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Arsenic Trioxide

Pronunciation

(AR se nik tri OKS id)

Index Terms

  • Arsenic (III) Oxide
  • As2O3
  • ATO

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Trisenox: 10 mg/10 mL (10 mL)

Brand Names: U.S.

  • Trisenox

Pharmacologic Category

  • Antineoplastic Agent, Miscellaneous

Pharmacology

Induces apoptosis in APL cells via morphological changes and DNA fragmentation; also damages or degrades the fusion protein promyelocytic leukemia (PML)-retinoic acid receptor (RAR) alpha

Distribution

Vdss: Arsenious acid (AsIII): 562 L; widely distributed throughout body tissues; dependent on body weight and increases as body weight increases; orally administered arsenic trioxide distributes into the CNS

Metabolism

Arsenic trioxide is immediately hydrolyzed to the active form, arsenious acid (AsIII) which is methylated (hepatically) to the less active pentavalent metabolites, monomethylarsonic acid (MMAv) and dimethylarsinic acid (DMAv) by methyltransferases; AsIII is also oxidized to the minor metabolite, arsenic acid (Asv)

Excretion

Urine (MMAv, DMAv, and 15% of a dose as unchanged AsIII)

Time to Peak

AsIII: At the end of infusion (2 hours); MMAv and DMAv; ~10 to 24 hours

Half-Life Elimination

AsIII: 10 to 14 hours; MMAv: ~32 hours; DMAv: ~72 hours

Special Populations: Renal Function Impairment

Results from a pharmacokinetic study in patients with advanced malignancies showed that mean AUC for AsIII was ~48% higher in patients with several renal impairment (CrCl <30 mL/min) than in patients with normal renal function (CrCl >80 mL/min). Systemic exposure to metabolites MMAV and DMAV may also be increased in patients with renal impairment.

Special Populations: Hepatic Function Impairment

A small pharmacokinetic study in patients with hepatocellular carcinoma showed that the mean dose-normalized AUC and Cmax values were 40% and 70% higher, respectively, in a patient with severe hepatic impairment (Child-Pugh class C) versus patients with normal hepatic function. Additionally, the mean dose-normalized trough plasma levels for metabolites MMAV and DMAV were 2.2-fold and 4.7-fold higher, respectively, than levels in patients with normal hepatic function.

Use: Labeled Indications

Acute promyelocytic leukemia: Remission induction and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression

Use: Unlabeled

Initial treatment of APL, treatment of myelodysplastic syndrome (MDS)

Contraindications

Hypersensitivity to arsenic or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Pregnancy; breast-feeding

Dosing: Adult

Note: Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.

Acute promyelocytic leukemia (APL), relapsed or refractory: IV:

Induction: 0.15 mg/kg once daily until bone marrow remission; maximum: 60 doses for induction

Consolidation: 0.15 mg/kg once daily starting 3 to 6 weeks after completion of induction therapy; maximum: 25 doses over a period of up to 5 weeks for consolidation

APL, newly diagnosed (off-label use): IV:

Low/intermediate risk (Lo-Coco 2013):

Induction: 0.15 mg/kg/day; administer daily until bone marrow remission (in combination with tretinoin)

Consolidation: 0.15 mg/kg/day; administer 5 days/week for 4 weeks every 8 weeks for a total of 4 cycles (in combination with tretinoin)

High-risk:

Consolidation therapy after remission induction with tretinoin, daunorubicin and cytarabine (Powell 2010): Two consolidation courses (2 weeks apart): 0.15 mg/kg/day 5 days/week for 5 weeks

In combination with tretinoin in patients unable to tolerate anthracycline-based therapy (Estey 2006; Ravandi 2009):

Induction (beginning 10 days after initiation of tretinoin): 0.15 mg/kg/day until bone marrow remission; maximum: 75 doses for induction

Consolidation: 0.15 mg/kg/day Monday through Friday for 4 weeks every 8 weeks for 4 cycles (weeks 1 to 4, 9 to 12, 17 to 20, and 25 to 28)

APML 4 protocol (Iland 2012):

Induction: 0.15 mg/kg/day over 2 hours on days 9 to 36 (in combination with tretinoin and age-adjusted idarubicin)

Consolidation (2 cycles): 0.15 mg/kg/day on days 1 to 28 of consolidation cycle 1 (in combination with tretinoin); 0.15 mg/kg/day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and 29 to 33 of consolidation cycle 2 (in combination with tretinoin)

Dosing: Pediatric

Note: Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

Acute promyelocytic leukemia (APL), relapsed or refractory: Children ≥4 years (US labeling) or ≥5 years (Canadian labeling): IV: Refer to adult dosing. Note: The Canadian labeling recommends dosing obese pediatric patients based on ideal body weight.

