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warnings and cautions
5 WARNINGS AND PRECAUTIONS Thrombocytopenia : Monitor platelet counts at baseline, during treatment, and as clinically indicated. Dose delay or dose reduction may be required to allow recovery of platelets. ( 2.3 , 5.1 ) Neutropenia : Monitor neutrophil counts at baseline, during treatment and as clinically indicated. Monitor patients with neutropenia for signs of infection. Dose delay or dose reduction may be required to allow recovery of neutrophils. ( 2.3 , 5.2 ) Anemia : Monitor red blood cell counts at baseline, during treatment, and as clinically indicated. ( 5.3 ) Infections : Monitor for signs/symptoms of infection and treat promptly. ( 5.4 ) Increased Risk of Mortality with PEPAXTO at Dosages Higher than the Recommended Dosage : Dosages exceeding the recommended dose for PEPAXTO may be associated with mortality. ( 1 , 5.5 , 13.2 ) Secondary Malignancies : Monitor patients long-term for the development of secondary malignancies. ( 5.6 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 Thrombocytopenia Thrombocytopenia was reported in 99% of 157 patients who received PEPAXTO with dexamethasone. Grade 3 thrombocytopenia was reported in 26% and Grade 4 thrombocytopenia was reported in 54% of patients [see Adverse Reactions (6.1) ] . Thrombocytopenia may lead to hemorrhage. Any Grade hemorrhage was reported in 28% of 157 patients. Grade 3 hemorrhage was reported in 3.2% and Grade 4 hemorrhage was reported in <1% of patients [see Adverse Reactions (6.1) ] . Grade 3 or 4 thrombocytopenia occurred in 43% of patients during the first cycle, with a median time to onset of 15 days from the first dose. Monitor platelets at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment with PEPAXTO. Do not administer PEPAXTO if the platelet count is less than 50 × 10 9 /L. Withhold PEPAXTO until platelet count 50 × 10 9 /L or greater and resume at same or reduced dose based on duration of interruption. Adjust dose and/or dose schedule based on signs and symptoms of bleeding [see Dosage and Administration (2.3) ]. 5.2 Neutropenia Neutropenia was reported in 95% of 157 patients who received PEPAXTO with dexamethasone. Grade 3 neutropenia was reported in 41% and Grade 4 neutropenia was reported in 40% of patients. Febrile neutropenia was reported in 6% of patients [see Adverse Reactions (6.1) ] . Neutropenia may lead to infection. Grade 3 or 4 neutropenia occurred in 50% during the first cycle, with a median time to onset of 15 days from the first dose. Monitor neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment with PEPAXTO. Do not administer PEPAXTO if absolute neutrophil count less than 1 × 10 9 /L. Withhold PEPAXTO until absolute neutrophil count is 1 × 10 9 /L or greater and resume at same or reduced dose based on duration of interruption [see Dosage and Administration (2.3) ] . Consider leukocyte growth factor as clinically appropriate. 5.3 Anemia Anemia was reported in 84% of 157 patients who received PEPAXTO with dexamethasone. Grade 3 anemia was reported in 50% of 157 patients [see Adverse Reactions (6.1) ] . Monitor red blood cell counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment with PEPAXTO. Treat anemia as clinically indicated and as per standard guidelines. Dosage modification and dose delay of PEPAXTO may be required to allow for recovery of red blood cells. 5.4 Infections Fatal infections were reported in <1% of 157 patients who received PEPAXTO with dexamethasone. Any Grade infection was reported in 58% of 157 patients who received PEPAXTO and dexamethasone. Grade 3 infections were reported in 20% and Grade 4 infection was reported in 1.9% of patients. Respiratory tract infection occurred in 24% (Grade ≥3 in 5%), pneumonia in 13% (Grade ≥3 in 11%), and sepsis in 3.8% (Grade ≥3 in 3.2%) of patients [see Adverse Reactions (6.1) ] . Consider antimicrobials as clinically appropriate. 5.5 Increased Risk of Mortality with PEPAXTO at Dosages Higher than the Recommended Dosage A nonclinical safety study in dogs with melphalan flufenamide at dosages exceeding the recommended dose for relapsed or refractory multiple myeloma was associated with mortality [see Nonclinical Toxicology (13.2) ] . There is limited clinical experience of PEPAXTO at dosages higher than recommended. The safety and efficacy of PEPAXTO has not been established for use as a conditioning regimen in patients receiving transplant. 5.6 Secondary Malignancies Secondary malignancies such as myelodysplastic syndromes or acute leukemia have occurred in patients with multiple myeloma who have received PEPAXTO. Monitor patients long-term for the development of secondary malignancies. 5.7 Embryo-Fetal Toxicity Based on its mechanism of action, PEPAXTO can cause fetal harm when administered to a pregnant woman because it is genotoxic and targets actively dividing cells. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with PEPAXTO and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEPAXTO and for 3 months after the last dose [see Use In Specific Populations (8.1 , 8.3) ] .
