Gallium Nitrate (Systemic)


VA CLASSIFICATION
Primary: HS309

Commonly used brand name(s): Ganite.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antihypercalcemic—

Indications

Accepted

Hypercalcemia, associated with neoplasms (treatment)—Gallium nitrate is indicated in the treatment of hypercalcemia of malignancy that is inadequately managed by oral hydration alone. It is used with saline hydration and may be used with diuretics. {01} {03} {05} {21}

Acceptance not established
Gallium nitrate has been used to treat moderate to severe symptoms of Paget's disease of bone (osteitis deformans), characterized by abnormal and accelerated bone metabolism in one or more bones {21} {22} {23} {24}. However, data are limited and further study is required to define the role of gallium nitrate in this condition.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Gallium nitrate is a hydrated nitrate salt of the group IIIa element gallium {01}.
Molecular weight—
    417.87 {01}

Mechanism of action/Effect:

In vivo studies indicate that gallium nitrate preferentially accumulates in metabolically active areas of high bone turnover, where it reversibly inhibits osteoclast-mediated bone resorption {17} {25} {26}.

Hypercalcemia of malignancy—Bone resorption is increased in the presence of neoplastic tissue. Gallium nitrate inhibits abnormal bone resorption and reduces the flow of calcium from the resorbing bone into the blood, effectively decreasing total and ionized serum calcium. When kidney function is adequate for the fluid load, hydration with saline increases urine output and the use of diuretics increases the rate of calcium excretion. {01}

Distribution:

Vol D—1.27 liters per kg of body weight (L/kg) {27}.

Biotransformation:

None. {01}

Half-life:

Alpha—1 hour. {04}

Beta—24 hours, but lengthens to 72 to 115 hours with prolonged intravenous infusion. {01}

Duration of action:

Studies have reported a median duration of 6 to 8 days (range, 0 to 15+ days) {02} {03}.

Elimination:
    Renal. {01}


Precautions to Consider

Carcinogenicity

Long-term carcinogenicity studies have not been performed in animals. {01}

Mutagenicity

Gallium nitrate has not been found to be mutagenic in standard tests such as Ames and chromosomal aberration studies on human lymphocytes. {01}

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans. {01}

Studies have not been done in animals {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether gallium nitrate is distributed into breast milk. It is recommended that mothers taking gallium nitrate not breast-feed because of potentially serious adverse effects in nursing infants. {01}

Pediatrics

No information is available on the relationship of age to the effects of gallium nitrate in pediatric patients. Safety and efficacy have not been established. {04}


Geriatrics


Although appropriate studies on the relationship of age to the effects of gallium nitrate have not been performed in the geriatric population, no geriatrics-specific problems have been documented to date. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving gallium nitrate.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Nephrotoxic medications, other (See Appendix II )    (the possibility of additive toxicity should be considered if these medications are used concurrently with gallium nitrate {01} {03})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Gallium citrate Ga 67 scintigraphy for tumor or abscess localization    (gallium nitrate competes with gallium citrate Ga 67 for plasma protein binding sites, resulting in reduced tumor or abscess uptake and increased skeletal uptake, increased renal excretion, and reduced liver uptake of gallium citrate Ga 67 {18} {19})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Renal function impairment when serum creatinine is greater than 2.5 mg per deciliter (mg/dL)    (condition may be exacerbated {01})


Risk-benefit should be considered when the following medical problem exists
» Renal function impairment when serum creatinine is 2 to 2.5 mg/dL    (frequent monitoring of patient's renal status is recommended; gallium nitrate treatment should be discontinued if serum creatinine exceeds 2.5 mg/dL {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Albumin concentrations, serum and{01}
Calcium concentrations, serum and{01}
Phosphorus concentrations, serum{01}    (serum calcium should be monitored daily, serum phosphorus two times a week, and serum albumin before and after each course of therapy {14} {15}; serum proteins, especially albumin, may influence the ratio of free and bound calcium; corrected serum calcium values should be calculated by using an established algorithm; albumin-corrected serum calcium determinations may be useful when the signs and symptoms of hypercalcemia are inconsistent with unadjusted calcium values)


» Renal function determinations, especially serum creatinine and blood urea nitrogen (BUN)    (recommended daily to every 2 to 3 days {10} {11} {12} {13} {14} during therapy; treatment should be discontinued if serum creatinine is greater than 2.5 mg per dL {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Note: Decreased serum bicarbonate, possibly secondary to mild respiratory alkalosis, has been reported. It has been asymptomatic and has not required specific treatment {01}.


