Quadramet causes bone marrow suppression. In clinical trials, white blood cell counts and platelet counts decreased to a nadir of approximately 40% to 50% of baseline in 123 (95%) of patients within 3 to 5 weeks after Quadramet, and tended to return to pretreatment levels by 8 weeks. The grade of marrow toxicity is shown in Table 5 below.

* Toxicity Grade based upon National Cancer Institute Criteria; normal levels are Hemoglobin >10g/dL, Leucocyte ≥ 4.0 x 10³ mL, and Platelets ≥ 150,000/mL.

Before Quadramet is administered, consideration should be given to the patient's current clinical and hematologic status and bone marrow response history to treatment with myelotoxic agents. Metastatic prostate and other cancers can be associated with disseminated intravascular coagulation (DIC); caution should be exercised in treating cancer patients whose platelet counts are falling or who have other clinical or laboratory findings suggesting DIC. Because of the unknown potential for additive effects on bone marrow, Quadramet should not be given concurrently with chemotherapy or external beam radiation therapy unless the clinical benefits outweigh the risks. Use of Quadramet in patients with evidence of compromised bone marrow reserve from previous therapy or disease involvement is not recommended unless the potential benefits of the treatment outweigh the risks. Blood counts should be monitored weekly for at least 8 weeks, or until recovery of adequate bone marrow function.

Pregnancy: As with other radiopharmaceutical drugs, Quadramet can cause fetal harm when administered to a pregnant woman. Adequate and well controlled studies have not been conducted in animals or pregnant women. Women of childbearing age should have a negative pregnancy test before administration of Quadramet. If this drug is used during pregnancy, or if a patient becomes pregnant after taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant soon after receiving Quadramet. Men and women patients should be advised to use an effective method of contraception after the administration of Quadramet.

EDTMP is a chelating agent. Although the chelating effects have not been evaluated thoroughly in humans, dogs that received non-radioactive samarium EDTMP (6 times the human dose based on body weight, 3 times based on surface area) developed a variety of electrocardiographic (ECG) changes (with or without the presence of hypocalcemia). The causal relationship between the hypocalcemia and ECG changes has not been studied. Whether Quadramet causes electrocardiographic changes or arrhythmias in humans has not been studied. Caution and appropriate monitoring should be given when administering Quadramet to patients.

Because concomitant hydration is recommended to promote the urinary excretion of Quadramet, appropriate monitoring and consideration of additional supportive treatment should be used in patients with a history of congestive heart failure or renal insufficiency.

This drug should be used with caution in patients with compromised bone marrow reserves. See Warnings.

Skeletal: Spinal cord compression frequently occurs in patients with known metastases to the cervical, thoracic or lumbar spine. In clinical studies of Quadramet, spinal cord compression was reported in 7% of patients who received placebo and in 8.3% of patients who received 1.0 mCi/kg Quadramet. Quadramet is not indicated for treatment of spinal cord compression. Quadramet administration for pain relief of metastatic bone cancer does not prevent the development of spinal cord compression. When there is a clinical suspicion of spinal cord compression, appropriate diagnostic and therapeutic measures must be taken immediately to avoid permanent disability.

Radiopharmaceutical agents should be used only by physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides.

Quadramet, like other radioactive drugs, must be handled with care, and appropriate safety measures must be taken to minimize radiation exposure of clinical personnel and others in the patient environment.

Special precautions, such as bladder catheterization, should be taken with incontinent patients to minimize the risk of radioactive contamination of clothing, bed linen, and the patient's environment. Urinary excretion of radioactivity occurs over about 12 hours (with 35% occurring during the first 6 hours). Studies have not been done on the use of Quadramet in patients with renal impairment.

Laboratory Tests: Because of the potential for bone marrow suppression, beginning 2 weeks after Quadramet administration, blood counts should be monitored weekly for at least 8 weeks, or until recovery of adequate bone marrow function.

In a subset of 31 patients who had serum calcium monitored during the first 2 hours after Quadramet infusion, a clear pattern of calcium change was not identified. However, 10 (32%) patients had at least one serum calcium level that was below normal (7.16 to 8.28). The extent to which samarium-153-EDTMP is related to this hypocalcemia is not known. Caution should be exercised when administering Quadramet to patients at risk for developing hypocalcemia.

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.

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