DESCRIPTION

Each vial contains a sterile, non-pyrogenic, lyophilized mixture of

      Disofenin - 20 mg

      Stannous Chloride, minimum (SnCL2•2H20) - 0.24mg

      Total Tin, maximum (SnCL2•2H20) - 0.6 mg

Prior to lyophilization the pH is adjusted to between 4-5 with HCL and/or NaOH. The contents of the vial are lyophilized and stored under nitrogen.

The drug is administered by intravenous injection for diagnostic use after reconstitution with sterile, non-pyrogenic, oxidant-free Sodium Pertechnetate Tc99m Injection.

The structure of disofenin is shown below:

The precise structure of stannous technetium-disofenin complex is unknown at this time.

PHYSICAL CHARACTERISTICS

Technetium Tc99m decays by isomeric transition with a physical half-life of 6.02 hours.1 Photons that are useful for detection and imaging studies are listed in Table 1.

1Kocher, David C., Radioactive Decay Data Tables, DOE/TIC-11026, 108 (1981).

External Radiation

The specific gamma ray constant for Tc99m is 5.4 microcoulombs/kg-MBq-hr (0.78R/mCi-hr) at 1cm. The first half value layer is 0.017cm of Pb. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of lead (Pb) is shown in Table 2. To facilitate control of the radiation exposure from MBq (mCi) amounts of this radionuclide, the use of a 0.25cm thickness of lead (Pb) will attenuate the radiation emitted by a factor of 1,000.

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

*Calibration time

CLINICAL PHARMACOLOGY

Disofenin (Hepatolite) is an iminodiacetic acid derivative with no known pharmacologic actions at the doses recommended.

Technetium Tc99m Disofenin is rapidly cleared from the circulation of normal individuals following intravenous administration; about 8% of the injected activity remains in the circulation 30 minutes post-injection. About 9% of the administered activity is excreted in the urine over the first two hours post-injection. The remainder of the activity is essentially quantitatively cleared through the hepatobiliary system. In fasting normal individuals, peak liver uptake occurs by 10 minutes post-injection and peak gallbladder accumulation by 30-40 minutes post-injection. Gallbladder visualization and visualization of intestinal activity occurs by 60 minutes post-injection in individuals with normal hepatobiliary function.

As the serum bilirubin level increases, the blood clearance becomes progressively delayed, resulting in higher background-to-liver radioactivity ratios. Kidney visualization becomes progressively prolonged compared with that in patients with normal biliary excretion. In patients with hepatocellular disease or partial biliary obstruction, there is delayed transit of the radiopharmaceutical to the gut.

Morphine administration has been reported to be effective in shortening the 4 hours usually required for observations, to 90 minutes. In patients who do not have acute cholecystitis, the use of morphine may result in visualization of the gall bladder within an additional 30 minutes.

False negative visualization of the gallbladder in cases of acute cholecystitis, and false positive failure of a normal gallbladder to visualize have been reported with both morphine augmentation and the standard 4 hours of observation.

INDICATIONS AND USAGE

Technetium Tc99m Disofenin is indicated as a hepatobiliary imaging agent. Hepatolite is indicated in the diagnosis of acute cholecystitis as well as to rule out the occurrence of acute cholecystitis in suspected patients with right upper quadrant pain, fever, jaundice, right upper quadrant tenderness and mass or rebound tenderness, but not limited to these signs and symptoms.

In otherwise healthy individuals, non-visualization of the gallbladder 4 hours after administration of Hepatolite following a 2-6 hour fast and in the presence of activity in the small intestine is indicative of a diagnosis of acute cholecystitis. Under the same conditions in an otherwise healthy person, visualization of the gallbladder during a 1 hour scintigraphy is effective in excluding a diagnosis of acute cholecystitis. If the gallbladder is not visualized by 1 hour, scanning must continue for four hours or until the gallbladder is visualized.

When the gall bladder fails to appear within the first 60 minutes of imaging
after the administration of Hepatolite, a single 0.04mg/kg dose of intravenous morphine, diluted in 10mL normal saline may be administered over 3 minutes. (See CLINICAL PHARMACOLOGY section)

CONTRAINDICATIONS

None known.

WARNINGS

The possibility of allergic reactions should be considered.

PRECAUTIONS

The preparation contains no bacteriostatic preservative. Technetium Tc99m Disofenin should be used within six hours of preparation.

In cases where there has been no visualization of the gallbladder after 60 minutes of scanning, morphine may be carefully administered provided there is no contraindication to the use of narcotics. There should be clear evidence of patency of the common duct, such as observed entry of radiopharmaceutical into the small bowel, prior to the administration of morphine to such patients.

Morphine augmentation has not been associated with any serious adverse events in the reported cases, but the administration of morphine in biliary colic may increase patient discomfort, and the recommended dose of 0.04mg/kg (2-4mg) may be associated with significant respiratory depression and/or postural syncope in vulnerable patients.

Facilities using morphine augmentation should be able to monitor patients for the adverse effects of narcotics and have the means at hand to manage them, including the ready availability of a specific narcotic antagonist such as naloxone.

