BRIEF SUMMARY

MELPHALAN FLUFENAMIDE -(Feb 2021)

Indn-   For the  treatment of certain patients with relapsed or refractory multiple myeloma    

Comp- For injection: 20 mg melphalan flufenamide as a lyophilized powder in single-dose vial for reconstitution and dilution.    Recommended dosage is 40 mg intravenously over 30 minutes on Day 1 of each 28-day treatment cycle, in combination with dexamethasone.

ADR-   Most common adverse reactions are fatigue, nausea, diarrhea, pyrexia and respiratory tract infection.

CI- History of serious hypersensitivity reaction to melphalan flufenamide or melphalan. 

WARNINGS-

 Thrombocytopenia: Monitor platelets counts at baseline, during treatment, and as clinically indicated. Dose delay or dose reduction may be required to allow recovery of platelets.

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.

Pat Inform-

Advise patients that the drug 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

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 10

Name of the Drug-    PEPAXTO

Active Ingredient -    Melphalan  Flufenamide

Pharmacological Classification-    For the  treatment of certain patients with                                                                       relapsed or refractory multiple myeloma                                                                                                                                                          Date of Approval-          2/26/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                               PEPAXTO safely and effectively.                                                                                   See full prescribing information for PEPAXTO. PEPAXTO® (melphalan flufenamide) for injection, for intravenous use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE

 PEPAXTO is an alkylating drug indicated in combination with dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.

 This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

 Limitations of Use: PEPAXTO is not indicated and is not recommended for use as a conditioning regimen for transplant outside of controlled clinical trials.

ADVERSE REACTIONS

 Most common adverse reactions (> 20%) are fatigue, nausea, diarrhea, pyrexia and respiratory tract infection.

 Most common laboratory abnormalities (=50%) are leukocytes decrease, platelets decrease, lymphocytes decrease, neutrophils decrease, hemoglobin decrease and creatinine increase.

CONTRAINDICATIONS

 History of serious hypersensitivity reaction to melphalan flufenamide or melphalan. 

WARNINGS AND PRECAUTIONS

 Thrombocytopenia: Monitor platelets counts at baseline, during treatment, and as clinically indicated. Dose delay or dose reduction may be required to allow recovery of platelets.

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.

Anemia: Monitor red blood cell counts at baseline, during treatment, and as clinically indicated.

Infections: Monitor for signs/symptoms of infection and treat promptly.

 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.

Secondary Malignancies: Monitor patients long-term for the development of secondary malignancies.

Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception

DOSAGE AND ADMINISTRATION

 Recommended dosage of PEPAXTO is 40 mg intravenously over 30 minutes on Day 1 of each 28-day treatment cycle, in combination with dexamethasone.

 See Full Prescribing Information for instructions on preparation and administration. 

DOSAGE FORMS AND STRENGTHS-                                                                             - For injection: 20 mg melphalan flufenamide as a lyophilized powder in single-dose vial for reconstitution and dilution.

 PATIENT COUNSELING INFORMATION -

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Thrombocytopenia, Neutropenia and Anemia -                                                          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

Infections -                                                                                                                  Advise 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 

Secondary Malignancies-                                                                                        Advise patients on the risk of second primary malignancies

Embryo-Fetal Toxicity -                                                                                              Advise pregnant women and females of reproductive potential of the potential risk to a fetus.                                                                                                                         

 Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy .

 Advise females of reproductive potential to use effective contraception during treatment with PEPAXTO and 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

Lactation -                                                                                                                        Advise women not to breastfeed during treatment with PEPAXTO and for 1 week after the last dose 

Manufactured for: Oncopeptides AB (publ), Stockholm, Sweden.

Distributed by: Oncopeptides Inc. 200 Fifth Avenue, Suite #1030 Waltham, MA 02451, USA PEPAXTO is a registered trademark of Oncopeptides AB (publ)

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                             Melphalan flufenamide is a 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, crosslinking 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.

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 Electrophysiology- The effect of PEPAXTO on QT interval has not been fully characterized.

3. Pharmacokinetics-                                                                                             Melphalan flufenamide peak plasma concentrations were reached during the 30-minute infusion.

Peak plasma concentrations of the active metabolite melphalan were reached 4 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 µg/mL?hr (28%) for melphalan after a single dose.

The mean (CV%) Cmax was 419 ng/mL (33%) and AUC0-INF was 2,933 µg/mL?hr (29%) for melphalan at steady-state.

Distribution-                                                                                                                     In 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 L (71%) for melphalan flufenamide and 76 L (32%) for melphalan after a single dose.

Elimination-                                                                                                                      After 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.

Metabolism-                                                                                                          Melphalan 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 Populations -                                                                                                  Higher 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 1 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.

 USE IN SPECIFIC POPULATIONS

1 Pregnancy-                                                                                                                  Risk Summary- Based on its mechanism of action [see Clinical Pharmacology (12.1)], PEPAXTO can cause fetal harm when administered to a pregnant woman.

There are no available data on PEPAXTO use in pregnant women to evaluate for a drugassociated risk. PEPAXTO is a genotoxic drug 

. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

2. Lactation-Summary -                                                                                                     There 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 1 week after the last dose.

3. Females and Males of Reproductive Potential -                                                         PEPAXTO can cause fetal harm when administered to a pregnant woman

Pregnancy Testing -Verify pregnancy status in females of reproductive potential prior to initiating PEPAXTO.

Contraception-                                                                                                                 Females- Advise females of reproductive potential to use effective contraception during treatment with PEPAXTO and for 6 months after the last dose.

Males -Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with PEPAXTO and for 3 months after the last dose 

Infertility- Females -PEPAXTO can cause amenorrhea in premenopausal women and result in infertility.

Males- Based 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.

4. Pediatric Use-                                                                                                            The safety and effectiveness of PEPAXTO have not been established in pediatric patients.

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. 

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..

PEPAXTO has not been studied in patients with CLcr 15 to 44 mL/min.