Quadramet

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.

Samarium Sm 153 lexidronam is a radiopharmaceutical. Radiopharmaceuticals are radioactive agents that may be used to diagnose some diseases by studying the function of the body's organs or to treat certain diseases.

Samarium Sm 153 lexidronam is used to help relieve the bone pain that may occur with certain kinds of cancer. The radioactive samarium is taken up in the bone cancer area and gives off radiation that helps provide relief of pain.

Samarium Sm 153 lexidronam is to be given only by or under the direct supervision of a doctor with specialized training in nuclear medicine or radiation oncology.

Your doctor may have special instructions for you to follow to get ready for your treatment. If you do not understand them or if you have not received such instructions, check with your doctor in advance.

This radiopharmaceutical may accumulate in your bladder. Therefore, to increase the flow of urine and lessen the amount of radiation to your bladder your doctor may instruct you to drink plenty of liquids before receiving samarium Sm 153 lexidronam and urinate often afterwards.

If you have a problem controlling your bladder, tell your doctor before receiving samarium Sm 153 lexidronam. Special precautions will need to be taken to prevent radiation contamination of clothing, bed linens, and the environment.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• If you have an allergy to Quadramet (samarium sm 153 lexidronam) or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding. Do not breast-feed while you take Quadramet.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take Quadramet. This includes your doctors, nurses, pharmacists, and dentists.
• If you have a latex allergy, talk with your doctor.
• It may take a few weeks to see the full effect.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• This medicine is radioactive. You will need to follow what the doctor has told you to lessen being exposed to this medicine. Talk with the doctor.
• Empty your bladder often for the first 12 hours after getting Quadramet.
• Use the toilet instead of a urinal.
• Use the same toilet each time you use the bathroom in your home. Sit down on the toilet to urinate to keep urine from splashing or spraying. Flush the toilet a few times after each use.
• Clean up any spilled urine right away. Wash your hands well after cleaning up.
• If blood or urine gets onto clothing, wash the clothing by itself. You may also store the clothing for 1 to 2 weeks until the drug goes away.
• If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for some time after care ends. Use birth control that you can trust. Talk with your doctor to see how long to use birth control after you stop this medicine.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• A pregnancy test will be done to show that you are NOT pregnant before starting Quadramet. If you get pregnant while taking this medicine, call your doctor right away.
• Use birth control that you can trust to prevent pregnancy during care and for some time after care ends. Talk with your doctor to see how long to use birth control after you stop Quadramet.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into a vein.
• Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

Quadramet® (samarium Sm-153 EDTMP) has an affinity for bone and concentrates in areas of bone turnover in association with hydroxyapatite. In clinical studies employing planar imaging techniques, more Quadramet® accumulates in osteoblastic lesions than in normal bone with a lesion-to-normal bone ratio of approximately 5. The mechanism of action of Quadramet® in relieving the pain of bone metastases is not known.

Distribution

Human protein binding has not been studied; however, in dog, rat and bovine studies, less than 0.5% of samarium-153 EDTMP is bound to protein. At physiologic pH, >90% of the complex is present as 153Sm[EDTMP]-5, and <10% as 153SmH[EDTMP]-4. The octanol/ water partition coefficient is <10-5.

Skeletal Uptake

The greater the number of metastatic lesions, the more skeletal uptake of Sm-153 radioactivity. The relationship between skeletal uptake and the size of the metastatic lesions has not been studied. The total skeletal uptake of radioactivity was 65.5% ± 15.5% of the injected dose in 453 patients with metastatic lesions from a variety of primary malignancies. In a study of 22 patients with a wide range in the number of metastatic sites, the % of the injected dose (% ID) taken up by bone ranged from 56.3% in a patient with 5 metastatic lesions to 76.7% in a patient with 52 metastatic lesions. If the number of metastatic lesions is fixed, over the range 0.1 to 3.0 mCi/kg, the % ID taken up by bone is the same regardless of the dose.

