CLINICAL NEWS
Prothrombin Complex Concentrate Versus Fresh Frozen Plasma for Warfarin Reversal
When patients receiving the anticoagulant warfarin experience a major bleeding event or have to undergo emergency surgery , they need rapid and effective reversal of warfarin ’ s anticoagulant effect . However , there is no consensus about the optimal strategy for reversal , the most common being coagulation factor replacement therapy with prothrombin complex concentrate ( PCC ) or fresh frozen plasma ( FFP ).
In a systematic literature review published in the Journal of Thrombosis and Haemostasis , Chatree Chai-
Adisaksopha , PhD , of the Department of Medicine at McMaster University in Canada , and authors analyzed 13 studies investigating the efficacy and safety of PCCs or FFP for warfarin reversal , finding that reversal with PCC was associated with a significant reduction in all-cause
4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity ( e . g ., angioedema , Stevens-Johnson syndrome , toxic epidermal necrolysis ) to lenalidomide [ see Warnings and Precautions ( 5.8 )].
5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy . Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [ see Use in Specific Populations ( 8.1 )]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy , similar to birth defects observed in humans following exposure to thalidomide during pregnancy .
REVLIMID is only available through the REVLIMID REMS™ program ( formerly known as the “ RevAssist ® program ”) [ see Warnings and Precautions ( 5.2 )].
Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy , during therapy , during dose interruptions and for at least 4 weeks after completing therapy .
Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control , beginning 4 weeks prior to initiating treatment with REVLIMID , during therapy , during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy .
Two negative pregnancy tests must be obtained prior to initiating therapy . The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month , then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [ see Use in Specific Populations ( 8.6 )].
Males Lenalidomide is present in the semen of patients receiving the drug . Therefore , males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID , even if they have undergone a successful vasectomy . Male patients taking REVLIMID must not donate sperm [ see Use in Specific Populations ( 8.6 )].
Blood Donation Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID .
5.2 REVLIMID REMS™ Program Because of the embryo-fetal risk [ see Warnings and Precautions ( 5.1 )], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy ( REMS ), the REVLIMID REMS™ program ( formerly known as the “ RevAssist ® ” program ).
Required components of the REVLIMID REMS™ program include the following :
• Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements .
• Patients must sign a Patient-Physician agreement form and comply with the REMS requirements . In particular , female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [ see Use in Specific Populations ( 8.6 )] and males must comply with contraception requirements [ see Use in Specific Populations ( 8.6 )].
• Pharmacies must be certified with the REVLIMID REMS™ program , must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements .
Further information about the REVLIMID REMS™ program is available at www . celgeneriskmanagement . com or by telephone at 1-888-423-5436 .
5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia . Monitor patients with neutropenia for signs of infection . Advise patients to observe for bleeding or bruising , especially with use of concomitant medication that may increase risk of bleeding . Patients taking REVLIMID should have their complete blood counts assessed periodically as described below [ see Dosage and Administration ( 2.1 , 2.2 , 2.3 )].
Patients taking REVLIMID in combination with dexamethasone for MM should have their complete blood counts ( CBC ) assessed every 7 days ( weekly ) for the first 2 cycles , on Days 1 and 15 of Cycle 3 , and every
28 days ( 4 weeks ) thereafter . A dose interruption and / or dose reduction may be required [ see Dosage and Administration ( 2.1 )].
Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter . Grade 3 or 4 hematologic toxicity was seen in 80 % of patients enrolled in the MDS study . In the 48 % of patients who developed Grade 3 or 4 neutropenia , the median time to onset was 42 days ( range , 14-411 days ), and the median time to documented recovery was 17 days ( range , 2-170 days ). In the 54 % of patients who developed Grade 3 or 4 thrombocytopenia , the median time to onset was 28 days ( range , 8-290 days ), and the median time to documented recovery was 22 days ( range , 5-224 days ) [ see Boxed Warning and Dosage and Administration ( 2.2 )].
Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle ( 28 days ), every 2 weeks during cycles 2-4 , and then monthly thereafter . Patients may require dose interruption and / or dose reduction . In the MCL trial , Grade 3 or 4 neutropenia was reported in 43 % of the patients . Grade 3 or 4 thrombocytopenia was reported in 28 % of the patients .
5.4 Venous and Arterial Thromboembolism Venous thromboembolic events ( deep venous thrombosis and pulmonary embolism ) and arterial thromboses are increased in patients treated with REVLIMID . A significantly increased risk of DVT ( 7.4 %) and of PE ( 3.7 %) occurred in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group ( 3.1 % and 0.9 %) in clinical trials with varying use of anticoagulant therapies . In the newly diagnosed multiple myeloma ( NDMM ) study in which nearly all patients received antithrombotic prophylaxis , DVT was reported as a serious adverse reaction ( 3.6 %, 2.0 %, and 1.7 %) in the Rd Continuous , Rd18 , and MPT Arms , respectively . The frequency of serious adverse reactions of PE was similar between the Rd Continuous , Rd18 , and MPT Arms ( 3.8 %, 2.8 %, and 3.7 %, respectively ) [ see Boxed Warning and Adverse Reactions ( 6.1 )].
Myocardial infarction ( 1.7 %) and stroke ( CVA ) ( 2.3 %) are increased in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated with placebo and dexamethasone ( 0.6 %, and 0.9 %) in clinical trials . In the NDMM study , myocardial infarction ( including acute ) was reported as a serious adverse reaction ( 2.3 %, 0.6 %, and 1.1 %) in the Rd Continuous , Rd18 , and MPT Arms , respectively . The frequency of serious adverse reactions of CVA was similar between the Rd Continuous , Rd18 , and MPT Arms ( 0.8 %, 0.6 %, and 0.6 %, respectively ) [ see Adverse Reactions ( 6.1 )]. Patients with known risk factors , including prior thrombosis , may be at greater risk and actions should be taken to try to minimize all modifiable factors ( e . g . hyperlipidemia , hypertension , smoking ).
In controlled clinical trials that did not use concomitant thromboprophylaxis , 21.5 % overall thrombotic events ( Standardized MedDRA Query Embolic and Thrombotic events ) occurred in patients with refractory and relapsed multiple myeloma who were treated with REVLIMID and dexamethasone compared to 8.3 % thrombosis in patients treated with placebo and dexamethasone . The median time to first thrombosis event was 2.8 months . In the NDMM study in which nearly all patients received antithrombotic prophylaxis , the overall frequency of thrombotic events was 17.4 % in patients in the combined Rd Continuous and Rd18 Arms , and was 11.6 % in the MPT Arm . The median time to first thrombosis event was 4.37 months in the combined Rd Continuous and Rd18 Arms . Thromboprophylaxis is recommended . The regimen of thromboprophylaxis should be based on an assessment of the patient ’ s underlying risks . Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events . ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving
REVLIMID [ see Drug Interactions ( 7.2 )].
5.5 Increased Mortality in Patients with CLL In a prospective randomized ( 1:1 ) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia , single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil . In an interim analysis , there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm , and hazard ratio for overall survival was 1.92 [ 95 % CI : 1.08 – 3.41 ], consistent with a 92 % increase in the risk of death . The trial was halted for safety in July 2013 .
Serious adverse cardiovascular reactions , including atrial fibrillation , myocardial infarction , and cardiac failure occurred more frequently in the REVLIMID treatment arm . REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials .