Cyramza® (ramucirumab): Användning med antikoagulantia

Information from Summary of Product Characteristics

Ramucirumab is an antiangiogenic therapy and may increase the risk of severe bleeding. Ramucirumab should be permanently discontinued in patients who experience Grade 3 or 4 bleeding. Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants or other concomitant medicinal products that increase the risk of bleeding.¹

Coagulation Requirements for Clinical Study Participation

Patients who participated in ramucirumab clinical trials generally must have had adequate coagulation function as defined by INR ≤1.5 or PT ≤1.5 times the ULN, and PTT/aPTT ≤1.5 times the ULN.^2-5

Relevant Protocol Inclusion and Exclusion Criteria by Study

REGARD Study

Patients were eligible for participation if they had adequate coagulation function as defined by

• INR ≤1.5, and

• PTT ≤5 seconds above the ULN (unless receiving anticoagulation therapy).²

Patients were excluded if they were receiving

• anticoagulation therapy with unresected primary tumors or local tumor recurrence following resection, or

• current chronic antiplatelet therapy, including

  • aspirin

  • NSAIDs (including ibuprofen, naproxen, and others)

  • dipyridamole or clopidogrel, or

  • similar agents.²

Patients were also permitted to participate if receiving 

• full-dose anticoagulation provided that they were on a stable dose (minimum duration 14 days) of oral anticoagulant or LMWH

• once daily aspirin use (maximum dose 325 mg/day), or

• warfarin, provided that they had

  • an INR ≤3.0 and

  • no active bleeding (ie, no bleeding within 14 days prior to first dose of study therapy) or pathological condition present that carried a high risk of bleeding (eg, tumor involving major vessels or known varices).²

RAINBOW and REVEL Studies

Patients were eligible for participation if they had adequate coagulation function as defined by

• INR ≤1.5 or PT ≤1.5 times the ULN, and

• PTT/aPTT ≤1.5 times the ULN.^3,5

Patients were excluded if they were receiving 

• therapeutic anticoagulation with

  • warfarin

  • LMWH, or

  • similar agents

• chronic therapy with

  • NSAIDs (eg, indomethacin, ibuprofen, naproxen, or similar agents), or

  • other antiplatelet agents (eg, clopidogrel, ticlopidine, dipyridamole, anagrelide).^3,5

Patients were also permitted to participate if receiving 

• prophylactic, low-dose anticoagulation therapy provided that the coagulation parameters defined in the inclusion criteria were met (INR ≤1.5 and PTT/aPTT ≤1.5 times ULN) or (PT ≤1.5 times ULN and PTT/aPTT ≤1.5 times ULN), or

• once daily aspirin (maximum dose 325 mg/day).^3,5

RAISE Study

Patients were eligible for participation if they had adequate coagulation function as defined by

• INR ≤1.5, and

• PTT ≤1.5 times the ULN (unless receiving anticoagulation therapy).⁴

Patients were also permitted to participate if receiving 

• full-dose anticoagulation provided that they were on a stable dose (minimum duration 14 days) of oral anticoagulant or LMWH, or 

• warfarin, provided that they had

  • an INR ≤3.0 and

  • no clinically significant active bleeding (ie, bleeding within 14 days prior to randomization) or pathological condition present that carried a high risk of bleeding (eg, intact primary tumor with a history of clinically significant bleeding, or tumor involving major vessels or known esophageal varices).⁴

Treatment of Thrombotic Events While on Ramucirumab Therapy

Patients who developed grade 3-4 venous thrombotic events may have continued study therapy if

• the event was not considered to be life-threatening in the opinion of the investigator, or

• the patient was asymptomatic and the event could be adequately treated with LMWH-based therapy (REGARD)/anticoagulation therapy (RAINBOW, REVEL, RAISE).^2,4-6

Patients with unresected primary tumors (or local recurrence) who developed grade 3-4 venous thromboembolism may have also received anticoagulation and continued study therapy, provided that the tumor did not confer an excessive bleeding risk, in the opinion of the investigator (REGARD only).²

Patients were warranted for discontinuation of study therapy if they experienced 

• grade 3-4 ATEs (RAINBOW, REVEL, RAISE, REGARD), or 

• any PE/DVT that occurred or intensified during anticoagulant therapy (REGARD, RAINBOW, RAISE).^2,4-6

References

1. Cyramza [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31-39. http://dx.doi.org/10.1016/S0140-6736(13)61719-5.

3. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. http://dx.doi.org/10.1016/S0140-6736(14)60845-X

4. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499-508. http://dx.doi.org/10.1016/S1470-2045(15)70127-0

5. Wilke W, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70420-6/fulltext

6. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

aPTT = activated partial thromboplastin time

ATE = arterial thromboembolic event

DVT = deep vein thrombosis

INR = international normalized ratio

LMWH = low-molecular-weight heparin

NSAID = nonsteroidal anti-inflammatory drug

PE = pulmonary embolism

PT = prothrombin time

PTT = partial thromboplastin time

ULN = upper limit of normal