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Octreoscan Kit for the Preparation of Indium In 111 Pentetreotide Diagnostic - For Intravenous Use. Rx only | OCTREOSCAN [Curium US LLC] | BioPortfolio

17:46 EST 26th January 2019 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

Octreoscan is a kit for the preparation of indium In-111 pentetreotide, a diagnostic radiopharmaceutical. It is a kit consisting of two components:

1)     A 10-mL Octreoscan Reaction Vial which contains a lyophilized mixture of:

(i) 10 μg pentetreotide [N-(diethylenetriamine-N,N,N',N”-tetraacetic acid-N”-acetyl)-D-phenylalanyl-L-hemicystyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-L-hemicystyl-L-threoninol cyclic (2→7) disulfide], (also known as octreotide DTPA),(ii) 2.0 mg gentisic acid [2, 5-dihydroxybenzoic acid],(iii) 4.9 mg trisodium citrate, anhydrous,(iv) 0.37 mg citric acid, anhydrous, and(v) 10.0 mg inositol.

Pentetreotide has the following structural formula:

 

Prior to lyophilization, sodium hydroxide or hydrochloric acid may have been added for pH adjustment. The vial contents are sterile and nonpyrogenic. No bacteriostatic preservative is present.

2)     A 10-mL vial of Indium In-111 Chloride Sterile Solution, which contains: 1.1 mL or 111 MBq/mL (3.0 mCi/mL) indium In-111 chloride in 0.02N HCl at time of calibration. The vial also contains ferric chloride at a concentration of 3.5 μg/mL (ferric ion, 1.2 μg/mL). The vial contents are sterile and nonpyrogenic. No bacteriostatic preservative is present.

Indium In-111 pentetreotide is prepared by combining the two kit components (see INSTRUCTIONS FOR THE PREPARATION OF INDIUM In-111 PENTETREOTIDE ). Indium In-111 reacts with the diethylenetriaminetetraacetic acid portion of the pentetreotide molecule to form indium In 111 pentetreotide. The pH of the resultant indium In-111 pentetreotide solution is between 3.8 and 4.3. No bacteriostatic preservative is present.

The indium In-111 pentetreotide solution is suitable for intravenous administration as is, or it may be diluted to a maximum volume of 3.0 mL with 0.9% Sodium Chloride Injection, U.S.P., immediately before intravenous administration. In either case, the labeling yield of indium In-111 pentetreotide should be determined before administration to the patient. A method recommended for determining the labeling yield is presented at the end of this package insert.

Indium In-111 decays by electron capture to cadmium-111 (stable) and has a physical half-life of 2.805 days (67.32 hours) (see Table 2).The principal photons that are useful for detection and imaging are listed in Table 1.

The specific gamma ray constant for In-111 is 3.21 R/hr-mCi at 1 cm. The first half-value thickness of lead (Pb) for In-111 is 0.023 cm. Selected coefficients of attenuation are listed in Table 2 as a function of lead shield thickness. For example, the use of 0.834 cm of lead will attenuate the external radiation by a factor of about 1000.

Table 3 lists fractions remaining at selected time intervals before and after calibration. This information may be used to correct for physical decay of the radionuclide.

Table 1. Principal Radiation Emission DataKocher, David C., "Radioactive Decay Data Tables,” DOE/TIC-11026, 115 (1981). 
 Radiation  Mean Percent Per Disintegration  Energy (keV)
 Gamma-2  90.2  171.3
 Gamma-3  94.0  245.4
Table 2. Radiation Attenuation by Lead Shielding
 Shield Thickness (Pb) cm  Coefficient of Attenuation
 0.023        0.5
 0.203        0.1
 0.513        0.01
 0.834        0.001
 1.12        0.0001
Table 3. Physical Decay Chart: Indium In-111, Half-life 2.805 Days (67.32 hours)
 Hours  Fraction Remaining  Hours  Fraction Remaining
 -72  2.100  0Calibration time  1.000
 -60  1.854  3  0.970
 -48  1.639  6  0.940
 -36  1.448  12  0.885
 -24  1.280  24  0.781
 -12  1.131  36  0.690
 -6  1.064  48  0.610

