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CLINICAL PHARMACOLOGY Actions Local irradiation by beta emission.

Phosphocol® P 32 (chromic phosphate P 32) Suspension Therapeutic intraperitoneal or intracavitary injection only for treatment of peritoneal or pleural effusions caused by metastatic disease. DESCRIPTION Phosphocol® P 32 is supplied as a sterile, nonpyrogenic aqueous suspension in a 30% dextrose solution with 2% benzyl alcohol added as preservative. Each milliliter contains 1 mg sodium acetate. Sodium hydroxide or hydrochloric acid may be present for pH adjustment.

INDICATIONS Phosphocol P 32 is employed by intracavitary instillation for the treatment of peritoneal or pleural effusions caused by metastatic disease, and may be injected interstitially for the treatment of cancer. DOSAGE AND ADMINISTRATION The suggested dose range employed in the average patient (70 kg) is: Intraperitoneal instillation: 370 to 740 megabecquerels (10 to 20 millicuries) Intrapleural instillation: 222 to 444 megabecquerels (6 to 12 millicuries) Doses for interstitial use should be based on estimated gram weight of tumor, about 3.7 to 18.5 MBq/gm (0.1 to 0.5 mCi/gm). The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. Physical Characteristics Phosphorus P 32 decays by beta emission with a physical half-life of 14.3 days.1 The mean energy of the beta particle is 695 keV. Table 1. Principal Radiation Emission Data Radiation Mean Percent/ Disintegration Mean Energy (keV) Beta-1 100.0 694.9 The range of the phosphorus P 32 beta particle, which has a maximum energy of 1.71 MeV, is 2.9 mm of aluminum. To correct for physical decay of this radionuclide, the percentages that remain at selected time intervals before and after the day of calibration are shown in Table 2. Table 2. Physical Decay Chart; Phosphorus P 32, Half-life 14.3 days Days Fraction Remaining Days Fraction Remaining Days Fraction Remaining -15 2.07 2 0.908 35 0.183 -10 1.62 5 0.785 40 0.144 -5 1.27 10 0.616 45 0.113 -2 1.10 15 0.483 50 0.089 -1 1.05 20 0.379 55 0.070 0* 1.00 25 0.298 60 0.055 1 0.953 30 0.234 65 0.043 *Calibration Day Radiation Dosimetry The effective half-life of phosphorus P 32 is considered to be equal to its physical half-life, with a residence time of 495 hours. The radiation dose from a uniformly distributed concentration of 37 kilobecquerels (1 microcurie) per gram within a 16-gram prostate is estimated to be equivalent to about 7.3 grays (730 rads)2. Table 3 shows the estimated radiation doses to the prostate and the pleural or peritoneal surfaces3 of an average patient (70 kg) from a dose of 740 megabecquerels (20 millicuries) of phosphorus P 32. In comparison to the distribution in the prostate, the distribution of phosphorus P 32 on the pleural and peritoneal surfaces is non-uniform, with great extremes in local doses. To obtain an estimate of the average dose, the surface area of the pleural and peritoneal cavities can be assumed to amount to 4,000 and 5,000 cm2, respectively. The estimated radiation doses to an average patient (70 kg) with 90% retention of a dose of 740 megabecquerels (20 millicuries) of phosphorus P 32 distributed uniformly over these areas are shown in Table 3. The decreases of the averaged radiation doses at various tissue depths away from the surfaces of the pleural and peritoneal cavities are also tabulated. Table 3. Estimated Radiation Doses Surface/Organ Pleural Peritoneal Prostate % Retention Area/wt 90 4000 cm2 90 5000 cm2 100 16 gm Depth in tissue (cm) Dose Rate Tissue Dose/74 0 MBq (20 mCi) mGy-cm2 MBq-s rad-cm2 µCi-h grays rads grays rads grays rads 0.006 0.75 10 178 17800 134 13400 9180 918000 0.018 0.53 7 125 12500 94 9360 0.03 0.42 5.6 100 10000 74.9 7490 0.12 0.15 2 36 3570 26.7 2670 0.21 0.064 0.85 15 1520 11.4 1140 0.3 0.023 0.31 5.5 550 4.1 410 0.4 0.0047 0.062 1 110 0.83 83 HOW SUPPLIED Catalog Number 470 Phosphocol P 32 - Chromic Phosphate P 32 Suspension (NDC No. 0019-N470-P0) is available in 10 milliliter vials containing 555 megabecquerels (15 millicuries) with a concentration of 185 megabecquerels (5 millicuries) per milliter. The radiopharmaceutical is manufactured with a specific activity of 122 megabecquerels (3.3 millicuries) per milligram Chromic Phosphate at the time of standardization. The U.S. Nuclear Regulatory Commission has approved distribution of this radiopharmaceutical to persons licensed to use byproduct material listed in Section 35.300, and to persons who hold an equivalent license issued by an Agreement State. Storage And Handling Store at controlled room temperature 20 to 25°C (68 to 77°F). REFERENCES 1 Stabin MG, da Luz CQPL. New Decay Data for Internal and External Dose Assessment, Health Phys. 83(4):471-475, 2002. 2 Stabin MG. A Model of the Prostate Gland for Use in Internal Dosimetry. J Nucl Med 35(3):516-520, 1994. 3 Watson EE, Stabin MG, Davis JL and Eckerman KF. A Model of the Peritoneal Cavity for Use in Internal Dosimetry. J Nucl Med 30:2002-2011, 1989. Revised 020308. Mallinckrodt Inc. Hazelwood, MO 63042 U.S.A.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE No information provided. CONTRAINDICATIONS Chromic phosphate P 32 therapy should not be used in the presence of ulcerative tumors. Administration should not be made in exposed cavities or where there is evidence of loculation unless the extent of loculation is determined.

