Diagnogreen

Diagnogreen

indocyanine green

Manufacturer:

Daiichi Sankyo

Distributor:

Zuellig Pharma

Marketer:

Daiichi Sankyo
Full Prescribing Info
Contents
Indocyanine green.
Description
Diagnogreen is 2-[7-1,1-Dimethyl-3-(4-sulfobutyl) benz[e] indolin-2-ylidene]-1, 3, 5-heptatrienyl]-1, 1- (dimethyl-3-(4-sulfobutyl)-1H-benz[e]indolium hydroxide, inner salt, sodium salt. Its empirical formula is C43H47N2NaO6S2 and molecular weight is 774.96. Indocyanine green is a dark, green-blue, odorless, lump, soluble in water or methanol and practically insoluble in acetone.
Indocyanine green is unstable in aqueous solution but is stable in the solutions containing protein or in the dry form. Its melting point is 230°C (decomposition). It has a pH of 5-7 and an osmotic pressure ratio to physiological saline of about 0.01 when 1 vial of Diagnogreen is dissolved in 5 mL water for injection (0.5% aqueous solution).
Action
Pharmacology: Pharmacodynamics: Indocyanine green exhibits no pharmacological effects when administered IV and is suitable for liver function tests and chorioretinal angiography.
Absorption Wavelength: After administered IV, indocyanine green is rapidly bound to serum proteins and photochemically stabilized. The maximum absorption wavelength (785 nanometer in aqueous solution) rapidly increases to 805 nanometer in blood, which corresponds to the isosbestic point where the absorption curves of blood oxidized hemoglobin and reduced hemoglobin intersect one another. Measurement on this wavelength is not affected by blood oxygen saturation.
Pharmacokinetics: Blood Concentration: Plasma Concentration: After IV administration of indocyanine green at a dose of 0.25 mg/kg to healthy adults, the plasma concentration of the drug decreases in an exponential manner. The time-concentration curve shows the biphasic profile, with a rapid elimination phase within the 1st 15 min followed by a slow elimination phase. In healthy adults, the biological half-life (t½) of indocyanine green is 3-4 min.
Serum Protein Binding: In healthy adults, 80% of indocyanine green in the serum is bound to globulin fractions. Indocyanine green is supposed to be bound mainly to α1-lipoprotein of globulin fractions. The affinity of this binding is much stronger than that of the binding between albumin and the pigment.
Distribution Reference (Animal Studies): In the mouse whole-body autoradiogram, uniform distribution of 35S-indocyanine green in the systemic vascular system was shown. This was conspicuously distributed especially in the lung, heart, kidney and liver, 1 and 5 min after IV administration. At 15 min after the administration, the hepatic concentration of the compound achieved near maximum, and the compound was excreted into the gallbladder and distributed in the bile duct. A higher level of radioactivity was observed in the stomach and intestinal tract at 30 and 60 min after the administration. After 24 hrs, a slight amount of the tracer was detected in the liver and intestinal tract.
Metabolism: Indocyanine green is not supposed to undergo chemical or biological transformations in the body.
Excretion: After IV administration, indocyanine green is selectively taken up into the liver and then rapidly excreted into bile in an unchanged form. Enterohepatic circulation and urinary excretion were not observed.
Pharmacokinetic Change After Co-Administration with Fluorescein (Animal Studies): Pharmacokinetic parameters of indocyanine green (0.5 mg/kg IV) co-administered with fluorescein (10 mg/kg) in beagle dog shows no significant change compared to that after single administration.
Toxicology: Preclinical Safety Data: Single Dose Toxicity: LD50 of IV injection are 64.3-72.8 mg/kg in mice, 87.1-97.9 mg/kg in rats and >90 mg/kg in dogs.
Repeated Dose Toxicity: In 1 month repeated IV dose study, 5 female rats in 20 mg/kg/day showed prone position, sedation, ptosis, lacrimation and respiration distress on day 5 or 6, of which 2 females were dead. No toxicity were noted in other groups (20 mg/kg/day in males, and 0.8 and 4 mg/kg/day in both sexes) or rabbits (5-50 mg/kg/day).
Reproduction Toxicity: No teratogenicity is noted in mice or rats (5-40 mg/kg/day ip). No genitoxicity, local irritation or carcinogenicity studies are conducted.
Indications/Uses
Liver function test (determination of hepatic function). Chorioretinal angiography. (See Dosage & Administration.)
Dosage/Direction for Use
Adults: Liver Function Test: For Determination of Plasma Elimination Rate and Blood Retention Rate: 0.5 mg/kg of body weight as indocyanine green is diluted to a concentration of 5 mg/mL with water for injection and is injected IV gradually into the cubitus vein within 30 sec with careful observation of the symptoms.
Principles: Determination of Plasma Elimination Rate: After IV injection, indocyanine green is uniformly distributed in the blood within 2-3 min and its blood concentration then decreases in an exponential manner for about 20 min. Therefore, for a period of 5-15 min after injection, the blood samples should be collected twice or more. After plasma separation, the concentration of indocyanine green is determined to obtain the plasma indocyanine green elimination rate constant (K).
