NeutroSpec

NEUTROSPEC- technetium (99m tc) fanolesomab
Mallinckrodt Inc.

Diagnostic Radiopharmaceutical
For intravenous use only
Rx ONLY CONTAINS SODIUM HYDROSULFITE

DESCRIPTION

NeutroSpecTM [Kit for the Preparation of Technetium (99m Tc) fanolesomab] is a radiodiagnostic agent consisting of a murine IgM monoclonal antibody, formulated to be labeled with technetium Tc 99m. Each NeutroSpecTM kit contains all the excipients needed to reconstitute and to radiolabel this imaging agent with sodium pertechnetate Tc 99m Injection, USP. The murine monoclonal antibody fanolesomab is produced in suspension culture of hybridoma cells. NeutroSpecTM [Technetium (99m Tc) fanolesomab] is an in vivo diagnostic radiopharmaceutical that can be visualized by nuclear medicine instrumentation.

Each NeutroSpecTM kit contains a single use vial of fanolesomab as a sterile, non-pyrogenic, lyophilized mixture of 0.25 mg fanolesomab; 12.5 mg maltose monohydrate; 0.522 mg sodium potassium tartrate tetrahydrate, USP; 0.221 mg succinic acid; 54 mcg stannous tartrate (minimum stannous 7 mcg; maximum total stannous and stannic tin 24 mcg); 28 mcg glycine, USP; and 9.3 mcg disodium edetate dihydrate, USP. The lyophilized powder contains no preservatives and has no US standard of potency.

When sterile, pyrogen-free sodium pertechnetate Tc 99m Injection, USP in isotonic saline (no preservatives) is added to the single use fanolesomab vial, a Tc 99m complex of fanolesomab is formed with an approximate pH of 6.2.

Physical Characteristics of Technetium Tc 99m

Technetium 99m decays by isomeric transition with a physical half-life of 6.02 hours. The photon that is useful for imaging studies is listed in Table 1.

Table 1. Principal radiation emission data for technetium Tc 99m
Radiation Mean Percent per Disintegration Mean Energy (keV)
Gamma-2 89.07 140.5

External Radiation

The specific gamma-ray constant for technetium Tc 99m is 5.4 μC·kg-1 ·MBq-1 ·h-1 (0.78 R/mCi·h) at 1 cm. The first half-value thickness of lead for Tc 99m is 0.017 cm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from the interposition of various thicknesses of lead is shown in Table 2. For example, the use of a 0.25 cm thickness of lead will decrease the external radiation exposure by a factor of 1,000.

Table 2. Radiation attenuation by lead shielding
Lead Shield Thickness (cm) Coefficient of Attenuation
0.017 0.5
0.08 0.1
0.16 0.01
0.25 0.001
0.33 0.0001

To correct for physical decay of this radionuclide, the fractions that remain at selected time intervals after the time of calibration are shown in Table 3.

Table 3. Physical decay chart—technetium Tc 99m half-life 6.02 hours

* Calibration Time (time of preparation)

Hours Fraction Remaining Hours Fraction Remaining
0* 1.00 7 0.45
1 0.89 8 0.40
2 0.79 9 0.36
3 0.71 10 0.32
4 0.63 11 0.28
5 0.56 12 0.25
6 0.50 18 0.13

CLINICAL PHARMACOLOGY

Pharmacodynamics

Fanolesomab is directed against the carbohydrate moiety 3-fucosyl-N -acetyllactosamine that defines the cluster of differentiation 15 (CD15) antigen. NeutroSpecTM [Technetium (99m Tc) fanolesomab] radiolabels human white blood cells and myeloid precursors. The CD15 antigen is expressed on the surface of polymorphonuclear neutrophils (PMNs), eosinophils and monocytes. Monocytes and eosinophils constitute approximately 5% of circulating leukocytes; therefore, most of the circulating blood cellular activity resides on PMNs. In blood cell fractions isolated from healthy volunteers who had received NeutroSpecTM , radioactivity was associated with PMNs (25%) or plasma (72%) when measured one hour after injection. The binding of fanolesomab to its antigenic sites on human PMNs has an apparent K d = 1.6 × 10-11 M.

Cross-reactivity studies indicate the presence of CD15 antigenic sites on many human tissues.

Pharmacokinetics

In a study of 10 healthy volunteers, following intravenous injection of NeutroSpecTM , blood concentrations of radioactivity decreased rapidly with an initial half-life of 0.3 hours and a second phase half-life of approximately eight hours. Whole-body scintigraphy at two hours post-injection indicated that the liver had the highest radioactivity uptake and retention (50% of the injected dose), followed by the kidney, spleen and red marrow. Over the 26–33 hours after injection, 38% of the injected dose of radioactivity was recovered in urine.

CLINICAL STUDIES

A multicenter, single-arm study evaluated 200 patients (5 to 86 years of age) with equivocal signs and symptoms of appendicitis defined as absence of one or more of the following: periumbilical pain migrating to right lower quadrant (RLQ), gradual onset of pain, increasing intensity of pain over time, pain aggravated by movement and coughing, McBurney’s point tenderness, referred tenderness to RLQ with palpation in other quadrants, abdominal muscular spasm with RLQ tenderness, temperature > 1010 F, white blood cell count > 10,500/mm3. Readers blinded to clinical information (except for age, gender and body habitus) assessed the diagnosis of appendicitis by NeutroSpecTM imaging. The diagnosis by the blinded readers was compared with a final clinical diagnosis based upon a surgical pathology report (in cases that proceeded to appendectomy) or upon two weeks of follow-up (in cases without surgical intervention). The study investigators had access to other diagnostic modalities (e.g., CT scan and ultrasound) and were instructed not to rely on NeutroSpecTM imaging for their diagnosis of appendicitis. Appendicitis prevalence in this study was 30%. The image evaluation was limited to the assessment of the planar images performed in specified projections at defined time points and single photon emission tomography was not used to assess performance in this study.

The performance rates for the diagnosis of appendicitis by the blinded readers and by the clinical investigators are shown in Table 4.

Table 4. Diagnostic performance of NeutroSpecTM
Performance Rates(n=200)
Evaluation Blinded Readerspercentages (95%CI) Study Investigatorspercentages(95%CI)
Sensitivity 75 (62, 85) 91 (80, 97)
Specificity 93 (87, 97) 86 (79, 91)
Accuracy 87 (82, 92) 87 (81, 91)
Positive Predictive Value 82 (69, 91) 74 (62, 84)
Negative Predictive Value 90 (84, 94) 96 (90, 99)

In a supportive single-arm, two-center study of the detection of appendicitis in 56 patients of whom 50% had a final diagnosis of appendicitis, the diagnostic performance of NeutroSpecTM was similar to the performance observed in the larger study.

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