Pamidronate Disodium (Page 5 of 8)

Musculoskeletal Pain

In post marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. However, such reports have been infrequent. This category of drugs includes pamidronate disodium. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Laboratory Tests

Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment. Serum calcium, electrolytes, phosphate, magnesium, and CBC, differential, and hematocrit/hemoglobin must be closely monitored in patients treated with pamidronate disodium. Patients who have preexisting anemia, leukopenia, or thrombocytopenia should be monitored carefully in the first 2 weeks following treatment.


Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of pamidronate disodium.

Caution is indicated when pamidronate disodium is used with other potentially nephrotoxic drugs.

In multiple myeloma patients, the risk of renal dysfunction may be increased when pamidronate disodium is used in combination with thalidomide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104 week carcinogenicity study (daily oral administration) in rats, there was a positive dose response relationship for benign adrenal pheochromocytoma in males (P<0.00001). Although this condition was also observed in females, the incidence was not statistically significant. When the dose calculations were adjusted to account for the limited oral bioavailability of pamidronate disodium in rats, the lowest daily dose associated with adrenal pheochromocytoma was similar to the intended clinical dose. Adrenal pheochromocytoma was also observed in low numbers in the control animals and is considered a relatively common spontaneous neoplasm in the rat. Pamidronate disodium (daily oral administration) was not carcinogenic in an 80 week study in mice.

Pamidronate disodium was nonmutagenic in six mutagenicity assays: Ames test, Salmonella and Escherichia /liver-microsome test, nucleus-anomaly test, sister-chromatid-exchange study, point-mutation test, and micronucleus test the rat.

In rats, decreased fertility occurred in first-generation offspring of parents who had received 150 mg/kg of pamidronate disodium orally; however, this occurred only when animals were mated with members of the same dose group. Pamidronate disodium has not been administered intravenously in such a study.

Animal Toxicology

In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion) administration of pamidronate disodium.

Two 7-day intravenous infusion studies were conducted in the dog wherein pamidronate disodium was given for 1, 4, or 24 hours at doses of 1-20 mg/kg for up to 7 days. In the first study, the compound was well tolerated at 3 mg/kg (1.7 x highest recommended humandose [HRHD] for a single intravenous infusion) when administered for 4 or 24 hours, but renal findings such as elevated BUN and creatinine levels and renal tubular necrosis occurred when 3 mg/kg was infused for 1 hour and at doses of ≥10 mg/kg. In the second study, slight renal tubular necrosis was observed in 1 male at 1 mg/kg when infused for 4 hours. Additional findings included elevated BUN levels in several treated animals and renal tubular dilation and/or inflammation at ≥1 mg/kg after each infusion time.

Pamidronate disodium was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6, and 20 mg/kg as a 1-hour infusion, once a week, for 3 months followed by a 1-month recovery period. In rats, nephrotoxicity was observed at ≥6 mg/kg and included increased BUN and creatinine levels and tubular degeneration and necrosis. These findings were still present at 20 mg/kg at the end of the recovery period. In dogs, moribundity/death and renal toxicity occurred at 20 mg/kg as did kidney findings of elevated BUN and creatinine levels at ≥6 mg/kg and renal tubular degeneration at ≥4 mg/kg. The kidney changes were partially reversible at 6 mg/kg. In both studies, the dose level that produced no adverse renal effects was considered to be 2 mg/kg (1.1 x HRHD for a single intravenous infusion).


Teratogenic Effects: Pregnancy Category D (see WARNINGS)

There are no adequate and well-controlled studies in pregnant women.

Bolus intravenous studies conducted in rats and rabbits determined that pamidronate disodium produces maternal toxicity and embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. As it has been shown that pamidronate disodium can cross the placenta in rats and has produced marked maternal and nonteratogenic embryo/fetal effects in rats and rabbits, it should not be given to women during pregnancy.

Bisphosphonates are incorporated into the bone matrix from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systematic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.

Nursing Mothers

Itis not known whether pamidronate disodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when pamidronate disodium is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of pamidronate disodium in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of pamidronate disodium, approximately 20% were 65 and over, while approximately 15% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.


