ADVERSE REACTIONS SECTION.

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)].. 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 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 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 x 109/L or higher and platelet count of 75 109/L or greater. Among patients who received PEPAXTO, 29% were exposed for 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 summarizes the adverse reactions in HORIZON.Table 3: Adverse reactions (>=10%) in Patients with RRMM Who Received PEPAXTO with Dexamethasone in HORIZONAdverse ReactionPEPAXTO with Dexamethasone(N=157)All Grades(%)Grade or 4(%)General disorders and administration site disordersFatigueFatigue incudes fatigue and asthenia 556PyrexiaNo Grade adverse reactions occurred 241.9Edema peripheral 141.3Gastrointestinal disordersNausea 320.6Diarrhea270Constipation 150.6Vomiting130InfectionsRespiratory tract infection Respiratory tract infection includes upper respiratory tract infection, lower respiratory tract infection, respiratory tract infection and respiratory tract infection viral 245PneumoniaPneumonia includes pneumonia, pneumocystis jirovecii pneumonia and pneumonia viral 1311Respiratory, thoracic and mediastinal disordersCough 170Dyspnea 111.3Dyspnea exertional100Metabolism and nutrition disordersDecreased appetite 140.6Hypokalemia 141.3Hypocalcemia 100.6Nervous system disordersHeadache130Dizziness110Musculoskeletal and connective tissue disordersBone pain 131.9Pain in extremity 131.9Back pain 120.6Arthralgia100Psychiatric disordersInsomnia 110.6Clinically 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 or hemorrhages (3.8%) Table summarizes the laboratory abnormalities in HORIZON.Table 4: Laboratory Abnormalities (>=50%) That Worsened from Baseline in Patients in HORIZONLaboratory AbnormalityPEPAXTO with DexamethasoneDenominators for percentages are the number of patients with assessments at baseline and post-baseline (N=157 for all abnormalities) All GradesPatients with any worsening grade (%)Grade 3- 4Patients with worsening to Grade or 4, respectively (%)Leukocytes decrease9988Platelets decrease9980Lymphocytes decrease9795Neutrophils decrease9582Hemoglobin decrease8450Creatinine increase681No Grade laboratory abnormality occurred.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Melphalan flufenamide is peptide conjugated alkylating drug. Due to its lipophilicity, melphalan flufenamide is passively distributed into cells and thereafter enzymatically hydrolyzed to melphalan. Similar to other nitrogen mustard drugs, cross-linking of DNA is involved in the antitumor activity of melphalan flufenamide. In cellular assays, melphalan flufenamide inhibited proliferation and induced apoptosis of hematopoietic and solid tumor cells. Additionally, melphalan flufenamide showed synergistic cytotoxicity with dexamethasone in melphalan resistant and non-resistant multiple myeloma cell lines.. 12.2 Pharmacodynamics. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of PEPAXTO have not been fully characterized.. Cardiac ElectrophysiologyThe effect of PEPAXTO on QT interval has not been fully characterized.. 12.3 Pharmacokinetics. Melphalan flufenamide peak plasma concentrations were reached during the 30-minute infusion. Peak plasma concentrations of the active metabolite melphalan were reached to 15 minutes after the end of infusion of PEPAXTO 40 mg. Following PEPAXTO 40 mg, the mean (CV%) Cmax was 432 ng/mL (30%) and AUC0-INF was 3,143 ug/mLhr (28%) for melphalan after single dose. The mean (CV%) Cmax was 419 ng/mL (33%) and AUC0-INF was 2,933 ug/mLhr (29%) for melphalan at steady-state.. DistributionIn vivo the disappearance of melphalan flufenamide from plasma is rapid and is attributed to distribution to peripheral tissues with no late redistribution back to plasma.The mean (CV%) volume of distribution was 35 (71%) for melphalan flufenamide and 76 (32%) for melphalan after single dose.. EliminationAfter the end of infusion of PEPAXTO 40 mg, the mean (CV%) elimination half-life of melphalan flufenamide is 2.1 minutes (34%). The mean (CV%) elimination half-life of melphalan is 70 minutes (21%). The mean (CV%) clearance of melphalan flufenamide and melphalan is 692 L/hr (49%) and 23 L/hr (23%), respectively, at the recommended dosage of PEPAXTO 40 mg.. MetabolismMelphalan flufenamide is metabolized in tissues to desethyl-melphalan flufenamide and melphalan. Melphalan is metabolized primarily by spontaneous hydrolysis to monohydroxy-melphalan and dihydroxy-melphalan.. Specific PopulationsHigher melphalan exposures were observed in patients with lower body surface area. No clinically meaningful differences in the PK of melphalan were observed based on age (35 to 85 years old), renal impairment (CLcr 45 to 89 mL/min) and mild hepatic impairment (total bilirubin <= ULN and AST ULN, or total bilirubin to 1.5 ULN and any AST).The effect of sex, race/ethnicity, moderate to severe hepatic impairment (total bilirubin >1.5 ULN and any AST), and renal impairment (CLcr 15 to 44 mL/min) on melphalan flufenamide and melphalan PK is unknown.