BESREMi - PharmaEssentia USA | PharmaEssentia Corporation, Taichung Plant

BESREMi is indicated for the treatment of adults with essential thrombocythemia.

BESREMi is indicated for the treatment of adults with polycythemia vera.

Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with BESREMi [see Use in Specific Populations (8.3)].

Essential Thrombocythemia:

• The recommended dose of BESREMi is:
  • A starting dose of 250 mcg by subcutaneous injection.
  • At 2 weeks, increase the dose to 350 mcg by subcutaneous injection.
  • At 4 weeks, increase to the maintenance dosage of 500 mcg by subcutaneous injection every 2 weeks.
• Maintain an every 2-week schedule throughout treatment unless dose modification is required for safety or tolerability.
• Consider dose re-escalation in case of prior dose reduction, recovery, and lack of hematologic response (platelets less than 400 × 10⁹/L and leukocytes less than 10 × 10⁹/L).
• Monitor complete blood counts every 2 weeks during titration and every 3 to 6 months during maintenance.

Polycythemia Vera:

Patients Not Already on Hydroxyurea

• The recommended BESREMi starting dosage for patients not on hydroxyurea is 100 mcg by subcutaneous injection every two weeks.
• Increase the dose by 50 mcg every two weeks (up to a maximum of 500 mcg), until the hematological parameters are stabilized (hematologic response: hematocrit less than 45%, platelets less than 400 × 10⁹/L, and leukocytes less than 10 × 10⁹/L).
• Consider dose re-escalation in case of prior dose reduction, recovery, and lack of hematologic response.

Patients Transitioning from Hydroxyurea

• When transitioning to BESREMi from hydroxyurea, start BESREMi at 50 mcg by subcutaneous injection every two weeks in combination with hydroxyurea.
• Gradually taper off the hydroxyurea by reducing the total biweekly dose by 20-40% every two weeks during Weeks 3-12.
• Increase the dose of BESREMi by 50 mcg every two weeks (up to a maximum of 500 mcg), until the hematological parameters are stabilized (hematocrit less than 45%, platelets less than 400 × 10⁹/L, and leukocytes less than 10 × 10⁹/L).
• Discontinue hydroxyurea by Week 13.

Maintain the two-week dosing interval of BESREMi at which hematological stability is achieved for at least 1 year. After achievement of hematological stability for at least 1 year on a stable dose of BESREMi, the dosing interval may be expanded to every 4 weeks.

Monitor patients closely especially during the titration phase. Perform complete blood counts (CBC) regularly, every 2 weeks during the titration phase and every 3-6 months during the maintenance phase (after the patient’s optimal dose is established). Monitor CBC more frequently if clinically indicated. Phlebotomy as rescue treatment to normalize blood hyperviscosity may be necessary during the titration phase [see Clinical Pharmacology (12.2)].

Essential Thrombocythemia:

If dose interruption occurs, resume dosing at previously attained levels. If drug-related toxicities arise, reduce the dose to the next lower level or interrupt in accordance with the tables below (Table 1 and Table 2).

Polycythemia Vera:

Monitor CBC every 2 weeks during the titration phase and dose modification phase. Phlebotomy as rescue treatment to normalize blood hyperviscosity may be necessary [see Clinical Pharmacology (12.2)].

If dose interruption occurs, resume dosing at previously attained levels. If drug-related toxicities arise, reduce the dose to the next lower level or interrupt in accordance with the table below (Table 3). If there is insufficient efficacy at the decreased dose following dose modification, a dose increase attempt to the next higher dose level should be considered after recovery to grade 1 toxicity.

Read the INSTRUCTIONS FOR USE before administering the single-dose BESREMi prefilled syringe or prefilled pen injector. BESREMi is for subcutaneous injection only and may be administered by either a healthcare professional, a patient or a caregiver. Before a decision is made to allow BESREMi to be administered by a patient or caregiver, ensure that the patient is an appropriate candidate for self-administration or administration by a caregiver. Proper training on storage, preparation and administration technique should be provided. If a patient or caregiver is not an appropriate candidate for any reason, then BESREMi should be administered by a healthcare professional.

Before each injection, remove the carton that contains the BESREMi prefilled syringe or prefilled pen injector from the refrigerator. Keep the prefilled syringe or prefilled pen injector in the carton and lay it flat on a clean work surface for 15-30 minutes to allow the prefilled syringe or prefilled pen injector to reach room temperature [59˚F to 77˚F (15˚C to 25˚C)].

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit (do not use if the solution in the syringe or pen injector is cloudy, discolored, contains particulate matter or if the syringe or pen injector shows any sign of damage).