Clinical Studies

Hypercalcemia of Malignancy

Transient mild elevation of temperature by at least 1°C was noted 24 to 48 hours after administration of pamidronate disodium in 34% of patients in clinical trials. In the saline trial, 18% of patients had a temperature elevation of at least 1°C 24 to 48 hours after treatment.

Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on palpation) at the site of catheter insertion were most common in patients treated with 90 mg of pamidronate disodium. Symptomatic treatment resulted in rapid resolution in all patients.

Rare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one case of scleritis, and one case of uveitis upon separate rechallenges.

Five of 231 patients (2%) who received pamidronate disodium during the four U.S. controlled hypercalcemia clinical studies were reported to have had seizures, 2 of whom had preexisting seizure disorders. None of the seizures were considered to be drug-related by the investigators. However, a possible relationship between the drug and the occurrence of seizures cannot be ruled out. It should be noted that in the saline arm 1 patient (4%) had a seizure.

There are no controlled clinical trials comparing the efficacy and safety of 90 mg pamidronate disodium over 24 hours to 2 hours in patients with hypercalcemia of malignancy. However, a comparison of data from separate clinical trials suggests that the overall safety profile in patients who received 90 mg pamidronate disodium over 24 hours is similar to those who received 90 mg pamidronate disodium over 2 hours. The only notable differences observed were an increase in the proportion of patients in the pamidronate disodium 24 hour group who experienced fluid overload and electrolyte/mineral abnormalities.

At least 15% of patients treated with pamidronate disodium for hypercalcemia of malignancy also experienced the following adverse events during a clinical trial:

General: Fluid overload, generalized pain

Cardiovascular: Hypertension

Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting

Genitourinary: Urinary tract infection

Musculoskeletal: Bone pain

Laboratory abnormalit: Anemia, hypokalemia, hypomagnesemia, hypophosphatemia

Many of these adverse experiences may have been related to the underlying disease state.

The following table lists the adverse experiences considered to be treatment-related during comparative, controlled U.S. trials.

Treatment-Related Adverse Experiences Reported in Three U.S. Controlled Clinical Trials
Percent of Patients
Pamidronate Disodium Etidronate Disodium Saline
60 mg over 4 hr 60 mg over 24 hr 90 mg over 24 hr 7.5 mg/kg x 3 days
n=23 n=73 n=17 n=35 n=23
Edema 0 1 0 0 0
Fatigue 0 0 12 0 0
Fever 26 19 18 9 0
Fluid overload 0 0 0 6 0
Infusion-site reaction 0 4 18 0 0
Moniliasis 0 0 6 0 0
Rigors 0 0 0 0 4
Abdominal pain 0 1 0 0 0
Anorexia 4 1 12 0 0
Constipation 4 0 6 3 0
Diarrhea 0 1 0 0 0
Dyspepsia 4 0 0 0 0
Gastrointestinal hemorrhage 0 0 6 0 0
Nausea 4 0 18 6 0
Stomatitis 0 1 0 3 0
Vomiting 4 0 0 0 0
Dyspnea 0 0 0 3 0
Rales 0 0 6 0 0
Rhinitis 0 0 6 0 0
Upper respiratory infection 0 3 0 0 0
Anxiety 0 0 0 0 4
Convulsions 0 0 0 3 0
Insomnia 0 1 0 0 0
Nervousness 0 0 0 0 4
Psychosis 4 0 0 0 0
Somnolence 0 1 6 0 0
Taste perversion 0 0 0 3 0
Atrial fibrillation 0 0 6 0 4
Atrial flutter 0 1 0 0 0
Cardiac failure 0 1 0 0 0
Hypertension 0 0 6 0 4
Syncope 0 0 6 0 0
Tachycardia 0 0 6 0 4
Hypothyroidism 0 0 6 0 0
Hemic and Lymphatic
Anemia 0 0 6 0 0
Leukopenia 4 0 0 0 0
Neutropenia 0 1 0 0 0
Thrombocytopenia 0 1 0 0 0
Myalgia 0 1 0 0 0
Uremia 4 0 0 0 0
Laboratory Abnormalities
Hypocalcemia 0 1 12 0 0
Hypokalemia 4 4 18 0 0
Hypomagnesemia 4 10 12 3 4
Hypophosphatemia 0 9 18 3 0
Abnormal liver function 0 0 0 3 0

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