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Quadramet

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Quadramet

Quadramet

CLINICAL PHARMACOLOGY

QUADRAMET® (samarium sm 153 lexidronam) (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® (samarium sm 153 lexidronam) accumulates in osteoblastic lesions than in normal bone with a lesion-to-normal bone ratio of approximately 5. The mechanism of action of QUADRAMET® (samarium sm 153 lexidronam) 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 o 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® (samarium sm 153 lexidronam) , 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)

Blood: 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.

Urine: 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

Elderly: 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.

Hepatic Insufficiency: 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.

Renal Insufficiency: 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 an average of 3.1 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% agreemen 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.

Clinical Trials

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® (samarium sm 153 lexidronam) , 1.0 mCi/kg QUADRAMET® (samarium sm 153 lexidronam) , or a placebo intravenous injection. In study B, 152 patients were randomized to receive either 1.0 mCi/kg QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam) (1.0 mCi/kg). In study A, pain (the AUPC) decrease from baseline was significantly different in QUADRAMET® (samarium sm 153 lexidronam) 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® (samarium sm 153 lexidronam) 1.0 mCi/kg and placebo groups at weeks 2, 3 and 4.

Table 3: COMPARISON OF WEEKLY PAIN SCORES (a) AFTER QUADRAMET® (samarium sm 153 lexidronam) 1.0mCi/kg or PLACEBO IV [Intent to Treat]

  STUDY A (n= 73) (b) STUDY B (n= 150) (c)
WEEK Placebo
N=36
1.0 mCi/kg
N=37
Placebo
N=50
1.0 mCi/kg
N=100
Baseline 26.5 (11.8) 28.7 (12.3) 28.5 (14.1) 28.1 (12.9)
1 26.1 (10.3) 27.6 (14.1) 27.9 (14.6) 25.8 (13.1)
2 24.4 (10.4) 23.8 (13.7) 28.1 (15.4) 20.6 (13.9)*
3 24.3 (11.0) 20.5 (11.5)* 25.8 (16.1) 20.1 (13.3)*
4 24.7 (12.1) 18.8 (10.8)* 24.7 (15.3) 19.9 (13.7)*
(a) Area Under the Pain Curve (SD).
(b) Excludes 5 patients with missing baseline or extreme values; and all 40 patients who received 0.5 mCi QUADRAMET® (samarium sm 153 lexidronam) . QUADRAMET® (samarium sm 153 lexidronam) 0.5 mCi/kg can not be distinguished from placebo.
(c) Excludes 2 patients with missing baseline values.
(*) Statistically significant difference in change from baseline in comparison to placebo.

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® (samarium sm 153 lexidronam) and placebo treatment groups; however, the difference between the QUADRAMET® (samarium sm 153 lexidronam) and placebo group change from baseline i not statistically significant. In study B, the placebo treated patients increased their use of opioid analgesics, while the QUADRAMET® (samarium sm 153 lexidronam) treated patients decreased their use of opioid analgesics.

Table 4: COMPARISON OF WEEKLY MEAN ANALGESIC USE (a) BETWEEN QUADRAMET® (samarium sm 153 lexidronam) 1.0 mCi/kg AND PLACEBO GROUPS [Intent to Treat]

  STUDY A (n= 73) (b) STUDY B (n= 150) (c)
WEEK Placebo
N=36
1.0 mCi/kg
N=37
Placebo
N=50
1.0 mCi/kg
N=100
Baseline 93.5 (154.0)(a) 127.1 (189.9) 78.4 (83.1) 96.5 (166.6)
1 106.8 (173.8) 125.7 (192.6) 84.5 (91.1) 93.5 (165.5)
2 127.1 (238.4) 144.8 (276.7) 85.6 (90.9) 82.9 (122.9)
3 133.9 (254.0) 146.6 (278.2) 100.1 (119.4) 79.6 (131.2)*
4 135.6 (222.0) 135.1 (274.0) 106.3 (161.0) 76.8 (132.3)*
(a) Mean Analgesic Use (SD) is in morphine equivalent units; 0 = none.
(b) Excludes 5 patients with missing baseline or with extreme values; and all 40 patients who received 0.5 mCi QUADRAMET® (samarium sm 153 lexidronam) . QUADRAMET® (samarium sm 153 lexidronam) 0.5 mCi/kg can not be distinguished from placebo.
(c) Excludes 2 patients with missing baseline values.
(*) Statistically significant difference in change from baseline in comparison to placebo.

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® (samarium sm 153 lexidronam) 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 (samarium sm 153 lexidronam) ® treated patients and 11/51 (22%) of the placebo treated patients.

Last reviewed on RxList: 10/8/2008
This monograph has been modified to include the generic and brand name in many instances.

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