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of PEPAXTO in combination with dexamethasone was evaluated in HORIZON [NCT02963493], multicenter, single-arm trial. Eligible patients were required to have relapsed or refractory multiple myeloma. Patients received PEPAXTO 40 mg intravenously on Day and dexamethasone 40 mg orally (20 mg for patients >=75 years of age) on Day 1, 8, 15 and 22 of each 28-day cycle until disease progression or unacceptable toxicity.A total of 157 patients accepting central venous catheter and with estimated creatinine clearance by Cockcroft-Gaut formula >=45 mL/min were enrolled. Patients with primary refractory disease (i.e. never responded with at least minimal response to any prior treatment) were excluded. Ninety seven patients had received four or more prior lines of therapies and were refractory to at least one proteasome inhibitor, at least one immunomodulatory agent and CD38-directed monoclonal antibody. The median age was 65 years (range: 35 to 86 years); 58% were male, 87% were White and 6% were Black or African American. Disease characteristics in these 97 patients are summarized in Table 5.The major efficacy outcome measure was overall response rate (ORR) and Duration of Response (DoR) assessed according to the International Myeloma Working Group (IMWG) Criteria by investigators. Efficacy results in the 97 patients are provided in Table 6. The median time to first response was 2.1 months (range: 1.0 to 6.1 months). Table 5: Disease Characteristics (HORIZON)ParameterPEPAXTO with Dexamethasone(N=97)Years from diagnosis to start of PEPAXTO, median (range)6.4 (2.1 to 24.6)Prior treatment regimens, median (range)6 (4 to 12)Documented refractory status, (%) Lenalidomide94 Pomalidomide92 Bortezomib74 Carfilzomib63 Daratumumab93Alkylator refractory, (%)75Previous stem cell transplant, (%)70International Staging System at Baseline, (%) I30 II32 III34 Missing/Unknown4High-risk cytogeneticsdel(17p), t(4;14),t(14;16), gain (1q) and t(14;20) at study entry, (%)33Extramedullary disease (EMD), (%)41Table 6: Efficacy Results (HORIZON)PEPAXTO with Dexamethasone(N=97)Overall response rate (ORR), (%)(95% CI)23 (23.7)(15.7, 33.4) Stringent complete response (sCR)0 Complete Response (CR)0 Very good partial response (VGPR), (%)9 (9.3) Partial response (PR), (%)14 (14.4)Median duration of response in months(95% CI)4.2(3.2, 7.6).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 x 109/L or higher and platelet count of 75 109/L or greater. Among patients who received PEPAXTO, 29% were exposed for 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 summarizes the adverse reactions in HORIZON.Table 3: Adverse reactions (>=10%) in Patients with RRMM Who Received PEPAXTO with Dexamethasone in HORIZONAdverse ReactionPEPAXTO with Dexamethasone(N=157)All Grades(%)Grade or 4(%)General disorders and administration site disordersFatigueFatigue incudes fatigue and asthenia 556PyrexiaNo Grade adverse reactions occurred 241.9Edema peripheral 141.3Gastrointestinal disordersNausea 320.6Diarrhea270Constipation 150.6Vomiting130InfectionsRespiratory tract infection Respiratory tract infection includes upper respiratory tract infection, lower respiratory tract infection, respiratory tract infection and respiratory tract infection viral 245PneumoniaPneumonia includes pneumonia, pneumocystis jirovecii pneumonia and pneumonia viral 1311Respiratory, thoracic and mediastinal disordersCough 170Dyspnea 111.3Dyspnea exertional100Metabolism and nutrition disordersDecreased appetite 140.6Hypokalemia 141.3Hypocalcemia 100.6Nervous system disordersHeadache130Dizziness110Musculoskeletal and connective tissue disordersBone pain 131.9Pain in extremity 131.9Back pain 120.6Arthralgia100Psychiatric disordersInsomnia 110.6Clinically 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 or hemorrhages (3.8%) Table summarizes the laboratory abnormalities in HORIZON.Table 4: Laboratory Abnormalities (>=50%) That Worsened from Baseline in Patients in HORIZONLaboratory AbnormalityPEPAXTO with DexamethasoneDenominators for percentages are the number of patients with assessments at baseline and post-baseline (N=157 for all abnormalities) All GradesPatients with any worsening grade (%)Grade 3- 4Patients with worsening to Grade or 4, respectively (%)Leukocytes decrease9988Platelets decrease9980Lymphocytes decrease9795Neutrophils decrease9582Hemoglobin decrease8450Creatinine increase681No Grade laboratory abnormality occurred.