Prefilled Syringe Preparation

• Remove the prefilled syringe cap by unscrewing it counterclockwise.
• Attach the covered needle to the prefilled syringe by firmly pushing it onto the collar of the syringe and then screwing (turn clockwise) it on until it feels securely attached.
• Choose one of the following injection sites: Lower stomach (abdomen) area, at least 2 inches away from the belly button, or top of thighs. Rotate (change) the injection site for each injection. Do not inject into skin that is irritated, red, bruised, infected, or scarred; clean the chosen injection site with an alcohol swab and let air dry.
• Uncap needle and move air bubbles to top. Pull the pink needle shield back and hold the syringe from the syringe body. Remove the clear needle cap by pulling it straight off. Throw away the needle cap into the trash. Hold the prefilled syringe with the needle pointing up. Tap on the body of the prefilled syringe to move any air bubbles to the top.

Set Injection Dose

• The dose markings on the prefilled syringe are in 50 mcg increments.
• Depending on the prescribed dose, the amount of dose in the syringe may need to be adjusted by discarding some of the medication.
• Hold the prefilled syringe at eye level with the needle pointing straight up over a paper towel, sink, or trash can. Check that you can see the dose lines and number markings on the prefilled syringe.
• Pinch the end of the plunger and slowly push up to remove liquid medicine until the top edge of the gray stopper lines up with the marking for the prescribed dose.

Inject BESREMi

• Pinch the chosen injection site. While pinching the skin, insert needle at a 45- to 90-degree angle into the pinched skin, then release the pinched skin.
• Inject BESREMi by slowly pressing on the plunger all the way until it stops. After all the liquid medicine is injected, remove the needle from the skin.

Dispose of Used Prefilled Syringe

• Carefully push the pink needle shield over the needle until it snaps into place and covers the needle. Do not recap the needle using the needle cap; only use the pink needle shield to cover the needle.
• Throw away the used prefilled syringe with the needle still attached, into an FDA-cleared sharps disposal container.

Prefilled Pen Injector Preparation

• The prefilled pen injector delivers BESREMi in 50 mcg increments.
• Remove the prefilled pen injector cap by pulling it straight off.
• Choose one of the following injection sites: Lower stomach (abdomen) area, at least 2 inches away from the belly button, or top of thighs. Rotate (change) the injection site for each injection. Do not inject into skin that is irritated, red, bruised, infected, or scarred; clean the chosen injection site with an alcohol swab and let air dry.
• Clean the rubber stopper on the tip of the prefilled pen injector with an alcohol swab. Peel off the protective seal from the needle. Attach the capped needle by pushing it straight onto the prefilled pen injector until you feel or hear it snap into place. Turn or rotate the needle until it “clicks” into place. The needle is attached when it no longer turns or rotates freely.
• Remove the needle cover by pulling off the needle cover and throw it away.

Remove Air/Flow Check

• Turn the dose selector knob until the drop symbol is centered in the dose window. Hold the prefilled pen injector with the needle pointing up and press the injection button all the way in until it stops and the dose window returns to “0”. Repeat these steps 3 more times for a total of 4 cycles.
• Look for liquid medicine at the tip of the needle. If you do not see liquid at the tip of the needle, repeat these steps up to 3 more times for a total of 7 cycles or until you see liquid medicine at the tip of the needle.

Inject BESREMi

• Set your dose by turning the dose selector clockwise until the prescribed dose is centered in the dose window. Check the number in the dose window to make sure you have dialed the correct prescribed dose before giving the injection.
• If you accidentally dial past the prescribed dose, dial the dose selector back to the correct dose.
• Hold the prefilled pen injector straight (90 degrees) over the cleaned injection site.
• Push the prefilled pen injector down to fully insert the needle without touching the injection button.
• Press and hold the injection button all the way until it stops. The number in the dose window will go back to “0”.
• Keep holding the injection button down after the dose window returns to “0” and count to 5 to make sure the full dose is delivered.
• Note: There may still be liquid remaining in the prefilled pen injector after the injection. This is normal.
• Remove the needle from the skin by lifting straight up.

Dispose of Used Prefilled Pen Injector

• Do not recap the needle or attempt to remove it. Throw away the used prefilled pen injector with the needle still attached into a sharps disposal container.

Life-threatening or fatal neuropsychiatric reactions have occurred in patients receiving interferon alfa products, including BESREMi. These reactions may occur in patients with and without previous psychiatric illness. Psychiatric reactions have been observed in 10% of BESREMi-treated patients with essential thrombocythemia including depression, adjustment disorder with depressed mood, and depressed mood. Serious neuropsychiatric reactions have been observed in 3% of BESREMi-treated patients with polycythemia vera, including depression, depressive symptoms, depressed mood, and listlessness. Of these cases, 3.4% of the patients recovered with temporary drug interruption and 2.8% stopped BESREMi treatment.