Metabolism

The complex formed by samarium and EDTMP is excreted as an intact, single species that consists of one atom of the Sm-153 and one molecule of the EDTMP, as shown by an analysis of urine samples from patients (n=5) administered samarium Sm-153 EDTMP. Metabolic products of samarium Sm-153 EDTMP were not detected in humans.

Elimination

For Quadramet®, calculations of the % ID detected in the whole body, urine and blood were corrected for radionuclide decay. The clearance of activity through the urine is expressed as the cumulated activity excreted. The whole body retention is the simple reciprocal of the cumulated urine activity. (See Skeletal Uptake Section).

Clearance of radioactivity from the blood demonstrated biexponential kinetics after intravenous injection in 19 patients (10 men, 9 women) with a variety of primary cancers that were metastatic to bone. Over the first 30 minutes, the radioactivity (mean ± SD) in the blood decreased to 15% (±8%) of the injected dose with a t 1/2 of 5.5 min (±1.1 min). After 30 minutes, the radioactivity cleared from the blood more slowly with a t1/2 of 65.4 min (± 9.6 min). Less than 1% of the dose injected remained in the blood 5 hr after injection.

Samarium Sm-153 EDTMP radioactivity was excreted in the urine after intravenous injection. During the first 6 hours, 34.5% (±15.5%) was excreted. Overall, the greater the number of metastatic lesions, the less radioactivity was excreted.

Gender Differences

Gender did not affect the samarium Sm-153 EDTMP blood pharmacokinetics, the cumulative % of radioactivity excreted in urine, or the % radioactivity retained in the skeleton when the number of metastatic lesions is taken into account.

Special Populations

The pharmacokinetics of samarium Sm-153 EDTMP did not change with age as seen from comparison of values from people in the age range of 22 to 64 compared to the range 65 to 86 years.

Samarium Sm-153 EDTMP scintiscans in 5 patients with metastatic bone disease did not reveal accumulation of activity in the liver or the intestine; this suggests that hepatobiliary excretion did not occur.

Patients with renal insufficiency have not been studied.

Drug/Drug Interaction

Drug-drug interaction studies have not been studied.

Pharmacodynamics

The beta particle of 153Sm-EDTMP travels a maximum distance of 3.0 mm in soft tissue and 1.7 mm in bone. In clinical trials of 78 patients with metastatic bone lesions who had 13 specific bone scan sites evaluated, the presence or absence of 153Sm-EDTMP uptake is similar to the presence or absence of 99mTc diphosphonate uptake (range 67 to 96% agreement depending upon the blinded reader and the site of the body). Whether the amount of 153Sm-EDTMP uptake varies with the size of the lesion or to the presence of osteolytic components has not been studied. The clinical benefit of Sm-153-EDTMP in patients with osteolytic lesions is not known. The relationship of different tumor cell types to clinical response has not been studied.

Quadramet® is contraindicated in patients who have known hypersensitivity to EDTMP or similar phosphonate compounds.

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 (See Laboratory Tests).

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.

INFORMATION FOR PATIENTS

Patients who receive Quadramet® should be advised that for several hours following administration, radioactivity will be present in excreted urine. To help protect themselves and others in their environment, precautions need to be taken for 12 hours following administration. Whenever possible, a toilet should be used, rather than a urinal, and the toilet should be flushed several times after each use. Spilled urine should be cleaned up completely and patients should wash their hands thoroughly. If blood or urine gets onto clothing, the clothing should be washed separately, or stored for 1-2 weeks to allow for decay of the Sm-153.

Some patients have reported a transient increase in bone pain shortly after injection (flare reaction). This is usually mild and self-limiting and occurs within 72 hours of injection. Such reactions are usually responsive to analgesics.

Patients who respond to Quadramet® might begin to notice the onset of pain relief one week after Quadramet®. Maximal pain relief generally occurs at 3-4 weeks after injection of Quadramet®. Patients who experience a reduction in pain may be encouraged to decrease their use of opioid analgesics.

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.

DRUG INTERACTIONS

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

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.