Constant K, which represents the blood pigment uptake and excretory function in the liver, is lower in patients with hepatic diseases (liver cirrhosis, liver cancer, jaundice, hepatitis, gallstone, cholecystitis, Banti’s syndrome, portal disorder) than in healthy individuals.
Determination of Blood Retention Rate: This simple method is sufficiently effective and can be used in place of determination of plasma elimination rate method for measuring the plasma elimination rate in routine examinations. Fifteen (15) min after IV injection of indocyanine green, the blood sample is collected and the retention rate is calculated. The retention rate is higher in patients with various liver diseases than in healthy individuals.
Adults: Chorioretinal Angiography: 25 mg is dissolved in 2 mL of water for injection and immediately injected usually via the cubital vein.
Principle and Findings of the Test: Indocyanine green has maximum blood absorption and fluorescence wavelengths in the near infrared region. Wavelengths in the near infrared range easily reach retinal pigment epithelium and then choroid membrane, and indocyanine green in the choroid membrane is excited to cause fluorescence. Therefore, indocyanine green has high permeability not only to retinal pigment epithelium and macular xanthophyll but to subretinal serous fluid, haemorrhage and exudate.
In addition, since indocyanine green fundus angiography has excitation light and fluorescence in the near infrared region, a special fundus camera is required for test. The following symptoms are observed from early to later period of angiography depending on the elapsed time after the administration.
Choroidal Arterial Phase: In choroidal angiography of the posterior fundus, imaging begins when indocyanine green is flown into short posterior ciliary artery, and the starting times of choroidal arteriography in each controlled area are slightly different. Thereafter, indocyanine green is immediately transferred to choroidal capillaries via small choroidal artery.
Choroidal Arteriovenous Phase: Then, indocyanine green rapidly appears in the choroidal venous system, and choroidal fluorescence reaches maximum intensity in the medium and large choroidal veins within 3-5 sec after injection.
Choroidal Venous Phase: Thereafter, fluorescence in the choroidal artery is decreased, and that in the choroidal venous vessels predominates for 10-15 min after injection.
Elimination Phase in Choroid Membrane: Eventually the pigment disappears from the medium and large choroidal veins, and diffuse background fluorescence is found in the choroidal membrane. At this time, low fluorescence is observed in large choroidal vessels and retinal vessels.
Positioning of Indocyanine Green Fundus Angiography Compared with Fluorescein Fundus Angiography: For the diagnosis of chorioretinal diseases, clinical conditions and affected areas should be clarified in order to confirm the diagnosis and decide therapeutic policy, and thus, fundus angiography is required. In cases where chorioretinal disease is suspected from ophthalmoscopic findings, fluorescein fundus angiography is usually conducted to clarify the affected areas first, then followed by indocyanine green fundus angiography if needed. During a follow-up period after the 1st test, however, only indocyanine green fundus angiography may be conducted.
Determination of Plasma Elimination Rate Method: Preparation of a Calibration Curve: Dissolve 25 mg or 1 vial of Diagnogreen in distilled water and adjust the volume accurately to 250 mL. Quickly take 1, 2, 3, 5 and 10 mL of this solution in five 100 mL measuring flasks, respectively. Quickly add about 0.5 mL of normal serum to them for stabilization. After mixing, dilute the mixed solutions with distilled water and adjust the total volume of the respective solutions to 100 mL. Take 1 mL of each of the 5 mixed solutions in the 5 test tubes (A, B, C, D, and E). Add 1 mL of plasma (serum) and 1 mL of physiological saline to each tube and mix sufficiently. (The solutions prepared as mentioned are equivalent to the blood (plasma/serum) specimens containing indocyanine green at the rates of 0.1, 0.2, 0.3, 0.5 and 1 mg/dL, respectively). Add 1 mL of physiological saline and 1 mL of plasma (serum) to 1 mL of distilled water. Use this solution as a blank and measure the absorbance of the solutions in the above concentrations on a wavelength of 805 nanometer. Use graph paper to plot the actual measurement values by taking the absorbance along the vertical axis and the concentration along the horizontal axis. Connect these points with a straight line and draw a calibration curve. Update the calibration curve at least every 3 months.
Operation: Collect 3 mL of blood in a spit tube treated with sodium bisulfite-free heparin to obtain the plasma for the blank test in advance. 5, 10 and 15 min after IV injection of Diagnogreen, collect 3 mL of blood from 1 side of cubital vein in a spit tube treated with sodium bisulfite-free heparin. Centrifuge these blood samples along with the blood samples for the blank test. Separate 1 mL of plasma and mix with 2 mL of physiological saline to the plasma. Use the plasma for the blank test as a blank and measure the absorbance of the plasma samples on a wavelength of 805 nanometer. Use the calibration curve to obtain the concentration.
