Rinavir

Rinavir

ritonavir

Manufacturer:

GPO

Distributor:

GPO
Full Prescribing Info
Contents
Ritonavir.
Description
Each tablet contains ritonavir 100 mg.
Excipients/Inactive ingredients: Copovidone, Sodium chloride, Sorbitan monolaurate, Colloidal silicon dioxide, Sodium stearyl fumarate, Hydroxypropylmethyl cellulose, Hydroxypropyl cellulose, Titanium dioxide, Talcum, Polyethylene glycol and Polysorbate 80.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Ritonavir, a synthetic antiretroviral agent, is a human immunodeficiency virus (HIV) proteases inhibitor (PI). Ritonavir apparently inhibits replication of retroviruses by interfering with HIV proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor that leads to the production of noninfectious immature HIV-1 particles.
Pharmacokinetics: Absorption: Ritonavir is well absorbed following oral administration. After a 600 mg of oral solution, peak concentrations of ritonavir were achieved approximately 2 and 4 hours after dosing under fasting and non-fasting conditions, respectively.
A food effect is observed for ritonavir. Food decreased the bioavailability of ritonavir when a single 100 mg dose of ritonavir was administered. Under high-fat conditions, a 23% decrease in mean area under the curve (AUC0-∞) and a 23% decrease in mean Cmax were observed relative to fasting conditions. Under moderate-fat conditions, a 21% decrease in mean AUC0-∞ and a 22% decrease in mean Cmax were observed relative to fasting conditions.
However, the type of meal administered did not change ritonavir bioavailability when high-fat meals were compared with moderate-fat meals.
Distribution: Ritonavir distribute with high concentrations in serum and lymph nodes. The volume of distribution is 0.16 - 0.66 L/kg. Ritonavir bind to plasma protein at 98 - 99 %.
Metabolism: Ritonavir undergoes hepatic metabolism by CYP3A4 and 2D6. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidative metabolite (M2) appears to be the major metabolite which has antiviral activity similar to that of ritonavir; however, only very low concentrations of this metabolite are present in plasma.
Elimination: The elimination half-life is about 3-5 hours. Ritonavir is excreted principally both unchanged drug and metabolite, in the feces approximately 86% (as ~ 34% unchanged drug), and in the urine approximately 11% (~ 4% as unchanged drug).
Indications/Uses
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of patients with HIV-infection when therapy is warranted based on clinical and/or immunological evidence of disease progression.
Dosage/Direction for Use
Adults: The recommended dose of ritonavir is 600 mg twice daily by mouth and should be given with food.
Use of a dose titration schedule may help to reduce treatment emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily for 3 days, and increased by 100 mg twice daily increment up to 600 mg twice daily over a period of no longer than 14 days.
Dual PI containing combination regimens: Ritonavir extensively inhibits the metabolism of most available PIs. Hence, any consideration of dual therapy with ritonavir should take into account the pharmacokinetic interaction and safety data of involved agents. There is extensive cross-resistance in this class of agents. The combination of two PIs with the least overlapping patterns of resistance should be considered.
For the use of ritonavir with saquinavir, a cautious titration of the dose has been used by initiating ritonavir dosing at 300 mg twice daily.
For the use of ritonavir with indinavir, a cautious titration of the dose has been used by initiating ritonavir dosing at 200 mg twice daily increasing by 100 mg twice daily reaching 400 mg twice daily within two weeks.
Pediatrics: Ritonavir should be used in combination with other antiretroviral agents. The recommended dosage of ritonavir in children > 1 month is 350 - 400 mg/m2 of body surface area twice daily by mouth and should not exceed 600 mg twice daily. Ritonavir should be started at 250 mg/m2 and increased at 2-3 day intervals by 50 mg/m2 twice daily. If patient do not tolerate the maximum daily dose due to adverse events, the highest tolerated dose should be used for maintenance therapy in combination with other antiretroviral agents. When possible, dose should be administered using a calibrated dosing syringe. (See Table.)

Click on icon to see table/diagram/image

Special populations: Pediatric patients: Ritonavir steady-state oral clearance (CL/F/m2) was approximately 1.5-1.7 times faster in children than in adults. However, after administration with 350 or 450 mg/m2 twice daily in children younger than 2 years, ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice daily. The area under the ritonavir plasma concentration-time curve (AUC) and trough concentrations obtained after administration with 350 or 450 mg/m2 twice daily in children younger than 2 years were approximately 16% and 60% lower, respectively, than those obtained in adults receiving 600 mg twice daily.
