Lymphoseek

Lymphoseek is a brand name medication.

Technetium Tc 99m tilmanocept injection is a radiopharmaceutical. Radiopharmaceuticals are radioactive agents, which may be used to find and treat certain diseases or to study the function of the body's organs.

Technetium Tc 99m tilmanocept injection is used to find lymph node in patients with solid tumors. It is also used to find sentinel lymph nodes in patients with breast, skin or oral cavity cancer.

This medicine is to be given only by or under the direct supervision of a doctor with specialized training in nuclear medicine.

A doctor or other trained health professional will give you this medicine. Depending on your medical problem, this medicine is given as a shot under your skin, into your skin, around the tumor, or below the areola of the breast.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

Incidence not known

• Difficulty with breathing or swallowing
• fast heartbeat
• skin itching, rash, or redness
• swelling of the face, throat, or tongue

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Rare

• Pain or irritation at the injection site

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Overview of Clinical Studies

The efficacy and safety of Lymphoseek were assessed in three open-label, multicenter, single arm trials of patients with melanoma, breast cancer, or squamous cell carcinoma (SCC) of the oral cavity, skin, and lip (Studies 1, 2, and 3). Prior to the lymph node mapping and sentinel lymph node biopsy procedures, patients had no known regional nodal or metastatic disease by standard clinical staging criteria.

• In Studies 1 and 2, Lymphoseek was evaluated in patients with breast cancer and melanoma. Diagnostic efficacy for lymphatic mapping was determined by the number of histology-confirmed lymph nodes detected by Lymphoseek and/or the blue dye comparator. Lymphoseek was injected into patients at least 15 minutes prior to initiating lymphatic mapping procedures, and preoperative scintigraphic imaging was performed in 91% of patients. Separately, blue dye was injected shortly prior to initiation of the surgery. Lymphatic mapping was performed intraoperatively using a handheld gamma detection probe followed by excision of lymph nodes identified by Lymphoseek, blue dye, or the surgeon’s visual and palpation examination. The resected lymph nodes were evaluated by histopathology.  Lymphoseek localization rate in pathology-positive lymph nodes was also determined. o In Study 1, of 179 patients who received Lymphoseek, 94 (53%) had known or suspected breast cancer and 85 (47%) had known or suspected melanoma. The median age was 59 years (range 20 to 90 years) and most (72%) were women. o In Study 2, of 153 patients who received Lymphoseek, 77 (50%) had known or suspected breast cancer and 76 (50%) had known or suspected melanoma. The median age was 61 years (range 26 to 88 years) and most (68%) were women. • In Study 3, Lymphoseek was evaluated primarily in patients with SCC of the oral cavity (T1-T4a, N0, M0). Diagnostic efficacy was determined by the patient level false negative rate of sentinel lymph node detection by Lymphoseek as confirmed by pathologic assessment of all lymph nodes removed during a planned elective neck dissection (END). Lymphoseek was administered at least 15 minutes prior to the scheduled surgery and preoperative scintigraphic imaging was performed in all patients. Lymphatic mapping was performed intraoperatively using a handheld gamma counter followed by excision of sentinel lymph nodes identified by Lymphoseek. Additional lymph nodes were removed during the END based upon tumor location and surgical practice. All resected lymph nodes (sentinel and non-sentinel) were evaluated for histopathology at the local site. Lymphoseek-identified nodes determined negative for cancer were further evaluated by a central pathology laboratory using additional step sectioning and cytokeratin staining. o Of the 85 patients who received Lymphoseek, 79 (93%) had intraoral SCC and 6 (7%) had cutaneous SCC. The median age was 59 years (range 23 to 87 years) and most (75%) were men.

Lymphoscintigraphy

An analysis of the three studies was performed to evaluate the agreement in location of lymph nodes identified by scintigraphic imaging and the handheld gamma counter. At least one scintigraphic “hot spot” was identified in 95% of patients imaged; the percentages were similar across tumor types. Overall, there was 84% agreement on a nodal level (when considering all missing observations as disagreement, as worst case scenario) between the location of preoperative scintigraphic imaging hot spots and the intraoperative lymph node findings (Table 7). Missing observations took the following form: 43 hot spots without corresponding hot nodes and 31 hot nodes without corresponding hot spots.