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dosage of PEPAXTO is 40 mg intravenously over 30 minutes on Day of each 28-day treatment cycle, in combination with dexamethasone. (2.1)See Full Prescribing Information for instructions on preparation and administration. (2.4). Recommended dosage of PEPAXTO is 40 mg intravenously over 30 minutes on Day of each 28-day treatment cycle, in combination with dexamethasone. (2.1). See Full Prescribing Information for instructions on preparation and administration. (2.4). 2.1 Recommended Dosage. The recommended dosage of PEPAXTO is 40 mg administered intravenously over 30 minutes on Day of each 28-day cycle until disease progression or until unacceptable toxicity. Administer dexamethasone 40 mg orally or intravenously on Days 1, 8, 15 and 22 of each cycle. For patients 75 years of age or older, reduce the dose of dexamethasone to 20 mg. Refer to the prescribing information for dexamethasone for additional dosing information [see Clinical Studies (14)].. 2.2 Recommended Premedication and Concomitant Medications. Consider providing serotonin-3 (5-HT3) receptor antagonist or other antiemetics prior to and during the treatment with PEPAXTO. 2.3 Dosage Modifications for Adverse Reactions. Withold PEPAXTO if the neutrophil count is less than x 109/L or the platelet count is less than 50 109/L.The recommended dose reductions and dosage modifications for adverse reactions for PEPAXTO are presented in Table and Table 2, respectively.Table 1: Recommended Dose Reductions for Adverse Reactions of PEPAXTODose ReductionDosageAdministered intravenously on Day of each 28-day cycle. For dosage modifications, see Table 2. First30 mgSecond20 mgSubsequentPermanently discontinue PEPAXTO in patients who are unable to tolerate 20 mg.Table 2: Recommended Dosage Modifications for Adverse Reactions of PEPAXTOAdverse ReactionSeverityDosage ModificationMyelosuppression [see Warnings and Precautions (5.1, 5.2)] Platelet count less than 50 109/L on an intended PEPAXTO dosing dayWithhold PEPAXTO and monitor platelet count weekly until platelet count is 50 109/L or greater.Resume PEPAXTO-at same dose if delay is weeks or less.-at dose level lower if delay is more than weeks. Absolute neutrophil count less than x 109/L on an intended PEPAXTO dosing dayWithhold PEPAXTO and monitor neutrophil count weekly until neutrophil count is x 109/L or greater.Resume PEPAXTO-at same dose if delay is weeks or less.-at dose level lower if delay is more than weeks. Grade hematological adverse reaction on an intended PEPAXTO dosing day in consecutive cyclesResume PEPAXTO at dose level lower.Non-Hematologic Adverse Reaction [see Adverse Reactions (6.1)] Grade 2Consider withholding PEPAXTO until resolved to at least Grade or baseline.Consider resuming PEPAXTO at dose level lower.Grade or 4Withhold PEPAXTO until resolved to at least Grade or baseline.Resume PEPAXTO at dose level lower as clinically appropriate.. Withhold PEPAXTO and monitor platelet count weekly until platelet count is 50 109/L or greater.. Resume PEPAXTO-at same dose if delay is weeks or less.-at dose level lower if delay is more than weeks. -at same dose if delay is weeks or less.. -at dose level lower if delay is more than weeks.. Withhold PEPAXTO and monitor neutrophil count weekly until neutrophil count is x 109/L or greater.. Resume PEPAXTO-at same dose if delay is weeks or less.-at dose level lower if delay is more than weeks. -at same dose if delay is weeks or less.. -at dose level lower if delay is more than weeks.. Resume PEPAXTO at dose level lower.. Consider withholding PEPAXTO until resolved to at least Grade or baseline.. Consider resuming PEPAXTO at dose level lower.. Withhold PEPAXTO until resolved to at least Grade or baseline.. Resume PEPAXTO at dose level lower as clinically appropriate.. 2.4 Preparation and Administration. PEPAXTO is hazardous drug. Follow applicable special handling and disposal procedures.1 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if visibly opaque particles, discoloration or foreign particles are observed.Reconstitute and dilute PEPAXTO prior to infusion.. Additional agents required for preparation:5% Dextrose Injection, USP (room temperature)250 mL bag of cold (2C to 8C 36F to 46F) 0.9% Sodium Chloride Injection, USP (refrigerate for at least hours). 5% Dextrose Injection, USP (room temperature). 