Hepatic impairment: No dosage adjustment is recommended in patients with mild hepatic impairment. However, ritonavir levels may be decreased in moderate hepatic impairment and patients response should be monitored. Ritonavir has not been studied in patients with severe hepatic impairment.
Ritonavir is principally metabolized by the liver. Therefore, exercise caution when administrating this drug to patient with impaired hepatic function.
Renal function impairment: No dosage adjustment necessary.
Elderly: Make dose selection for an elderly patient usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
Mode of Administration: Ritonavir is administered orally and should be taken with meals. It should be swallowed whole, and not chewed, broken, or crushed.
Overdosage
Symptoms: Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose.
Treatment: Treatment of overdose with ritonavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with ritonavir. If indicated, achieve elimination of unabsorbed drug by emesis or gastric lavage; observe usual precautions to maintain the airway. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Because ritonavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug.
Contraindications
Ritonavir is contraindicated in patients with known hypersensitivity to ritonavir or any of its ingredients.
Co-administration of ritonavir is contraindicated with the following drugs: alfuzosin, amiodarone, cisapride, dihydroergotamine, ergonovine, ergotamine, flecainide, lovastatin, methylergonovine, oral midazolam, pimozide, propafenone, quinidine, St. John’s wort (Hypericum perforatum), sildenafil (only when used for the treatment of pulmonary arterial hypertension (PAH)), simvastatin, triazolam, voriconazole.
Special Precautions
Co-administration of ritonavir with sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse reactions due to possible effect of ritonavir on the hepatic metabolism of certain drugs.
Pancreatitis: Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis. Consider pancreatitis if clinical symptoms (e.g., nausea, vomiting, abdominal pain) or abnormalities in laboratory values (e.g., increased serum lipase or amylase values) suggestive of pancreatitis occur. Evaluate patients who exhibit these signs or symptoms and discontinue ritonavir therapy if a diagnosis of pancreatitis is made.
Diabetes mellitus/Hyperglycemia: New-onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases.
Resistance/Cross-resistance: Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.
Hemophilia: There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors.
PR Interval Prolongation: Ritonavir prolongs the PR interval in some patients. Use with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.
Fat redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy.
Lipid disorder: Treatment with ritonavir therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total triglycerides and cholesterol. Perform triglyceride and cholesterol testing prior to initiating ritonavir therapy and at periodic intervals during therapy. Manage lipid disorders as clinically appropriate.
Immune reconstitution syndrome: Immune reconstitution syndrome has been reported in patients infected with HIV treated with combination antiretroviral therapy, including ritonavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis).
Hypersensitivity: Allergic reactions (e.g., urticaria, mild skin eruptions, bronchospasm, angioedema) have been reported. Rare cases of anaphylaxis and Stevens-Johnson syndrome also have been reported. Discontinue treatment if severe reactions develop.
Hepatic effects: Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretoviral drugs. There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, exercise caution when administering ritonavir to patients with preexisting liver disease, liver enzyme abnormalities, or hepatitis. Consider increased AST/ALT monitoring in these patients, especially during the first 3 months of ritonavir treatment.
Effect on ability to drive and use machine: No data.
Use In Pregnancy & Lactation
Pregnancy: US pregnancy category B.
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, only use this drug during pregnancy if clearly needed.
Labor and delivery: Data is not available.
Lactation: The Centers for Disease Control and Prevention recommend that mothers who are HIV-infected do not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether ritonavir is secreted in human breast milk. Because of the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, instruct mothers not to breast-feed if they are receiving ritonavir.
Adverse Reactions
Cardiovascular: Edema (including peripheral edema), flushing, hypertension, syncope, vasodilation.
Central nervous system: Anxiety, confusion, depression, disturbance in attention, dizziness, drowsiness, fatigue, headache, insomnia, malaise, paresthesia, peripheral neuropathy.
Dermatologic: Acne vulgaris, diaphoresis, pruritus, skin rash.
Endocrine & metabolic: hypertriglyceridaemia, increased serum triglycerides, increased uric acid, lipodystrophy (acquired).
Gastrointestinal: Abdominal pain, anorexia, diarrhea, dysgeusia, dyspepsia, flatulence, gastrointestinal hemorrhage, increased serum amylase (pediatric), nausea, throat irritation (local), vomiting.
