Professional Drug Information > Pamidronate Disodium

Pamidronate (Systemic)

VA CLASSIFICATION
Primary: HS302
Secondary: HS303

Commonly used brand name(s): Aredia.

Another commonly used name is
APD . ^{02}
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Bone resorption inhibitor—

antihypercalcemic—

Indications

Accepted

Hypercalcemia, associated with neoplasms (treatment)—Pamidronate disodium is indicated for the treatment of hypercalcemia of malignancy, with or without bone metastases, that is inadequately managed by oral hydration alone. It is used with saline hydration and may be used with loop diuretics. ^{{01} {02} {03} {04} {05} {06}}

Paget's disease of bone (treatment)—Pamidronate is indicated in the treatment of symptomatic Paget's disease (osteitis deformans), characterized by abnormal and accelerated bone metabolism in one or more bones. Signs and symptoms may include bone pain, deformity, and/or fractures; increased concentrations of serum alkaline phosphatase and/or urinary hydroxyproline; neurologic disorders associated with skull lesions and spinal deformities; and elevated cardiac output and other vascular disorders associated with increased vascularity of bones. ^{{09} {10} {11} {12} {13} {14} {33} {34}}

Metastases, osteolytic (treatment adjunct)¹—Pamidronate is used in the treatment of osteolytic bone metastases sometimes found with breast cancer and myeloma. ^{{15} {16} {17} {18} {37} {38} {40} {41}}

Unaccepted
The safety and efficacy of pamidronate disodium in the treatment of hypercalcemia associated with hyperparathyroidism or other nontumor-related conditions have not been established. ^{01}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    369.11 ^{08}

Mechanism of action/Effect:

Pamidronate inhibits bone resorption and is believed to accomplish this by several mechanisms. It adsorbs onto the surface of hydroxyapatite crystals in mineralized bone matrix, thus reducing the solubility of the mineralized matrix and rendering it more resistant to osteoclastic resorption. By impairing attachment of osteoclast precursors to mineralized matrix, pamidronate blocks their transformation into mature, functioning osteoclasts. ^{{01} {07}}

Hypercalcemia of malignancy—Bone resorption is increased in the presence of neoplastic tissue. Pamidronate inhibits abnormal bone resorption and reduces the flow of calcium from the resorbing bone into the blood, effectively decreasing total and ionized serum calcium. ^{07} When kidney function is adequate for the fluid load, hydration with saline increases urine output and the use of loop diuretics increases the rate of calcium excretion.

Paget's disease—Pamidronate reduces the rate of bone turnover, by an initial blocking of bone resorption, resulting in decreases in serum alkaline phosphatase (reflecting decreased bone formation) and decreases in urinary hydroxyproline excretion (reflecting decreased bone resorption, i.e., breakdown of collagen). ^{{07} {09} {11}}

Osteolytic metastases—Osteolytic metastases result from accelerated bone resorption induced by the tumor via an activation of osteoclasts. ^{17} By inhibiting bone resorption, pamidronate may reduce morbidity of bone metastases from breast cancer and myeloma. ^{07}

Distribution:

In cancer patients, 45 to 53% of an intravenous dose of 60 mg infused over 24 hours is adsorbed to bone preferentially in areas of high turnover. ^{07}

Half-life:

Alpha—1.6 hours. ^{01}

Beta—27.2 hours.

Elimination:
    51% of drug excreted unchanged in urine within 24 hours after an intravenous dose of 60 mg infused over 4 to 24 hours. ^{01}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to any bisphosphonate may also be sensitive to pamidronate. ^{01}

Carcinogenicity

A 104-week carcinogenicity study with daily oral pamidronate administration in rats found a positive dose-response relationship for benign adrenal pheochromocytoma in males. The condition was observed in females, but was not statistically significant. Another 80-week study in mice found that daily oral pamidronate administration was not carcinogenic. ^{01}

Mutagenicity

Pamidronate was nonmutagenic in the Ames test, nucleus-anomaly test, sister-chromatid-exchange study, and point-mutation test. ^{01}

