43-8200
`
`®
`
`Rubidium Rb 82 Generator
`
`For Elution of Rubidium Chloride
`Rb 82 Injection
`
`Diagnostic: Intravenous
`
`JUBILANT EXHIBIT 1026
`Jubilant v. Bracco, IPR2018-01449
`
`

`

`DESCRIPTION
`Cardiogen-82® (Rubidium Rb 82 Generator) contains acceler-
`ator produced strontium Sr 82 adsorbed on stannic oxide in a
`lead-shielded column and provides a means for obtaining ster-
`ile nonpyrogenic solutions of rubidium chloride Rb 82 injection.
`The chemical form of rubidium 82 is 82RbCl.
`The amount (millicuries) of Rb-82 obtained in each elution
`will depend on the potency of the generator.
`When eluted at a rate of 50 mL/minute, each generator elu-
`ate at the end of elution should not contain more than 0.02
`microcurie of strontium Sr 82 and not more than 0.2 microcurie
`of strontium Sr 85 per millicurie of rubidium chloride Rb 82
`injection, and not more than 1 microgram of tin per mL of elu-
`ate.
`PHYSICAL CHARACTERISTICS
`Rubidium Rb 82 decays by positron emission and associated
`gamma emission with a physical half-life of 75 seconds.1 The
`annihilation photons released following positron emission
`which are useful for detection and imaging studies are shown
`in Table 1.
`
`TABLE 1
`Principal Radiation Emission Data
`Mean Percent
`Mean Energy
`Per Disintegration
`(keV)
`
`Radiation
`Annihilation
`511 (each)
`191.01
`photons (2)
`1Table of Isotopes, 7th Edition, M. Letterer and V. Shirley.
`External Radiation
`The specific gamma ray constant for Rb-82 is 6.1 R/hour-mil-
`licurie at 1 centimeter. The first half-value layer is 0.7 centime-
`ter of lead (Pb). A range of values for the relative attenuation
`of the radiation emitted by this radionuclide that results from
`interposition of various thicknesses of Pb is shown in Table 2.
`For example, the use of a 7.0 centimeter thickness of Pb will
`attenuate the radiation emitted by a factor of about 1,000.
`
`1
`
`

`

`TABLE 2
`Radiation Attenuation by Lead Shielding
`Shield Thickness
`Attenuation
`(Pb) cm
`Factor
`0.7
`0.5
`2.3
`10-1
`4.7
`10-2
`7.0
`10-3
`9.3
`10-4
`
`Strontium Sr 82 decays to rubidium Rb 82 with a strontium
`Sr 82 half-life of 25 days (600 hrs). The Sr-82 is produced in
`an accelerator by proton spallation of molybdenum, Mo (p,
`spall) Sr-82 or by the reaction Rb-85 (p, 4n) Sr-82. The Sr-82
`produced has no carrier added. To correct for physical decay
`of strontium Sr 82, the fractions that remain at selected inter-
`vals after the time of calibration are shown in Table 3.
`TABLE 3
`Physical Decay Chart: Sr-82 half-Iife 25 days
`Fraction
`Fraction
`Fraction
`Days Remaining
`Days Remaining Days Remaining
`0*
`1.000
`11
`0.737
`21
`0.559
`1
`0.973
`12
`0.717
`22
`0.543
`2
`0.946
`13
`0.697
`23
`0.529
`3
`0.920
`14
`0.678
`24
`0.514
`4
`0.895
`15
`0.660
`25
`0.500
`5
`0.871
`16
`0.642
`26
`0.486
`6
`0.847
`17
`0.624
`27
`0.473
`7
`0.824
`18
`0.607
`28
`0.460
`8
`0.801
`19
`0.591
`29
`0.448
`9
`0.779
`20
`0.574
`30
`0.435
`10
`0.758
`*Calibration time
`
`2
`
`