Calculation: Use semilog graph paper to plot the actual measurement values at the specified time points (5, 10 and 15 min after injection) by taking the concentration along the vertical axis (logarithmic scale) and the time along the horizontal axis. Draw a straight line that connects these 3 points. Use this line to obtain the t½ of concentration. Calculate the plasma elimination rate (K) using the following equation: K=0.693/t½.
Determination of Blood Retention Rate Method: Preparation of a Calibration Curve: Follow the procedure mentioned in Determination of Plasma Elimination Rate Method: Preparation of Calibration Curve as previously mentioned.
Operation: Follow the procedure mentioned in Determination of Plasma Elimination Rate: Operation as previously mentioned. After IV injection of Diagnogreen, the blood sample should be collected only once, 15 min later.
Calculation: Calculate the mean rate of retention of Diagnogreen Retention rate15 using the following formula: Retention rate15= C15/1×100 (%).
C15: Concentration of indocyanine green in the plasma 15 min after injection (mg/dL).
1: Mean concentration of indocyanine green in the plasma at the time of injection (mg/dL)
Reference: Normal Results of Liver Function Test: Plasma Elimination Rate: (K) ≥0.195±0.037.
Mean Retention Rate: R15 ≤10%.
Overdosage
There is no data available describing the signs and symptoms or laboratory finding.
Contraindications
Hypersensitivity to iodides and to any of the excipients of Diagnogreen.
Special Precautions
Indocyanine green should be administered with care in the patients with any allergic predisposition.
Clinically Significant Adverse Reactions: Shock or anaphylactoid symptoms may occur with the use of indocyanine green. Therefore, patients should be carefully monitored during treatment and the following actions should be taken as needed if any abnormality is noted: In case of prodromal for shock or anaphylactoid symptoms eg, oral numbness, nausea, chest distress, bulbar conjunctival congestion and edema of the eyelids develop during injection of indocyanine green, the injection should be immediately discontinued. In the event of shock or anaphylactoid symptoms, according to the condition, appropriate first-aid measures should be immediately provided, including fluid infusion, vasopressor use, cardiotonic therapy, corticosteroid treatment, airway control, artificial ventilation, oxygen inhalation, cardiac massage and appropriate postural regulation.
Physicians should carefully determine for which conditions Diagnogreen is indicated, and caution must be exercised in terms of the following points if the use of Diagnogreen is necessary based on a clinical diagnosis: Sufficient history should be obtained to predict any adverse reactions including shock; indocyanine green should be dissolved thoroughly in the attached solvent. Other solvents (eg, physiological saline) should not be used for this purpose. (Injection of a solution containing undissolved indocyanine green may be associated with nausea, fever and shock-like symptoms. In the process of dissolution, the vial should be turned upside down several times and shaken gently so that the drug attaching to the internal side of the rubber stopper can be thoroughly dissolved. Then, the vial should be rotated horizontally on a flat surface. The wall of vial should be attentively observed to ensure that no undissolved drug remains. Complete dissolution of the drug attaching to the rubber stopper or the cap should also be confirmed); first-aid drugs and devices should be prepared in advance; patients should be kept calm and thoroughly observed during the whole process of test. (The patients should lie on their back for liver function tests.)
Effects on the Ability to Drive or Operate Machinery: Attention is drawn, especially drivers and machine operators, about the risk of blurred vision associated with the use of indocyanine green.
Use in Pregnancy: Category C: Indocyanine green should not be administered to pregnant women or women who may possibly be pregnant unless the benefits outweigh the potential risks based on the diagnosis, since the safety of the drug used during pregnancy has not been established.
Use in Lactation: It is not known whether or not indocyanine green is secreted in human breast milk. Use of indocyanine green in nursing mothers is not recommended. If use of indocyanine green is judged to be essential, breastfeeding must be discontinued during treatment. The safety of indocyanine green in nursing mothers has not been established.
Use in Children: In the clinical study of chorioretinal angiography diagnostics, the safety of indocyanine green in low-birth-weight infants, newborns, nursing infants, infants or children has not been established. (There is no clinical experience.)