Pregnancy/Reproduction
Fertility—
In rats, decreased fertility occurred in first-generation offspring of parents who had received 150 mg of oral pamidronate per kg of body weight (mg/kg). This occurred only when animals were mated with members of the same dose group. ^{01}

Pregnancy—
Adequate and well-controlled studies have not been done in pregnant women. ^{01}

Adequate and well-controlled studies with intravenous pamidronate have not been done in animals. However, oral doses of 60 and 150 mg/kg of body weight a day increased the length of gestation and parturition in rats and increased pup mortality. Oral doses of 25 to 150 mg/kg a day during gestation failed to demonstrate any teratogenic, fetotoxic, or embryotoxic effects in rats or rabbits. ^{01}

FDA Pregnancy Category C. ^{01}

Breast-feeding

It is not known if pamidronate is distributed into breast milk. ^{01}

Pediatrics

No information is available on the relationship of age to the effects of pamidronate in pediatric patients. Safety and efficacy have not been established.


Geriatrics


Appropriate studies have not been performed in the geriatric population. However, elderly patients may be more prone to overhydration when treated with parenteral pamidronate in conjunction with hydration therapy. Careful monitoring of fluid and electrolyte status or infusing pamidronate in a smaller volume of fluid ^{19} is recommended. ^{14}

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):


Note: Combinations containing any of the following, depending on the amount present, may also interact with this medication.

» Calcium-containing preparations or
» Vitamin D, including calcifediol and calcitriol    (concurrent use may antagonize the effects of pamidronate in the treatment of hypercalcemia ^{14})


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).


Risk-benefit should be considered when the following medical problems exist
» Cardiac failure    (overhydration should be avoided when pamidronate is used in patients with cardiac failure; infusing pamidronate in a smaller volume of fluid is recommended ^{{01} {26}})


» Renal function impairment when serum creatinine is 5 mg per dL or greater    (pamidronate is excreted via the kidneys; use of pamidronate in patients with renal function impairment may require a lower dose and slower rate of infusion ^{{01} {20}})



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):

Alkaline phosphatase concentrations serum    (determinations recommended periodically during therapy for Paget's disease as a marker for disease activity ^{27})


Calcium, serum and
Magnesium, serum and
Phosphate, serum and
Potassium, serum    (determinations recommended periodically during therapy; some clinicians recommend monitoring serum magnesium and potassium concentrations only with concurrent diuretic use ^{21}; serum ionized calcium concentrations are preferable to determine free and bound calcium, but may not be available from a reliable lab ^{{01} {28}})


Complete blood count with differential and
Hematocrit and
Hemoglobin    (determinations recommended periodically during therapy, especially for patients who develop fever during pamidronate use ^{21}; patients with pre-existing anemia, leukopenia, or thrombocytopenia should be carefully monitored for the first 2 weeks of therapy ^{01})


Creatinine, serum and^{01}
Renal function^{01}    (determinations recommended periodically during therapy; if serum creatinine exceeds 5 mg per dL, risk-benefit of continued treatment or reduction of dosage ^{22} should be considered ^{01})




Side/Adverse Effects

Note: Fluid overload, hypokalemia, hypomagnesemia, and hypophosphatemia may occur due to concurrent fluid and diuretic use. ^{{01} {07} {29}}

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:

Those indicating need for medical attention
Incidence more frequent ^{{01} {07}}
    
Hypocalcemia (abdominal cramps; confusion; muscle spasms)
    
leukopenia or lymphopenia (fever, chills, or sore throat)
Note: Hypocalcemia occurs less frequently when doses of 60 mg, rather than 90 mg, are used. ^{07}





Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
—at higher doses^{01}{07}    
Fever, transient
    
nausea
    
pain and swelling at injection site

Incidence less frequent
    
Muscle stiffness ^{07}{22}





Overdose
For specific information on the agents used in the management of pamidronate overdose, see:    • Calcium Supplements (Systemic) monograph.