Pentetreotide is a DTPA conjugate of octreotide, which is a long-acting analog of the human hormone, somatostatin. Indium In-111 pentetreotide binds to somatostatin receptors on cell surfaces throughout the body. Within an hour of injection, most of the dose of indium In-111 pentetreotide distributes from plasma to extravascular body tissues and concentrates in tumors containing a high density of somatostatin receptors. After background clearance, visualization of somatostatin receptor-rich tissue is achieved. In addition to somatostatin receptor-rich tumors, the normal pituitary gland, thyroid gland, liver, spleen and urinary bladder also are visualized in most patients, as is the bowel, to a lesser extent. Excretion is almost exclusively via the kidneys.

Radioactivity leaves the plasma rapidly; one third of the radioactive injected dose remains in the blood pool at 10 minutes after administration. Plasma levels continue to decline so that by 20 hours post-injection, about 1% of the radioactive dose is found in the blood pool. The biological half-life of indium In-111 pentetreotide is 6 hours.

Half of the injected dose is recoverable in urine within six hours after injection, 85% is recovered in the first 24 hours, and over 90% is recovered in urine by two days.

Hepatobiliary excretion represents a minor route of elimination, and less than 2% of the injected dose is recovered in feces within three days after injection.

For several hours after administration, plasma radioactivity is predominantly in parent form. Ten percent of the radioactivity excreted is nonpeptide-bound.

Indium In-111 pentetreotide binds to cell surface receptors for somatostatin. In nonclinical pharmacologic studies, the hormonal effect of Octreoscan in vitro is one-tenth that of octreotide. Since diagnostic imaging doses of indium In-111 pentetreotide are lower than the therapeutic doses of octreotide, indium In-111 pentetreotide is not expected to exert clinically significant somatostatin effects.

Indium In-111 pentetreotide is cleared from the body primarily by renal excretion. Indium In-111 pentetreotide elimination has not been studied in anephric patients or in those with poorly functioning kidneys. It is not known whether indium In-111 pentetreotide can be removed by dialysis. Dosage adjustments in patients with decreased renal function have not been studied.

Octreoscan was studied in nine unblinded clinical studies in a total of 365 patients. Of these patients, 174 were male and 191 were female. Their mean age was 54.0 years (range 1.8 to 86 years). One patient was under the age of 2 and 2 patients were between the ages of 2 and 12; 223 patients (61.1%) were between 18 and 60 years; and 136 patients (37.3%) were older than 60 years. A racial distribution is not available.

Eligible patients had a demonstrated or high clinical suspicion of a neuroendocrine tumor. The most common tumors were carcinoids (132 of 309 evaluable patients). Scintigraphic results were compared to results of conventional localization procedures (CT, ultrasound, MRI, angiography, surgery and/or biopsy). The mean dose of radioactivity administered was 173.4 MBq (4.7 mCi).

Octreoscan results were consistent with the final diagnosis (success) in 267 of 309 evaluable patients (86.4%). Compared with carcinoids and gastrinomas, lower success rates were noted for localization of insulinomas, neuroblastomas, pituitary adenomas and medullary thyroid carcinomas. Octreoscan success was observed in 27 of 32 patients (84.4%) with clinically nonfunctioning neuroendocrine tumors (i.e., no symptom of a clinical syndrome mediated by abnormally elevated hormones).

Octreoscan localized previously unidentified tumors in 57/204 patients. In 55/195 patients, indium In-111 pentetreotide uptake occurred in lesions not thought to have somatostatin receptors. In a small subgroup of 39 patients who had tissue confirmation, the sensitivity rate for Octreoscan scintigraphy was 85.7%; for CT/MRI the rate was 68%. The specificity rate for Octreoscan scintigraphy was 50%, the rate for CT/MRI was 12%. Larger studies are needed to confirm these comparisons. Overall, including all tumor types with or without the presence of somatostatin receptors, there were 3/508 false positives and 104/508 false negatives.

Of the 309 patients, 87 had received octreotide for therapeutic purposes within 72 hours of Octreoscan administration. These patients had an overall 95% success rate. The effect of different dose levels of octreotide on success rates has not been evaluated.

