Quadramet (Intravenous)

QUADRAMET® (samarium sm 153 lexidronam) is supplied frozen in a single-dose 10 mL glass vial containing 1850 ± 185 MBq/mL (50 ± 5 mCi/mL) of samarium-153, at calibration.

QUADRAMET® (samarium sm 153 lexidronam) is available in the following size:

NDC# 50419-209-03.................3mL fill size with total activity of 5550 MBq (150mCi).

The vial is shipped in a lead shield; a package insert is included.

The drug product expires 48 hours after the time of calibration noted on the label, or 8 hours after thawing, whichever is earlier.

Storage: Store frozen at -10° to -20°C in a lead shielded container.

Storage and disposal of QUADRAMET® (samarium sm 153 lexidronam) should be controlled in a manner that complies with the appropriate regulations of the governmen agency authorized to license the use of this radionuclide.

This radioactive drug is approved for distribution to persons licensed pursuant to the Code of Massachusetts Regulations 105 CMR 120.500 for the uses listed in 105 CMR 120.537 or under equivalent licenses of the U.S. Nuclear Regulatory Commission, an Agreement State or a Licensing State.

THIS PRODUCT INFORMATION ISSUED September 2003. Mfd by: Bristol Myers Squibb, Medical Imaging, N. Billerica, MA 01862. Mfd for: Cytogen Corporation, Princeton, New Jersey, USA. For Product Inquiries, call 1-800-833-3533 FDA Rev date: 4/12/1999

QUADRAMET® (samarium sm 153 lexidronam) is indicated for relief of pain in patients with confirmed osteoblastic metastatic bone lesions that enhance on radionuclide bone scan.

The recommended dose of QUADRAMET® (samarium sm 153 lexidronam) is 1.0 mCi/kg, administered intravenously over a period of one minute through a secure in-dwelling catheter and followed with a saline flush. Dose adjustment in patients at the extremes of weight have not been studied. Caution should be exercised when determining the dose in very thin or very obese patients.

The dose should be measured by a suitable radioactivity calibration system, such as a radioisotope dose calibrator, immediately before administration.

The dose of radioactivity to be administered and the patient should be verified before administering QUADRAMET® (samarium sm 153 lexidronam). Patients should not be released until their radioactivity levels and exposure rates comply with federal and local regulations.

The patient should ingest (or receive by i.v. administration) a minimum of 500 mL (2 cups) of fluids prior to injection and should void as often as possible after injection to minimize radiation exposure to the bladder.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should not be used if it is cloudy or if it contains particulate matter.

QUADRAMET® (samarium sm 153 lexidronam) contains calcium and may be incompatible with solutions that contain molecules that can complex with and form calcium precipitates.

QUADRAMET® (samarium sm 153 lexidronam) should not be diluted or mixed with other solutions.

Thaw at room temperature before administration and use within 8 hours of thawing.

Radiation Dosimetry: The estimated absorbed radiation doses to an average 70 kg adult patient from an i.v. injection of QUADRAMET® (samarium sm 153 lexidronam) are shown in Table 7. The dosimetry estimates were based on clinical biodistribution studies using methods developed for radiation dose calculations by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine. Radiation exposure is based on a urinary voiding interval of 4.8 hours.

Radiation dose estimates for bone and marrow assume that radioactivity is deposited on bone surfaces, as noted in autoradiograms of biopsy bone samples in 7 patients who received QUADRAMET® (samarium sm 153 lexidronam). Although electron emissions from ¹⁵³Sm are abundant, with energies up to 810 keV, rapid blood clearance of QUADRAMET® (samarium sm 153 lexidronam) and low energy and abundant photon emissions generally result in low radiation doses to those parts of the body where the complex does not localize.

When blastic osseous lesions are present, significantly enhanced localization of the radiopharmaceutical will occur, with correspondingly higher doses to the lesions compared with normal bones and other organs. (See CLINICAL PHARMACOLOGY, Skeletal Uptake and Pharmacodynamics Sections).

TABLE 7: RADIATION ABSORBED DOSES

QUADRAMET® (samarium sm 153 lexidronam) is contraindicated in patients who have known hypersensitivity to EDTMP or similar phosphonate compounds.

WARNINGS

QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam) , and tended to return to pretreatment levels by 8 weeks. The grade of marrow toxicity is shown in Table 5 below.

