For Patients and Caregivers

Indication: VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

It is not known if VENCLEXTA is safe and effective in children. Actor portrayals.

VENCLEXTA enables targeted, fixed-duration regimens in CLL1

1L CLL:

VENCLEXTA + acalabrutinib

Complete in

Discover the AMPLIFY Study
1L CLL:

VENCLEXTA + GAZYVA® (obinutuzumab)

Complete in

Explore the CLL14 Study
R/R CLL:

VENCLEXTA + RITUXAN® (rituximab)

Complete in

Learn about the MURANO Study

The VEN+A regimen is designed to be completed after 12 cycles (twelve 28-day treatment cycles), preceded by a 2-cycle acalabrutinib initiation phase. Acalabrutinib is taken orally 100 mg approximately every 12 hours starting on Cycle 1, Day 1, for a total of 14 cycles or until disease progression or unacceptable toxicity. VENCLEXTA is taken orally 400 mg/day until disease progression, unacceptable toxicity, or for a total of 12 cycles after the 2-cycle acalabrutinib initiation phase, starting with the 5-week VENCLEXTA dose ramp-up schedule. AMPLIFY was a randomized, multicenter, open-label trial in patients with previously untreated CLL without TP53 mutation or 17p deletion (VEN+A: N=291; CIT: N=290) and with a median follow-up of 42.6 months (range: 1-59 months) in the VEN+A arm. VEN+A reduced the risk of progression or death by 35% vs CIT (HR=0.65; 95% CI: 0.49-0.87 [P<0.0038]). Median PFS was NR with VEN+A vs 47.6 months with CIT (95% CI: 43.3-NR).

The VEN+G regimen is designed to be completed after 12 months (twelve 28-day treatment cycles): GAZYVA® (obinutuzumab) is administered in Cycles 1-6, and VENCLEXTA is taken orally 400 mg/day from Cycle 3, Day 1, after the first 2 cycles of GAZYVA and the 5-week VENCLEXTA dose ramp-up. CLL14 was a randomized clinical trial of 432 patients (VEN+G: N=216; GClb: N=216) with previously untreated CLL and with a median follow-up of 28 months (range: 0-36 months). VEN+G reduced the risk of progression or death by 67% vs GCIb (HR=0.33; 95% CI: 0.22-0.51 [P<0.0001]). Median PFS was not reached in either arm.

The VEN+R regimen is designed to be completed after 24 months (twenty-four 28-day treatment cycles after the 5-week VENCLEXTA dose ramp-up): rituximab is administered in Cycles 1-6; VENCLEXTA is taken 400 mg/day orally from Cycle 1, Day 1 of rituximab through Cycle 24. MURANO was a randomized clinical trial of 389 patients (VEN+R: N=194; BR: N=195) with previously treated CLL and with a median follow-up of 23.4 months (range: 0-37.4+ months). VEN+R reduced the risk of progression or death by 81% vs BR (HR=0.19; 95% CI: 0.13-0.28 [P<0.0001]). Median PFS was not reached with VEN+R vs 18.1 months with BR (95% CI: 15.8-22.3).1

VENCLEXTA fixed-duration regimens give your patients the chance to experience the freedom of time off treatment1

No continuous therapy

No ongoing treatment exposure

No ongoing out-of-pocket costs*

Explore the impact of time off treatment

*Coverage and patient out-of-pocket costs for VEN+A, VEN+G, and VEN+R vary by health plan. Patients may still incur out-of-pocket costs for other treatments or tests as directed by their healthcare providers.

CLL Society Patient Preference Survey

Uncover the insights
Understand how to initiate patients on VENCLEXTA
Contact a VENCLEXTA Representative

†See NCCN Guidelines® for CLL/SLL, Version 2.2026, for complete recommendations. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
1L=first line; BR=bendamustine-rituximab; CI=confidence interval; CIT=chemoimmunotherapy; CLL=chronic lymphocytic leukemia; FCR=fludarabine-cyclophosphamide-rituximab; GClb=GAZYVA + chlorambucil; HR=hazard ratio; NR=not reached; PFS=progression-free survival; R/R=relapsed/refractory; SLL=small lymphocytic lymphoma; TP53=tumor protein 53; VEN+A=VENCLEXTA + acalabrutinib; VEN+G=VENCLEXTA + GAZYVA; VEN+R=VENCLEXTA + rituximab.

US-VENC-250248

Important Safety Information & Indication

Indication

  • VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Important Safety Information

Contraindication

  • Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during the ramp-up phase is contraindicated in patients with CLL/SLL due to the potential for increased risk of tumor lysis syndrome (TLS).