Those indicating need for medical attention
Incidence more frequent
    
Hypophosphatemia{01}{02}{03} (bone pain; loss of appetite; muscle weakness){06}
    
nephrotoxicity (blood in urine; greatly increased or decreased frequency of urination or amount of urine; increased thirst; loss of appetite; nausea; vomiting){01}{04}{25}

Incidence less frequent
    
Hypocalcemia (abdominal cramps; confusion; muscle spasms){01}{05}{06}{07}

Incidence rare
    
Anemia (unusual tiredness or weakness)—with doses of up to 1400 mg per square meter of body surface area{01}{25}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Diarrhea {09}
    
metallic taste {09}
    
nausea {01}{03}
    
vomiting {01}{04}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Gallium Nitrate (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:





Breast-feeding—Not known if distributed into breast milk; may cause potentially serious adverse effects in nursing infants
Other medications, especially nephrotoxic medications
Other medical problems, especially renal function impairment

Proper use of this medication

» Proper dosing

» Proper storage

Precautions while using this medication
Importance of close monitoring by physician


Side/adverse effects
Signs of potential adverse effects, especially hypophosphatemia, nephrotoxicity, hypocalcemia, and anemia


General Dosing Information
The daily dose is usually diluted in 1000 mL of 0.9% sodium chloride injection or 5% dextrose injection. The diluted dose should be administered over a period of twenty-four hours. {01} The solution can also be delivered undiluted via a metered ambulatory infusion pump {28}.

During acute therapy for hypercalcemia, {28}patients should maintain a urinary output of at least 2000 mL per day to decrease the chance of nephrotoxicity. {04}


Parenteral Dosage Forms

GALLIUM NITRATE INJECTION

Usual adult and adolescent dose
Hypercalcemia (treatment)
Intravenous infusion, 100 to 200 mg per square meter of body surface area per day, administered over a period of twenty-four hours, for five days. {01}


Note: If serum calcium concentrations decrease to normal in less than five days, treatment should be discontinued {01}.
Some clinicians recommend that therapy be repeated, if needed, after a waiting period of two to four weeks. {11} {13} {16} {24}


Usual pediatric dose
Safety and efficacy have not been established.

Usual geriatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


25 mg per mL (Rx) [Ganite]

Canada—
Gallium nitrate is not commercially available in Canada; however, it is available by emergency drug release from the Health Protection Branch. {08}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
The daily dose is usually diluted in 1000 mL of 0.9% sodium chloride injection or 5% dextrose injection. {01}

Stability:
Diluted solution may be stored at controlled room temperature for 48 hours and under refrigeration for 7 days without loss of potency. {01}



Revised: 08/05/1997



References
  1. Ganite product information (Fujisawa—US), Rec 2/91, Rev 1/91.
  1. Warrell R, Murphy W, Schulman P, et al. A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. J Clin Oncol 1991; 9: 1467-75.
  1. Warrell R, Israel R, Frisone M, et al. Gallium nitrate for acute treatment of cancer-related hypercalcemia. Ann Intern Med 1988; 108(5): 669-74.
  1. Gallium nitrate information, Orphan Drug and Biological Listing, USP DI, Section VII: 33-4.
  1. Warrell R, Bockman R, Coonley C, et al. Gallium nitrate inhibits calcium resorption from bone and is effective treatment for cancer-related hypercalcemia. J Clin Invest 1984; 73: 1487-90.
  1. Berkow R, editor. The merck manual of diagnosis and therapy. 14th ed. Rahway, NJ: Merck & Co., 1982.
  1. Hypocalcemia. Dorland's Medical Dictionary. 27th ed. Philadelphia: W.B. Saunders, 1988: 802.
  1. Personal communication, 4/1/91.
  1. Foster B, Clagett-Carr K, Hoth D, et al. Gallium nitrate: the second metal with clinical activity. Cancer Treat Rep 1986; 70: 1311-9.
  1. Panelist comment, 1991.
  1. Panelist comment, 1991.
  1. Panelist comment, 1991.
  1. Panelist comment, 1991.
  1. Panelist comment, 1991.
  1. Reviewer comment, 1991.
  1. Panelist comment, 1996.
  1. Blair HC, Teitelbaum SL, Tan HF, et al. Reversible inhibition of osteoclastic activity by bone-bound gallium (III). J Cell Biochem 1992; 48: 401-10.
  1. Reviewer comment, 1992.
  1. Study G. Drug-induced alterations: reported instances. In: Hladik W, Saher G, editors. Essentials of nuclear medicine science. Baltimore: Williams & Wilkins, 1987: 213.
  1. Ganite package insert (SoloPak—US), Rev 2/95, Rec 10/95.
  1. Matkovic V, Apseloff G, Shepard D, et al. Use of gallium to treat Paget's disease of bone: a pilot study. Lancet 1990; 335: 72-5.
  1. Bockman R, Bosco B. Treatment of patients with advanced Paget's disease of bone with two cycles of gallium nitrate. Semin Arth Rheumat 1994; 23: 268-9.
  1. Warrell R, Bosco B, Weinerman S, et al. Gallium nitrate for advanced Paget's disease of bone: effectiveness and dose-response analysis. Ann Intern Med 1990; 113: 847-51.
  1. Bockman R, Wilhelm F, Siris E, et al. 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.
  1. Bockman R, Boskey A, Blumenthal N, et al. Gallium increases bone calcium and crystallite perfection of hydroxyapatite. Calcif Tissue Int 1986; 39: 376-81.
  1. Bockman R, Repo M, Warrell R, et al. Distribution of trace levels of therapeutic gallium in bone as mapped by synchrotron x-ray microscopy. Proc Natl Acad Sci, USA 1990; 87: 4149-53.
  1. Hall S, Yeung K, Benjamin R, et al. Kinetics of gallium nitrate, a new anticancer agent. Clin Pharmacol Ther 1979; 25: 82-7.
  1. Reviewer comment, 1996.
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