Ganite
Generic Name: gallium nitrate
Dosage Form: Injection
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.
Ganite 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•9H2O 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.
Ganite - 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
| Mean Change in Time
Period1 (hours) |
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.
Indications and Usage for Ganite
Ganite is indicated for the treatment of clearly symptomatic
cancer-related hypercalcemia that has not responded to adequate
hydration. In general, patients with a serum calcium (corrected for
albumin) < 12 mg/dL would not be expected to be symptomatic. Mild
or asymptomatic hypercalcemia may be treated with conservative measures
(i.e., saline hydration, with or without diuretics). In the treatment of
cancer-related hypercalcemia, it is important first to establish
adequate hydration, preferably with intravenous saline, in order to
increase the renal excretion of calcium and correct dehydration caused
by hypercalcemia.
Contraindications
Ganite should not be administered to patients with severe renal
impairment (serum creatinine > 2.5 mg/dL).
Warnings
(See boxed WARNING.) The hypercalcemic state in cancer patients is commonly
associated with impaired renal function. Abnormalities in renal function (elevated BUN and/or serum creatinine) have been observed in clinical
trials with Ganite. It is strongly recommended
that serum creatinine be monitored during Ganite therapy.
Since patients with cancer-related hypercalcemia are frequently
dehydrated, it is important that such patients be adequately hydrated
with oral and/or intravenous fluids (preferably saline) and that a
satisfactory urine output (a urine output of 2 L/day is recommended) be
established before therapy with Ganite is started. Adequate hydration
should be maintained throughout the treatment period, with careful
attention to avoid overhydration in patients with compromised
cardiovascular status. Diuretic therapy should not be employed prior to
correction of hypovolemia. Ganite therapy should be discontinued if the
serum creatinine level exceeds 2.5 mg/dL.
The use of Ganite in patients with marked renal insufficiency
(serum creatinine > 2.5 mg/dL) has not been systematically
examined. If therapy is undertaken in patients with moderately impaired
renal function (serum creatinine 2.0 to 2.5 mg/dL), frequent monitoring
of the patient’s renal status is recommended. Treatment should
be discontinued if the serum creatinine level exceeds 2.5 mg/dL.
Combined use of Ganite with other potentially nephrotoxic drugs
(e.g., aminoglycosides, amphotericin B) may increase the risk of developing renal insufficiency in patients with cancer-related
hypercalcemia (see boxed WARNING).
Precautions
General
Asymptomatic or mild to moderate hypocalcemia (6.5 - 8.0 mg/dL,
corrected for serum albumin) occurred in approximately
38% of patients treated with Ganite in the controlled
clinical trial. One patient exhibited a positive
Chvostek’s sign. If hypocalcemia occurs, Ganite
therapy should be stopped and short-term calcium therapy may be
necessary.
Laboratory Tests Renal function (serum creatinine and BUN) and
serum calcium must be closely monitored during Ganite therapy.
In addition to baseline assessment, the suggested frequency of
calcium and phosphorus determinations is daily and twice weekly,
respectively. Ganite should be discontinued if the serum
creatinine exceeds 2.5 mg/dL.
Drug
Interactions The concomitant use of highly nephrotoxic
drugs in combination with Ganite may increase the risk for
development of renal insufficiency (see WARNINGS). Available information does not indicate any adverse
interaction with diuretics such as furosemide. A symptom complex
of dyspnea (associated with interstitial pneumonitis in some
instances), mouth soreness, and asthenia has been reported in a
small number of multiple myeloma patients receiving low dose (40
mg) gallium nitrate subcutaneously in addition to oral
cyclophosphamide and prednisone. The serious nature of the
underlying condition of these patients precludes a precise
understanding of the relationship of these events to either
gallium nitrate treatment alone or with
cyclophosphamide.
Carcinogenesis,
Mutagenesis, Impairment of Fertility Long-term
studies in animals have not been performed to evaluate the
carcinogenic potential of gallium nitrate. Gallium nitrate is
not mutagenic in standard tests (i.e., Ames test and chromosomal
aberration studies on human lymphocytes).
Usage in
Pregnancy Pregnancy Category C. Animal reproduction studies
have not been conducted with gallium nitrate. It is also not
known whether gallium nitrate can cause fetal harm when
administered to a pregnant woman or can affect reproductive
capacity. Ganite should be administered to a pregnant woman only
if clearly needed.
Nursing
Mothers It is not known whether gallium nitrate is
excreted in human milk. Because of the potential for serious
adverse reactions in nursing infants from gallium nitrate, a
decision should be made whether to discontinue nursing or
discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
The safety and effectiveness of Ganite in children have not been
established.
Adverse Reactions
Kidney
Adverse renal effects, as demonstrated by rising BUN and
creatinine, have been reported in about 12.5% of
patients treated with Ganite. In a controlled clinical trial of
patients with cancer-related hypercalcemia, two patients
receiving Ganite and one patient receiving calcitonin developed
acute renal failure. Due to the serious nature of the
patients’ underlying conditions, the relationship of
these events to the drug was unclear. Ganite should not be
administered to patients with serum creatinine >2.5 mg/dL
(see CONTRAINDICATIONS and WARNINGS).
