NETSPOT (Page 4 of 5)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ga 68 dotatate binds to somatostatin receptors, with highest affinity for subtype 2 receptors (sstr2). It binds to cells that express somatostatin receptors, including malignant cells, which overexpress sstr2 receptors. Gallium 68 (68 Ga) is a β+ emitting radionuclide with an emission yield that allows positron emission tomography (PET) imaging.

12.2 Pharmacodynamics

The relationship between Ga 68 dotatate plasma concentrations and successful imaging was not explored in clinical trials.

12.3 Pharmacokinetics

Distribution

Ga 68 dotatate distributes to all sstr2-expressing organs, such as pituitary, thyroid, spleen, adrenals, kidney, pancreas, prostate, liver, and salivary glands. There is no uptake in the cerebral cortex or in the heart, and usually thymus and lung uptakes are low.

Elimination

A total of 12% of the injected dose is excreted in urine in the first four hours post-injection.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies on fertility, embryology, mutagenic potential, or carcinogenic potential have been conducted with Ga 68 dotatate. However, genotoxicity studies conducted with a very similar molecule (mixture Lu 175 dotatate/dotatate) shows that these non-radioactive compounds do not induce mutation at the TK locus of L5178Y mouse lymphoma cells in vitro, nor reverse mutation in Salmonella typhimurium , or Escherichia coli (both in the absence or presence of S9 metabolic activation).

14 CLINICAL STUDIES

The efficacy of NETSPOT was established in three open label single center studies (Study A-C).

In Study A, 97 adult patients (mean age 54; 41 men and 56 women) with known or suspected neuroendocrine tumors (NETs) were evaluated with Ga 68 dotatate PET. The Ga 68 dotatate images were read by two independent readers blinded to clinical information. The reads were compared to CT and/or MR images and to indium In 111 pentetreotide images obtained with Single Photon Emission Computed Tomography (SPECT) within previous 3 years. Among 78 patients in whom CT and/or MR images and In 111 pentetreotide images were available, Ga 68 dotatate PET was in agreement with the CT and/or MR images in 74 patients. Out of 50 patients with NETs localized by CT and/or MR imaging, Ga 68 dotatate was positive in 48 patients, including 13 patients in whom In 111 pentetreotide was negative. Ga 68 dotatate was negative in 26 out of 28 patients in whom CT and/or MR imaging was negative.

Study B was a published study which involved 104 patients (mean age 58; 52 men and 52 women) with suspected NETs due to clinical symptoms, elevated levels of tumor markers, or indeterminate tumors suggestive of NET. Diagnostic performance of Ga 68 dotatate PET in localizing tumor sites was retrospectively assessed using a reference standard: histopathology (n = 49) or clinical follow up of up to 5-month duration (n = 55). Images were interpreted by consensus between two on-site readers who were not blinded to clinical information. NET sites were localized by reference standard in 36 patients (all by histopathology). Out of these, Ga 68 dotatate was positive, correctly identifying an NET site, in 29 patients and was falsely negative in seven. In 68 patients with no NET identified by a reference standard, the images were negative in 61 and falsely positive in seven patients.

Study C was a published study which involved 63 patients (mean age 58; 34 men and 29 women) evaluated for NET recurrence using a reference standard as described for Study B. Ga 68 dotatate images were interpreted independently by two central readers blinded to clinical information. Reader 1 correctly localized NETs in 23 out of 29 reference standard-positive patients and reader 2 correctly localized NETs in 22 such patients. In 34 patients with no NET identified by a reference standard, reader 1 was correct in 29 patients and reader 2 in 32.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

NETSPOT is supplied as a single-dose kit (NDC# 69488-001-40) for preparing a single dose of gallium 68 (Ga 68) radiolabeled dotatate injection.

The kit contains:

  • Vial 1 (10-mL Ultra inert Type I Plus glass vial, light-blue flip-off cap): 40 mcg of dotatate, 5 mcg 1,10-phenanthroline, 6 mcg gentisic acid, 20 mg mannitol as lyophilized powder (NDC# 69488-001-04)
  • Vial 2 (10-mL cyclic olefin polymer vial, with a yellow flip-off cap): reaction buffer solution (approximately 1 mL volume), 60 mg formic acid, 56.5 mg sodium hydroxide and water for injection (NDC# 69488-001-01)

The radionuclide is not part of the kit. Before reconstitution and radiolabeling with Ga 68, the contents of this kit are not radioactive.

Expiry date is indicated on the original outer packaging, and on the vials. This medicinal product must not be used beyond the date indicated on the packaging.

16.2 Storage and Handling

For prolonged storage, store NETSPOT in its original packaging at room temperature below 25°C (77°F) (do not freeze). After reconstitution and radiolabeling [see Dosage and Administration (2.3)] with activities of up to 1,110 MBq (30 mCi), keep Ga 68 dotatate injection upright with an appropriate shielding to protect from radiation, at a temperature below 25°C (77°F) (do not freeze), and for a maximum of 4 hours. NETSPOT should not be used more than 4 hours after reconstitution and radiolabeling; discard if not used within 4 hours. The storage of the radiolabeled product must comply with regulatory requirements for radioactive materials.

17 PATIENT COUNSELING INFORMATION

Adequate Hydration

Advise patients to drink a sufficient amount of water to ensure adequate hydration before their PET study and urge them to drink and urinate as often as possible during the first hours following the administration of Ga 68 dotatate injection, in order to reduce radiation exposure [see Dosage and Administration (2.3)].

Lactation

Advise a lactating woman to interrupt breastfeeding and pump and discard breast milk for 12 hours after Ga 68 dotatate injection administration in order to minimize radiation exposure to a breastfed infant [see Use in Specific Populations (8.2)].

Close contact

Advise patients to avoid close contact with infants and pregnant women during the first 12 hours after administration of Ga 68 dotatate.

Distributed by:

Advanced Accelerator Applications USA, Inc. Millburn, NJ 07041

T2021-168

PRINCIPAL DISPLAY PANEL

NDC 69488-001-40

Rx Only

NETSPOT®

(kit for the preparation of
Ga 68 dotatate injection)

For Intravenous Use Only

carton
(click image for full-size original)

PRINCIPAL DISPLAY PANEL

NETSPOT®

40 mcg dotatate per vial

Vial 1 (Reaction vial with lyophilized powder)

For Intravenous Use Only

NDC 69488-001-04

Rx Only

Single-dose vial

Discard unused portion

dotatate, 40 mcg

VIAL 1 – 3 LAYER label
(click image for full-size original)
VIAL 1 – 3 LAYER label
(click image for full-size original)
VIAL 1 – 3 LAYER label
(click image for full-size original)

PRINCIPAL DISPLAY PANEL

NETSPOT®

For adjusting pH of Ga 68 dotatate injection

For pH adjustment of radiolabeled Netspot only

1 mL in 10 mL Vial

Vial 2 (Buffer)

NDC 69488-001-01

Rx Only

Discard unused portion

Single-dose vial

Discard unused portion

VIAL 2 – 3 LAYER label
(click image for full-size original)
VIAL 2 – 3 LAYER label
(click image for full-size original)
VIAL 2 – 3 LAYER label
(click image for full-size original)

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