APL, newly diagnosed (off-label use): IV:

Induction, consolidation, and maintenance (Mathews 2006):

Induction: 0.15 mg/kg/day (maximum dose: 10 mg); administer daily until bone marrow remission; maximum: 60 doses for induction

Consolidation: 0.15 mg/kg/day (maximum dose: 10 mg) for 4 weeks, starting 4 weeks after completion of induction therapy

Maintenance: 0.15 mg/kg/dose (maximum dose: 10 mg) administered 10 days per month for 6 months, starting 4 weeks after completion of consolidation therapy

Children >1 year and Adolescents (APML 4 protocol; Iland 2012):

Induction: 0.15 mg/kg/day over 2 hours on days 9 to 36 (in combination with tretinoin and idarubicin)

Consolidation (2 cycles): 0.15 mg/kg/day on days 1 to 28 of consolidation cycle 1 (in combination with tretinoin); 0.15 mg/kg/day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and 29 to 33 of consolidation cycle 2 (in combination with tretinoin)

Dosing: Renal Impairment

Mild-to-moderate impairment (CrCl ≥30 mL/minute): There are no dosage adjustments provided in the manufacturer’s labeling.

Severe renal impairment (CrCl <30 mL/minute): Use with caution (systemic exposure to metabolites may be higher); may require dosage reduction; monitor closely for toxicity.

Dialysis patients: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Patients with severe impairment (Child-Pugh class C) should be monitored closely for toxicity.

Dosing: Adjustment for Toxicity

Consider delaying infusion if a severe non-hematologic reaction occurs (eg, neurologic or dermatologic toxicity) until the toxicity has improved to ≤grade 1.

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Dilute with 100 to 250 mL D5W or 0.9% NaCl. Discard unused portion of ampule.

Administration

Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011). For relapsed/refractory APL, administer as an IV infusion over 1 to 2 hours. For newly diagnosed APL (off-label use), infusion rate may vary; refer to specific protocol. If acute vasomotor reactions occur, the infusion duration may be extended to up to 4 hours. Does not require administration via a central venous catheter.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze. Following dilution, solution for infusion is stable for 24 hours at room temperature or 48 hours when refrigerated.

Drug Interactions

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Tachycardia (55%), edema (40%), prolonged Q-T interval on ECG (40%; >500 msec), chest pain (25%; grades 3/4: 5%), hypotension (25%; grades 3/4: 5%)

Central nervous system: Fatigue (63%), headache (60%), insomnia (43%), rigors (38%), paresthesia (33%), anxiety (30%), dizziness (23%), depression (20%), pain (15%)

Dermatologic: Dermatitis (43%), pruritus (33%), xeroderma (15%), diaphoresis (13%), erythema (13%)

Endocrine & metabolic: Hypokalemia (50%; grades 3/4: 13%), hyperglycemia (45%; grades 3/4: 13%), hypomagnesemia (45%; grades 3/4: 13%), hyperkalemia (18%; grades 3/4: 5%), weight gain (13%)

Gastrointestinal: Nausea (75%), abdominal pain (58%), vomiting (58%), diarrhea (53%), sore throat (35%), constipation (28%), anorexia (23%), decreased appetite (15%)

Genitourinary: Vaginal hemorrhage (13%)

Hematologic & oncologic: Leukocytosis (50%; grades 3/4: 3%), APL differentiation syndrome (23%; grades 3/4: 8%), anemia (20%; grades 3/4: 5%), bruise (20%), thrombocytopenia (18%; grades 3/4: 13%), febrile neutropenia (13%; grades 3/4: 8%)

Hepatic: Increased serum ALT (20%; grades 3/4: 5%), increased serum AST (13%; grades 3/4: 3%)

Infection: Herpes simplex infection (13%)

Local: Pain at injection site (20%), erythema at injection site (13%)

