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GALLIUM NITRATE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Gallium nitrate is a hydrated nitrate salt of the group IIIa element, Gallium. It is a calcium regulating agent. Because of its ability to inhibit calcium resorption from bone, it is used in the treatment of hypercalcemia of malignancy.

Specific Substances

    1) Gallium(III) nitrate (1:3)
    2) Nitric acid, gallium(3+) salt
    3) NSC 15200
    4) Molecular formula: Ga(NO3)3
    5) NIOSH/RTECS LW 9625000
    6) CAS 13494-90-1

Available Forms Sources

    A) FORMS
    1) Gallium nitrate is available as 500 mg (25 mg/mL) in 20 mL single-dose, flip-top vials for injection (Prod Info Ganite(R), gallium nitrate injection, 1991).
    B) SOURCES
    1) Gallium nitrate is formed by the reaction of elemental gallium with nitric acid, followed by crystallization of the drug from the solution (Prod Info Ganite(R), gallium nitrate injection, 1991).
    C) USES
    1) Gallium nitrate is indicated for the treatment of symptomatic hypercalcemia of malignancy that is refractory to hydration measures (Prod Info Ganite(R), gallium nitrate injection, 1991).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Hypocalcemia, hypophosphatemia, and decreased serum bicarbonate may frequently occur with gallium nitrate therapy.
    2) Other adverse effects that may occur following therapeutic administration of gallium nitrate include lethargy, confusion, paresthesias, anemia, leukopenia, visual and hearing impairment, respiratory insufficiency, nausea, vomiting, diarrhea, lower extremity edema, and skin rash. However, due to the underlying medical conditions and concomitant medications given to patients in clinical trials, the relationship of these effects to gallium nitrate therapy is unknown.
    3) When combined with other nephrotoxic drugs, renal failure may occur.
    B) WITH POISONING/EXPOSURE
    1) In overdose, nausea, vomiting and renal failure may develop.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Significant cardiac events may occur including tachycardia, atrial fibrillation, atrial flutter, supraventricular tachycardia, myocardial infarction, and congestive heart failure.
    0.2.6) RESPIRATORY
    A) ANIMAL STUDIES - Pneumonitis has been reported in rodents following treatment with gallium nitrate.
    B) WITH THERAPEUTIC USE
    1) Tachypnea, with respiratory alkalosis, may be seen.
    2) A pulmonary syndrome, characterized by dyspnea, crackles, rhonchi, pleural effusion, and pulmonary infiltrates, has been reported.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Lethargy, confusion, and paresthesias may occur.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, diarrhea, and constipation have been reported during therapy.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Acute renal failure and elevated BUN and serum creatinine levels have been reported with gallium nitrate therapy.
    2) There does not appear to be cumulative renal toxicity in patients receiving intermittent gallium nitrate infusions for periods greater than 18 months.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH THERAPEUTIC USE
    1) Hypocalcemia is a common occurrence following gallium nitrate therapy.
    2) Transient hypophosphatemia may occur in hypercalcemic patients following gallium nitrate treatment.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Anemia has been commonly reported.
    2) Leukopenia and thrombocytopenia are infrequent occurrences with gallium nitrate therapy.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) A skin rash may occur.
    2) When gallium nitrate was given subcutaneously, minor discomfort at the injection site was frequently reported.
    0.2.20) REPRODUCTIVE
    A) Gallium nitrate is classified as FDA pregnancy category C.

Laboratory Monitoring

    A) Monitor serum BUN and creatinine, electrolytes including calcium and phosphorous, a CBC, and urine output during gallium nitrate therapy or following overdose.
    B) An ECG should be obtained and evaluated for evidence of hypocalcemia (prolonged QTc interval, prolonged ST segment, Torsades de Pointes) or other electrolyte abnormalities.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) Treatment is symptomatic and supportive.
    B) Renal toxicity can be prevented or mitigated by hyperhydration prior to treatment and by giving gallium nitrate by continuous intravenous administration.
    C) In overdose, as allowed by cardiovascular function, vigorous intravenous hydration, with or without diuretics, should be performed for 2 to 3 days.

Range Of Toxicity

    A) A specific minimum toxic dose has not been established.
    B) Toxicity is dependent on the total dose, the rate at which it is given, underlying pathology, and interactions with other nephrotoxic drugs. Doses up to 1400 mg/m2 have been used in clinical trials.

Clinical Effects

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) RESPIRATORY ALKALOSIS
    1) WITH THERAPEUTIC USE
    a) Decreased serum bicarbonate, possibly secondary to respiratory alkalosis, occurred in 40% to 50% of patients given gallium nitrate for treatment of hypercalcemia of malignancy (Prod Info GANITE(TM) injection, 2003).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Anemia has been commonly reported.
    2) Leukopenia and thrombocytopenia are infrequent occurrences with gallium nitrate therapy.
    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia was associated with high-dose gallium nitrate therapy (up to 1400 mg/m(2)) in patients with advanced cancer (Prod Info GANITE(TM) injection, 2003).
    b) Blood transfusions for anemia were required in all patients treated for androgen-metastatic prostate cancer with gallium nitrate 150 to 200 mg/m(2)/day for 7 days administered every 21 days (Senderowicz et al, 1999).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been associated with gallium nitrate therapy, but the relationship between its occurrence and gallium nitrate therapy is unknown (Prod Info GANITE(TM) injection, 2003).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia may rarely (one of 38 patients) occur (Weick et al, 1983).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA
    a) MONKEY - Gallium nitrate doses of 5 mg/kg/day for 5 days in rhesus monkeys were not toxic, producing no changes in blood chemistry or hematology. Doses of 10 mg/kg/day for 5 days produced slight anemia, and doses of 20 mg/kg/day were lethal (Hart et al, 1971).
    2) LEUKOCYTOSIS
    a) DOG - Dogs are more sensitive than rhesus monkeys to the toxic effect of gallium nitrate. Doses as low as 1.25 mg/kg/day for 5 days produced leukocytosis and a shift to the left in the differential count (Hart et al, 1971).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) A skin rash may occur.
    2) When gallium nitrate was given subcutaneously, minor discomfort at the injection site was frequently reported.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) A skin rash may occur with gallium nitrate therapy (Prod Info GANITE(TM) injection, 2003).
    B) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Following subcutaneous administration of gallium nitrate at doses of 0.25 to 0.5 mg/kg/day, minor discomfort at the injection site was frequently reported (Bockman et al, 1995).
    b) Gallium nitrate administered subcutaneously at a dose of 30 mg/m(2)/day for 14 days caused transient focal stinging and burning at the injection site. There was no evidence of local ulceration (Warrell et al, 1993).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Musculoskeletal pain was reported in 5 of 15 patients, with metastatic breast cancer, treated with gallium nitrate, 300 mg/m(2)/day for 7 days every 3 weeks by continuous intravenous infusion, administered concomitantly with oral calcium supplementation and oral hydration (Jabboury et al, 1989).

Reproductive

    3.20.1) SUMMARY
    A) Gallium nitrate is classified as FDA pregnancy category C.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) It is not known whether gallium nitrate can cause fetal harm when administered to a pregnant woman (Prod Info Ganite(R), gallium nitrate injection, 1991).
    B) ANIMAL STUDIES
    1) ANIMAL DATA
    a) MICE - Embryo/fetal toxicity of mice was evidenced by a decrease in the number of viable implants, a reduction in fetal weight, and an increase in the number of skeletal variations at doses up to 100 mg/kg/day; however, there was no significant increase in the incidence of malformations observed at doses below 100 mg/kg/day (Gomez et al, 1992).
    b) MICE - The no-observable-adverse effect level (NOAEL) for developmental toxicity of gallium nitrate, in mice, was less than 12.5 mg/kg (Gomez et al, 1992).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Gallium nitrate is classified by the manufacturer as FDA pregnancy category C (Prod Info Ganite(R), gallium nitrate injection, 1991).
    B) ANIMAL DATA
    1) MICE - Pregnant Swiss mice, given gallium nitrate intraperitoneally at doses up to 100 mg/kg/day during multiple days of gestation, demonstrated maternal toxicity in all treated groups (Gomez et al, 1992).
    2) MICE - The no-observable-adverse-effect level (NOAEL) for maternal toxicity of gallium nitrate was less than 12.5 mg/kg (Gomez et al, 1992).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether gallium nitrate is excreted in human milk (Prod Info Ganite(R), gallium nitrate injection, 1991).
    3.20.5) FERTILITY
    A) ANIMAL DATA
    1) MICE - Male mice injected subcutaneously at doses up to 96 mg/kg/day every other day for 14 days showed no difference from controls in infertility and reproductive performance. Sperm counts and percentage of motile cells were comparable with controls. Histopathological examination of the testes and epididymis did not reveal any changes at any dose of gallium nitrate up to 96 mg/kg/day, which is approximately 30 times higher than the current doses administered to humans (Colomina et al, 1993).

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Hypocalcemia, hypophosphatemia, and decreased serum bicarbonate may frequently occur with gallium nitrate therapy.
    2) Other adverse effects that may occur following therapeutic administration of gallium nitrate include lethargy, confusion, paresthesias, anemia, leukopenia, visual and hearing impairment, respiratory insufficiency, nausea, vomiting, diarrhea, lower extremity edema, and skin rash. However, due to the underlying medical conditions and concomitant medications given to patients in clinical trials, the relationship of these effects to gallium nitrate therapy is unknown.
    3) When combined with other nephrotoxic drugs, renal failure may occur.
    B) WITH POISONING/EXPOSURE
    1) In overdose, nausea, vomiting and renal failure may develop.

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH THERAPEUTIC USE
    1) TACHYPNEA, with respiratory alkalosis, may occur (Prod Info GANITE(TM) injection, 2003).
    3.3.3) TEMPERATURE
    A) HYPERTHERMIA
    1) WITH THERAPEUTIC USE
    a) Hyperthermia or fever may occur with gallium nitrate administration (Prod Info Ganite(R), gallium nitrate injection, 1991; Prod Info GANITE(TM) injection, 2003).
    b) Fever was reported in a patient receiving 150 to 200 mg/m(2)/day of gallium nitrate (Senderowicz et al, 1999).
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) HYPOTENSION - A decrease in mean systolic and diastolic blood pressure may be seen several days after gallium nitrate therapy. It is usually asymptomatic and not requiring treatment (Prod Info GANITE(TM) injection, 2003).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) TACHYCARDIA - Tachycardia may occur following therapeutic administration of gallium nitrate (Prod Info GANITE(TM) injection, 2003).

Heent

    3.4.3) EYES
    A) OPTIC NEURITIS
    1) WITH THERAPEUTIC USE
    a) Less than 1% of patients in clinical trials developed acute optic neuritis. These patients typically received multiple high doses of gallium nitrate as well as other anticancer drugs. Contribution of gallium nitrate to the optic neuritis is unknown. Most patients had a full visual recovery. At least one case of persistent visual impairment has been reported (Prod Info GANITE(TM) injection, 2003).
    B) DIMINISHED VISION
    1) WITH THERAPEUTIC USE
    a) Two of 38 patients developed diminished vision during the third course of treatment with gallium nitrate. The vision corrected spontaneously within 3 months in both patients (Weick et al, 1983).
    b) Complete blindness has been reported with partial reversal occurring over 12 months (Senderowicz et al, 1999).
    c) Two of fourteen patients with refractory non-Hodgkin's lymphoma, who were treated with gallium nitrate (200 to 350 mg/m(2) by continuous intravenous infusion) plus hydroxyurea, complained of a decrease in visual acuity (Chitambar et al, 1997).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) TINNITUS - Tinnitus and partial loss of auditory acuity have been reported in less than 1% of patients receiving high-dose gallium nitrate as an anticancer treatment (Prod Info GANITE(TM) injection, 2003).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) METALLIC TASTE - At doses of 750 mg/m(2) or greater, nearly all patients complained of an offensive metallic taste approximately 1 hour after the administration of gallium nitrate (Krakoff et al, 1979).
    2) STOMATITIS - Stomatitis was seen in 5 of 15 patients, with metastatic breast cancer, treated with 300 mg/m(2)/day of gallium nitrate for 7 days every 3 weeks by continuous infusion administered concomitantly with oral calcium supplementation and oral hydration (Jabboury et al, 1989).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Significant cardiac events may occur including tachycardia, atrial fibrillation, atrial flutter, supraventricular tachycardia, myocardial infarction, and congestive heart failure.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Tachycardia may occur following gallium nitrate administration but the relationship between the occurrence of tachycardia and gallium nitrate therapy is unknown (Prod Info GANITE(TM) injection, 2003).
    b) Following gallium nitrate therapy, six of 45 patients developed significant cardiac events, primarily atrial dysrhythmias, but also including atrial fibrillation, atrial flutter, supraventricular tachycardia, myocardial infarction, and congestive heart failure (Dreicer et al, 1997).