SIDE EFFECTS Untoward effects may be associated with use of chromic phosphate P 32. These include transitory radiation sickness, bone marrow depression, pleuritis, peritonitis, nausea and abdominal cramping. Radiation damage may occur if accidentally injected interstitially or into a loculation. Post-marketing Experience The following adverse reactions associated with the use of Phosphocol P 32 have been identified during post approval use: Leukemia in Children (see WARNINGS) Radiation injury (necrosis and fibrosis) to the small bowel, cecum, and bladder following administration of P 32 into the peritoneal cavity. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. DRUG INTERACTIONS No information provided.

WARNINGS Not for intravascular use. This radiopharmaceutical should not be administered to patients who are pregnant or during lactation unless the therapeutic benefits outweigh the potential hazards. Radiopharmaceuticals should be used only by physicians who are qualified by specific training in the safe use and handling of radionuclides produced by nuclear reactor or particle accelerator and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides. Leukemia Phosphocol P 32 may increase the risk for leukemia in certain situations. Two children (ages 9 and 14) with hemophilia developed acute lymphocytic leukemia approximately 10 months after intra-articular injections of Phosphocol P 32 (0.6 and 1.5 mCi total dose). Phosphocol P 32 is not indicated in the intra-articular treatment of hemarthroses. PRECAUTIONS General As in the use of any other radioactive material care should be taken to insure minimum radiation exposure to the patient, consistent with proper patient management, and to insure minimum radiation exposure to occupational workers. Careful intracavitary instillation is required to avoid placing the dose of chromic phosphate P 32 into intrapleural or intraperitoneal loculations, bowel lumen or into the body wall. Intestinal fibrosis or necrosis and chronic fibrosis of the body wall have been reported to result from unrecognized misplacement of the therapeutic agent. The presence of large tumor masses indicates the need for other forms of treatment. However, when other forms of treatment fail to control the effusion, chromic phosphate P 32 may be useful. In bloody effusion, treatment may be less effective. Pediatric Use Safety and effectiveness in pediatric patients has not been established. Risk of Malignancy Acute lymphocytic leukemia has been reported in children following the intra-articular administration of Phosphocol P 32 (see WARNINGS).