QUADRAMET® PRESCRIBING INFORMATION

Therapeutic – For Intravenous Administration

QUADRAMET® is a therapeutic agent consisting of radioactive samarium and a tetraphosphonate chelator, ethylenediaminetetramethylenephosphonic acid (EDTMP). QUADRAMET® is formulated as a sterile, non-pyrogenic, clear, colorless to light amber isotonic solution of samarium-153 lexidronam for intravenous administration. QUADRAMET® does not contain a preservative.

Each milliliter contains 35 mg EDTMP∙H2O, 5.3 mg Ca [as Ca(OH)2], 14.1 mg Na [as NaOH], equivalent to 44 mg Ca/Na EDTMP (anhydrous calc.), 5-46 µg samarium (specific activity of approximately 1.0-11.0 mCi/µg Sm), and 1850 ± 185 MBq (50 ± 5 mCi) of samarium-153 at calibration.

The structural formula of samarium lexidronam pentasodium is:

The ionic formula is 153Sm+3 [CH2N(CH2PO3-2)2]2 and the ionic formula weight is 581.1 daltons (pentasodium form, 696).

The pH of the solution is 7.0 to 8.5.

QUADRAMET® is supplied frozen in single-dose glass vials containing 3 mL with 5550 MBq (150 mCi) of samarium-153 at calibration.

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.

Overall QUADRAMET® was evaluated in 580 patients (see Adverse Events Section for demographic description). Of these patients, 270 (244 men, 26 women) were studied in two randomized, blinded, placebo controlled clinical trials. These patients had a mean age of 67, and a range 22 to 87 years. Eligible patients had painful metastatic bone lesions that had failed other treatments, had at least a 6 month expected survival and had a positive radionuclide bone scan. Routine x-rays to evaluate the metastatic lesions were not part of the protocol.

In study A, 118 patients were randomized to receive 0.5 mCi/kg QUADRAMET®, 1.0 mCi/kg QUADRAMET®, or a placebo intravenous injection. In study B, 152 patients were randomized to receive either 1.0 mCi/kg QUADRAMET® or a placebo intravenous injection. Both studies were double blind over a 4 week period. Patients scored their daily pain intensity on a visual analogue scale rated from 0 (no or low pain) to 10 (excruciating pain). The area under the pain curve (AUPC) was obtained by integrating the daily pain scores by week. Opioid analgesic use was recorded daily and averaged over each week and expressed in oral morphine milligram equivalents.

Of the 270 patients studied, 232 (86%) had prostate cancer and 38 (14%) had other primary cancers. In study A, 80 (68%) of the patients had prostate cancer and 38 (32%) had a variety of other primary tumors. In study B, all (100%) patients had prostate cancer.

The results of the patients' AUPC scores are shown in Table 3. In both trials for each of the 4 weeks of study, the mean AUPC scores decreased in patients who received QUADRAMET® (1.0 mCi/kg). In study A, pain (the AUPC) decrease from baseline was significantly different in QUADRAMET® 1.0 mCi/kg and placebo groups at weeks 3 and 4. In study B, pain (the AUPC) decrease from baseline was significantly different in QUADRAMET® 1.0 mCi/kg and placebo groups at weeks 2, 3 and 4.

In the two clinical trials, the patient use of analgesics differed. In Study A, the patients did not receive specific instructions on analgesic reduction. In Study B, patients were encouraged to adjust their pain medication as needed. As shown in Table 4, the morphine equivalent analgesic use in study A generally increased from baseline in both the QUADRAMET® and placebo treatment groups; however, the difference between the QUADRAMET® and placebo group change from baseline is not statistically significant. In study B, the placebo treated patients increased their use of opioid analgesics, while the QUADRAMET® treated patients decreased their use of opioid analgesics.

In both studies, the numbers of patients who experienced any decrease in AUPC score without any increase in analgesic use at weeks 3 and 4 were also evaluated. In study A, this occurred in 20/37 (54%) of the patients who received QUADRAMET® 1.0 mCi/kg and 9/36 (25%) of the placebo treated patients. In study B, this occurred in 48/100 (48%) of the QUADRAMET® treated patients and 11/51 (22%) of the placebo treated patients.

QUADRAMET® is indicated for relief of pain in patients with confirmed osteoblastic metastatic bone lesions that enhance on radionuclide bone scan.

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

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.

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.

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 impairment.

Renal Impairment: Because approximately one third of Samarium Sm-153 EDTMP is excreted in the urine, clearance may be reduced in patients with renal impairment; it is not known if dose adjustment is needed.

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

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 (81%) 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 (48%) 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.

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.

Overdosage with QUADRAMET® has not been reported. An antidote for QUADRAMET® 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.

The recommended dose of QUADRAMET® 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®. 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® contains calcium and may be incompatible with solutions that contain molecules that can complex with and form calcium precipitates.

QUADRAMET® should not be diluted or mixed with other solutions.

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

QUADRAMET® 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® is available in the following size:

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

The drug product expires 56 hours after the time of calibration noted on the label, or 8 hours after thawing, whichever is earlier.

This radioactive drug is approved for distribution to persons licensed pursuant to the Code of Massachusetts Regulations 105 CMR 120.100 for the uses listed in 105 CMR 120.589 or under equivalent regulations of the U.S. Nuclear Regulatory Commission, an Agreement State or a Licensing State.

THIS PRODUCT INFORMATION ISSUED March 2018.

Lantheus Medical Imaging, Inc.
331 Treble Cove Road
N. Billerica, Massachusetts 01862
USA

For Ordering Call Toll Free: 800-299-3431
All other business: 800-362-2668
For Massachusetts and International call: 978-667-9531

Printed in U.S.A.

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513145-0318
March 2018

Quadramet® Samarium Sm153 Lexidronam Injection

Sterile, Non-pyrogenic, Intravenous Injection
Contents & Assay: 35 mg/mL EDTMP•H2O; 5.3 mg/mL
Ca[as Ca(OH)2]; 14.1 mg/mL Na[as NaOH]; 5-46 µg Samarium;
1850 ± 185 MBq/mL (50 ± 5 mCi/mL) of Samarium–153
at calibration. Store frozen at -10° to -20°C (14° to -4° F).
Thaw at room temperature before administration
and use within 8 hours of thawing. Rx only
See Package Insert for dosing information.
Vial Stopper Contains Dry Natural Rubber Latex.

Caution: Radioactive Material

Manufacturer:
Lantheus
Medical Imaging
N. Billerica, MA 01862

515127-0114