Cholescintigraphy is only partially effective in the diagnosis or excluding the diagnosis of acute cholecystitis in other conditions such as trauma, intercurrent disease, total parenteral nutrition (TPN) and nothing by mouth (NPO) status, all of which frequently result in false positive results (non-visualization). False negatives (visualization) are rarely seen in certain patients with cholelithiasis (myriad of small stones).

ADVERSE REACTIONS

Itching at the site of injection progressing to erythema multiforme has been reported following single administration. Rare cases of chills and nausea have been reported with related compounds. Infrequently, death has been reported in association with the use of this class of agents.

DOSAGE AND ADMINISTRATION

The suggested dose range for i.v. administration, to be employed in the average patient (70kg) is:

      Non-Jaundiced patient: 37 - 185 MBq (1-5 mCi)

      Patient with serum bilirubin level greater than 5 mg/dL: 111 - 296 MBq (3-8 mCi)

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to patient administration. (If blood is drawn into the syringe, any unnecessary delay prior to injection may lead to clot formation in situ.) Do not backflush the syringe; slow injection is recommended. Radiochemical purity should be checked prior to patient administration.

Store at controlled room temperature (20-25°C) before and after reconstitution.

The patient should be in a fasting state; 4 hours is preferable. False positives (non-visualization) may result if the gallbladder has been emptied by ingestion of food.

This preparation is usually administered to a patient only once. However, should a second dose be required, the interval between doses should not be less than 24 hours.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

INSTRUCTIONS FOR PREPARATION OF TECHNETIUM Tc99m DISOFENIN

Preparation of Technetium Tc99m Disofenin from Kit for the Preparation of Technetium Tc99m Disofenin is done by the following aseptic procedure:

a. Prior to adding the Sodium Pertechnetate Tc99m Injection to the vial, write the estimated activity, date, and time of preparation in the space provided on the vial label. Then tear off a radiation symbol and attach it to the neck of the vial.

b. Waterproof gloves should be worn during the preparation procedure. Remove the central plastic disk from the vial and swab the top of the vial closure with alcohol to sanitize the surface.

c. Place the reaction vial in a suitable radiation shield with a fitted radiation shield cap.

d. With a sterile, shielded syringe, aseptically obtain and add to the reaction vial 4-5 ml of sterile, non-pyrogenic, additive-free Sodium Pertechnetate Tc99m Injection containing 444MBq to 3.7GBq (12 to 100mCi) of Tc99m. Note: If Sodium Pertechnetate Tc99m Injection must be diluted for use with Hepatolite, only preservative free sodium chloride injection, USP should be used. Be sure to maintain a nitrogen atmosphere in the vial by not introducing air during reconstitution.

e. Place the radiation shield cap on the vial shield and swirl the contents of the vial for one minute and let stand for 4 minutes.

f. Maintain adequate shielding during the life of the product by using the radiation vial shield with the radiation shield cap in place and by using a syringe shield for withdrawing and injecting the preparation.

g. Using proper shielding, the vial containing the reconstituted solution should be visually inspected to insure that it is free of particulate matter and discoloration prior to injection.

h. Assay the product in a suitable dose calibrator, then complete and affix the “radioactive contents” label to the vial shield.

i. Aseptically withdraw material for use within six (6) hours. Store reconstituted vial at controlled room temperature (20°-25°C). The vial contains no preservative.

RADIATION DOSIMETRY

The estimated absorbed radiation doses2 to organs and tissues of an average patient (70kg) from an intravenous injection of Technetium Tc99m Disofenin are shown in Tables 4 and 5.

*This value assumes that 80% of the activity localizes in the liver, and that 10% of the liver activity is cleared to the gallbladder.

**Based on kinetic data for jaundiced patients with malignant obstructive disease.

2 April 1989. Oak Ridge Assoc.Universities.

HOW SUPPLIED

HEPATOLITE® Kit for the Preparation of Technetium Tc99m Disofenin for Injection is supplied as a set of five or thirty vials, sterile and non-pyrogenic.

Prior to lyophilization the pH is adjusted to between 4-5 with hydrochloric acid and/or sodium hydroxide solution. The contents of the vial are lyophilized and stored under nitrogen. Store at controlled room temperature (20 - 25°C) before and after reconstitution. Protect from light. The lyophilized drug product is light sensitive. Technetium Tc99m Disofenin contains no preservatives. Included in each five (5) vial kit is one (1) package insert and twelve (12) radiation labels. Included in each thirty (30) vial kit is one (1) package insert and seventy-two (72) radiation labels.

This reagent kit for the preparation of a radiopharmaceutical is approved for use by persons licensed pursuant to Section 120.547, Code of Massachusetts Regulation 105,
or under equivalent license of the U.S. Nuclear Regulatory Commission or an Agreement State.

Manufactured by:
Pharmalucence, Inc.