Hematologic & oncologic: Anemia (pediatric), neutropenia (pediatric), thrombocytopenia (pediatric).
Hepatic: Hepatitis, increased gamma-glutamyl transferase, increased serum ALT, increased serum AST.
Hypersensitivity: Hypersensitivity reaction.
Neuromuscular & Skeletal: Increased creatine phosphokinase, musculoskeletal pain (arthralgia and back pain), myalgia and weakness.
Ophthalmic: Blurred vision.
Renal: Polyuria.
Respiratory: Cough, oropharyngeal pain, pharyngitis.
Miscellaneous: Fever.
Rare but important or life-threatening: Adrenal suppression, adrenocortical cortex insufficiency, anaphylaxis, amnesia, angioedema, aphasia, asthma, atrioventricular block (first, second, or third degree), cachexia, cerebral ischemia, chest pain, cholestatic jaundice, coma, Cushing's syndrome, dementia, depersonalization, diabetes mellitus, diabetic ketoacidosis, esophageal ulcer, gastroenteritis, gastroesophageal reflux disease, gout, hallucination, hematologic disease (myeloproliferative), hemorrhage (in patients with hemophilia A or B), hepatic coma, hepatitis, hepatomegaly, hepatosplenomegaly, hyperglycemia, hypotension, hypothermia, hypoventilation, immune reconstitution syndrome, intestinal obstruction, leukemia (acute myeloblastic), leukopenia, lymphadenopathy, lymphocytosis, malignant melanoma, manic behavior, myocardial infarction, neuropathy, orthostatic hypotension, palpitations, pancreatitis, paralysis, pneumonia, prolongation P-R interval on ECG, prolonged Q-T interval on ECG, pseudomembranous colitis, rectal hemorrhage, redistribution of body fat, renal failure, renal insufficiency, right bundle branch block, seizure, Stevens-Johnson syndrome, subdural hematoma, syncope, tachycardia, torsades de pointes, toxic epidermal necrolysis, ulcerative colitis, vasospasm, venous thrombosis (cerebral).
Drug Interactions
Ritonavir has been found to be a substrate of CYP1A2 (minor), 2B6 (minor), 2D6 (minor), 3A4 (major), P-glycoprotien; an inhibitor of CYP2C19 (weak), 2C8 (strong), 2C9 (weak), 2D6 (strong), 2E1 (weak), 3A4 (strong), P-glycoprotein; and an inducer of cytochrome P450; CYP1A2 (moderate), 2C9 (moderate), 3A4 (weak).
Aldesleukin: Ritonavir concentrations may be elevated. Adjust ritonavir dose as needed.
Anticonvulsants (e.g., carbamazepine, divalproex, ethosuximide, lamotrigine, phenytoin): Carbamazepine may decrease ritonavir levels, resulting in treatment failure. Ritonavir may increase plasma concentrations of carbamazepine and ethosuximide. Divalproex, lamotrigine and phenytoin levels may be decreased; therefore, a dose increase may be needed when coadministered with ritonavir. Adjust the dose of one or both drugs as needed.
Azole antifungals (fluconazole, itraconazole, ketoconazole): Ritonavir plasma concentrations may be elevated. Ketoconazole AUC increased 3.4-fold and the Cmax increased by 55%. Itraconazole and ketoconazole levels may be increased. Voriconazole levels may be decreased when coadministered with ritonavir and may loss antifungal response. High dose of ketoconazole or itraconazole (> 200 mg/day) are not recommended.
Clarithromycin: Concurrent use may increase ritonavir and clarithromycin levels. Dosage adjustment is not needed in patients with healthy renal function.
Immunosuppressants (e.g., cyclosporine, rapamycin, sirolimus, tacrolimus): Plasma concentrations and pharmacologic effects of both drugs may increase when immunosuppressants and ritonavir are coadministered. Adjust the dose accordingly.
Mefloquine: Plasma concentrations of ritonavir may be reduced. Adjust the ritonavir dose as needed.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs, e.g., delavirdine, efavirenz, nevirapine): Ritonavir plasma levels and clinical efficacy may be reduced when coadministered with efavirenz and nevirapine. Delavirdine may increase ritonavir AUC and Cmax. The combination of atazanavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir should not be coadministered with NNRTIs.