250 mL bag of cold (2C to 8C 36F to 46F) 0.9% Sodium Chloride Injection, USP (refrigerate for at least hours). Preparation Steps:Read the complete instructions prior to starting preparation.Steps to must be completed within 30 minutes.Reconstitution and dilution stepsStep 1Determine the dose, the total volume of reconstituted PEPAXTO solution required, and the number of PEPAXTO vials needed. More than one vial may be needed for full dose. Place PEPAXTO vial(s) at room temperature for at least 30 minutes.Step 2Shake the vial(s) vigorously or vortex to disintegrate the lyophilized PEPAXTO powder cake into loose powder.Step to must be completed within 30 minutesStep 3Aseptically reconstitute each vial with 40 mL of 5% Dextrose Injection, USP to obtain final concentration of 0.5 mg/mL. Ensure the 5% Dextrose Injection, USP is room temperature (20C to 25C 68F to 77F). Shake the vial(s) vigorously until solution is clear.Let the vial(s) stand to allow air bubbles to dissipate to confirm clear solution.Step 4Withdraw 80 mL from refrigerated (2C to 8C 36F to 46F) 250 mL infusion bag of 0.9% Sodium Chloride Injection, USP. Discard the withdrawn 80 mL.Step 5Withdraw the required volume of reconstituted solution from the PEPAXTO vial(s) and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP to obtain final concentration of 0.1 mg/mL to 0.16 mg/mL. Discard any unused portion left in the vial(s).Gently invert the bag to mix the solution. Do not shake. Check that the PEPAXTO solution is clear and colorless to pale yellow. Do not use if solution discoloration or particles are observed.. Storage timelines:PEPAXTO degrades in solution, especially at room temperature, and the storage timelines for diluted solution should not be exceeded:For immediate administration:Infusion of the diluted PEPAXTO solution must begin within 60 minutes of start of reconstitution (step 3).For delayed administration:If not used for immediate administration, the diluted PEPAXTO solution should be placed in refrigerator (2C to 8C 36F to 46F) within 30 minutes after initial reconstitution (step 3) and store for up to hours. Administration:Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if visibly opaque particles, discoloration or foreign particles are observed.Administration stepsStep Administer PEPAXTO as 30-minute intravenous infusion via central venous access device, for example mediport, PICC or tunneled central venous catheter. If the infusion bag has been stored in refrigerator, allow to reach to room temperature (20C to 25C 68F to 77F). Start infusion within 30 minutes of removing the diluted PEPAXTO solution from the refrigerator.Step 7Administer PEPAXTO as an intravenous infusion via central catheter over 30 minutes.Step Upon completion of PEPAXTO infusion, flush the central catheter per individual institutional guidelines.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Thrombocytopenia, Neutropenia and AnemiaAdvise patients that PEPAXTO can cause myelosuppression. Advise patients to immediately report signs or symptoms of thrombocytopenia (bleeding and easy bruising), neutropenia (symptoms of infection, such as fever, chills, cough, pain, or burning during urination) and anemia (fatigue and shortness of breath) to their healthcare provider.Advise patients that complete blood counts will be monitored at baseline, during treatment, and as clinically indicated [see Warnings and Precautions (5.1, 5.2, 5.3)]. Advise patients that PEPAXTO can cause myelosuppression. Advise patients to immediately report signs or symptoms of thrombocytopenia (bleeding and easy bruising), neutropenia (symptoms of infection, such as fever, chills, cough, pain, or burning during urination) and anemia (fatigue and shortness of breath) to their healthcare provider.. Advise patients that complete blood counts will be monitored at baseline, during treatment, and as clinically indicated [see Warnings and Precautions (5.1, 5.2, 5.3)]. InfectionsAdvise patients that PEPAXTO can cause infections. Instruct patients to immediately report new or worsening signs or symptoms (e.g., chills, fever) of infection to their healthcare provider [see Warnings and Precautions (5.4)]. Secondary MalignanciesAdvise patients on the risk of second primary malignancies [see Warnings and Precautions (5.6)]. Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with PEPAXTO and months after the last dose [see Use in Specific Populations (8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEPAXTO and for months after the last dose [see Use in Specific Populations (8.3)]. Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with PEPAXTO and months after the last dose [see Use in Specific Populations (8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEPAXTO and for months after the last dose [see Use in Specific Populations (8.3)]. LactationAdvise women not to breastfeed during treatment with PEPAXTO and for week after the last dose [see Use in Specific Populations (8.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Melphalan flufenamide peak plasma concentrations were reached during the 30-minute infusion. Peak plasma concentrations of the active metabolite melphalan were reached to 15 minutes after the end of infusion of PEPAXTO 40 mg. Following PEPAXTO 40 mg, the mean (CV%) Cmax was 432 ng/mL (30%) and AUC0-INF was 3,143 ug/mLhr (28%) for melphalan after single dose. The mean (CV%) Cmax was 419 ng/mL (33%) and AUC0-INF was 2,933 ug/mLhr (29%) for melphalan at steady-state.. DistributionIn vivo the disappearance of melphalan flufenamide from plasma is rapid and is attributed to distribution to peripheral tissues with no late redistribution back to plasma.The mean (CV%) volume of distribution was 35 (71%) for melphalan flufenamide and 76 (32%) for melphalan after single dose.. EliminationAfter the end of infusion of PEPAXTO 40 mg, the mean (CV%) elimination half-life of melphalan flufenamide is 2.1 minutes (34%). The mean (CV%) elimination half-life of melphalan is 70 minutes (21%). The mean (CV%) clearance of melphalan flufenamide and melphalan is 692 L/hr (49%) and 23 L/hr (23%), respectively, at the recommended dosage of PEPAXTO 40 mg.. MetabolismMelphalan flufenamide is metabolized in tissues to desethyl-melphalan flufenamide and melphalan. Melphalan is metabolized primarily by spontaneous hydrolysis to monohydroxy-melphalan and dihydroxy-melphalan.. Specific PopulationsHigher melphalan exposures were observed in patients with lower body surface area. No clinically meaningful differences in the PK of melphalan were observed based on age (35 to 85 years old), renal impairment (CLcr 45 to 89 mL/min) and mild hepatic impairment (total bilirubin <= ULN and AST ULN, or total bilirubin to 1.5 ULN and any AST).The effect of sex, race/ethnicity, moderate to severe hepatic impairment (total bilirubin >1.5 ULN and any AST), and renal impairment (CLcr 15 to 44 mL/min) on melphalan flufenamide and melphalan PK is unknown.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 02/2021 PATIENT INFORMATIONPEPAXTO (peh-PAX-toe)(melphalan flufenamide)for injection, for intravenous useWhat is PEPAXTOPEPAXTO is prescription medicine used in combination with the medicine dexamethasone to treat adults with multiple myeloma who did not respond to or stopped responding to at least four prior medicines including at least one proteasome inhibitor, one immunomodulatory agent and one CD38-directed antibody.PEPAXTO is not for use to prepare for transplant.It is not known if PEPAXTO is safe and effective in children.Do not receive PEPAXTO if you have history of severe allergic reaction to melphalan flufenamide or melphalan.Before receiving PEPAXTO, tell your healthcare provider about all of your medical conditions, including if you:have an infectionare pregnant or plan to become pregnant. PEPAXTO may harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with PEPAXTO.You should use an effective method of birth control (contraception) during treatment and for months after the last dose of PEPAXTO.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with PEPAXTO. Males with female partners who are able to become pregnant: You should use an effective method of birth control (contraception) during treatment and for months after the last dose of PEPAXTO.Talk to your healthcare provider about effective methods of birth control that you can use during this time. are breastfeeding or plan to breastfeed. It is not known if PEPAXTO passes into breast milk. Do not breastfeed during treatment with and for week after the last dose of PEPAXTO.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will receive PEPAXTOPEPAXTO is given to you by your healthcare provider into your vein through intravenous (IV) infusion over 30 minutes.PEPAXTO is usually given time every 28 days.Your healthcare provider will decide how many treatments you need.Your healthcare provider will do blood tests before and during your treatment with PEPAXTO to check for side effects.Your healthcare provider may prescribe medicines to help prevent nausea before your infusion and during treatment with PEPAXTO.What are the possible side effects of PEPAXTOPEPAXTO may cause serious side effects, including:Low blood cell counts are common with PEPAXTO and can be serious. Your healthcare provider will do blood tests as needed to check