Other central nervous system effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been observed with other interferon alfa products. BESREMi is contraindicated in patients with a history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt [see Contraindications (4)].

Closely monitor patients for any symptoms of psychiatric disorders and consider psychiatric consultation and treatment if such symptoms emerge. If psychiatric symptoms worsen, it is recommended to discontinue BESREMi therapy.

Endocrine toxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include worsening hypothyroidism and hyperthyroidism. Autoimmune thyroiditis and hyperglycemia, including new onset type 1 diabetes, have been reported in patients receiving interferon alfa-2b products. Endocrine toxicities included hyperthyroidism (1.1%), hypothyroidism (1.1%), autoimmune thyroiditis (0.5%), and thyroiditis (0.5%) in BESREMi-treated patients with essential thrombocythemia. Endocrine toxicities included hyperthyroidism (4.5%), hypothyroidism (3.9%), and autoimmune thyroiditis/thyroiditis (2.8%) in BESREMi-treated patients with polycythemia vera.

Do not use BESREMi in patients with active serious or untreated endocrine disorders associated with autoimmune disease [see Contraindications (4)]. Evaluate thyroid function in patients who develop symptoms suggestive of thyroid disease during BESREMi therapy. Discontinue BESREMi in patients who develop endocrine disorders that cannot be adequately managed during treatment with BESREMi.

Cardiovascular toxicity has occurred in patients receiving interferon alfa products, including BESREMi. Toxicities may include cardiomyopathy, myocardial infarction, atrial fibrillation, coronary artery ischemia, and acute coronary syndrome [see Adverse Reactions (6.1)]. Three thrombotic events of transient ischemic attack (grade 2, 1 patient), pulmonary embolism (grade 3, 1 patient), and peripheral vein thrombosis (grade 2, 1 patient) occurred in the essential thrombocythemia Phase 3 SURPASS ET study. Patients with a history of cardiovascular disorders and/or thrombotic events should be closely monitored for cardiovascular toxicity and/or thrombotic events during BESREMi therapy. Avoid use of BESREMi in patients with severe or unstable cardiovascular disease (e.g., uncontrolled hypertension, congestive heart failure (≥ NYHA class 2), serious cardiac arrhythmia, significant coronary artery stenosis, unstable angina) or recent stroke or myocardial infarction.

Decreased peripheral blood counts have occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include thrombocytopenia (increasing the risk of bleeding), anemia, and leukopenia (increasing the risk of infection). In BESREMi-treated patients with essential thrombocythemia, anemia of grade 3 or greater occurred in 1% of patients. Leukopenia of grade 3 or greater occurred in 2% of patients. Infection occurred in 45% of patients, while serious infections occurred in 4% of patients. Essential thrombocythemia-related hemorrhagic cases occurred in 6% of patients and included gingival bleeding, tongue hemorrhage, epistaxis, purpura, and retinal hemorrhage. In BESREMi-treated patients with polycythemia vera, thrombocytopenia of grade 3 (platelet counts <50,000 – 25,000/mm³) or greater occurred in 2% of patients. Anemia of grade 3 (Hgb <8 g/dL) or greater occurred in 1% of patients. Leukopenia of grade 3 (WBC counts <2,000 – 1,000/mm³) or greater occurred in 2% of patients. Infection occurred in 48% of patients, while serious infections occurred in 8% of patients. Monitor complete blood counts at baseline, during titration and every 3-6 months during the maintenance phase. Monitor patients for signs and symptoms of infection or bleeding.

Hypersensitivity reactions have occurred in patients receiving interferon alfa products, including BESREMi. BESREMi is contraindicated in patients with hypersensitivity reactions to interferon products or any of the inactive ingredients in BESREMi [see Contraindications (4)]. Toxicities may include serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis, drug eruption). If such reactions occur, discontinue BESREMi and institute appropriate medical therapy immediately. Transient rashes may not necessitate interruption of treatment.

Pancreatitis has occurred in patients receiving interferon alfa products, including BESREMi. Pancreatitis was reported in 2.2% of patients receiving BESREMi for polycythemia vera. Symptoms may include nausea, vomiting, upper abdominal pain, bloating, and fever. Patients may experience elevated lipase, amylase, white blood cell count, or altered renal/hepatic function. Interrupt BESREMi treatment in patients with possible pancreatitis and evaluate promptly. Consider discontinuation of BESREMi in patients with confirmed pancreatitis.

Serious and, in very rare cases potentially life-threatening ulcerative or hemorrhagic/ischemic colitis have occurred in patients receiving interferon alfa products, some cases occurring as early as 12 weeks after start of treatment. Symptoms may include abdominal pain, bloody diarrhea, and fever. Discontinue BESREMi in patients who develop these signs or symptoms. Colitis may resolve within 1 to 3 weeks of stopping treatment.