Respiratory

    3.6.1) SUMMARY
    A) ANIMAL STUDIES - Pneumonitis has been reported in rodents following treatment with gallium nitrate.
    B) WITH THERAPEUTIC USE
    1) Tachypnea, with respiratory alkalosis, may be seen.
    2) A pulmonary syndrome, characterized by dyspnea, crackles, rhonchi, pleural effusion, and pulmonary infiltrates, has been reported.
    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH THERAPEUTIC USE
    a) Tachypnea, with respiratory alkalosis, may be seen, with a fall in bicarbonate (Prod Info GANITE(TM) injection, 2003).
    B) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) A pulmonary syndrome, characterized by dyspnea, crackles, rhonchi, pleural effusion, and pulmonary infiltrates, has been reported following gallium nitrate administration, but due to the serious nature of the underlying condition of these patients, the relationship of these events to gallium nitrate therapy is unknown (Prod Info GANITE(TM) injection, 2003; Prod Info Ganite(R), gallium nitrate injection, 1991).
    b) Pulmonary infiltrates, hypoxemia, and fever occurred in a patient receiving 150 to 200 mg/m(2)/day of gallium nitrate (Senderowicz et al, 1999).
    c) Grade 4 pulmonary toxicity occurred in a patient receiving 300 mg/m(2) of gallium nitrate as a continuous infusion for 7 days every 4 weeks (Chang et al, 1995).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PNEUMONITIS
    a) MOUSE - In mice, gallium nitrate resulted in pneumonitis and chronic inflammatory infiltration of the alveolar septa and capillaries (Hart et al, 1971).
    b) RAT - Interstitial pneumonitis with slight pleural effusion occurred in rats following treatment with gallium nitrate (Hart et al, 1971).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Lethargy, confusion, and paresthesias may occur.
    3.7.2) CLINICAL EFFECTS
    A) LETHARGY
    1) WITH THERAPEUTIC USE
    a) Lethargy and confusion have been reported in association with gallium nitrate treatment for cancer and cancer-related hypercalcemia, however due to the serious nature of the underlying condition of these patients, the relationship of these events to therapy with gallium nitrate is unknown (Prod Info GANITE(TM) injection, 2003).
    B) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Severe paresthesias were reported in a patient following gallium nitrate therapy (Baselga et al, 1993).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, diarrhea, and constipation have been reported during therapy.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, diarrhea, and constipation have been reported during gallium nitrate therapy, and may occur due to rapid intravenous infusion of gallium nitrate or use of doses higher than the recommended doses of 200 mg/m(2) (Prod Info GANITE(TM) injection, 2003; Scher et al, 1987).
    b) Nausea and vomiting occurred in 55% of the patients (n=11) who received gallium nitrate therapy (up to 300 mg/m(2)/day) during a phase II clinical trial (Baselga et al, 1993).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may develop after overdose (Prod Info GANITE(TM) injection, 2003).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PERITONITIS
    a) RAT - Slight-to-moderate chemical peritonitis following intraperitoneal gallium nitrate administration was seen in rats (Hart et al, 1971).
    2) WEIGHT DECREASE
    a) RAT - In the adult female Sprague-Dawley rat, gallium nitrate can cause great weight loss with low lethality (Hart et al, 1971).
    b) MONKEY - Doses of 5 mg/kg/day gallium nitrate for 5 days in rhesus monkeys were not toxic, producing no changes in blood chemistry or hematology. Doses of 10 mg/kg/day for 5 days produced loss of weight and slight anemia. Doses of 20 mg/kg/day were lethal (Hart et al, 1971).
    c) DOG - Dogs are more sensitive than rhesus monkeys to the toxic effect of gallium nitrate. Doses as low as 1.25 mg/kg/day for 5 days produced weight loss (Hart et al, 1971).