`

`To correct for physical decay of rubidium Rb 82, the fraction
`of rubidium chloride Rb 82 injection remaining in all 15 second
`intervals up to 300 seconds after time of calibration are shown
`in Table 4.
`
`Seconds
`165
`180
`195
`210
`225
`240
`255
`270
`285
`300
`
`TABLE 4
`Physical Decay Chart: Rb-82 half-life 75 seconds
`Fraction
`Fraction
`Remaining
`Remaining
`1.000
`.218
`.871
`.190
`.758
`.165
`.660
`.144
`.574
`.125
`.500
`.109
`.435
`.095
`.379
`.083
`.330
`.072
`.287
`.063
`.250
`
`Seconds
`0*
`15
`30
`45
`60
`75
`90
`105
`120
`135
`150
`*Elution time
`CLINICAL PHARMACOLOGY
`Following intravenous administration, rubidium Rb 82 rapidly
`clears the blood and is extracted by myocardial tissue in a
`manner analogous to potassium. In human studies, myocardial
`activity was noted within the first minute after injection. When
`areas of myocardial infarction are detected with rubidium chlo-
`ride Rb 82 injection, they are visualized within two to seven
`minutes after injection as photon-deficient or "cold areas" on
`the myocardial scan. Uptake is also observed in kidney, liver,
`spleen, and lung.
`INDICATIONS AND USAGE
`Rubidium chloride Rb 82 injection is a myocardial perfusion
`agent that is useful in distinguishing normal from abnormal
`myocardium in patients with suspected myocardial infarction.
`
`3
`
`

`

`Cardiogen-82 (Rubidium Rb 82 Generator) must be used
`with an infusion system specifically labeled for use with the
`generator and capable of accurate measurement and delivery
`of doses of rubidium chloride Rb 82 injection not to exceed a
`single dose of 2220 MBq (60 mCi) and a cumulative dose of
`4440 MBq (120 mCi) at a rate of 50 mL/min with a maximum
`volume per infusion of 100 mL and a cumulative volume not to
`exceed 200 mL. These performance characteristics reflect the
`conditions of use under which the drug development clinical
`trials were conducted.
`Adequate data from clinical trials to determine precise local-
`ization of myocardial infarction or identification of stress-
`induced ischemia have not been collected.
`Positron emission tomographic (PET) instrumentation is rec-
`ommended for use with rubidium chloride Rb 82 injection.
`CONTRAINDICATIONS
`None known.
`WARNINGS
`Caution should be used during infusion as patients with con-
`gestive heart failure may experience a transitory increase in
`circulatory volume load.These patients should be observed for
`several hours following the Rb-82 procedure to detect delayed
`hemodynamic disturbances.
`PRECAUTIONS
`General
`Data are not available concerning the effect of marked alter-
`ations in blood glucose, insulin, or pH (such as is found in dia-
`betes mellitus) on the quality of rubidium chloride Rb 82
`scans. Attention is directed to the fact that rubidium is physio-
`logically similar to potassium, and since the transport of potas-
`sium is affected by these factors, the possibility exists that
`rubidium may likewise be affected.
`Rubidium chloride Rb 82 injection must be administered only
`with an appropriate infusion system capable of meeting the
`performance characteristics previously described.
`(See
`INDICATIONS AND USAGE). The drug should be used only
`by those practitioners with a thorough understanding of the
`use and performance of the infusion system.
`Repeat doses of Rubidium chloride Rb 82 injection may lead
`to an accumulation of the longer lived radioactive contami-
`nants strontium Sr 82 and strontium Sr 85.
`4
`
`

`

`Since eluate obtained from the generator is intended for
`intravenous administration, aseptic techniques must be strictly
`observed in all handling. Only additive free Sodium Chloride
`Injection USP should be used to elute the generator. Do not
`administer eluate from the generator if there is any evidence of
`foreign matter.
`As in the use of any radioactive material, care should be
`taken to minimize radiation exposure to the patient consistent
`with proper patient management and to insure minimum radi-
`ation exposure to occupational workers.
`Radiopharmaceuticals should be used only by physicians
`who are qualified by training and experience in the safe use
`and handling of radionuclides and whose experience and
`training have been approved by the appropriate government
`agency authorized to license the use of radionuclides.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`No long-term studies have been performed to evaluate car-
`cinogenic potential, mutagenicity potential, or to determine
`whether rubidium Rb 82 may affect fertility in males or
`females.
`Pregnancy Category C
`Animal reproductive studies have not been conducted with
`rubidium Rb 82. It is also not known whether rubidium Rb 82
`can cause fetal harm when administered to a pregnant woman
`or can affect reproductive capacity. Rubidium Rb 82 should be
`given to pregnant women only if the expected benefits to be
`gained clearly outweigh the potential hazards.
`Ideally, examinations using radiopharmaceuticals, especially
`those examinations which are elective in nature, in women of
`childbearing capability should be performed during the first few
`(approximately 10) days following the onset of menses.
`Nursing Mothers
`It is not known whether rubidium Rb 82 is excreted in human
`milk. Due to the short half-life of rubidium Rb 82 (75 sec) it is
`unlikely that the drug would be excreted in human milk during
`lactation. However, because many drugs are excreted in
`human milk, caution should be exercised when rubidium Rb 82
`is administered to nursing women.
`Pediatric Use
`Safety and effectiveness in children have not been established.
`5
`
`