Indium In-111 pentetreotide is an agent for the scintigraphic localization of primary and metastatic neuroendocrine tumors bearing somatostatin receptors.

None known.

DO NOT ADMINISTER IN TOTAL PARENTERAL NUTRITION (TPN) ADMIXTURES OR INJECT INTO TPN INTRAVENOUS ADMINISTRATION LINES; IN THESE SOLUTIONS, A COMPLEX GLYCOSYL OCTREOTIDE CONJUGATE MAY FORM.

The sensitivity of scintigraphy with indium In-111 pentetreotide may be reduced in patients concurrently receiving therapeutic doses of octreotide acetate. Consideration should be given to temporarily suspending octreotide acetate therapy before the administration of indium In-111 pentetreotide and to monitoring the patient for any signs of withdrawal.

Studies have not been performed with indium In-111 pentetreotide to evaluate carcinogenic potential or effects on fertility. Pentetreotide was evaluated for mutagenic potential in an in vitro mouse lymphoma forward mutation assay and an in vivo mouse micronucleus assay; evidence of mutagenicity was not found.

Animal reproduction studies have not been conducted with indium In-111 pentetreotide. It is not known whether indium In-111 pentetreotide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Therefore, indium In-111 pentetreotide should not be administered to a pregnant woman unless the potential benefit justifies the potential risk to the fetus.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when indium In-111 pentetreotide is administered to a nursing woman.

Safety and effectiveness in pediatric patients have not been established.

The following adverse effects were observed in clinical trials at a frequency of less than 1% of 538 patients: dizziness, fever, flush, headache, hypotension, changes in liver enzymes, joint pain, nausea, sweating, and weakness. These adverse effects were transient. Also in clinical trials, there was one reported case of bradycardia and one case of decreased hematocrit and hemoglobin.

Pentetreotide is derived from octreotide which is used as a therapeutic agent to control symptoms from certain tumors. The usual dose for indium In-111 pentetreotide is approximately 5 to 20 times less than for octreotide and is subtherapeutic. The following adverse reactions have been associated with octreotide in 3% to 10% of patients: nausea, injection site pain, diarrhea, abdominal pain/discomfort, loose stools, and vomiting. Hypertension and hyper- and hypoglycemia have also been reported with the use of octreotide.

Before administration, a patient should be well hydrated. After administration, the patient must be encouraged to drink fluids liberally. Elimination of extra fluid intake will help reduce the radiation dose by flushing out unbound, labelled pentetreotide by glomerular filtration. It is also recommended that a mild laxative (e.g., bisacodyl or lactulose) be given to the patient starting the evening before the radioactive drug is administered, and continuing for 48 hours. Ample fluid uptake is necessary during this period as a support both to renal elimination and the bowel-cleansing process. In a patient with an insulinoma, bowel-cleansing should be undertaken only after consultation with an endocrinologist.

The recommended intravenous dose for planar imaging is 111 MBq (3.0 mCi) of indium In-111 pentetreotide prepared from an Octreoscan kit. The recommended intravenous dose for SPECT imaging is 222 MBq (6.0 mCi) of indium In-111 pentetreotide.

The dose should be confirmed by a suitably calibrated radioactivity ionization chamber immediately before administration.

As with all intravenously administered products, Octreoscan should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Preparations containing particulate matter or discoloration should not be administered. They should be disposed of in a safe manner, in compliance with applicable regulations.

Aseptic techniques and effective shielding should be employed in withdrawing doses for administration to patients. Waterproof gloves should be worn during the administration procedure.

Do not administer Octreoscan in TPN solutions or through the same intravenous line.

The estimated radiation dosesto the average adult (70 kg) from intravenous administration of 111 MBq (3 mCi) and 222 MBq (6 mCi) are presented in Table 4. These estimates were calculated by Oak Ridge Associated Universities using the data published by Krenning, et al.

Table 4. Estimated Absorbed Radiation Doses after Intravenous Administration of Indium In-111 PentetreotideAssumes 4.8 hour voiding interval and International Commission on Radiological Protection (ICRP) 30 model for the gastrointestinal tract calculations.to a 70 kg Patient
   PLANAR  SPECT
 Organ  mGy/111 MBq  rads/3 mCi  mGy/222 MBq  rads/6 mCi
 Kidneys  54.16  5.42  108.32  10.83
 Liver  12.15  1.22  24.31  2.43
 Spleen  73.86  7.39  147.73  14.77
 Uterus  6.34  0.63  12.67  1.27
 Ovaries  4.89  0.49  9.79  0.98
 Testes  2.90  0.29  5.80  0.58
 Red Marrow  3.46  0.35  6.91  0.69
 Urinary Bladder Wall  30.24  3.02  60.48  6.05
 GI Tract        
 Stomach Wall  5.67  0.57  11.34  1.13
 Small Intestine  4.78  0.48  9.56  0.96
 Upper Large Intestine  5.80  0.58  11.59  1.16
 Lower Large Intestine  7.73  0.77  15.46  1.55
 Adrenals  7.55  0.76  15.11  1.51
 Thyroid  7.43  0.74  14.86  1.49
   mSv/111 MBq  rem/3 mCi  mSv/222 MBq  rem/6 mCi
 Effective DoseEstimated according to ICRP Publication 53.Equivalent  13.03  1.30  26.06  2.61

The Octreoscan kit (NDC 69945-050-40) is supplied with the following components:

In addition, the kit also contains the following items: (1) a 25 G x 5/8” needle (B-D, Monoject) used to transfer Indium In-111 Chloride Sterile Solution to the Octreoscan Reaction Vial, (2) pressure sensitive label, and (3) a package insert.

The Octreoscan kit should be stored refrigerated at 2° to 8°C (36° to 46°F). After reconstitution, store at or below 25°C (77°F). Indium In-111 pentetreotide must be used within six hours of preparation.

Note: Read complete directions thoroughly before starting preparation.

This radiopharmaceutical is licensed by the Illinois Department of Nuclear Safety for distribution to persons licensed pursuant to 330.260(a) for the radioactive material specified in 32 IL. Adm. Code 335.4010 or under equivalent licenses of the U.S. Nuclear Regulatory Commission, an Agreement State, or a Licensing State.

Curium and the Curium logo are trademarks of a Curium company.©2018 Curium US LLC. All Rights Reserved. 

Sep-Pak is a trademark of Waters Technologies Corporation.

Manufactured by:Curium US LLCMaryland Heights, MO 63043 

Made in USA

A050I0

R12/2018

CURIUM™

Octreoscan Reaction Vial Sterile, non-pyrogenic. For intravenous use after drug preparation. See package insert for directions for use. Vial contains:10 µg Pentetreotide2.0 mg Gentisic Acid4.9 mg Sodium Citrate, Anhydrous0.37 mg Citric Acid, Anhydrous10.0 mg Inositol Prior to lyophilization, sodium hydroxide or hydrochloric acid may be added for pH adjustment. The pH of the reconstituted drug is between 3.8 and 4.3. Contents are sealed under nitrogen. Manufactured by:Curium US LLCMaryland Heights, MO 63043

Made in USA Store refrigerated at 2° to 8°C (36° to 46°F). Protect from light. Use only with Indium In 111 Chloride Sterile Solution. Rx only CURIUM™ A050V0

R12/2018

Indium In 111 ChlorideSterile Solution Sterile, non-pyrogenic solution, contains no bacteriostatic preservation. NOT FOR DIRECT ADMINISTRATION For intravenous use after drug preparation. See package insert for directions for use. Vial contains 1.1 mL of 111 MBq/mL (3.0mCi/mL) aqueous indium In 111 chloride and 3.5 µg/mL ferric chloride (1.2 µg/mL ferric ion) in 0.02N hydrochloric acid. Store at or below 25°C (77°F). Rx only WARNING: Radioactive drugs must be handled only by qualified personnel in conformity with regulations of the U.S. Nuclear Regulatory Commission or state regulatory agencies where applicable. Bottle containing drug should be kept in this container or within a heavier shield. Manufactured by:Curium US LLCMaryland Heights, MO 63043

Made in USA CURIUM™ CAUTION RADIOACTIVE MATERIAL A117C0

R12/2018

Manufacturer

Curium US LLC

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