your blood cell counts during your treatment with PEPAXTO.Low platelet counts: Tell your healthcare provider right away if you have bleeding or bruising under the skin.Low red blood cell counts: Tell your healthcare provider if you are feeling weak, tired or you get tired easily, you look pale, or if you feel short of breath.Low white blood cell counts: low white blood cell count increases the risk of infections. Infections. PEPAXTO can cause infections that have led to death. Tell your healthcare provider right away if you develop new or worsening signs or symptoms of infection such as fever, chills, cough, pain, or burning during urination during treatment with PEPAXTO. Secondary cancers. New cancers such as myelodysplastic syndromes or acute leukemia have happened in people with multiple myeloma who have received PEPAXTO. Your healthcare provider will monitor you for new cancers.Your healthcare provider may change your dose of PEPAXTO, stop your treatment for period of time, or completely stop your treatment if you have certain side effects. PEPAXTO may cause fertility problems in males and females, which may affect your ability to have children. Talk with your healthcare provider if you have concerns about fertility. The most common side effects of PEPAXTO include, low blood cell counts, fatigue, nausea, diarrhea, fever, and cold-like symptoms (respiratory tract infection).These are not all of the possible side effects of PEPAXTO. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. General information about the safe and effective use of PEPAXTO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about PEPAXTO that is written for health professionals.What are the ingredients in PEPAXTOActive ingredient: melphalan flufenamideInactive ingredient: sucroseManufactured for Oncopeptides AB (publ), Stockholm, Sweden.Marketed and distributed by Oncopeptides Inc., 200 Fifth Avenue, Suite 1030 Waltham, MA 02451, USA.PEPAXTO is registered trademark of Oncopeptides AB (publ).For more information, go to www.PEPAXTO.com or call 1-866-522-8894.. have an infection. are pregnant or plan to become pregnant. PEPAXTO may harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with PEPAXTO.You should use an effective method of birth control (contraception) during treatment and for months after the last dose of PEPAXTO.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with PEPAXTO. Males with female partners who are able to become pregnant: You should use an effective method of birth control (contraception) during treatment and for months after the last dose of PEPAXTO.Talk to your healthcare provider about effective methods of birth control that you can use during this time. Your healthcare provider will check to see if you are pregnant before you start treatment with PEPAXTO.. You should use an effective method of birth control (contraception) during treatment and for months after the last dose of PEPAXTO.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with PEPAXTO.. You should use an effective method of birth control (contraception) during treatment and for months after the last dose of PEPAXTO.. Talk to your healthcare provider about effective methods of birth control that you can use during this time.. are breastfeeding or plan to breastfeed. It is not known if PEPAXTO passes into breast milk. Do not breastfeed during treatment with and for week after the last dose of PEPAXTO.. PEPAXTO is given to you by your healthcare provider into your vein through intravenous (IV) infusion over 30 minutes.. PEPAXTO is usually given time every 28 days.. Your healthcare provider will decide how many treatments you need.. Your healthcare provider will do blood tests before and during your treatment with PEPAXTO to check for side effects.. Your healthcare provider may prescribe medicines to help prevent nausea before your infusion and during treatment with PEPAXTO.. Low blood cell counts are common with PEPAXTO and can be serious. Your healthcare provider will do blood tests as needed to check your blood cell counts during your treatment with PEPAXTO.Low platelet counts: Tell your healthcare provider right away if you have bleeding or bruising under the skin.Low red blood cell counts: Tell your healthcare provider if you are feeling weak, tired or you get tired easily, you look pale, or if you feel short of breath.Low white blood cell counts: low white blood cell count increases the risk of infections. Low platelet counts: Tell your healthcare provider right away if you have bleeding or bruising under the skin.. Low red blood cell counts: Tell your healthcare provider if you are feeling weak, tired or you get tired easily, you look pale, or if you feel short of breath.. Low white blood cell counts: low white blood cell count increases the risk of infections.. Infections. PEPAXTO can cause infections that have led to death. Tell your healthcare provider right away if you develop new or worsening signs or symptoms of infection such as fever, chills, cough, pain, or burning during urination during treatment with PEPAXTO. Secondary cancers. New cancers such as myelodysplastic syndromes or acute leukemia have happened in people with multiple myeloma who have received PEPAXTO. Your healthcare provider will monitor you for new cancers.