Metabolic
Hypocalcemia may occur after Ganite treatment (see PRECAUTIONS).
Transient hypophosphatemia of mild-to-moderate degree may
occur in up to 79% of hypercalcemic patients following
treatment with Ganite. In a controlled clinical trial,
33% of patients had at least 1 serum phosphorus
measurement between 1.5-2.4 mg/dL, while 46% of patients
had at least 1 serum phosphorus value <1.5 mg/dL.
Patients who develop hypophosphatemia may require oral
phosphorus therapy.
Decreased serum bicarbonate, possibly secondary to mild
respiratory alkalosis was reported in 40-50% of cancer
patients treated with Ganite. The cause for this effect is not
clear. This effect has been asymptomatic and has not required
specific treatment.
Hematologic
The use of very high doses of gallium nitrate (up to 1400
mg/m2) in treating patients for advanced cancer
has been associated with anemia, and several patients have received red blood cell transfusions. Due to the serious nature
of the underlying illness, it is uncertain that the anemia was
caused by gallium nitrate.
Blood
Pressure A decrease in mean systolic and diastolic
blood pressure was observed several days after treatment with
gallium nitrate in a controlled clinical trial. The decrease in
blood pressure was asymptomatic and did not require specific
treatment.
Visual and
Auditory In cancer chemotherapy trials, a small
proportion (<1%) of patients treated with
multiple high doses of gallium nitrate combined with other
investigational anticancer drugs, have developed acute optic
neuritis. While these patients were critically ill and had
received multiple drugs, a reaction to high-dose gallium nitrate
is possible. Most patients had full recovery; however, at least
one case of permanent blindness has been reported. One patient
with cancer-related hypercalcemia was reported to develop
decreased hearing following gallium nitrate administration. Due
to the patient’s underlying condition and concurrent
therapies, the relationship of this event to gallium nitrate
administration is unclear. Tinnitus and partial loss of auditory
acuity have been reported rarely (<1%) in
patients who received high-dose gallium nitrate as anticancer
treatment.
Miscellaneous
Other clinical events reported in association with gallium
nitrate treatment for cancer as well as cancer-related
hypercalcemia include: nausea and/or vomiting, tachycardia,
lethargy, confusion, dreams and hallucinations, diarrhea,
constipation, lower extremity edema, hypothermia, fever,
dyspnea, rales and rhonchi, anemia, leukopenia, paresthesia,
skin rash, pleural effusion, and pulmonary infiltrates. Due to the serious nature of the underlying condition of these
patients, the relationship of these events to therapy with
gallium nitrate is unknown. A single case of encephalopathy
followed rapidly by coma and death has been reported after
treatment in a cancer chemotherapy trial with gallium nitrate
300 mg/m2/day for 7 days. Treatment with gallium
nitrate other than as described in this labeling may be
complicated by adverse events not listed.
Overdosage
Rapid intravenous infusion of gallium nitrate or use of doses
higher than recommended (200 mg/m2) may cause nausea and
vomiting and a substantially increased risk of renal insufficiency. In
the event of overdosage, further drug administration should be
discontinued, serum calcium should be monitored, and the patient should
receive vigorous intravenous hydration, with or without diuretics, for
2-3 days. During this time period, renal function and urinary output
should be carefully monitored so that fluid intake and output are
balanced.
Ganite Dosage and Administration
The usual recommended dose of Ganite is 200 mg per square meter
of body surface area (200 mg/m2) daily for 5 consecutive days. In patients with mild hypercalcemia and few symptoms, a lower
dosage of 100 mg/m2/day for 5 days may be considered. If
serum calcium levels are lowered into the normal range in less than 5
days, treatment may be discontinued early. The daily dose must be
administered as an intravenous infusion over 24 hours. The daily dose
should be diluted, preferably in 1,000 mL of 0.9% Sodium
Chloride Injection USP, or 5% Dextrose Injection USP, for
administration as an intravenous infusion over 24 hours. Adequate
hydration must be maintained throughout the treatment period, with
careful attention to avoid overhydration in patients with compromised
cardiovascular status. Controlled studies have not been undertaken to
evaluate the safety and effectiveness of retreatment with gallium
nitrate.
When Ganite is added to either 0.9% Sodium Chloride
Injection USP or 5% Dextrose Injection USP, it is stable for 48
hours at room temperature (15°C to 30°C) or for 7 days
if stored under refrigeration (2°C to 8°C). Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container
permit.
How is Ganite Supplied
Ganite™ (gallium nitrate injection) is supplied as a
5-unit carton, NDC 66657-301-05.
Each carton contains 5 single-dose, flip-top vials (NDC
66657-301-01) each containing 500 mg of gallium nitrate (25 mg/mL) in 20
mL.
Store at controlled room temperature 20°-25°C
(68°-77°F).
Contains no preservative. Discard unused portion.
Rx only
Ganite™ is a trademark of Genta Incorporated.
Manufactured for:
Genta Incorporated
Berkeley Heights, NJ
07922
1-888-TO-GENTA
Rev: September 2003
30105901
Revised: 03/2007
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