For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Specific treatment
Hypocalcemia resulting from overdose should be treated with intravenous calcium. ^{01}


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

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

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to etidronate or pamidronate





Use in the elderly—Elderly patients may be more prone to overhydration when treated with pamidronate in conjunction with hydration therapy
Other medications, especially calcium- and vitamin D–containing preparations
Other medical problems, especially cardiac failure and renal function impairment

Proper use of this medication

» Proper dosing

Precautions while using this medication
Importance of close monitoring by physician

For patients with hypercalcemia
Possible need for calcium and vitamin D restriction, including calcifediol and calcitriol


Side/adverse effects
Signs of potential adverse effects, especially hypocalcemia, leukopenia, and lymphopenia


General Dosing Information
The U.S. product manufacturer recommends that the daily dose of pamidronate be reconstituted and diluted in 1000 mL of 0.45% or 0.9% sodium chloride or 5% dextrose injection. The Canadian products should be reconstituted and diluted in 0.9% sodium chloride or 5% dextrose injection to a maximum concentration of 30 mg of pamidronate per 250 mL of solution. ^{{34} {36}} The diluted dose should be administered over a period of 24 hours. ^{01} However, some clinicians recommend that the daily dose be diluted in as little as 500 mL of fluid and administered over 4 to 24 hours. ^{23}

Fluid overload, hypokalemia, hypomagnesemia, and hypophosphatemia may occur due to concurrent fluid and diuretic use. ^{{01} {07} {29}}


Parenteral Dosage Forms

PAMIDRONATE DISODIUM FOR INJECTION

Usual adult dose
Hypercalcemia
Intravenous infusion, 60 mg administered over a period of four to ^{24} twenty-four hours. ^{{01} {07}}

Note: Patients with renal failure or mild hypercalcemia may receive 30 mg of pamidronate over a period of four to twenty-four hours. ^{{24} {25}}
Patients with more severe hypercalcemia (corrected serum calcium greater than 13.5 mg per dL) may receive 90 mg of pamidronate over a period of twenty-four hours. ^{01} Retreatment with pamidronate may be considered if hypercalcemia recurs; however, seven days should elapse before retreatment. ^{01}


Paget's disease of bone (treatment)
Intravenous infusion, a total dose of 90 to 180 mg per treatment period, administered at a rate of 15 mg per hour. Dosage may be administered between the range of 30 mg per day on three consecutive days up to 30 mg once a week for six weeks. Alternatively, three doses of 60 mg may be administered every second week. The regimen may need to be repeated in some patients. ^{{33} {34}}

Note: Some clinicians have found that a single dose of 60 to 90 mg is effective in some cases. ^{{10} {35}}


Osteolytic metastases (treatment adjunct)

In breast cancer:
Intravenous infusion, 90 mg over a period of two hours once every three or four weeks ^{40}.

In myeloma:
Intravenous infusion, 90 mg over a period of two to four hours once a month ^{{37} {42}}.


Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


30 mg per vial (Rx) [Aredia]


60 mg per vial (Rx) [Aredia]


90 mg per vial (Rx) [Aredia]

Canada—


30 mg per vial (Rx) [Aredia]


60 mg per vial (Rx) [Aredia]


90 mg per vial (Rx) [Aredia]

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

Preparation of dosage form:
Each vial should be reconstituted with 10 mL of sterile water for injection. The daily dose should then be diluted in 1000 mL of 0.45% or 0.9% sodium chloride or 5% dextrose injection. ^{01}

Stability:
The diluted infusion solution is stable for twenty-four hours at room temperature. ^{01}

Incompatibilities:
Pamidronate should not be mixed with calcium-containing infusion solutions, such as Ringer's solution. ^{01}

Revised: 08/18/1997

References

1. Aredia package insert (Ciba—US), Rec 11/91.
   

2. Coleman R, Rubens R. 3(amino-1,1-hydroxypropylidene) bisphosphonate (APD) for hypercalcemia of breast cancer. Br J Cancer 1987; 56: 465-9.
   

3. Morton A, Cantrill J, Craig A, et al. Single dose versus daily intravenous aminohydroxypropylidene biphosphonate (APD) for the hypercalcemia of malignancy. Br Med J 1988; 296: 811-4.
   

4. Thiébaud D, Jaeger P, Jacquet A, et al. Dose-response in the treatment of hypercalcemia of malignancy by a single infusion of bisphosphonate AHPrBP. J Clin Oncol 1988; 6: 762-8.
   

