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. (1)

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). (1)

LimitationsofUse: PEPAXTO is not indicated and is not recommended for use as a conditioning regimen for transplant outside of controlled clinical trials. (1, 5.5)

------------------------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. (2.1)

·        See Full Prescribing Information for instructions on preparation and administration. (2.4)

---------------------DOSAGE FORMS AND STRENGTHS----------------------

For injection: 20 mg melphalan flufenamide as a lyophilized powder in single-dose vial for reconstitution and dilution. (3)

-------------------------------CONTRAINDICATIONS-------------------------------

History of serious hypersensitivity reaction to melphalan flufenamide or melphalan. (4)

------------------------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. (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)

·        SecondaryMalignancies: Monitor patients long-term for the development of secondary malignancies. (5.6)

·        Embryo-FetalToxicity: 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)

-------------------------------ADVERSE     REACTIONS------------------------------

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.

--------------------------USE IN SPECIFIC POPULATIONS---------------------

Lactation: Advise not to breastfeed. (8.2)

See 17 for PATIENT COUNSELING INFORMATION and

FDA-approved patient labeling.

Revised: 2/2021

FULL PRESCRIBING INFORMATION: CONTENTS*

1    INDICATIONS AND USAGE

2    DOSAGE AND ADMINISTRATION

2.1    Recommended Dosage

2.2    Recommended Premedication and Concomitant Medication

2.3    Dosage Modification for Adverse Reactions

2.4    Preparation and Administration

3    DOSAGE FORMS AND STRENGTHS

4    CONTRAINDICATIONS

5    WARNINGS AND PRECAUTIONS

5.1    Thrombocytopenia

5.2    Neutropenia

5.3    Anemia

5.4    Infections

5.5    Increased Risk of Mortality with PEPAXTO at Dosages Higher than the Recommended Dosage

5.6    Secondary Malignancies

5.7    Embryo-Fetal Toxicity

6    ADVERSE REACTIONS

6.1    Clinical Trials Experience

8    USE IN SPECIFIC POPULATIONS

8.1    Pregnancy

8.2    Lactation

8.3    Females and Males of Reproductive Potential

8.4    Pediatric Use

8.5    Geriatric Use

8.6    Renal Impairment

11     DESCRIPTION

12     CLINICAL PHARMACOLOGY

12.1     Mechanism of Action

12.2     Pharmacodynamics

12.3     Pharmacokinetics

13     NONCLINICAL TOXICOLOGY

13.1     Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2   Animal Toxicology and/or Pharmacology

14     CLINICAL STUDIES

15     REFERENCES

16     HOW SUPPLIED/STORAGE AND HANDLING

17     PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

1   INDICATIONS AND USAGE

PEPAXTO is 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) [see Clinical Studies (14)].

LimitationsofUse

PEPAXTO is not indicated and is not recommended for use as a conditioning regimen for transplant outside of controlled clinical trials[see Warnings and Precautions (5.5)].

2.1   Recommended Dosage

The recommended dosage of PEPAXTO is 40 mg administered intravenously over 30 minutes on Day 1 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)].

Consider providing a serotonin-3 (5-HT3) receptor antagonist or other antiemetics prior to and during the treatment with PEPAXTO.

Withold PEPAXTO if the neutrophil count is less than 1 x 109/L or the platelet count is less than 50 x 109/L.

The recommended dose reductions and dosage modifications for adverse reactions for PEPAXTO are presented in Table 1 and Table 2, respectively.

* Administered intravenously on Day 1 of each 28-day cycle. For dosage modifications, see Table 2.

PEPAXTO is a 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.

·              5% Dextrose Injection, USP (room temperature)

·              250 mL bag of cold (2°C to 8°C / 36°F to 46°F) 0.9% Sodium Chloride Injection, USP (refrigerate for at least 4 hours)

Read the complete instructions prior to starting preparation. Steps 3 to 5 must be completed within 30 minutes.

PEPAXTO degrades in solution, especially at room temperature, and the storage timelines for diluted solution should not be exceeded:

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.

For Injection: 20 mg melphalan flufenamide as a sterile lyophilized white to off-white powder in a single-dose vial for reconstitution and further dilution.

PEPAXTO is contraindicated in patients with a history of serious hypersensitivity reaction to melphalan flufenamide or melphalan [see Adverse Reactions (6.1)].

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 x 109/L. Withhold PEPAXTO until platelet count 50 x 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)].

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 x 109/L. Withhold PEPAXTO until absolute neutrophil count is less 1 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.

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.

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.

A nonclinical safety study in dogs with melphalan flufenamide at dosages exceeding the recommended dose for relapsed and 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.

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.

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)].

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)].

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.

RelapsedRefractoryMultipleMyeloma(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 x 109/L or higher and platelet count of 75 x 109/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.