Table 5: NUMBER AND PERCENT OF PATIENTS WHO EXPERIENCED MARROW TOXICITY IN CLINICAL TRIALS OF QUADRAMET (samarium sm 153 lexidronam)

Before QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam) should no be given concurrently with chemotherapy or external beam radiation therapy unless the clinical benefits outweigh the risks. Use of QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam). 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® (samarium sm 153 lexidronam). Men and women patients should be advised to use an effective method of contraception after the administration of QUADRAMET® (samarium sm 153 lexidronam).

PRECAUTIONS

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® (samarium sm 153 lexidronam) causes electrocardiographic changes or arrhythmias in humans has not been studied. Caution and appropriate monitoring should be given when administering QUADRAMET® (samarium sm 153 lexidronam) to patients (See Laboratory Tests).

Because concomitant hydration is recommended to promote the urinary excretion of QUADRAMET® (samarium sm 153 lexidronam) , 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® (samarium sm 153 lexidronam) , 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® (samarium sm 153 lexidronam). QUADRAMET® (samarium sm 153 lexidronam) is not indicated for treatment of spinal cord compression. QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam) , 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® (samarium sm 153 lexidronam) in patients with renal impairment.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis in humans given EDTMP, in QUADRAMET® (samarium sm 153 lexidronam) , 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® (samarium sm 153 lexidronam) on fertility.

Pregnancy

Pregnancy Category D. See WARNINGS Section.

Nursing Mothers

It is not known whether QUADRAMET® (samarium sm 153 lexidronam) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from QUADRAMET® (samarium sm 153 lexidronam) , a decision should be made whether to continue nursing or to administer the drug. If QUADRAMET® (samarium sm 153 lexidronam) 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.

SIDE EFFECTS

Adverse events were evaluated in a total of 580 patients who received QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam). Seriou events occurred an average of 46 days (1 - 118) after QUADRAMET® (samarium sm 153 lexidronam). 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 treatmen and QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam). 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® (samarium sm 153 lexidronam) (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® (samarium sm 153 lexidronam) , are given in Table 6.

TABLE 6: SELECTED ADVERSE EVENTS REPORTED IN GREATER THAN OR EQUAL TO 1.0 % OF PEOPLE WHO RECEIVED QUADRAMET® (samarium sm 153 lexidronam) OR PLACEBO IN CONTROLLED CLINICAL TRIALS

In an additional 200 patients who received QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam) 1.0 mCi/kg in any clinical trial include: alopecia, angina, congestive heart failure, sinus bradycardia, and vasodilation.

DRUG INTERACTIONS

The potential for additive bone marrow toxicity of QUADRAMET® (samarium sm 153 lexidronam) with chemotherapy or external beam radiation has not been studied. QUADRAMET® (samarium sm 153 lexidronam) should not be given concurrently with chemotherapy or external beam radiation therapy unless the benefit outweighs the risks. QUADRAMET® (samarium sm 153 lexidronam) should not be given after either of these treatments until there has been time for adequate marrow recovery. (See WARNINGS Section).

Pregnancy Category D. See WARNINGS Section.

Adverse events were evaluated in a total of 580 patients who received QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam). Seriou events occurred an average of 46 days (1 - 118) after QUADRAMET® (samarium sm 153 lexidronam). 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 treatmen and QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam). 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® (samarium sm 153 lexidronam) (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® (samarium sm 153 lexidronam) , are given in Table 6.

TABLE 6: SELECTED ADVERSE EVENTS REPORTED IN GREATER THAN OR EQUAL TO 1.0 % OF PEOPLE WHO RECEIVED QUADRAMET® (samarium sm 153 lexidronam) OR PLACEBO IN CONTROLLED CLINICAL TRIALS

In an additional 200 patients who received QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam) 1.0 mCi/kg in any clinical trial include: alopecia, angina, congestive heart failure, sinus bradycardia, and vasodilation.

Overdosage with QUADRAMET® (samarium sm 153 lexidronam) has not been reported. An antidote for QUADRAMET® (samarium sm 153 lexidronam) overdosage is not known. The anticipated complications of overdosage would likely be secondary to bone marrow suppression from the radioactivity of ¹⁵³Sm, or secondary to hypocalcemia and cardiac arrhythmias related to the EDTMP.