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Thrombocytopenia [see Warnings and Precautions (5.1) ]. Neutropenia [see Warnings and Precautions (5.2) ]. Anemia [see Warnings and Precautions (5.3) ]. Infections [see Warnings and Precautions (5.4) ] . Most common adverse reactions (> 20%) are fatigue, nausea, diarrhea, pyrexia and respiratory tract infection. ( 6.1 ) Most common laboratory abnormalities (≥50%) are leukocytes decrease, platelets decrease, lymphocytes decrease, neutrophils decrease, hemoglobin decrease and creatinine increase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Oncopeptides Inc at 1-866-522-8894 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed Refractory Multiple Myeloma (RRMM) The safety of PEPAXTO was evaluated in HORIZON [see Clinical Studies (14) ] . Patients received PEPAXTO 40 mg intravenously on Day 1 of each 28-day cycle, in combination with dexamethasone 40 mg orally (or 20 mg for patients 75 years and older) on Days 1, 8, 15 and 22 of each cycle (N=157). Patients were enrolled if they had absolute neutrophil count of 1 × 10 9 /L or higher and platelet count of 75 × 10 9 /L or greater. Among patients who received PEPAXTO, 29% were exposed for 6 months or longer and 6% were exposed for greater than one year. Serious adverse reactions occurred in 49% of patients who received PEPAXTO. Serious adverse reactions in >3% of patients included pneumonia (10%), respiratory tract infection (6%), thrombocytopenia (5%), febrile neutropenia (5%) and sepsis (3.2%). Fatal adverse reactions occurred in 10 patients (6%) who received PEPAXTO, where general physical health deterioration (1.9%) and respiratory failure (1.3%) represented more than 1%. Permanent discontinuation of PEPAXTO due to an adverse reaction occurred in 22% of patients. Adverse reactions which resulted in permanent discontinuation of PEPAXTO in >3% of patients included thrombocytopenia (11%). Dosage interruptions of PEPAXTO due to an adverse reaction occurred in 62% of patients. The adverse reactions which resulted in dosage interruption of PEPAXTO in >3% of patients included thrombocytopenia (43%), neutropenia (29%), anemia (10%), respiratory tract infection (7%), leukopenia (6%) and pyrexia (4.5%). Dose reductions of PEPAXTO due to an adverse reaction occurred in 27% of patients. Adverse reactions which resulted in dose reductions of PEPAXTO in >3% patients included thrombocytopenia (22%) and neutropenia (6%). The most common adverse reactions (≥20%) were fatigue, nausea, diarrhea, pyrexia and respiratory tract infection. The most common laboratory abnormalities (≥50%) were leukocytes decreased, platelets decreased, lymphocytes decreased, neutrophils decreased, hemoglobin decreased and creatinine increased. Table 3 summarizes the adverse reactions in HORIZON. Table 3: Adverse reactions (≥10%) in Patients with RRMM Who Received PEPAXTO with Dexamethasone in HORIZON Adverse Reaction PEPAXTO with Dexamethasone (N=157) All Grades (%) Grade 3 or 4 (%) General disorders and administration site disorders Fatigue Fatigue incudes fatigue and asthenia 55 6 Pyrexia No Grade 4 adverse reactions occurred 24 1.9 Edema peripheral 14 1.3 Gastrointestinal disorders Nausea 32 0.6 Diarrhea 27 0 Constipation 15 0.6 Vomiting 13 0 Infections Respiratory tract infection , Respiratory tract infection includes upper respiratory tract infection, lower respiratory tract infection, respiratory tract infection and respiratory tract infection viral 24 5 Pneumonia Pneumonia includes pneumonia, pneumocystis jirovecii pneumonia and pneumonia viral 13 11 Respiratory, thoracic and mediastinal disorders Cough 17 0 Dyspnea 11 1.3 Dyspnea exertional 10 0 Metabolism and nutrition disorders Decreased appetite 14 0.6 Hypokalemia 14 1.3 Hypocalcemia 10 0.6 Nervous system disorders Headache 13 0 Dizziness 11 0 Musculoskeletal and connective tissue disorders Bone pain 13 1.9 Pain in extremity 13 1.9 Back pain 12 0.6 Arthralgia 10 0 Psychiatric disorders Insomnia 11 0.6 Clinically relevant adverse reactions in <10% of patients who received PEPAXTO in combination with dexamethasone (N=157) included: Allergic conditions: hypersensitivity reaction (7%) Blood and lymphatic system disorders: febrile neutropenia (6%) Infections : sepsis (3.8%) Hemorrhages: Grade 3 or 4 hemorrhages (3.8%) Table 4 summarizes the laboratory abnormalities in HORIZON. Table 4: Laboratory Abnormalities (≥50%) That Worsened from Baseline in Patients in HORIZON Laboratory Abnormality PEPAXTO with Dexamethasone Denominators for percentages are the number of patients with assessments at baseline and post-baseline (N=157 for all abnormalities) All Grades Patients with any worsening grade (%) Grade 3- 4 Patients with worsening to Grade 3 or 4, respectively (%) Leukocytes decrease 99 88 Platelets decrease 99 80 Lymphocytes decrease 97 95 Neutrophils decrease 95 82 Hemoglobin decrease 84 50 Creatinine increase 68 1 No Grade 4 laboratory abnormality occurred