Quadramet

QUADRAMET- samarium sm-153 lexidronam pentasodium injection, solution
Jazz Pharmaceuticals, Inc.

DESCRIPTION

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•H2 O, 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:

Structural formula of samarium lexidronam pentasodium.

The ionic formula is 153 Sm+3 [CH2 N(CH2 PO3 -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.

Physical Characteristics

Samarium-153 is produced in high yield and purity by neutron irradiation of isotopically enriched samarium Sm 152 oxide (152 Sm2 O3 ). It emits both medium-energy beta particles and a gamma photon, and has a physical half-life of 46.3 hours (1.93 days). Samarium-153 has average and maximum beta particle ranges in water of 0.5 mm and 3.0 mm, respectively. The primary radiation emissions of samarium-153 are shown in Table 1.

TABLE 1 — SAMARIUM-153 PRINCIPAL RADIATION EMISSION DATA

Radiation
Energy
( keV )*

Abundance

Beta

640

30%

Beta

710

50%

Beta

810

20%

Gamma

103

29%

External Radiation

The specific gamma-ray constant for samarium-153 is 0.46 R/mCi-hr at 1 cm (1.24×10-5 mSv/MBq- hr at 1 Meter). The half-value thickness of lead (Pb) for samarium-153 is approximately 0.10 mm. The use of 1 mm of lead will decrease the external radiation exposure by a factor of approximately 1,000. QUADRAMET® should be stored in a lead-shielded container and frozen until use.

Radioactive decay factors to be applied to the stated value for radioactive concentration at calibration are given in Table 2. All radioactivity is calibrated to the reference date and time on the vial.

TABLE 2 — SAMARIUM-153 PHYSICAL DECAY CHART, HALF-LIFE 46.3 HOURS(1.93 DAYS)

Time
(hour)*

Factor

Time
(hour)*

Factor

-56.0

2.31

+1.0

0.99

-48.0

2.05

+2.0

0.97

-36.0

1.71

+3.0

0.96

-24.0

1.43

+4.0

0.94

-20.0

1.35

+6.0

0.91

-16.0

1.27

+8.0

0.89

-12.0

1.20

+12.0

0.84

-8.0

1.13

+16.0

0.80

-6.0

1.09

+20.0

0.74

-4.0

1.06

+24.0

0.70

-3.0

1.05

+36.0

0.58

-2.0

1.03

+48.0

0.49

-1.0

1.02

+56.0

0.43

CLINICAL PHARMACOLOGY

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 153 Sm[EDTMP]-5 , and <10% as 153 SmH[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.

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