Hepatic

    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) RAT - Gallium nitrate produced moderate liver damage in rats (Hart et al, 1971).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Acute renal failure and elevated BUN and serum creatinine levels have been reported with gallium nitrate therapy.
    2) There does not appear to be cumulative renal toxicity in patients receiving intermittent gallium nitrate infusions for periods greater than 18 months.
    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal failure was reported in two patients, with cancer-related hypercalcemia, who received gallium nitrate therapy. However, due to the serious nature of the patients underlying conditions, the relationship between the occurrence of renal failure and gallium nitrate therapy is unclear (Prod Info GANITE(TM) injection, 2003).
    b) Renal failure was reported in 8% of the patients (n=24) who received gallium nitrate for treatment of cancer-related hypercalcemia (Warrell et al, 1988).
    B) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Approximately 12.5% of patients receiving gallium nitrate therapy for hypercalcemia developed elevations of BUN and serum creatinine (Prod Info GANITE(TM) injection, 2003). Rapid intravenous infusion of gallium nitrate or use of doses greater than the recommended dose of 200 mg/m(2) may result in increased risk of renal insufficiency.
    b) Forty-one patients treated with gallium nitrate, 300 to 400 mg/m(2)/day as intermittent infusions for greater than 18 months, showed no cumulative renal toxicity. Doses less than 300 mg/m(2)/day, administered by continuous infusions, infrequently resulted in overt renal toxicity as evidenced by changes in the serum creatinine levels (Leyland-Jones et al, 1983).
    c) Nephrotoxicity was limiting at intravenous bolus doses up to 1400 mg/m(2), but it appeared that nephrotoxicity could be decreased by prolonging the length of intravenous infusion (Leyland-Jones, 1991).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RENAL TUBULAR DISORDER
    a) RODENT - Gallium nitrate caused some renal tubular damage in mice and kidney damage in rats (Hart et al, 1971).
    b) RAT - Gallium nitrate in rats resulted in the formation of renal precipitates composed of gallium complexed with calcium and phosphate, which occluded tubular lumina (Newman et al, 1979).
    2) RENAL FUNCTION ABNORMAL
    a) MOUSE - Gallium nitrate, at a dose of 213 mg/m(2)/day for 10 days in mice, resulted in elevated BUN levels (Whelan et al, 1992).
    b) DOG - Gallium nitrate doses as low as 1.25 mg/kg/day for 5 days produced renal injury (Hart et al, 1971).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum BUN and creatinine, electrolytes including calcium and phosphorous, a CBC, and urine output during gallium nitrate therapy or following overdose.
    B) An ECG should be obtained and evaluated for evidence of hypocalcemia (prolonged QTc interval, prolonged ST segment, Torsades de Pointes) or other electrolyte abnormalities.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Plasma concentrations of gallium nitrate are not readily available and are not used in monitoring therapy or in overdose.
    2) Serum BUN and creatinine should be monitored during gallium nitrate therapy or following overdose; therapy should be discontinued if the serum creatinine exceeds 2.5 mg/dL (Prod Info Ganite(R), gallium nitrate injection, 1991).
    3) Serum calcium, phosphorous, and electrolytes should be monitored daily during gallium nitrate therapy or following overdose.
    B) HEMATOLOGIC
    1) CBC should be monitored during gallium nitrate therapy or following overdose.
    4.1.3) URINE
    A) URINARY LEVELS
    1) A urine output of 2 L/day should be established before gallium nitrate therapy is initiated, and urine output should be monitored during gallium nitrate therapy or following overdose.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) An ECG should be obtained and monitored for evidence of hypocalcemia (QTc prolongation, (Torsades de Pointes) or other electrolyte abnormalities).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) A chest X-ray should be obtained in patients with pulmonary symptoms.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with significant symptoms or laboratory abnormalities should be admitted.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) A nephrologist should be consulted for significant renal impairment.
    B) A pulmonologist should be consulted for significant pulmonary impairment.
    C) A medical toxicologist should be consulted for significant toxicity.

Monitoring

    A) Monitor serum BUN and creatinine, electrolytes including calcium and phosphorous, a CBC, and urine output during gallium nitrate therapy or following overdose.
    B) An ECG should be obtained and evaluated for evidence of hypocalcemia (prolonged QTc interval, prolonged ST segment, Torsades de Pointes) or other electrolyte abnormalities.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY -
    1) Gallium nitrate is administered intravenously in therapeutic applications.
    2) There is no reported experience with oral exposure and it is not known whether gallium nitrate binds to activated charcoal.

