AZEDRA Solution for injection Ref.[10319] Active ingredients: Iobenguane ¹³¹I

2.1 Important Safety Information

AZEDRA is a radiopharmaceutical. Handle with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.1)]. Use waterproof gloves and effective radiation shielding when handling AZEDRA. Radiopharmaceuticals, including AZEDRA, should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.

Verify pregnancy status in females of reproductive potential prior to initiating AZEDRA [see Use in Specific Populations (8.1), (8.3)].

2.2 Recommended Dosage

Administer thyroid blockade and other pre- and concomitant medications as recommended [see Dosage and Administration (2.3)].

Dosimetric Dose

The recommended AZEDRA dosimetric dose administered as an intravenous injection is:

• Patients weighing greater than 50 kg: 185 to 222 MBq (5 or 6 mCi)
• Patients weighing 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg)

Dosimetry and Biodistribution Assessment

Following the AZEDRA dosimetric dose:

• Acquire anterior/posterior whole body gamma camera images within 1 hour of the AZEDRA dosimetric dose and prior to patient voiding (Day 0; Scan 1).
• Acquire additional images on Day 1 or 2 following patient voiding (Scan 2).
• Acquire additional images between Days 2-5 following patient voiding (Scan 3).

For each individual patient, calculate the radiation dose estimates to normal organs and tissues per unit activity [D (organ)] of administered dose using data extracted from these 3 images. Calculate in accordance with the Medical Internal Radiation Dose (MIRD) schema or related methodology. Whenever possible, use patient-specific organ masses (e.g., estimated from imaging).

Therapeutic Dosage

The recommended AZEDRA therapeutic dose is based on body weight and reduced, if necessary, based on the dosimetry data. Administer a total of 2 therapeutic doses intravenously a minimum of 90 days apart.

Weight Based Dose per Therapeutic Cycle:

• Patients weighing greater than 62.5 kg: 18,500 MBq (500 mCi)
• Patients weighing 62.5 kg or less: 296 MBq/kg (8 mCi/kg)

Determine if Dose Reduction Needed Based on Critical Organ Limits:

• Calculate the estimated critical organ absorbed-dose by multiplying the dosimetry-derived radiation absorbed-dose per unit activity [D (organ)] by weight based therapeutic total activity (Aw).
• If resulting estimated critical organ absorbed-dose is less than threshold absorbed-dose (T) shown in Table 1, no dose adjustment is necessary.
• If resulting estimated critical organ absorbed-dose exceeds threshold absorbed-dose (T) shown in Table 1, calculate the reduced therapeutic total activity (i.e., the cumulative activity that would be administered in 2 therapeutic cycles) using the following equation:

Reduced Therapeutic Total Activity= Aw ×[T ÷ {Aw × D (organ)}]

• Example: A 75 kg patient qualifies for a therapeutic total activity of 1000 mCi (Aw). For the kidneys, the dosimetry yields an estimated critical organ absorbed dose per unit activity of 0.027 Gy/mCi [D (kidney)]. Thus, the estimated critical organ absorbed-dose to the kidney is 27 Gy [Aw x D (organ)], which exceeds the threshold absorbed-dose for the kidneys (T) of 18 Gy (Table 1). Using the equation above the reduced therapeutic total activity to be administered to this patient is 666.7 mCi.

1000 mCi × [18 Gy ÷ {1000 mCi × 0.027 Gy/mCi}]

Table 1. Absorbed-dose Threshold Values for Radiation Toxicity in Critical Organs:

* Threshold of ~0.5 Gy for both heart and carotid artery, derived from experience with external-beam radiotherapy and associated with fractionated exposure, has also been proposed to support an ~1% mortality rate of cardiovascular and cerebrovascular deaths in >10-15 years; however, uncertainty is associated with the value ~0.5 Gy cited for vascular disease (ICRP publication 118, p.300, Table 4,5). Consider benefits/risks to patients.

2.3 Thyroid Blockade and Other Pre- and Concomitant Medications

Thyroid Blockade

Administer inorganic iodine starting at least 24 hours before and continuing for 10 days after each AZEDRA dose [see Warnings and Precautions (5.4)].

Hydration

Instruct patients to increase fluid intake to at least two liters a day starting at least 1 day before and continuing for 1 week after each AZEDRA dose to minimize irradiation to the bladder [see Warnings and Precautions (5.1)].

Drugs that Reduce Catecholamine Uptake or Deplete Stores

Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry dose or a therapeutic dose of AZEDRA. Do not administer these drugs until at least 7 days after each AZEDRA dose [see Drug Interactions (7.1)].

Antiemetic

Administer antiemetics 30 minutes prior to administering each AZEDRA dose.

2.4 Dose Modifications for Adverse Reactions

Recommended dose modifications of AZEDRA for adverse reactions are provided in Table 2 and the recommended dose or dose reduction for the second therapeutic dose of AZEDRA for myelosuppression are provided in Table 3.

