DRUG INTERACTIONS- (summary)

­ • Monitor patients taking CYP450 substrates with a narrow therapeutic index for adverse reactions to inform the need for dose adjustment of the concomitant drug

 • Avoid use with myelosuppressive agents and monitor patients receiving the combination for effects of excessive myelosuppression

 • Avoid use with narcotics, hypnotics or sedatives. Monitor patients receiving the combination for excessive central nervous system toxicity 

DRUG INTERACTIONS( details)

1 Drugs Metabolized by Cytochrome P450-                                                                  Certain proinflammatory cytokines, including interferons, can suppress CYP450 enzymes resulting in increased exposures of some CYP substrates 

Therefore, patients on BESREMi who are receiving concomitant drugs that are CYP450 substrates with a narrow therapeutic index should be monitored to inform the need for dosage modification for these concomitant drugs.

2. Myelosuppressive Agents-                                                                                   Concomitant use of BESREMi and myelosuppressive agents can produce additive myelosuppression. Avoid use and monitor patients receiving the combination for effects of excessive myelosuppression

3. Narcotics, Hypnotics or Sedatives-                                                                       Concomitant use of BESREMi and narcotics, hypnotics or sedatives can produce additive neuropsychiatric side effects. Avoid use and monitor patients receiving the combination for effects of excessive CNS toxicity [see Warnings and Precautions (5.1)].

BRIEF SUMMARY

ROPERGINTERFERON- (Nov 2021)

Indn-  To treat Polycythemia Vera in a Blood disease   that   causes the over production of Red Blood  cells

Comp-   • Injection: 500 mcg/mL solution in a single-dose prefilled syringe-  Recommended starting dose: 100 mcg by subcutaneous injection every 2 weeks (50 mcg if receiving hydroxyurea).                                                                                             

• Increase the dose by 50 mcg every 2 weeks (up to a maximum of 500 mcg) until hematological parameters are stabilized 

ADR-    The most common adverse reactions reported in > 40% of patients were influenza-like illness, arthralgia, fatigue, pruritus, nasopharyngitis, and musculoskeletal paN

CI-   Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation or suicide attempt

 • Hypersensitivity to interferon or to any component of BESREMi

 • Hepatic impairment (Child-Pugh B or C)

WARNINGS - 

­ Patients exhibiting the following events should be closely monitored and may require dose reduction or discontinuation of therapy:

• Depression and Suicide: Monitor closely for symptoms and need for treatment.

• Endocrine Toxicity: Discontinue if endocrine disorders occur that cannot be medically managed.

 Pat Inform-

Depression and Suicide- Inform patients, their caregivers, and family members that suicidal ideation and behavior, as well as new onset or worsening depression have been reported in patients treated 

Advise them to be aware of any unusual changes in mood or behavior, new onset or worsening of depression, or the emergence of suicidal thoughts or behavior

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U.S. FDA APPROVED DRUGS SURING 2021                                        

Serial No 43

Name of the Drug-    BESREMI

Active Ingredient -   Roperginterferon alfa-2b-njft

Pharmacological Classification- To treat Polycythemia Vera in a Blood disease                                                               that   causes the over production of Red Blood                                                               cells                                                                                                                                                                 

                                                                                                                                            Date of Approval-          11/12/21 

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                                   BESREMi safely and effectively.                                                                                     See full prescribing information for BESREMi. BESREMi (ropeginterferon alfa-2b-njft) injection, for subcutaneous use.

Initial U.S. Approval: 2021

WARNING: RISK OF SERIOUS DISORDERS-                                                                 See full prescribing information for complete boxed warning.

Risk of Serious Disorders: Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor closely and withdraw therapy with persistently severe or worsening signs or symptoms of the above disorders.

INDICATIONS AND USAGE-

BESREMi is an interferon alfa-2b indicated for the treatment of adults with polycythemia vera

ADVERSE REACTIONS-

­ The most common adverse reactions reported in > 40% of patients were influenza-like illness, arthralgia, fatigue, pruritus, nasopharyngitis, and musculoskeletal pain

CONTRAINDICATIONS-

­ • Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation or suicide attempt

 • Hypersensitivity to interferon or to any component of BESREMi

 • Hepatic impairment (Child-Pugh B or C)

 • History or presence of active serious or untreated autoimmune disease 

• Immunosuppressed transplant recipients 

WARNINGS AND PRECAUTIONS- 

­ Patients exhibiting the following events should be closely monitored and may require dose reduction or discontinuation of therapy:

• Depression and Suicide: Monitor closely for symptoms and need for treatment.

• Endocrine Toxicity: Discontinue if endocrine disorders occur that cannot be medically managed.

