3 •9H2 O is a white, slightly hygroscopic, crystalline powder of molecular weight 417.87, that is readily soluble in water. Each mL of Ganite (gallium nitrate injection) contains gallium nitrate 25 mg (on an anhydrous basis) and sodium citrate dihydrate 28.75 mg. The solution may contain sodium hydroxide or hydrochloric acid for pH adjustment to 6.0-7.0.

CLINICAL PHARMACOLOGY

Mechanism of Action Ganite exerts a hypocalcemic effect by inhibiting calcium resorption from bone, possibly by reducing increased bone turnover. Although in vitro and animal studies have been performed to investigate the mechanism of action of gallium nitrate, the precise mechanism for inhibiting calcium resorption has not been determined. No cytotoxic effects were observed on bone cells in drug-treated animals.

Pharmacokinetics Gallium nitrate was infused at a daily dose of 200 mg/m2 for 5 (n=2) or 7 (n=10) consecutive days to 12 cancer patients. In most patients apparent steady-state is achieved by 24 to 48 hours. The range of average steady-state plasma levels of gallium observed among 7 fully evaluable patients was between 1134 and 2399 ng/mL. The average plasma clearance of gallium (n=7) following daily infusion of gallium nitrate at a dose of 200 mg/m2 for 5 or 7 days was 0.15 L/hr/kg (range: 0.12 to 0.20 L/hr/kg). In one patient who received daily infusion doses of 100, 150 and 200 mg/m2 the apparent steady-state levels of gallium did not increase proportionally with an increase in dose. Gallium nitrate is not metabolized either by the liver or the kidney and appears to be significantly excreted via the kidney. Urinary excretion data for a dose of 200 mg/m2 has not been determined.

Cancer-Related Hypercalcemia Hypercalcemia is a common problem in hospitalized patients with malignancy. It may affect 10-20% of patients with cancer. Different types of malignancy seem to vary in their propensity to cause hypercalcemia. A higher incidence of hypercalcemia has been observed in patients with non-small cell lung cancer, breast cancer, multiple myeloma, kidney cancer, and cancer of head and neck. Hypercalcemia of malignancy seems to result from an imbalance between the net resorption of bone and urinary excretion of calcium. Patients with extensive osteolytic bone metastases frequently develop hypercalcemia: this type of hypercalcemia is common with primary breast cancer. Some of these patients have been reported to have increased renal tubular calcium resorption. Breast cancer cells have been reported to produce several potential bone-resorbing factors which stimulate the local osteoclast activity. Humoral hypercalcemia is common with the solid tumors of the lung, head and neck, kidney, and ovaries. Systemic factors (e.g., PTH-rP) produced either by the tumor or host cells have been implicated for the altered calcium fluxes between the extracellular fluid, the kidney, and the skeleton. About 30% of patients with myeloma develop hypercalcemia associated with extensive osteolytic lesions and impaired glomerular filtration. Myeloma cells have been reported to produce local factors that stimulate adjacent osteoclasts.

Hypercalcemia may produce a spectrum of signs and symptoms including: anorexia, lethargy, fatigue, nausea, vomiting, constipation, dehydration, renal insufficiency, impaired mental status, coma and cardiac arrest. A rapid rise in serum calcium may cause more severe symptoms for a given level of hypercalcemia. Since calcium is bound to serum proteins, which may fluctuate in concentration as a response to changes in blood volume, changes in total serum calcium (especially during rehydration) may not accurately reflect changes in the concentration of free-ionized calcium. In the absence of a direct measurement of free-ionized calcium, measurement of the serum albumin concentration and correction of the total serum calcium concentration may help in assessing the severity of hypercalcemia. The patient’s acid-base status should also be taken into consideration while assessing the degree of hypercalcemia. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without diuretics). The patient’s cardiovascular status should be taken into consideration in the use of saline. In patients who have an underlying cancer type that may be sensitive to corticosteroids (e.g., hematologic cancers), the use or addition of corticosteroid therapy may be indicated.

Hypocalcemic Activity A randomized double-blind clinical study comparing Ganite with calcitonin was conducted in patients with a serum calcium concentration (corrected for albumin) ≥ 12.0 mg/dL following 2 days of hydration. Ganite was given as a continuous intravenous infusion at a dose of 200 mg/m2 /day for 5 days and calcitonin was given intramuscularly at a dose of 8 I.U./kg every 6 hours for 5 days. Elevated serum calcium (corrected for albumin) was normalized in 75% (18 of 24) of the patients receiving Ganite and in 27% (7 of 26) of the patients receiving calcitonin (p=0.0016). The time-course of effect on serum calcium (corrected for albumin) is summarized in the following table.

Change in Corrected Serum Calcium by Time from Initiation of Treatment
Time Period1
(hours)
Mean Change in
Serum Calcium2 (mg/dL)
GANITE Calcitonin

1 Time after initiation of therapy in hours.

2 Change from baseline in serum calcium (corrected for albumin).

* Comparison between treatment groups (p< 0.01).

24

-0.4

-1.6*

48

-0.9

-1.4

72

-1.5

-1.1

96

-2.9*

-1.1

120

-3.3*

-1.3

The median duration of normocalcemia/hypocalcemia was 7.5 days for patients treated with Ganite and 1 day for patients treated with calcitonin. A total of 92% of patients treated with Ganite had a decrease in serum calcium (corrected for albumin) ≥ 2.0 mg/dL as compared to 54% of the patients treated with calcitonin (p=0.004).

An open-label, non-randomized study was conducted to examine a range of doses and dosing schedules of Ganite for control of cancer-related hypercalcemia. The principal dosing regimens were 100 and 200 mg/m2 /day, administered as continuous intravenous infusions for 5 days. Ganite, at a dose of 200 mg/m2 /day for 5 days was found to normalize elevated serum calcium levels (corrected for albumin) in 83% of patients as compared to 50% of patients receiving a dose of 100 mg/m2 /day for 5 days. A decrease in serum calcium (corrected for albumin) ≥ 2.0 mg/dL was observed in 83% and 94% of patients treated with Ganite at dosages of 100 and 200 mg/m2 /day for 5 days, respectively. There were no significant differences in the proportion of patients responding to Ganite when considering either the presence or absence of bone metastasis, or whether the tumor histology was epidermoid or nonepidermoid.

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