Table 2. Recommended Dose Modifications of AZEDRA for Adverse Reactions:

Table 3. Recommended Dose or Dose Reduction for Second Therapeutic Dose of AZEDRA for Myelosuppression:

2.5 Preparation and Administration

• Refer to the Package Handling Instructions supplied with the frozen vial. Discard if the temperature recording device displays an alarm icon indicating that the temperature exceeded -70ºC during shipment.
• Use aseptic technique and radiation shielding when administering the AZEDRA solution. Use tongs when handling vial to minimize radiation exposure.
• Confirm the amount of radioactivity of AZEDRA in the radiopharmaceutical vial with an appropriate dose calibrator prior to and after AZEDRA administration.
• Inspect visually for particulate matter and discoloration prior to administration whenever solution and container permit. The AZEDRA solution should be a clear, colorless to pale yellow solution without any particulate matter. Discard if particulate matter or discoloration is observed.

Dosimetric Dose Preparation:

• Thaw the vial to room temperature in lead pot. Do not heat or refreeze. Confirm complete thawing and gently swirl to ensure homogeneity.
• Insert a venting unit (consisting of a needle, 0.2-micron sterile filter, and a charcoal filter) to avoid pressurizing the contents of the vial during dilution. Swirl gently to ensure homogeneity.
• Add sufficient volume of 0.9% Sodium Chloride Solution, USP to the vial to yield a concentration of 1 mCi/mL (37 MBq/mL). Swirl gently to ensure homogeneity.
• Draw the dosimetric dose into a 10 mL shielded syringe and place in the dose calibrator to ensure that the activity is within ± 10% of dose. Discard unused medicinal product or waste material in accordance with local and federal laws.
• Maintain at room temperature and administer within 8 hours of retrieval from frozen storage.

Dosimetric Dose Administration:

• Administer the dosimetric dose over 60 seconds.

Therapeutic Dose Preparation:

• Thaw the appropriate number of vials (2 or 3) to room temperature in lead pots. Do not heat or refreeze.
• Swirl each AZEDRA vial to ensure homogeneity.
• Insert a venting unit into each AZEDRA vial to avoid pressurizing the contents of the vial during dilution.
• Insert a venting unit into a sterile 50-mL glass vial. Transfer the entire contents of the two therapeutic vials into a 50-mL glass vial. Measure the radioactivity.
  • If radioactivity in the 50-mL glass vial exceeds the therapeutic dose, withdraw and discard the appropriate volume using a shielded syringe. Add 0.9% Sodium Chloride Solution, USP to a total volume of 50 mL.
  • If radioactivity in the 50-mL glass vial is less than the therapeutic dose, use a shielded syringe to withdraw the appropriate volume from a third AZEDRA vial and add to the 50-mL glass vial. Add 0.9% Sodium Chloride Solution, USP to a total volume of 50 mL.
• Swirl gently to ensure homogeneity.
• Remove the venting unit and place the 50-mL glass vial into a dose calibrator to ensure that the activity is within ± 10% of therapeutic dose.
• Maintain at room temperature and administer within 8 hours of retrieval from frozen storage.
• Discard unused medicinal product or waste material in accordance with local and federal laws.

Therapeutic Dose Administration:

• Verify line patency by infusing 250 mL of 0.9% Sodium Chloride Solution, USP (primary intravenous line) at recommended rate of 200 mL/hour.
• Insert a venting unit into the 50-mL glass vial containing the AZEDRA therapeutic dose.
• Assemble a second intravenous line using a 19 Gauge x 5-inch aspirating needle, 24-inch M-M arterial pressure tubing and a primary set specific connector.
• Clamp the second intravenous line and connect it to the primary intravenous line using the primary set specific connector. Flush the second intravenous line by releasing the clamp and then re-clamp the second intravenous line.
• Insert the needle of the second intravenous line into the 50-mL glass vial containing the AZEDRA therapeutic dose. Ensure the needle reaches the bottom of the glass vial without touching the sides of the vial.
• Clamp the primary intravenous line just above the second intravenous line and remove the clamp from the secondary intravenous line.
• Administer the AZEDRA therapeutic dose over 30 minutes at a recommended rate of 100 mL/hour for adults; for pediatric patients 12 years and older administer over 60 minutes at a recommended rate of 50 mL/hr. Clamp the secondary intravenous line when the first air bubbles form.
• Remove the clamp from the primary intravenous line to flush any residual AZEDRA therapeutic dose within this intravenous line with at least 50 mL of 0.9% Sodium Chloride Solution, USP.
• Remove the clamp from the secondary intravenous line to flush any residual drug in the secondary intravenous line into the 50-mL glass vial.

2.6 Radiation Dosimetry

The mean of the estimated radiation absorbed doses for AZEDRA are shown in Table 4.

Table 4. Radiation Absorbed Dose Estimates^* by Target Organ Following Intravenous Administration of ~5 mCi AZEDRA:

* Table 1 tends to yield underestimates of absorbed dose for patients weighing less than 65 kg, and tends to yield overestimates for patients weighing more than 65 kg.
¹ LLI Wall – Lower Large Intestine Wall.
² ULI Wall – Upper Large Intestine Wall.

Store at -70°C (-94°F).

The shelf life is 6 days post calibration time. Discard appropriately at 144 hours.