 • Cardiovascular Toxicity: Avoid use in patients with severe, acute or unstable cardiovascular disease. Monitor patients with history of cardiovascular disorders more frequently.

 • Decreased Peripheral Blood Counts: Perform blood counts at baseline, every 2 weeks during titration, and at least every 3-6 months during maintenance treatment. 

• Hypersensitivity Reactions: Stop treatment and immediately manage reaction.

 • Pancreatitis: Consider discontinuation if confirmed pancreatitis

 • Colitis: Discontinue if signs or symptoms of colitis

 • Pulmonary Toxicity: Discontinue if pulmonary infiltrates or pulmonary function impairment 

 •  Ophthalmologic Toxicity: Advise patients to have eye examinations before and during treatment. Evaluate eye symptoms promptly and discontinue if new or worsening eye disorders.

 • Hyperlipidemia: Monitor serum triglycerides before BESREMi treatment and intermittently during therapy and manage when elevated.

 • Hepatotoxicity: Monitor liver enzymes and hepatic function at baseline and during treatment. Reduce dose or discontinue depending on severity.

 • Renal Toxicity: Monitor serum creatinine at baseline and during therapy. Discontinue if severe renal impairment develops.

 • Dental and Periodontal Toxicity: Advise patients on good oral hygiene and to have regular dental examinations.

 • Dermatologic Toxicity: Consider discontinuing if clinically significant dermatologic toxicity.

 • Driving and Operating Machinery: Advise patients to avoid driving or using machinery if they experience dizziness, somnolence, or hallucination.

DOSAGE AND ADMINISTRATION-

­ • Recommended starting dose: 100 mcg by subcutaneous injection every 2 weeks (50 mcg if receiving hydroxyurea).                                                                                             

• Increase the dose by 50 mcg every 2 weeks (up to a maximum of 500 mcg) until hematological parameters are stabilized                                                                             

• Interrupt or discontinue dosing if certain adverse reactions occur 

DOSAGE AND STRENGTHS-                                                                                            ­ • Injection: 500 mcg/mL solution in a single-dose prefilled syringe-

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

Depression and Suicide- Inform patients, their caregivers, and family members that suicidal ideation and behavior, as well as new onset or worsening depression have been reported in patients treated with BESREMi.

Advise them to be aware of any unusual changes in mood or behavior, new onset or worsening of depression, or the emergence of suicidal thoughts or behavior. Instruct patients, caregivers, and family members to report signs or symptoms of depression to their healthcare provider right away, but to discontinue BESREMi immediately and seek immediate medical attention if suicidal ideation or attempts occur

Endocrine Toxicity- Advise patients to report any signs or symptoms of diabetes or thyroid dysfunction.

Cardiovascular Toxicity -Advise patients to report signs or symptoms of cardiovascular toxicity to their healthcare provider 

Decreased Peripheral Blood Counts- Advise patients to seek prompt medical attention if they experience weakness/fatigue, fever, easy bruising, or frequent nose bleeds

Hypersensitivity- Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions

Pancreatitis- Advise patients to report signs or symptoms of pancreatitis

Colitis- Advise patients to report signs or symptoms of colitis

Pulmonary Toxicity -Advise patients to report signs or symptoms of pulmonary toxicity ].

Ophthalmologic Toxicity- Advise patients to report visual changes and to have eye examinations before and during treatment

Hyperlipidemia -Advise patients that BESREMi may increase blood triglycerides and that they will need blood testing to monitor for this toxicity

Hepatotoxicity- Advise patients to report signs or symptoms of hepatic toxicity to their healthcare provider

Renal Toxicity- Advise patients to report signs or symptoms of kidney disease

 Dental and Periodontal Toxicity- Advise patients to maintain good oral hygiene and to have regular dental examinations

Dermatologic Toxicity Advise patients to seek medical attention if significant pruritus, alopecia, rash and/or other dermatological toxicities occur

Hazardous Occupations/Operating Machinery- Advise patients to refrain from engaging in operating heavy or potentially dangerous machinery until they know how BESREMi will affect their abilities.