Neuromuscular & skeletal: Arthralgia (33%), myalgia (25%), ostealgia (23%), back pain (18%), limb pain (13%), neck pain (13%), tremor (13%)

Respiratory: Cough (65%), dyspnea (53%; grades 3/4: 10%), epistaxis (25%), hypoxia (23%), pleural effusion (20%), sinusitis (20%), post nasal drip (13%), upper respiratory tract infection (13%), wheezing (13%)

Miscellaneous: Fever (63%)

1% to 10%:

Cardiovascular: Hypertension (10%), flushing (10%), palpitations (10%), ECG abnormality (8%; non-QT prolongation), facial edema (8%), atrial arrhythmia (5%), torsades de pointes (3%)

Central nervous system: Drowsiness (8%), seizure (8%; grades 3/4: 5%), agitation (5%), coma (5%), confusion (5%)

Dermatologic: Pallor (10%), hyperpigmentation (8%), night sweats (8%), skin lesion (8%), urticaria (8%)

Endocrine & metabolic: Hypocalcemia (10%), hypoglycemia (8%), intermenstrual bleeding (8%), acidosis (5%)

Gastrointestinal: Dyspepsia (10%), loose stools (10%), abdominal distension (8%), abdominal tenderness (8%), bloody diarrhea (8%), fecal incontinence (8%), gastrointestinal hemorrhage (8%), oral bullae (8%), typhlitis (children: 8%), weight loss (8%), xerostomia (8%), oral candidiasis (5%)

Genitourinary: Oliguria (5%), urinary incontinence (5%)

Hematologic & oncologic: Neutropenia (10%; grades 3/4: 10%), disseminated intravascular coagulation (8%), hemorrhage (8%), lymphadenopathy (8%), petechia (8%)

Hypersensitivity: Hypersensitivity (5%)

Infection: Bacterial infection (8%), herpes zoster (8%), sepsis (5%; grades 3/4: 5%)

Local: Swelling at injection site (10%), local skin exfoliation (5%)

Neuromuscular & skeletal: Weakness (10%)

Ophthalmic: Blurred vision (10%), eye irritation (10%), xerophthalmia (8%), eyelid edema (5%), painful red eye (5%)

Otic: Otalgia (8%), tinnitus (5%)

Renal: Renal failure (8%; grades 3/4: 3%), renal insufficiency (8%)

Respiratory: Decreased breath sounds (10%), rales (10%), hemoptysis (8%), pulmonary edema (children: 8%), rhonchi (8%), tachypnea (8%), nasopharyngitis (5%)

<1% (Limited to important or life-threatening): Acute respiratory distress, atrioventricular block, capillary leak syndrome, cardiac failure, heart block, hypoalbuminemia, hyponatremia, hypophosphatemia, increased serum lipase, mitochondrial myopathy, pancytopenia, peripheral neuropathy, pneumonitis, pulmonary infiltrates, respiratory distress, stomatitis, ventricular premature contractions, ventricular tachycardia

ALERT: U.S. Boxed Warning

APL differentiation syndrome:

Patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide have experienced symptoms similar to a syndrome called the retinoic-acid-acute promyelocytic leukemia (RA-APL) or APL differentiation syndrome, characterized by fever, dyspnea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis. This syndrome can be fatal. High-dose steroids have been administered at the first suspicion of the APL differentiation syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), immediately initiate high-dose steroids (dexamethasone 10 mg intravenously [IV] twice daily), irrespective of the leukocyte count, and continue for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of arsenic trioxide therapy during treatment of the APL differentiation syndrome.

QT prolongation:

Before initiating therapy, perform a 12-lead ECG, assess serum electrolytes (potassium, calcium, and magnesium) and creatinine; correct preexisting electrolyte abnormalities and, consider discontinuing drugs that are known to prolong the QT interval. Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of torsade de pointes, preexisting QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. One patient (also receiving amphotericin B) had torsade de pointes during induction therapy for relapsed APL with arsenic trioxide.