5. Yates A, Murray R, Jerums G, et al. A comparison of single and multiple intravenous infusions of 3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (APD) in the treatment of hypercalcemia of malignancy. Aust NZ J Med 1987; 17: 387-91.
   

6. Cantwell B, Harris A. Effects of single high dose infusions of aminohydroxypropylidene diphosphonate on hypercalcemia caused by cancer. Br Med J 1987; 294: 467-9.
   

7. Fitton A, McTavish D. Pamidronate: a review of its pharmacological properties and therapeutic efficacy in resorptive bone diseases. Drugs 1991; 41[2]: 289-318.
   

8. Fleeger C, editor. USP dictionary of USAN and international drug names. 1992. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1991.
   

9. Fenton A, Gutteridge D, Kent N, et al. Intravenous aminobisphosphonate in Paget's disease: clinical, biochemical, histomorphometric and radiological responses. Clin Endocrinol 1991; 34: 197-204.
   

10. Thiébaud D, Jaeger P, Gobelet C, et al. A single infusion of the bisphosphonate AHP, BP (APD) as treatment of Paget's disease of bone. Am J Med 1988; 85: 207-2.
    

11. Harinck H, Papapoulos S, Blanksma H, et al. Paget's disease of bone: early and late response to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD). Br Med J 1987; 295: 1301-5.
    

12. Gray R, Salih A, Hall M. Treatment of Paget's disease of bone with intravenous pamidronate. Br J Rheumatol 9/90 abstracts supplement 2: 275.
    

13. Gallacher S, Jenkins A, Boyle I. A study of the effects of amino-hydroxypropylidene diphosphonate (APD) on the alleviation of symptoms in Paget's disease of bone. Scot Med J 1988; 33(2): 252.
    

14. Panel consensus, 1992.
    

15. Morton A, Cantril J, Pillai G, et al. Sclerosis of lytic bone metastases after disodium aminohydroxypropylidene bisphosphonate (APD) in patients with breast carcinoma. Br Med J 1988; 297: 772-3.
    

16. Coleman R, Woll P, Miles M, et al. Treatment of bone metastases from breast cancer with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD). Br J Cancer 1988; 58: 621-5.
    

17. Thiébaud D, Leyvraz S, von Fliedner V, et al. Treatment of bone metastases from breast cancer and myeloma with pamidronate. Eur J Cancer 1991; 27(1): 37-41.
    

18. Pelger R, Nijeholt A, Papapoulos S. Short-term metabolic effects of pamidronate in patients with prostatic carcinoma and bone metastases. Lancet 1989 Oct 7: 865.
    

19. Panel comment, 1992.
    

20. Panel comment, 1992.
    

21. Panel comments, 1992.
    

22. Panel comment, 1992.
    

23. Panel comments, 1992.
    

24. Panel comments, 1992.
    

25. Panel comment, 1992.
    

26. Panel comment, 1993.
    

27. Panel comments, 1993.
    

28. Panel comments, 1993.
    

29. Panel consensus, 1993.
    

30. Panel comments, 1993.
    

31. Panel comments, 1993.
    

32. Aredia (Ciba). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993.
    

33. Aredia package insert (Ciba—US), Rev 9/94, Rec 10/94.
    

34. Aredia package insert (Ciba—Canada), Rev 11/94, Rec 3/95.
    

35. Reviewer comment, 1995.
    

36. Personal communication, 7/26/95.
    

37. Aredia package insert (Ciba—US), Rev 8/95, Rec 9/95.
    

38. Berenson J, Lichtenstein A, Porter L, et al. Pamidronate disodium reduces the occurrence of skeletal-related events (SRE) in advanced multiple myeloma (MM). Blood 1994; 10(1): 386A.
    

39. Reviewer comments, 1996.
    

40. Aredia package insert (Ciba—US), Rev 8/96, Rec 9/96.
    

41. Conte PF, Latreille J, Mauriac L, et al. Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. J Clin Oncol 1996; 14: 2552-9.
    

42. Reviewer comments, 1996.
    

Link to this page

Printable Version

Email Page