Rifamycins (e.g., rifampin, rifabutin): Coadministration of ritonavir with rifampin may lead to loss of virologic respone to ritonavir. Coadministration of ritonavir with rifabutin may increase rifabutin (and its metabolites) concentrations. Dosage reduction of rifabutin is necessary.
St. John's wort (Hypericum perforatum): Coadministration is contraindicated. Coadministration may lead to loss of virologic response and possible resistance to ritonavir.
Alfuzosin: Coadministration is contraindicated. Alfuzosin blood concentrations may be elevated, increasing pharmacologic effects and adverse reactions such as hypotension.
Antiarrhythmic agents (e.g., amiodarone, bepridil, disopyramide, flecainide, lidocaine, mexiletine, propafenone, quinidine): Coadministration of ritonavir with amiodarone, bepridil, flecainide, propafenone, or quinidine is contraindicated because of the potential for serious and/or life-threatening cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics.
Coadministration of ritonavir with other antiarrhythmics (e.g., disopyramide, lidocaine, mexiletine) may also cause an increase in the antiarrhythmic concentration.
Antidepressants (e.g., bupropion, desipramine, nafazodone, selective serotonin reuptake inhibitors (SSRIs), fluoxetine, trazodone, tricyclics): A dosage decrease may be needed when these antidepressants are coadministered with ritonavir.
Antineoplastic agents (e.g., vinblastine, vincristine): Vinblastine and vincristine plasma concentrations may be elevated.
Antipsychotics (e.g., aripiprazole, olanzapine, perphenazine, pimozide, quetiapine, risperidone, thioridazine): Coadministration with pimozide is contraindicated because of the potential for cardiac arrhythmias. Aripiprazole, quetiapine, perphenazine, risperidone and thioridazine levels may be increased. Olanzapine levels may be decreased. Adjust dose as needed.
Atovaquone: Atovaquone level may be decreased. A dosage increase may be needed.
Benzodiazepines (e.g., alprazolam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam): Coadministration of ritonavir with oral midazolam or triazolam is contraindicated because of the risk of prolonged or increased sedation or respiratory depression. Plasma levels of the other benzodiazepines, including parenteral midazolam, may be increased; therefore, a decrease in the benzodiazepine dose may be needed.
Beta-blockers (e.g., metoprolol, timolol): Metoprolol and timolol concentrations may be increased. A dosage decrease of the beta-blocker may be needed.
Bosentan: Coadministration is contraindicated. Bosentan concentration may be elevated, increasing the risk of adverse reactions.
Buspirone: Increased serum buspirone levels may occur; therefore, a dosage decrease may be needed with coadministration.
Calcium channel blockers (e.g., amlodipine, diltiazem, nifedipien, verapamil): Calcium channel blocker level may be increased. A decrease in the calcium channel blocker dose may be needed.
Cisapride: Coadministration is contraindicated because of the risk of cardiac arrhythmias.
Colchicine: Colchicine plasma concentrations may be elevated, increasing the risk of toxicity. Coadministration is contraindicated in patients with hepatic or renal impairment.
Conivaptan: Coadministration is contraindicated because of the increased risk of adverse reactions.
Corticosteroids (e.g., dexamethasone, fluticasone, prednisone): Steroid levels may be increased. A decrease in dose may be needed for these drugs.
Hormonal contraceptives: Coadministration decreased the ethinyl estradiol AUC and Cmax. Consider alternative nonhormonal contraceptive measures.
Deferasirox: Plasma concentrations and pharmacologic effects of deferasirox may be decreased by ritonavir; avoid coadministration.
Didanosine: Coadministration for 4 days decreased the didanosine AUC and Cmax. These changes are not likely to be clinically important.
Digoxin: Digoxin levels may be elevated, increasing the risk of toxicity. Adjust dosage as needed.
Dronabinol: Dronabinol levels may be increased. A decrease in dosage of dronabinol may be needed.
Dronedarone: Coadministration is contraindicated. Dronedarone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions.
Eplerenone: Coadministration is contraindicated. Eplerenone levels may be elevated, increasing the risk for hyperkalemia and associated serious arrhythmias. Coadministration is contraindicated.
Ergot derivatives (e.g., dihydroergotamine, ergonovine, ergotamine, methyergonovine): Coadministration is contraindicated. The risk of ergot toxicity (e.g., vasospasm and ischemia of the extremities and other tissues including the CNS) may be increased.