`

`ADVERSE REACTIONS
`No adverse reactions specifically attributable to rubidium Rb
`82 have been reported during controlled clinical trials.
`DOSAGE AND ADMINISTRATION
`General
`As with all radiopharmaceuticals, only the lowest dose of
`rubidium Rb 82 necessary to obtain adequate visualization
`should be used. A lower dose provides less patient radiation
`and is consistent with the achievement of ALARA. Most pro-
`cedures do not require use of the maximum dose of rubidium
`Rb 82; the dose to be used should be carefully individualized
`and factors such as:
`age;
`body size;
`anticipated pathology;
`degree and extent of visualization required;
`structure(s) or area to be examined;
`disease processes affecting the patient and;
`equipment and technique to be employed;
`should be considered.
`Parenteral drug products should be inspected visually for
`particulate matter and discoloration prior to administration
`whenever solution and container permit.
`An appropriate infusion system labeled for use with
`Cardiogen-82 (Rubidium Rb 82 Generator) is required. Please
`see DIRECTIONS FOR ELUTING RUBIDIUM CHLORIDE Rb
`82 INJECTION below for additional information. (See also
`INDICATIONS AND USAGE).
`Rubidium Rb 82 assay and strontium Sr 82 breakthrough
`should be determined each day the generator is used (See
`directions below).
`Rubidium-82 Dosage
`Rubidium chloride Rb 82 injection obtained from Cardiogen-82
`(Rubidium Rb 82 Generator) is intended only for intravenous
`administration utilizing an appropriate infusion system that is
`labeled for use with the generator. The usual adult (70 kg)
`dose (single injection) is 1480 MBq (40 mCi) with a range of
`1110-2220 MBq (30-60 mCi). The dose must be administered
`at a rate of 50 mL/minute not to exceed a cumulative volume
`of 200 mL. (See also WARNINGS).
`
`6
`
`

`

`A single dose of 2220 MBq (60 mCi) should not be exceed-
`ed. The radiation dosimetry for a 2220 MBq (60 mCi) dose is
`presented in Table 5. No more than 4440 MBq (120 mCi)
`should be administered in a multiple injection series.
`Exceeding the recommended dosing limits should only be
`done after due consideration of: (a) the benefits to be obtained
`by the patient vs. the risks associated with additional radiation;
`(b) previous (or contemplated) procedures involving radiation
`which this patient has undergone or might undergo; and (c) the
`achievement of ALARA. Further consideration should be given
`to the effect of total volume of injectate, which increases with
`the number of injections, as discussed under WARNINGS.
`Radiation Dosimetry
`The estimated absorbed radiation doses to an average adult
`patient (70 kg) from an intravenous injection of a recommend-
`ed dose of 2220 MBq (60 mCi) of rubidium Rb 82 are shown
`in Table 5.
`
`TABLE 5
`Adult Absorbed Radiation Doses1
`mGy/2220 MBq
`rads/60 mCi
`2.15
`0.22
`1.91
`0.19
`3.11
`0.32
`1.91
`0.19
`1.91
`0.19
`4.22
`0.42
`19.1
`1.92
`1.91
`0.19
`3.77
`0.38
`0.84
`0.084
`1.38
`0.14
`0.0055
`0.00055
`0.0091
`0.0009
`0.84
`0.084
`0.67
`0.066
`0.95
`0.096
`
`Organ
`Adrenals
`Stomach
`Small Intestine
`Upper Large Intestine
`Lower Large Intestine
`Heart Wall
`Kidneys
`Liver
`Lungs
`Ovaries
`Pancreas
`Trabecular Bone
`Cortical Bone
`Red Marrow
`Testes
`Total Body
`
`7
`
`