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)] PEPAXTO can cause fetal harm when administered to pregnant woman. There are no available data on PEPAXTO use in pregnant women to evaluate for drug-associated risk. PEPAXTO is genotoxic drug [see Nonclinical Toxicology (13.1)]. Advise pregnant women of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataAnimal reproductive or developmental toxicity studies were not conducted with PEPAXTO. Melphalan flufenamide is genotoxic and was toxic to actively dividing cells in animal studies and thus it has the potential to cause teratogenicity and embryo-fetal lethality.. 8.2 Lactation. Risk SummaryThere is no data on the presence of melphalan flufenamide or its metabolites in human breast milk, or the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with PEPAXTO and for week after the last dose.. 8.3 Females and Males of Reproductive Potential. PEPAXTO can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1) ].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating PEPAXTO. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with PEPAXTO and for months after the last dose.. MalesBased on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with PEPAXTO and for months after the last dose [see Nonclinical Toxicology (13.1) ].. Infertility. FemalesPEPAXTO can cause amenorrhea in premenopausal women and result in infertility.. MalesBased on findings of melphalan flufenamide in animals, PEPAXTO may impair male fertility [see Nonclinical Toxicology (13.1) ]. Alkylating drugs, such as PEPAXTO, can also cause irreversible testicular suppression in patients.. 8.4 Pediatric Use. The safety and effectiveness of PEPAXTO have not been established in pediatric patients.. 8.5 Geriatric Use. Of the 157 patients with RRMM who received PEPAXTO, 50% were 65 years and older, while 16% were 75 years and older. No overall differences in safety were observed between these patients and younger patients. Clinical studies of PEPAXTO in patients with RRMM did not include sufficient numbers of patients 65 years of age and older to determine if they respond differently from younger adult patients.. 8.6 Renal Impairment. No dose adjustment of PEPAXTO is recommended in patients with creatinine clearance (CLcr) 45 to 89 mL/min calculated using Cockcroft-Gault equation [see Clinical Pharmacology (12.3)]. PEPAXTO has not been studied in patients with CLcr 15 to 44 mL/min.

WARNINGS AND PRECAUTIONS SECTION.

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 fetus and to use effective contraception. (5.7, 8.1, 8.3). 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 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 thrombocytopenia was reported in 26% and Grade 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 hemorrhage was reported in 3.2% and Grade hemorrhage was reported in <1% of patients [see Adverse Reactions (6.1)].Grade or thrombocytopenia occurred in 43% of patients during the first cycle, with 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 50 109/L. Withhold PEPAXTO until platelet count 50 109/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 neutropenia was reported in 41% and Grade 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 or neutropenia occurred in 50% during the first cycle, with 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 x 109/L. Withhold PEPAXTO until absolute neutrophil count is x 109/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 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 infections were reported in 20% and Grade 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. 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 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 pregnant woman because it is genotoxic and targets actively dividing cells. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with PEPAXTO and for months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEPAXTO and for months after the last dose [see Use In Specific Populations (8.1, 8.3)].