Use in the Elderly: Since elderly patients generally have reduced physiological functions, indocyanine green should be used with caution in such patients while monitoring the condition during treatment.
Use In Pregnancy & Lactation
Use in Pregnancy: Category C: Indocyanine green should not be administered to pregnant women or women who may possibly be pregnant unless the benefits outweigh the potential risks based on the diagnosis, since the safety of the drug used during pregnancy has not been established.
Use in Lactation: It is not known whether or not indocyanine green is secreted in human breast milk. Use of indocyanine green in nursing mothers is not recommended. If use of indocyanine green is judged to be essential, breastfeeding must be discontinued during treatment. The safety of indocyanine green in nursing mothers has not been established.
Adverse Reactions
Clinical Studies: Liver Function Test and Circulatory Function Test (Including Adverse Reactions Information From Circulatory Function Tests Which is Approved Indication in Japan): Adverse reactions associated with the use of indocyanine green have been reported in 0.17% (36 patients) of 21,278 patients who received the drug based on the Japanese literature (The reporting of adverse reactions is not included in the reexamination). Common adverse reactions included shock 0.02% (5 reactions), nausea 0.08% (16 reactions), vascular pain 0.04% (8 reactions) and pyrexia/hot feeling 0.02% (4 reactions).
Chorioretinal Angiography Diagnostic: In Japanese clinical study of chorioretinal angiography diagnostics, queasy was observed in 1 (1.8%) of 57 patients who received indocyanine green.
In Japanese post-marketing study of chorioretinal angiography diagnostics, adverse reactions were observed in 6 (0.62%) of 967 patients who received indocyanine green.
Undesirable Effects from Post-Marketing Studies and Adverse Drug Reactions Reports: The following undesirable effects are recognized for indocyanine green. The frequency are not defined:
Immune System Disorder: Anaphylactoid symptoms (see Precautions), Quincke’s oedema.
Vascular Disorders: Shock (see Precautions).
Gastrointestinal Disorders: Nausea, queasy, vomiting, feces discoloration (green).
Skin and Subcutaneous Tissue Disorder: Urticaria, pruritus, diaphoresis, hot flush, rash.
General Disorders and Administration Site Condition: Pyrexia.
Central Nervous System: Headache, dizziness.
Other Reactions: Transient elevation in serum unconjugated bilirubin.
Drug Interactions
Effects on the Laboratory Results: Administration of indocyanine green has been reported to cause and increase in serum inorganic iodide concentrations and decrease in radioactive iodide uptake in several patients due to sodium iodide in the product. Therefore, examinations using indocyanine green should be conducted with at least 1 week interval before the thyroid radioactive iodide uptake test, which may be influenced by the use of the drug. Heparin preparations containing sodium bisulfate should not be used as the anticoagulant for the collection of samples for analysis as these solutions reduce the peak absorption of indocyanine green in blood.
Precaution Concerning Diagnosis: There may be some errors in estimated values of liver function test in following cases: Effect of the Following Physical Condition: Chylous serum or extremely turbid or hemolytic serum; edema, emaciation, obesity or massive blood loss. (In this case, the plasma elimination rate method should be used for measurement)
Effect of Concomitant Therapy: Biliary contrast agents (eg, iotroxate meglumine), choleretic agents, rifampicin and antigout agents. (Concomitant use of these drugs with Diagnogreen may inhibit uptake of indocyanine green into hepatocytes).
Phenobarbital: It can decrease the t½ of indocyanine green, presumably because of an increase in hepatic dye transport induced by phenobarbital. Simultaneous administration of indocyanine green and sulfobromophthalein sodium (BSP) may result in an impairment of hepatic excretion of BSP, particularly in patients with hepatic impairment. The presence of BSP in blood may cause changes in the maximum absorption spectrum of indocyanine green, and simultaneous use of these agents should be avoided.
Effect of Substances Other Than Drug: Effect of Food: Hepatic blood flow may be increased. Intake of dietary fat may increase the blood lipid level and the serum may become clouded.
Incompatibilities: Indocyanine green should not be dissolved by normal saline solution (NSS).
Caution For Usage
Precautions Concerning Use: Diagnogreen should be reconstituted before use, and any unused solution must be discarded.
To avoid contamination with particles produced by cutting the ampoule of the attached injection solvent, wipe the ampoule head with an alcohol swab before opening the ampoule.
Vascular pain may be associated with IV administration of Diagnogreen.
Storage
Store below 25ºC. Avoid light.
Shelf-Life: 3 years.
ATC Classification
V04CX01 - indocyanine green ; Belongs to the class of other diagnostic agents.
Presentation/Packing
Powd for inj (vial + amp 10 mL solvent) 25 mg x 10's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in