Range Of Toxicity

Summary

    A) A specific minimum toxic dose has not been established.
    B) Toxicity is dependent on the total dose, the rate at which it is given, underlying pathology, and interactions with other nephrotoxic drugs. Doses up to 1400 mg/m2 have been used in clinical trials.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) The usual recommended dose is 200 milligrams/square meter of body surface area daily by continuous intravenous administration over 24 hours for 5 consecutive days (Prod Info GANITE(TM) injection, 2003).
    2) A dose of 100 milligrams/square meter of body surface area daily by continuous intravenous administration over 24 hours for 5 consecutive days may be considered for treating mild hypercalcemia with few symptoms (Prod Info GANITE(TM) injection, 2003).
    3) The dose should be reduced for age greater than 70 years, prior pelvic irradiation, prior cisplatin therapy, or prior nephrectomy (Einhorn et al, 1994).
    4) A urine output of 2 L/day should be established before gallium nitrate therapy is started (Prod Info GANITE(TM) injection, 2003).
    5) Gallium nitrate should not be administered if the serum creatinine is greater than 2.5 mg/dL, if there is a decline in creatinine clearance by more than 50% during therapy, or if gallium nitrate is administered concomitantly with other nephrotoxic drugs such as aminoglycosides (Prod Info GANITE(TM) injection, 2003).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Toxicity was not seen at a dose of 50 mg/m(2) or less (Krakoff et al, 1979).
    2) Nephrotoxicity was limiting at intravenous bolus doses up to 1400 mg/m(2), but it appeared that nephrotoxicity could be decreased by prolonging the length of intravenous infusion (Leyland-Jones, 1991).
    a) Doses up to 400 mg/m(2) by continuous intravenous infusion for 7 days have been well-tolerated, without signs of renal toxicity.
    3) Doses of 750 mg/m(2) as a 30- to 60-minute infusion every three weeks in 26 ovarian carcinoma patients resulted in only moderate nausea and vomiting, four patients with grade 2 anemia and four with grade 3 anemia,and one who developed grade 3 renal toxicity (creatinine 5.5) (Malfetano et al, 1991).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 4360 mg/kg (RTECS, 2001)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 600 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The specific mechanism by which gallium nitrate reduces serum calcium has not been established, however it is believed that gallium nitrate exerts a hypocalcemic effect by inhibiting calcium resorption from bone, possibly by reducing increased bone turnover (Prod Info Ganite(R), gallium nitrate injection, 1991).
    B) Pharmacokinetic studies suggest that a threshold plasma gallium concentration of approximately 1 mcg/mL must be attained to achieve acute normalization of elevated serum calcium levels (Warrell et al, 1986).
    C) Gallium localized in non-osseous malignant tissue. Most gallium is bound to the B-globulin transferrin in the serum. Tumor cells may then accumulate the gallium, probably by means of an active transport process of transferrin receptors on the cell surface (Sandler et al, 1998; Chitambar et al, 1997; Malfetano et al, 1991).
    D) Suspected mechanisms of cytotoxic action in the treatment of malignancies include the inhibition of cellular iron incorporation by binding to transferrin and inhibition of the enzyme ribonucleotide reductase (Sandler et al, 1998; Chitambar et al, 1997).

Physicochemical

Physical Characteristics

    A) Gallium nitrate is a white, slightly hygroscopic crystalline powder that is readily soluble in water (Prod Info Ganite(R), gallium nitrate injection, 1991).
    B) Gallium nitrate solution is clear, colorless, and odorless (Prod Info Ganite(R), gallium nitrate injection, 1991).

Molecular Weight

    A) 417.87 (Prod Info Ganite(R), gallium nitrate injection, 1991).

References

General Bibliography

    1) Akansel G, Liu Y, & Chitambar CR: Effect of gallium nitrate therapy on Ga-67 scintigraphic detection of lymphoma: case report. Clin Nuc Med 1997; 22:21-24.
    2) Baselga J, Kris MG, & Scher HI: Phase II trial of gallium nitrate in previously treated patients with small cell lung cancer. Invest New Drugs 1993; 11:85-86.
    3) Bockman RS, Wilhelm F, & Siris E: A multicenter trial of low dose gallium nitrate in patients with advanced Paget's Disease of bone. J Clin Endocrinol Metab 1995; 80:595-602.
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