Eszopiclone: Eszopiclone concentrations may be elevated, increasing the pharmacologic effects and risk for adverse reactions. Consider eszopiclone dosage reduction during coadministration of ritonavir.
HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin): Coadministration with lovastatin or simvastatin is contraindicated. Concurrent use increases the risk of myopathy, including rhabdomyolysis. If using atorvastatin or rosuvastatin, start with the lowest possible dose and monitor carefully or consider pravastatin or fluvastatin.
Iloperidone: Plasma concentrations and pharmacologic effects of iloperidone may be increased by ritonavir.Reduce dose of iloperidone when coadministered with ritonavir.
Ixabepilone: Ixabepilone plasma concentrations may be elevated, increasing the pharmacologic effects and risk for adverse reactions. Avoid coadministration.
Levothyroxine: Thyroxine serum concentrations may be increased or decreased. Adjust the levothyroxine dose as needed.
Maraviroc: Maraviroc plasma concentrations may be increased. When coadministered with ritonavir, maraviroc dosage adjustment may be necessary.
Muscarinic receptor antagonists (e.g., darifenacin, fesoterodine, solifenacin, tolterodine): Muscarinic receptor antagonist plasma concentrations may be increased by ritonavir.
Nilotinib: Nilotinib plasma concentrations may be elevated, increasing the pharmacologic effects and risk for adverse reactions. Avoid coadministration of ritonavir and nilotinib.
Opioid analgesics (e.g., fentanyl, meperidine, methadone, propoxyphene, tramadol): Plasma concentrations of alfentanil, buprenorphine, fentanyl, propoxyphene, sufentanil and tramadol may be increased, possibly causing toxicity. A dose decrease may be needed for these drugs when coadministered with ritonavir. Dosage increase and long-term use of meperidine with ritonavir are not recommended.
Phosphodiesterase type 5 inhibitors (PDE5 inhibitors) (e.g., sildenafil, tadalafil, vardenafil): Coadministration with sildenafil, when used for the treatment of PAH, is contraindicated.
Protease inhibitors (e.g., atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, tipranavir): Ritonavir may increase the AUC and Cmax of other coadministered PIs. Adjust the dose of one or both agents as needed.
Quinine: Quinine levels may be increased. A decrease of the quinine dose may be needed.
Ranolazine: Coadministration is contraindicated. Increased ranolazine concentrations may increase the risk of QT prolongation, torsades de pointes, and sudden death.
Salmeterol: Pharmacologic effects of salmeterol may be increased by ritonavir, increasing the risk of cardiovascular toxicity (e.g., QT prolongation, palpitations, sinus tachycardia). Coadministration is not recommended.
Selective 5-HT1 receptor agonists (e.g., electriptan): Ritonavir may increase plasma concentrations and pharmacologic effects of these agents.
Sulfamethoxazole: Coadministration of ritonavir with sulfamethoxazole/trimethoprim decreased sulfamethoxazole AUC but increased trimethoprim AUC. This decrease is not likely to be clinically important.
Trimethoprim: See sulfamethoxazole.
Theophylline: Coadministration decreased the theophylline AUC and Cmax. Increased dosage may be needed.
Tyrosine kinase receptor inhibitors (e.g., dasatinib): Ritonavir may elevate plasma concentrations, increasing the pharmacologic effects and risk for adverse reactions of these agents. Adjust the dose of tyrosine kinase receptor inhibitor as needed.
Warfarin: Initial frequent monitoring of international normalized ratio (INR) is indicated. Adjust the warfarin dose as needed.
Zidovudine: Coadministration decreased zidovudine AUC and Cmax. Adjust zidovudine dose as needed.
Zolpidem: Zolpidem levels may be increased, resulting in possible severe sedation and respiratory depression. Adjust the zolpidem dose as needed.
Drug/food interactions: Grapefruit juice may increase the plasma concentrations and pharmacologic effects of ritonavir. Adjust the ritonavir dose accordingly.
Food enhances absorption.
Storage
Do not store above 30°C. Store in original container.
MIMS Class
ATC Classification
J05AE03 - ritonavir ; Belongs to the class of protease inhibitors. Used in the systemic treatment of viral infections.
Presentation/Packing
FC tab 100 mg (white to off white, biconvex, oblong, one side debossed with "R100" and the other side plain) x 30's.
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