1 Fatigue incudes fatigue and asthenia

2 No Grade 4 adverse reactions occurred

3 Respiratory tract infection includes upper respiratory tract infection, lower respiratory tract infection, respiratory tract infection and respiratory tract infection viral

4 Pneumonia includes pneumonia, pneumocystis jirovecii pneumonia and pneumonia viral

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.

1 Denominators for percentages are the number of patients with assessments at baseline and post-baseline (N=157 for all abnormalities)

2 Patients with any worsening grade

3  Patients with worsening to Grade 3 or 4, respectively

4 No Grade 4 laboratory abnormality occurred

8.1   Pregnancy

RiskSummary

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 drug-  associated risk. PEPAXTO is a genotoxic drug[see Nonclinical Toxicology (13.1)]. 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.

Data

Animal Data

Animal 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.

RiskSummary

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.

PEPAXTO can cause fetal harm when administered to a pregnant woman[see Use in Specific Populations (8.1)].

PregnancyTesting

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 [see Nonclinical Toxicology (13.1)].

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.

The safety and effectiveness of PEPAXTO have not been established in pediatric patients.

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.

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.

Melphalan flufenamide is an alkylating drug. The chemical name is Ethyl (2S)-2-[[(2S)-2-amino-3-[4-[bis(2- chloroethyl)amino]phenyl]propanoyl]amino]-3-(4-fluorophenyl)propanoate hydrochloride and the molecular weight is 498.4 as free base and 534.9 as the hydrochloride salt. The structural formula is:

Cl

N

Cl

O H

N

H2N                             O

HCl       O

F

Melphalan flufenamide hydrochloride is soluble in most organic solvents, while sparsely soluble in aqueous solutions. The pKa value is 7.13.

PEPAXTO for injection is supplied as a sterile, white to off-white lyophilized powder in a single-dose vial for intravenous use. Each vial contains 20 mg melphalan flufenamide (equivalent to 21.48 mg melphalan flufenamide hydrochloride) and 1,000 mg sucrose.

12.1    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, 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.

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of PEPAXTO have not been fully characterized.

CardiacElectrophysiology

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

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/mLꞏhr (28%) for melphalan after a single dose. The mean (CV%) Cmax was 419 ng/mL (33%) and AUC0-INF was 2,933 µg/mLꞏhr (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.

SpecificPopulations

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.

13.1   Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted with melphalan flufenamide.

PEPAXTO is genotoxic. In studies conducted in vitro, melphalan flufenamide caused irreversible DNA damage.

Repeat-dose toxicity studies with melphalan flufenamide in animals showed adverse effects on male reproductive organs. Melphalan flufenamide was administered intravenously to rats at 20, 40, or 55 mg/m2, and to dogs at 0.45 or 0.90 mg/kg (9 or 18 mg/m2) every 21 days for two or three doses. Decreased testes weights and depletion of germ cells were observed in both species, and epididymal oligospermia was observed in dogs. Adverse effects on male reproductive organs were observed in dogs at dose levels less than the recommended clinical dose of 40 mg. The reversibility of adverse effects on male reproductive organs was not assessed.

Dogs were intravenously administered a single dose of melphalan flufenamide (17.5 mg/kg) or an equimolar dose of melphalan; these dose levels were representative of dosages needed for myeloablation. Increased mortality was observed in dogs administered melphalan flufenamide despite similar melphalan exposure in animals administered melphalan flufenamide or melphalan.

The efficacy of PEPAXTO in combination with dexamethasone was evaluated in HORIZON [NCT02963493], a multicenter, single-arm trial. Eligible patients were required to have relapsed or refractory multiple myeloma. Patients received PEPAXTO 40 mg intravenously on Day 1 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 a 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 a 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).

1 del(17p), t(4;14),t(14;16), gain (1q) and t(14;20) at study entry

15   REFERENCES

1.   “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

HowSupplied

PEPAXTO is a white to off-white lyophilized powder for reconstitution (after reconstitution the solution is clear and colorless to light yellow) supplied in a 50 mL single dose vial containing 20 mg melphalan flufenamide. Each 20 mg vial is packaged in a single carton (NDC 73657-020-01).

The vial stopper is not manufactured with natural rubber latex. Storage

Store refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light. Retain in original carton until use.

HandlingandDisposal

PEPAXTO is a hazardous drug. Follow special handling and disposal procedures.1 All materials that have been utilized for dilution and administration, including any reconstituted solution made over 30 minutes prior, should be disposed of

according to standard procedures for hazardous drugs.

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

·                   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)].

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 [see Warnings and Precautions (5.4)].

SecondaryMalignancies

Advise patients on the risk of second primary malignancies[see Warnings and Precautions (5.6)].

Embryo-FetalToxicity

·                   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[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 6 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 3 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with PEPAXTO and for 1 week after the last dose[see Use in Specific Populations (8.2)].

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)