Billerica, MA 01821

PL-000027

Rev 1.0

Jun 2018

For ordering Tel. Toll Free: 800-221-7554
(For International, call: 781-275-7120)

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 5 VIAL CONTAINER (10 mL)

NDC 45567-0475-1

Sterile, Non-Pyrogenic, Diagnostic Agent for Intravenous Use

Hepatolite®

Kit for the Preparation of Technetium Tc99m Disofenin for Injection

Contents and Storage Conditions:

Disofenin - 20mg

Stannous Chloride, minimum (SnCL2•2H20) - 0.24mg

Total Tin, maximum (SnCL2•2H20) - 0.6 mg

The pH is adjusted with HCL and/or NaOH

Store at controlled room temperature (20° - 25°C). Protect from light

Lyophilized and stored under nitrogen

Rx only

Manufactured By:

Pharmalucence, Inc.

Billerica, MA 01821

PL-000028

Rev 0.1

Jun 2012

Tc99m Activity

Time/Date Prepared

See Package Insert for dosage information

Reconstitute with additive-free Tc99m and store at controlled room temperature

Use within 6 hours

CONTAINS NO PRESERVATIVE

Lot No:

Exp. Date:

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 5 VIAL CARTON

NDC 45567-0475-1

Hepatolite®

Kit for the Preparation of Technetium Tc99m Disofenin for Injection

Sterile

Non-Pyrogenic

Diagnostic Agent for Intravenous Use

Lyophilized

5 vials

Manufactured By:

Pharmalucence, Inc.

Billerica, MA 01821

PL-000030

Rev 0.1

Jun 2012

CONTENTS AND STORAGE CONDITIONS:

1 Package Insert, 12 Radiation Labels and 5 Vials each containing:

Disofenin - 20mg

Stannous Chloride, minimum (SnCL2•2H20) - 0.24mg

Total Tin, maximum (SnCL2•2H20) - 0.6 mg

The pH is adjusted with HCL and/or NaOH

Store at controlled room temperature (20° - 25°C). Protect from light

CONTAINS NO PRESERVATIVE

See Package Insert for dosage information. Reconstitute with additive-free

Tc99m and store at controlled room temperature (20-25°C). Use within 6 hours

Rx Only

IMPORTANT: Read enclosed Package Insert for full information on preparation, use and indications.

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 radionuclides.

PACKAGE LABEL - PRINCIPAL DISPLAY LABEL - 30 VIAL CONTAINER (10 mL)

NDC 45567-0475-2

Sterile, Non-Pyrogenic, Diagnostic Agent for Intravenous Use

Hepatolite®

Kit for the Preparation of Technetium Tc99m Disofenin for Injection

Contents and Storage Conditions:

Disofenin - 20mg

Stannous Chloride, minimum (SnCL2•2H20) - 0.24mg

Total Tin, maximum (SnCL2•2H20) - 0.6 mg

The pH is adjusted with HCL and/or NaOH

Store at controlled room temperature (20° - 25°C). Protect from light

Lyophilized and stored under nitrogen

Rx only

Manufactured By:

Pharmalucence, Inc.

Billerica, MA 01821

PL-000028

Rev 0.1

Jun 2012

Tc99m Activity

Time/Date Prepared

See Package Insert for dosage information

Reconstitute with additive-free Tc99m and store at controlled room temperature

Use within 6 hours

CONTAINS NO PRESERVATIVE

Lot No:

Exp. Date:

PACKAGE LABEL - PRINCIPAL DISPLAY LABEL - 30 VIAL CARTON

NDC 45567-0475-2

CONVENIENCE PACK

Hepatolite®

Kit for the Preparation of Technetium Tc99m Disofenin for Injection

STERILE

NON-PYROGENIC

DIAGNOSTIC AGENT FOR

INTRAVENOUS USE

Manufactured By:

Pharmalucence, Inc.

Billerica, MA 01821

PL-000031

Rev 0.1

Jun 2012

For Customer Service call: 1-800-221-7554

Tear along perforations

Ready to dispense

Package Insert and Radiation Labels

inside bottom flap

Rx only

IMPORTANT: Read enclosed Package Insert for full information on preparation use and indications.

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 radionuclides.

Manufactured By:

Pharmalucence, Inc.

Billerica, MA 01821

For Customer Service call: 1-800-221-7554

Contents & Storage Conditions:

1 Package Insert, 72 Radiation Labels and 30 Vials each containing:

Disofenin - 20mg

Stannous Chloride, minimum (SnCL2•2H20) - 0.24mg

Total Tin, maximum (SnCL2•2H20) - 0.6 mg

The pH is adjusted with HCL and/or NaOH

Store at controlled room temperature (20° - 25°C)

Protect from light.

CONTAINS NO PRESERVATIVE.

See Package Insert for dosage information. Reconstitute with additive-free

Tc99m and store at controlled room temperature (20-25°C). Use within 6 hours.

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – RADIATION SHIELD

CAUTION:

RADIOACTIVE MATERIAL

Rx Only

Technetium Tc99m Disofenin for Injection

Contents

Disofenin – 20 mg

Stannous Chloride, minimum (SnCl2 · 2H2O) – 0.24mg

Total Tin, maximum (SnCl2 · 2H2O) – 0.6 mg

Use within 6 hours.

___________________________________________

MBq(mCi) Tc99m/ml

___________________________________________

Volume ml

___________________________________________

Time/Date Prepared

___________________________________________

Expiration Time Lot No.

PL-000029

Rev 0.1

Jun 2012