The potential for additive bone marrow toxicity of Quadramet with chemotherapy or external beam radiation has not been studied. Quadramet should not be given concurrently with chemotherapy or external beam radiation therapy unless the benefit outweighs the risks. Quadramet should not be given after either of these treatments until there has been time for adequate marrow recovery. (See Warnings Section).

Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis in humans given EDTMP, in Quadramet, is not likely. Osteosarcomas occurred in a 2-year toxicity/carcinogenicity study of EDTMP administered by gastric intubation to Sprague-Dawley rats, in male rats at 50 mg/kg/day and in male and female rats at 150 mg/kg/day (the dosage was increased to 333 mg/kg/day on day 329 of treatment). Osteosarcomas were not reported in a published chronic dietary study of up to 130 weeks of EDTMP in Fisher 344 rats, at dietary doses up to 100 mg/kg/day (not the maximum tolerated dose). However, at study termination in female Fisher 344 rats, this dose was associated with statistically significantly higher rate of pancreatic islet-cell adenomas and carcinomas.

The results of the following genotoxicity assays with non-radioactive samarium- EDTMP were negative: Salmonella reverse mutation (AMES) assay, unscheduled DNA synthesis in rat liver primary cell culture, chromosomal aberration assay in rat lymphocytes, CHO/HGPRT forward mutation assay, and mouse bone marrow micronucleus test.

Studies have not been performed to assess the effect of Quadramet on fertility.

Pregnancy Pregnancy Category D. See Warnings Section.

Nursing Mothers It is not known whether Quadramet is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Quadramet, a decision should be made whether to continue nursing or to administer the drug. If Quadramet is administered, formula feedings should be substituted for breast feedings.

Pediatric Use Safety and effectiveness in pediatric patients below the age of 16 years have not been established.

ADVERSE EVENTS
Adverse events were evaluated in a total of 580 patients who received Quadramet in clinical trials. Of the 580 patients, there were 472 men and 108 women with a mean age of 66 (range 20 to 87).

Of these patients, 472 (83%) had at least one adverse event. In a subgroup of 399 patients who received Quadramet 1.0 mCi/kg, there were 23 deaths and 46 serious adverse events. The deaths occurred an average of 67 days (9 to 130) after Quadramet. Serious events occurred an average of 46 days (1 - 118) after Quadramet. Although most of the patient deaths and serious adverse events appear to be related to the underlying disease, the relationship of end stage disease, marrow invasion by cancer cells, previous myelotoxic treatment and Quadramet toxicity can not be easily distinguished. In clinical studies, two patients with rapidly progressive prostate cancer developed thrombocytopenia and died 4 weeks after receiving Quadramet. One of the patients showed evidence of disseminated intravascular coagulation (DIC); the other patient experienced a fatal cerebrovascular accident, with a suspicion of DIC. The relationship of the DIC to the bone marrow suppressive effect of Samarium is not known. Marrow toxicity occurred in 277 (47%) patients (See Warnings section).

In controlled studies, 7% of patients receiving 1.0 mCi/kg Quadramet (as compared to 6% of patients receiving placebo) reported a transient increase in bone pain shortly after injection (flare reaction). This was usually mild, self-limiting, and responded to analgesics.

The most common adverse events observed in controlled clinical studies of Quadramet, are given in Table 6.

TABLE 6: SELECTED ADVERSE EVENTS REPORTED IN GREATER THAN OR EQUAL TO 1.0 % OF PEOPLE WHO RECEIVED QUADRAMET OR PLACEBO IN CONTROLLED CLINICAL TRIALS

ADVERSE EVENT	Placebo N = 90	Quadramet 1.0 mCi/kg N = 199
# Patients with Any Adverse Event	72 (80%)	169 (85%)
Body As A Whole	56 (62%)	100 (50%)
Pain Flare Reaction	5 (5.6%)	14 (7.0%)
Cardiovascular	19 (21%)	32 (16%)
Arrhythmias	2 (2.2%)	10 (5.0%)
Chest Pain	4 (4.4%)	8 (4.0%)
Hypertension	0	6 (3.0%)
Hypotension	2 (2.2%)	4 (2.0%)
Digestive	44 (49%)	82 (41%)
Abdominal Pain	7 (7.8%)	12 (6.0%)
Diarrhea	3 (3.3%)	12 (6.0%)
Nausea &/or Vomiting	37 (41.1%)	65 (32.7%)
Hematologic &  Lymphatic	12 (13%)	54 (27%)
Coagulation Disorder	0	3 (1.5%)
Hemoglobin Decreased	21 (23.3%)	81 (40.7%)
Leukopenia	6 (6.7%)	118(59.3%)
Lymphadenopathy	0	4 (2.0%)
Thrombocytopenia	8 (8.9%)	138(69.3%)
Any Bleeding Manifestations*	8 (8.9%)	32 (16.1%)
Ecchymosis	1 (1.1%)	3 (3.0%)
Epistaxis	1 (1.1%)	4 (2.0%)
Hematuria	3 (3.3%)	10 (5%)
Infection	10 (11.1%)	34 (17.1%)
Fever and/or Chills	10 (11.1%)	17 (8.5%)
Infection, Not Specified	4 (4.4%)	14 (7.0%)
Oral Moniliasis	1 (1.1%)	4 (2.0%)
Pneumonia	1 (1.1%)	3 (1.5%)
Musculoskeletal	28 (31%)	55 (27%)
Myasthenia	8 (8.9%)	13 (6.5%)
Pathologic Fracture	2 (2.2%)	5 (2.5%)
Nervous	39 (43%)	59 (30%)
Dizziness	1 (1.1%)	8 (4.0%)
Paresthesia	7 (7.8%)	4 (2.0%)
Spinal Cord Compression	5 (5.5%)	13 (6.5%)
Cerebrovascular Accident/Stroke	0	2 (1.0%)
Respiratory	24 (27%)	35 (18%)
Bronchitis/Cough Increased	2 (2.2%)	8 (4.0%)
Special Senses	11 (12%)	11 (6%)
Skin & Appendages	17 (19%)	13 (7%)
Purpura	0	2 (1%)
Rash	2 (2.2%)	2 (1%)

*Includes hemorrhage (gastrointestinal, ocular) reported in <1%.

In an additional 200 patients who received Quadramet in uncontrolled clinical trials, adverse events that were reported at a rate of greater than or equal to 1.0% were similar except for 9 (4.5%) patients who had agranulocytosis. Other selected adverse events that were reported in <1% of the patients who received Quadramet 1.0 mCi/kg in any clinical trial include: alopecia, angina, congestive heart failure, sinus bradycardia, and vasodilation.

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