Warnings/Precautions

Concerns related to adverse effects:

• APL differentiation syndrome: [US Boxed Warning]: May cause APL differentiation syndrome (formerly called retinoic-acid-APL [RA-APL] syndrome), which is characterized by dyspnea, fever, weight gain, pulmonary infiltrates, and pleural or pericardial effusions, with or without leukocytosis. May be fatal. High-dose steroids (dexamethasone 10 mg IV twice daily for at least 3 days or until signs/symptoms subside; initiate immediately if APL differentiation syndrome is suspected) have been used for treatment; in general, most patients may continue arsenic trioxide during treatment of APL differentiation syndrome.

• Gastrointestinal toxicity: Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

• Hyperleukocytosis: May lead to the development of hyperleukocytosis (leukocytes ≥10,000/mm3). Hyperleukocytosis did not correlate with baseline WBC counts. In general, WBC counts were not as high during consolidation as observed during induction treatment.

• QT prolongation: [US Boxed Warning]: May prolong the QT interval and lead to torsade de pointes or complete AV block, which may be fatal. Risk factors for torsade de pointes include extent of prolongation, HF, a history of torsade de pointes, preexisting QT interval prolongation, patients taking medications known to prolong the QT interval or potassium-wasting diuretics, and conditions which cause hypokalemia or hypomagnesemia. If possible, discontinue all medications known to prolong the QT interval. A baseline 12-lead ECG, serum electrolytes (potassium, calcium, magnesium), and creatinine should be obtained prior to treatment; preexisting electrolyte abnormalities should be corrected. QT prolongation was observed 1 to 5 weeks after infusion, and returned to baseline by 8 weeks after infusion. Monitor ECG at baseline and then weekly; more frequently if clinically indicated. If baseline QTc >500 msec, correct prior to treatment. If QTc >500 msec during treatment, reassess, correct contributing factors, and consider temporarily withholding treatment. If syncope or irregular heartbeat develop during therapy, hospitalize patient for monitoring; assess electrolytes and do not reinitiate until QTc <460 msec, electrolyte abnormalities are corrected and syncope/irregular heartbeat has resolved.

• Secondary malignancy: Arsenic trioxide is a carcinogen; monitor for the development of second primary malignancies.

Disease-related concerns:

• Electrolyte imbalances: Correct electrolyte abnormalities prior to treatment and monitor potassium and magnesium levels during therapy (maintain potassium >4 mEq/dL and magnesium >1.8 mg/dL). Monitor electrolytes at least twice a week during induction and weekly during consolidation (more frequently if clinically indicated).

• Hepatic impairment: Use with caution in patients with hepatic impairment; in patients with severe hepatic impairment, monitor closely for toxicity.

• Renal impairment: Use with caution in patients with severe renal impairment (dose reduction may be warranted); systemic exposure to metabolites may be higher. Has not been studied in dialysis patients.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Monitoring Parameters

Monitor electrolytes (potassium, calcium, and magnesium), CBC with differential, serum creatinine, hepatic function, blood glucose, and coagulation parameters at baseline then at least twice weekly during induction and at least weekly during consolidation; more frequent monitoring may be necessary in unstable patients; baseline then weekly 12-lead ECG; signs/symptoms of APL differentiation syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities)

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Arsenic crosses the human placenta. In studies of women exposed to high levels of arsenic from drinking water, cord blood levels were similar to maternal serum levels. Dimethylarsinic acid (DMA) was the form of arsenic found in the fetus. An increased risk of low birth weight and still births were observed in women who ingested high levels of dietary arsenic. Women of childbearing potential should avoid pregnancy; effective contraception should be used during and after therapy. The Canadian labeling contraindicates use in pregnant women. It also recommends that women of childbearing potential avoid pregnancy, and male patients wear condoms during intercourse with women who are pregnant or of childbearing potential during therapy and for 3 months following therapy discontinuation.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, constipation, abdominal pain, diarrhea, lack of appetite, weight gain, insomnia, bone pain, injection site pain or irritation, pale skin, anxiety, joint pain, muscle pain, back pain, pharyngitis, sweating a lot, painful extremities, dry skin, flushing, neck pain, tremors, or eye irritation. Have patient report immediately to prescriber abnormal heartbeat, signs of retinoic-acid-APL syndrome (fever, shortness of breath, trouble breathing, weight gain), signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), angina, tachycardia, angina, tachycardia, edema, severe dizziness, edema, severe dizziness, passing out, severe headache, loss of strength and energy, depression, seizures, burning or numbness feeling, blurred vision, or tremors (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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