Table 7. Location Agreement between Scintigraphic Imaging and Gamma Counter Findings

* Denominator equals total number of hot spots and/or hot nodes. Numerator equals the numbers where hot spots and hot nodes agreed in location. ** 95% Confidence Intervals.
	Melanoma	Breast Cancer	Head and Neck Cancer	Overall Results
Agreement of Hot Spot and Hot Node Location*	182/206; 88% (83%, 93%)**	116/147; 79% (70%, 88%)**	95/115; 83% (76%, 90%)**	393/468; 84% (81%, 87%)**

Lymphatic Mapping

In Studies 1 and 2 in melanoma and breast cancer, efficacy analyses were based upon comparisons of the number and proportion of resected lymph nodes that contained a lymph node tracer (Lymphoseek and/or blue dye) or neither tracer. Evaluable lymph nodes were resected from 176 Study 1 patients and 152 Study 2 patients who received Lymphoseek at the dose of 0.5 to 2 mCi in 50 mcg administered 15 minutes to 30 hours prior to surgery. Table 8 shows the distribution of resected lymph nodes by the presence or absence of a tracer. Most of the resected lymph nodes were identified by either Lymphoseek (LS) or blue dye (BD) or both. Significantly more resected lymph nodes were identified by Lymphoseek in comparison to blue dye.

Table 8. Resected Lymph Nodes and Content of Lymphoseek (LS) and/or Blue Dye (BD) from Studies in Breast Cancer and Melanoma

The percentages may not add to 100% due to rounding. 95% Confidence Intervals (CI) are based on Exact Binomial and represent the spread in the individual estimates.
Study	Tumor	Nodes n	BD Present % (95% CI)	LS Present % (95% CI)	Only BD Present % (95% CI)	Only LS Present % (95% CI)	Neither BD nor LS Present % (95% CI)
One	Melanoma	187	65% (57% , 72%)	93% (88% , 96%)	2% (0 , 5%)	29% (23% , 37%)	6% (3% , 10%)
	Breast Cancer	192	70% (63% , 77%)	89% (83% , 93%)	7% (4% , 12%)	26% (20% , 32%)	4% (2% , 8%)
Two	Melanoma	198	59% (51% , 66%)	99% (97% , 100%)	0 (0 , 2%)	41% (34% , 48%)	1% (0 , 3%)
	Breast Cancer	181	62% (55% , 70%)	100% (98% , 100%)	0 (0 , 2%)	38% (30% , 45%)	0 (0 , 2%)

In Studies 1 and 2 lymphatic mapping was performed in 328 patients with melanoma or breast cancer. The overall rate of lymph node detection by Lymphoseek at the patient level was 97% (319/328). The average number of lymph nodes detected by Lymphoseek was approximately 2 per patient.

In Study 3 lymphatic mapping was performed in 83 patients with SCC of the oral cavity. The rate of lymph node detection by Lymphoseek at the patient level was 98% (81/83) with a 95% confidence interval of 92% to 100%. The average number of lymph nodes identified was 4 per patient.

Guiding Sentinel Lymph Node Biopsy

In Study 3 in patients with SCC of the oral cavity (n=79), skin (n=5), and lip (n=1), pathology findings for Lymphoseek-identified nodes (sentinel lymph nodes) were compared to the pathology findings of all other lymph nodes removed during the scheduled elective node dissection to determine the false negative rate of Lymphoseek. Thirty-nine patients were determined to have pathology-positive regional lymph nodes. In these patients, the Lymphoseek false negative rate for detecting patients with cancer-positive nodes was 2.6% (95% CI: 0.06% to 13.5%). In this study the pathology-positive nodes were all found in patients with SCC of the oral cavity.

Supportive analyses were conducted in Studies 1 and 2 in patients with breast cancer or melanoma. The presence or absence of Lymphoseek in nodes resected from patients determined by pathology staging to have lymphatic spread of cancer (n=64) was evaluated. The overall patient level rate for identifying at least one cancer-positive node in these pathology-positive patients (both cancers combined) was 97%. Lymphoseek identified 27 out of 29 node positive breast cancer patients and all of the 35 node positive melanoma patients.

The Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept) injection (NDC 65857-425-05) includes:

• Five vials of Tilmanocept Powder, 250 mcg (NDC 65857-400-01) • Prescribing information • Five labels for shields • Twenty-five labels for product vials and individual syringes

The Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept) injection (NDC 65857-450-05) includes:

• Five vials of Tilmanocept Powder, 250 mcg (NDC 65857-400-01) • Five vials of DILUENT for Lymphoseek (NDC 65857-401-45) • Prescribing information • Five labels for shields • Twenty-five labels for product vials and individual syringes

Storage

Store Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept) injection in the original packaging at USP controlled room temperature 20°C - 25°C (68°F - 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Store radiolabeled Lymphoseek in radiation shielding at room temperature. 

Use radiolabeled Lymphoseek within 6 hours of preparation.

Handling

This Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept) injection is approved for distribution to persons licensed by the U.S. Nuclear Regulatory Commission to use by product material identified in 10 CFR 35.200 or under an equivalent license issued by an Agreement State.

• Advise patients to seek medical attention for reactions following injection of Lymphoseek such as difficulty breathing, skin rash, or other allergy manifestations. • Inform nursing women to pump and discard milk for at least 60 hours following administration of Lymphoseek injection [see Use in Specific Populations (8.3)].

Distributed by:

Cardinal Health 414, LLC
Dublin, OH 43017

Lymphoseek is a registered trademark of Cardinal Health 414, LLC.

Patent: www.Lymphoseek.com/patent-information

Revision date: 06/2017

Carton Label

Principal Panel

NDC 65857-425-05

Kit for the preparation of Lymphoseek®
(technetium Tc 99m tilmanocept) injection

250 mcg Tilmanocept per Vial

Contents:

• Five vials of Tilmanocept Powder, 250 mcg NDC 65857-400-01 • Prescribing information • Five Radioassay Information shield labels • Twenty-five labels for product vials and individual syringes

Use within 6 Hours after reconstitution.

Store at controlled room temperature, 20°C-25°C (68°F-77°F), in original package;
excursions permitted to 15°C to 30°C (59°F to 86°F).

Distributed by Cardinal Health 414, LLC
Dublin, OH 43017             Rx Only

Left Side

Kit for the preparation of Lymphoseek®
(technetium Tc 99m tilmanocept) injection

250 mcg Tilmanocept per Vial

Each sterile, non-pyrogenic, lyophilized Tilmanocept Powder vial contains:

Tilmanocept     250 mcg
Trehalose, Dihydrate     20 mg
Glycine     0.5 mg
Sodium Ascorbate     0.5 mg
Stannous Chloride, Dihydrate     0.075 mg
The Tilmanocept Powder vials are sealed under nitrogen at the time
of manufacture, and contain no preservatives.

Rx Only

For Customer Service call: 1-800-476-5270
Web Site: www.Lymphoseek.com

CardinalHealth™
Pat: www.Lymphoseek.com/patent-information

Kit for the preparation of
Lymphoseek® (technetium
Tc 99m tilmanocept)
injection

WARNING:

Radiopharmaceuticals
should be used by persons
who are qualified by specific
training in the safe use and
handling of radionuclides
and whose experience and
training have been approved
by the appropriate
governmental agency
authorized to license the use
of nuclides.

Back Panel

Kit for the preparation of Lymphoseek®
(technetium Tc 99m tilmanocept) injection

250 mcg Tilmanocept per Vial

Storage Conditions:
Store at controlled room temperature, 20°C-25°C (68°F-77°F), in original package;
excursions permitted to 15°C to 30°C (59°F to 86°F).

CardinalHealth™

7-C001838C

The U.S. Food and Drug Administration (FDA) has approved Lymphoseek (technetium Tc 99m tilmanocept) Injection, a novel product indicated for use in lymphatic mapping procedures to assist in the localization of lymph nodes draining a primary tumor in patients with breast cancer or melanoma. Lymphoseek is a receptor targeted radiopharmaceutical designed to identify these lymph nodes which have the highest probability of harboring cancer and thereby assist physicians in the staging of such patients.

Animal studies have not been conducted with this drug. There are no controlled data in human pregnancy. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus. US FDA pregnancy category: C Comment: All radiopharmaceuticals, including this drug, have a potential to cause fetal harm.