`

`1Calculated by the Internal Dosimetry Center at Oak Ridge
`Associated Universities
`Based on data collected by Ryan et al. in two human subjects
`(J Nuc Med 25(5): P94) and on rat data of Kearfott (J Nuc Med
`23(12):1128-1132. Contaminant levels of Sr-82 and Sr-85
`assumed to be 10-7 and 2.5 X 10-7 relative to Rb-82.
`For strontium, assumed distribution and retention:
`50% tb = ∞ (uniformity distributed throughout
`Bone
`volume)
`0.5% tb = 1.5 day
`Testes
`Remainder 49.5% tb = 1.5 day
`HOW SUPPLIED
`Cardiogen-82® (Rubidium Rb 82 Generator) is supplied in the
`form of strontium Sr 82 adsorbed on a hydrous stannic oxide
`column with an activity of 90-150 millicuries Sr-82 at calibra-
`tion time. The generator is encased in a lead shield surround-
`ed by a labeled plastic container. Complete assay data for
`each generator are provided on the container label. Directions
`for determining the activity of rubidium Rb 82 eluted from the
`generator are provided in this monograph. Cardiogen-82
`(Rubidium Rb 82 Generator) is intended for use only with an
`appropriate, properly calibrated infusion system labeled for
`use with the generator.
`
`Receipt, transfer, handling, possession or use of
`this product is subject to the radioactive material
`regulations and licensing requirements of the U.S.
`Nuclear Regulatory Commission, Agreement
`States or Licensing States as appropriate.
`
`DISPOSAL
`Hospital personnel should monitor the amount of radioactivity
`present at the generator prior to its disposal. The generator
`should not be disposed of in regular refuse systems. Storage
`and/or disposal of the generator should be in accordance with
`the conditions of NRC radioactive materials license pursuant
`to 10 CFR, Part 20, or equivalent conditions pursuant to
`Agreement State Regulation.
`
`8
`
`

`

`STORAGE
`The generator should be stored at 20-25°C (68-77°C) [See
`USP].
`EXPIRATION DATE
`The expiration date is provided on the generator container
`label. Due to the short half-life of Rb-82, virtually all the
`radioactivity in the eluate decays within 15 minutes from the
`end of elution.
`DIRECTIONS FOR ELUTING RUBIDIUM Rb 82
`An appropriate infusion system labeled for use with
`Cardiogen-82 (Rubidium Rb 82 Generator) is required. The
`applicable operator's manual should be consulted for detailed
`directions on generator hookup, elution, and patient adminis-
`tration. Prior to use with patients, a thorough understanding of
`the use and performance of the system should be established.
`The Cardiogen-82 (Rubidium Rb 82 Generator) package
`insert and the Rb-82 infusion system operator's manual should
`be read before beginning elution.
`Additional information concerning eluting the Cardiogen-82
`generator follows:
`NOTE: Waterproof gloves are to be worn during the prepa-
`ration and elution processes.
`Aseptic techniques should be employed throughout
`the preparation and elution processes.
`Allow at least 10 minutes between elutions for regen-
`eration of Rb-82.
`Elute with additive free Sodium Chloride Injection
`USP only.
`Discard the first 50 mL eluate each day the genera-
`tor is eluted. Since the eluate contains radioactivity, it
`must be handled employing proper safety precau-
`tions.
`DIRECTIONS FOR DETERMINATION OF Rb-82
`ASSAY AND MEASUREMENT OF Sr-82 AND Sr-85
`BREAKTHROUGH
`The rubidium chloride Rb 82 assay and strontium Sr 82 and
`strontium Sr 85 breakthrough are determined using an ioniza-
`tion chamber-type dose calibrator. Procedure 1 through 11
`below must be performed daily prior to the use of rubidium
`chloride Rb 82 injection.
`
`9
`
`