Tumor Lysis Syndrome

  • Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA.
  • VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during the ramp-up phase in all patients, and during reinitiation after dosage interruption in patients with CLL/SLL. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase. TLS, including fatal cases, has been reported after a single 20 mg dose.
  • In patients with CLL/SLL who followed the current (5-week) dose ramp-up and the TLS prophylaxis and monitoring measures, the rate of TLS was 2% in the VENCLEXTA CLL/SLL monotherapy trials. The rate of TLS remained consistent with VENCLEXTA in combination with obinutuzumab or rituximab. With a 2- to 3-week dose ramp-up and higher starting dose in patients with CLL/SLL, the TLS rate was 13% and included deaths and renal failure.
  • The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy. Splenomegaly may also increase the risk of TLS in patients with CLL/SLL.
  • Assess all patients for risk and provide appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA, follow dose modification guidance in the Prescribing Information.
  • Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors increases venetoclax exposure, which may increase the risk of TLS at initiation and during the ramp-up phase, and requires VENCLEXTA dose reduction.

Neutropenia

  • In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with VENCLEXTA in monotherapy and in combination studies with obinutuzumab or rituximab; febrile neutropenia occurred in 4% to 6% of patients. Grade 3 or 4 neutropenia developed in 38% of patients and Grade 4 neutropenia developed in 15% of patients when treated with VENCLEXTA in combination with acalabrutinib; febrile neutropenia occurred in 2% of patients.
  • Monitor complete blood counts. Interrupt dosing for severe neutropenia and resume at same or reduced dose. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF).

Infections

  • Fatal and serious infections, such as pneumonia and sepsis, have occurred in patients treated with VENCLEXTA. Monitor patients for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and 4 infection until resolution and resume at same or reduced dose.
  • In AMPLIFY, a randomized study in patients with previously untreated CLL/SLL, serious or Grade 3 or higher infections occurred in 14% of patients who received VENCLEXTA in combination with acalabrutinib (VEN+A), most commonly due to COVID-19; fatal infections occurred in 3.1% of patients.
  • In an additional cohort of patients receiving VENCLEXTA in combination with acalabrutinib and obinutuzumab (AVO) (an unapproved regimen for previously untreated CLL/SLL in AMPLIFY), serious or Grade 3 or higher infections occurred in 25%, most commonly due to COVID-19; fatal infections occurred in 6% of patients. The safety and effectiveness of AVO have not been established by the FDA in patients with previously untreated CLL/SLL.

Immunization

  • Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. Advise patients that vaccinations may be less effective.

Embryo-Fetal Toxicity

  • VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for 30 days after the last dose.

Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and Dexamethasone

  • In a randomized trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.

Adverse Reactions

  • In patients with CLL receiving combination therapy with acalabrutinib, serious adverse reactions were most often due to COVID-19 including COVID-19 pneumonia (9%), second primary malignancies (2.7%), and neutropenia (2.1%). The most common adverse reactions (≥20%) of any grade were neutropenia (78%), headache (35%), diarrhea (33%), musculoskeletal pain (25%), and COVID-19 (21%). Fatal adverse reactions occurred in 3.4% of patients, most often from COVID-19 and COVID-19 pneumonia.
  • In patients with CLL receiving combination therapy with obinutuzumab, serious adverse reactions were most often due to febrile neutropenia and pneumonia (5% each). The most common adverse reactions (≥20%) of any grade were neutropenia (60%), diarrhea (28%), and fatigue (21%). Fatal adverse reactions that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection.
  • In patients with CLL receiving combination therapy with rituximab, the most frequent serious adverse reaction (≥5%) was pneumonia (9%). The most common adverse reactions (≥20%) of any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), and nausea (21%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of the last rituximab were reported in 2% (4/194) of patients.

Drug Interactions

  • Concomitant use with a P-gp inhibitor or a strong or moderate CYP3A inhibitor increases VENCLEXTA exposure, which may increase VENCLEXTA toxicities, including the risk of TLS. Concomitant use with a strong CYP3A inhibitor at initiation and during ramp-up phase in patients with CLL/SLL is contraindicated. Consider alternative medications or adjust VENCLEXTA dosage and monitor more frequently for adverse reactions in patients taking a steady daily dosage (after ramp-up phase). Resume the VENCLEXTA dosage that was used prior to concomitant use of a P-gp inhibitor or a strong or moderate CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor.
  • Patients should avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain inhibitors of CYP3A.
  • Avoid concomitant use of strong or moderate CYP3A inducers.
  • Monitor international normalized ratio (INR) more frequently in patients receiving warfarin.
  • Avoid concomitant use of VENCLEXTA with a P-gp substrate. If concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA.

Lactation

  • Advise women not to breastfeed during treatment with VENCLEXTA and for 1 week after the last dose.

Females and Males of Reproductive Potential

  • Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for 30 days after the last dose.
  • Based on findings in animals, VENCLEXTA may impair male fertility.

Hepatic Impairment

  • Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more frequently for adverse reactions. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

Please see full Prescribing Information.

VENCLEXTA® and its design are registered trademarks of AbbVie Inc.
GAZYVA® is a registered trademark of Genentech, Inc.

    • VENCLEXTA Prescribing Information.

      VENCLEXTA Prescribing Information.

    • Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225​​-2236.

      Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225​​-2236.

    • GAZYVA Prescribing Information.

      GAZYVA Prescribing Information.

    • Data on file, AbbVie Inc. ABVRRTI69608.

      Data on file, AbbVie Inc. ABVRRTI69608.

    • Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23)(suppl):2225​​-2236.

      Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23)(suppl):2225​​-2236.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12)(suppl):1107-1120.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12)(suppl):1107-1120.

    • Data on file, AbbVie Inc. ABVRRTI69609.

      Data on file, AbbVie Inc. ABVRRTI69609.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140(8)(suppl):839​-850.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140(8)(suppl):839​-850.

    • Data on file, AbbVie Inc. ABVRRTI76640.

      Data on file, AbbVie Inc. ABVRRTI76640.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V.2.2026. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed December 22, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V.2.2026. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed December 22, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Data on file, AbbVie Inc. ABVRRTI71322.

      Data on file, AbbVie Inc. ABVRRTI71322.

    • Owen C, Christofides A, Johnson N, Lawrence T, MacDonald D, Ward C. Use of minimal residual disease assessment in the treatment of chronic lymphocytic leukemia [published online ahead of print May 16, 2017]. Leuk Lymphoma. 2017;58(12):2777​​-2785.

      Owen C, Christofides A, Johnson N, Lawrence T, MacDonald D, Ward C. Use of minimal residual disease assessment in the treatment of chronic lymphocytic leukemia [published online ahead of print May 16, 2017]. Leuk Lymphoma. 2017;58(12):2777​​-2785.

    • Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127(3):279​-286.

      Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127(3):279​-286.

    • US Food and Drug Administration. Hematologic malignancies: regulatory considerations for use of minimal residual disease in development of drug and biological products for treatment. Guidance for industry. January 2020. Accessed April 7, 2023. https://www.fda.gov/media/134605/download

      US Food and Drug Administration. Hematologic malignancies: regulatory considerations for use of minimal residual disease in development of drug and biological products for treatment. Guidance for industry. January 2020. Accessed April 7, 2023. https://www.fda.gov/media/134605/download

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax–rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax–rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

    • Greer JA, Amoyal N, Nisotel L, et al. A systematic review of adherence to oral antineoplastic therapies. Oncologist. 2016;21(3):354​-376.

      Greer JA, Amoyal N, Nisotel L, et al. A systematic review of adherence to oral antineoplastic therapies. Oncologist. 2016;21(3):354​-376.

    • Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009;59(1):56-66.

      Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009;59(1):56-66.

    • Giacomini KM, Huang S-M, Tweedie DJ, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215​-236.

      Giacomini KM, Huang S-M, Tweedie DJ, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215​-236.

    • Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol. 2013;61(25):2495​-2502.

      Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol. 2013;61(25):2495​-2502.

    • CRESEMBA Prescribing Information.

      CRESEMBA Prescribing Information.

    • Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration website. Updated June 5, 2023. Accessed May 1, 2024. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#cypEnzymes

      Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration website. Updated June 5, 2023. Accessed May 1, 2024. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#cypEnzymes

    • RITUXAN Prescribing Information.

      RITUXAN Prescribing Information.

    • Souers AJ, Leverson JD, Doghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202​-203.

      Souers AJ, Leverson JD, Doghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202​-203.

    • Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukemia (CLL14); follow-up results from a multicentre, open-label, randomized, phase 3 trial. Lancet Oncol. 2020;21:1188​-1200.

      Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukemia (CLL14); follow-up results from a multicentre, open-label, randomized, phase 3 trial. Lancet Oncol. 2020;21:1188​-1200.

    • Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the phase 3 CLL14 study. Blood. 2024;144(18):1924​-1935.

      Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the phase 3 CLL14 study. Blood. 2024;144(18):1924​-1935.

    • Data on file, AbbVie Inc. 6-year data. ABVRRTI76226.

      Data on file, AbbVie Inc. 6-year data. ABVRRTI76226.

    • Kater AP, Harrup R, Kipps TJ, et al. The MURANO study: final analysis and retreatment/cross over substudy of VenR for patients with relapsed/refractory CLL. Blood. 2025;145(23):2733​-2745.

      Kater AP, Harrup R, Kipps TJ, et al. The MURANO study: final analysis and retreatment/cross over substudy of VenR for patients with relapsed/refractory CLL. Blood. 2025;145(23):2733​-2745.

    • Data on file, AbbVie Inc. 7-year MURANO ABVRRTI76236.

      Data on file, AbbVie Inc. 7-year MURANO ABVRRTI76236.

    • Acalabrutinib Prescribing Information.

      Acalabrutinib Prescribing Information.

    • Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748​-762.

      Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748​-762.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140(8)(suppl):839​-850.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140(8)(suppl):839​-850.

    • Data on file, AbbVie Inc. ABVRRTI74115.

      Data on file, AbbVie Inc. ABVRRTI74115.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140(8):839​-850.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140(8):839​-850.

    • Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukemia (CLL14); follow-up results from a multicentre, open-label, randomized, phase 3 trial. Lancet Oncol 2020;21(9)(suppl):1188​-1200.

      Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukemia (CLL14); follow-up results from a multicentre, open-label, randomized, phase 3 trial. Lancet Oncol 2020;21(9)(suppl):1188​-1200.

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