Advise patients who experience dizziness, somnolence and hallucinations not to drive or use heavy machinery

Pregnancy and Contraception-                                                                                  Advise women about the need to use an effective method of contraception while taking BESREMi and for at least 8 weeks after the final dose 

Lactation -                                                                                                                         Advise women not to breastfeed during treatment and for 8 weeks after the final dose [s

Instruction on Injection Technique-                                                                                Instruct patients on proper storage, preparation and administration techniques for BESREMi. Instruct patients who are self-administering to inject the prescribed dose of BESREMi 

Manufactured by: PharmaEssentia Corporation 2F-5 No. 3 YuanQu Street Nangang Dist. Taipei, Taiwan U.S. License number xxxx Distributed by: PharmaEssentia USA Corporation 35 Corporate Dr, Suite 325, Burlington, MA 01803, USA © PharmaEssentia USA Corporation, 2021

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-                                                                                              Interferon alfa belongs to the class of type I interferons, which exhibit their cellular effects in polycythemia vera in the bone marrow by binding to a transmembrane receptor termed interferon alfa receptor (IFNAR).

2. Pharmacodynamics- The efficacy of ropeginterferon alfa-2b-njft is dependent on the stabilization of hematological parameters (hematocrit <45%, platelets <400 × 109 /L and leukocytes <10 × 109 /L).

Pharmacokinetic-pharmacodynamic analyses have demonstrated that the reduction in the individual hematological parameters is dependent on ropeginterferon alfa-2bnjft concentrations.

3. Pharmacokinetics- In patients with polycythemia vera, the estimated steady state Cmax, Cmin and area under the curve (AUC) after a twoweek dosing interval of BESREMi over a dose range of 100 mcg to 500 mcg ranged from 4.4 – 31 ng/mL, 1.4 – 12 ng/mL, and 1011 – 7809 ng×h/mL, respectively. The estimated steady state Cmax occurs between 2 to 5 days.

Absorption The estimated geometric mean (CV%) of the absorption rate constant of BESREMi is 0.12 day-1 (27%) in patients with polycythemia vera.

Distribution The estimated geometric mean (CV%) of apparent volume of distribution of BESREMi is 4.8 L (21%) in patients with polycythemia vera

Elimination- BESREMi undergoes receptor independent degradation/excretion and receptor binding and subsequent degradation of the drug-receptor complex.

The half-life and clearance of BESREMi is approximately 7 days and 1.7-2.5 L/h in patients with polycythemia vera over a dose range of 100 mcg to 500 mcg, respectively.

Specific Populations-                                                                                                     No clinically significant differences in the pharmacokinetics of BESREMi were observed based on age, sex, body surface area, and JAK2V617F mutation.

Drug Interactions-                                                                                                            Clinical Studies No clinical studies evaluating the drug interaction potential of BESREMi have been conducted.

In Vitro Studies In vitro studies indicate that BESREMi exhibited time-dependent inhibitory potential on CYP2A6. BESREMi did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 in human liver microsomes. BESREMi is not expected to induce CYP enzymes.

However, interferon may influence CYP450 through modulating transcription factors and altering protein expression and/or structure. As this mechanism requires more time to exert effect, it cannot be evaluated by in vitro assays.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                              Available human data with BESREMi use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

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

2. Lactation -                                                                                                               There are no data on the presence of BESREMi in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children from BESREMi, advise women not to breastfeed during treatment and for 8 weeks after the final dose.

3 Females and Males of Reproductive Potential-                                              BESREMi may cause embryo-fetal harm when administered to a pregnant woman

 Pregnancy Testing-                                                                                                     Pregnancy testing prior to BESREMi treatment is recommended for females of reproductive potential.

Contraception Females-                                                                                                  Advise female patients of reproductive potential to use effective contraception during treatment with BESREMi and for at least 8 weeks after the final dose.

Infertility Females-                                                                                                               Based on its mechanism of action, BESREMi can cause disruption of the menstrual cycle [see Clinical Pharmacology (12.1)]. No animal fertility studies have been conducted with BESREMi.

4 Pediatric Use-                                                                                                                 Safety and effectiveness in pediatric patients have not been established.

5 Geriatric Use-                                                                                                          Clinical studies of BESREMi did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.                                                                                        In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.

6. Renal Impairment-                                                                                                       No dose adjustment is necessary in patients with estimated glomerular filtration rate (eGFR) =30 mL/min

. Avoid use of BESREMi in patients with eGFR <30 mL/min 

7. Hepatic Impairment-                                                                                                    BESREMi is contraindicated in patients with hepatic impairment (Child-Pugh B or C) 

Increased liver enzyme levels have been observed in patients treated with BESREMi. When the increase in liver enzyme levels is progressive and persistent, reduce the dose of BESREMi.

If the increase in liver enzymes is progressive and clinically significant despite dose-reduction, or if there is evidence of hepatic impairment (Child-Pugh B or C), discontinue BESREMi .

 OVERDOSAGE-

Overdosage of BESREMi may result in influenza-like symptoms or other adverse reactions. There is no antidote to BESREMi overdosage. In case of an overdose, frequently monitor signs and symptoms for adverse reactions.