`

`The assay of rubidium chloride Rb 82 injection is determined
`as follows:
`1. Set a dose calibrator for Rb-82 as recommended by the
`manufacturer or use the Co-60 setting and divide the
`reading obtained by 0.548. Obtain the reading from the
`instrument in millicuries.
`2. Aseptically elute the generator with 50 mL of Sodium
`Chloride Injection USP and discard the eluent (first elu-
`tion).
`3. After allowing at least 10 minutes for the regeneration of
`Rb-82, aseptically elute the generator with 50 mL of
`Sodium Chloride Injection USP at a rate of 50 mL/min and
`collect the eluate in a stoppered glass vial (plastic con-
`tainers are not suitable). Note the exact time of end of elu-
`tion (E.O.E.).
`4. Using the dose calibrator, determine the activity of Rb-82
`and note the time of the reading. Correct the reading for
`decay to the E.O.E. using the appropriate decay factor for
`Rb-82 (see Table 4). Note: If the reading is taken 21/2
`minutes after E.O.E. decay correction can be made by
`multiplying the dose calibrator reading by 4.
`To measure the Sr-82 breakthrough in the eluate, proceed as
`follows:
`5. Using the sample obtained for the Rb-82 activity determi-
`nation, allow the sample to stand for at least one hour to
`allow for the complete decay of Rb-82.
`6. Measure the activity of the sample in a dose calibrator at
`the setting recommended by the manufacturer for Rb-82
`and/or Sr-82. As an alternative the Co-60 setting may be
`used and the reading obtained divided by 0.548. Obtain
`the reading from the instrument in microcuries.
`7. Calculate the ratio (R) of Sr-85/Sr-82 on the date of meas-
`urement using the Sr-85/Sr-82 ratio chart below (Table 6)
`and the ratio of Sr-85/Sr-82 on the day of calibration pro-
`vided on the generator label. Determine R using the fol-
`lowing equation:
`[Sr-85]
`[Sr-82]
`
`on calibration date x ratio factor on the date
`of measurement
`
`R =
`
`10
`
`

`

`8. Use a correction factor (F) of 0.478 to compensate for the
`contribution of Sr-85 to the reading.
`9. Calculate the amount of Sr-82 in the sample using the fol-
`lowing equation:
`Sr-82 (μCi) =
`
`dose calibration reading (μCi)
`[1 + (R) (F)]
`Example: dose calibrator reading (μCi) = 0.80
`Sr-85/Sr-82 ratio (R) = (1.48)
`Correction factor (F) = 0.478
`0.80
`Sr-82 (μCi) =
`[1 + (1.48)(0.478)]
`Sr-82 (μCi) = 0.47
`10. Determine the Sr-82 breakthrough by dividing the μCi of
`Sr-82 by the mCi of Rb-82 at E.O.E.
`Example:
`0.47 μCi of Sr-82
`50 mCi of Rb-82 E.O.E.
`0.47 μCi Sr-82 = 0.0094 = 9.4 X 10-3 μCi/mCi Rb-82
`50 mCi Rb-82
`The Sr-82 content must not be more than 2 x 10-2 μCi/mCi of
`Rb-82 at E.O.E.
`11. Determine the Sr-85 breakthrough by multiplying the
`result obtained in step 10 by (R) Sr-85/Sr-82 ratio.
`Example:
`9.4 x 10-3 x 1.48 = 1.4 x 10-2 μCi Sr-85/mCi Rb-82
`The Sr-85 content must not be more than 0.2 μCi/mCi of Rb-
`82 at E.O.E.
`
`11
`
`

`

`TABLE 6
`Sr-85/Sr-82 Ratio Chart
`Ratio Factor
`Days
`Days
`1.00
`16
`0*
`1.02
`17
`1
`1.03
`18
`2
`1.05
`19
`3
`1.07
`20
`4
`1.09
`21
`5
`1.11
`22
`6
`1.13
`23
`7
`1.15
`24
`8
`1.17
`25
`9
`1.19
`26
`10
`1.21
`27
`11
`1.23
`28
`12
`1.25
`29
`13
`1.27
`30
`14
`1.29
`15
`*Day of calibration
`
`Ratio Factor
`1.31
`1.34
`1.36
`1.38
`1.41
`1.43
`1.46
`1.48
`1.51
`1.53
`1.56
`1.59
`1.61
`1.64
`1.67
`
`Rx only
`Manufactured for
`Bracco Diagnostics Inc.
`Princeton, NJ 08543
`by Medi-Physics, Inc.,
`South Plainfield, NJ 07080
`
`Printed in USA
`
`Revised May 2000
`
`43-8200
`
`