Pulmonary toxicity has occurred in patients receiving interferon alfa products, including BESREMi. Pulmonary toxicity may manifest as dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, pleural effusion, and sarcoidosis. Some events have resulted in respiratory failure or death. Discontinue BESREMi in patients who develop pulmonary infiltrates or pulmonary function impairment.

Ophthalmologic toxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include severe eye disorders such as retinopathy, retinal hemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion which may result in blindness. During BESREMi therapy in patients with essential thrombocythemia, 23% of patients were identified with eye disorders. Eye disorders in ≥5% of patients included vision blurred (8%) and dry eye (7%). During BESREMi therapy in patients with polycythemia vera, 23% of patients were identified with an eye disorder. Eyes disorders ≥5% included cataract (6%) and dry eye (5%). Advise patients to have eye examinations before and during BESREMi therapy, specifically in those patients with a retinopathy-associated disease such as diabetes mellitus or hypertension. Evaluate eye symptoms promptly. Discontinue BESREMi in patients who develop new or worsening eye disorders.

Hyperlipidemia has occurred in patients treated with interferon alfa products, including BESREMi. Hypertriglyceridemia occurred in 9% of patients, hyperlipidemia occurred in 2% of patients, and dyslipidemia occurred in 0.5% of patients receiving BESREMi for essential thrombocythemia. Hyperlipidemia, hypertriglyceridemia, or dyslipidemia occurred in 3% of patients receiving BESREMi for polycythemia vera. Elevated triglycerides may result in pancreatitis [see Warnings and Precautions (5.6)]. Monitor serum triglycerides before BESREMi treatment and intermittently during therapy and manage when elevated. Consider discontinuation of BESREMi in patients with persistently, markedly elevated triglycerides.

Hepatotoxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include increases in serum ALT, AST, GGT, and bilirubin. BESREMi is contraindicated in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Contraindications (4)].

Increases in serum ALT ≥3 × the upper limit of normal (ULN), AST ≥3 × the ULN, GGT ≥3 × ULN, and bilirubin >2 × ULN have been observed in patients treated with BESREMi.

In BESREMi-treated patients with essential thrombocythemia, 4% of patients experienced Grade ≥3 liver enzyme elevations including alanine aminotransferase increased in 2.7% of patients, aspartate aminotransferase increased in 1.1% of patients, and blood bilirubin increased in 0.5% of patients. There were 20% of patients with alanine aminotransferase levels ≥3 × ULN and 9% of patients with aspartate aminotransferase levels ≥3 × ULN. A single Grade 4 adverse reaction of hepatitis was reported in an open-label single arm study of BESREMi in patients with essential thrombocythemia, with a time to recovery of 11 days.

In BESREMi-treated patients with polycythemia vera, 36 patients (20%) experienced liver enzyme elevations, 33 of whom had elevations of 1.25-5 × ULN. Patients were able to resume BESREMi upon resolution of liver enzyme elevations. Liver enzyme elevations have also been reported in patients after long-term BESREMi therapy.

Monitor liver enzymes and hepatic function at baseline and during BESREMi treatment. For dose modifications see Table 1 for patients with essential thrombocythemia and see Table 3 for patients with polycythemia vera [see Dosage and Administration (2.3)].

Discontinue BESREMi in patients who develop evidence of hepatic decompensation (characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome or variceal hemorrhage) during treatment [see Use in Specific Populations (8.7)].

Renal toxicity has occurred in patients receiving interferon alfa products, including BESREMi. During BESREMi therapy in patients with polycythemia vera, <1% of patients were reported to develop renal impairment and <1% of patients were reported to have toxic nephropathy. Monitor serum creatinine at baseline and during therapy. Avoid use of BESREMi in patients with eGFR <30 mL/min. Discontinue BESREMi if severe renal impairment develops during treatment [see Use in Specific Populations (8.6)].

Dental and periodontal toxicities may occur in patients receiving interferon alfa products, including BESREMi. These toxicities may include dental and periodontal disorders, which may lead to loss of teeth. In addition, dry mouth could have a damaging effect on teeth and oral mucous membranes during long-term treatment with BESREMi. Patients should have good oral hygiene and regular dental examinations.

Dermatologic toxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities have included skin rash, pruritus, alopecia, erythema, psoriasis, xeroderma, dermatitis acneiform, hyperkeratosis, and hyperhidrosis. Consider discontinuation of BESREMi if clinically significant dermatologic toxicity occurs.

BESREMi may impact the ability to drive and use machinery. Patients should not drive or use heavy machinery until they know how BESREMi affects their abilities. Patients who experience dizziness, somnolence or hallucination during BESREMi therapy should avoid driving or using machinery.

Based on the mechanism of action, BESREMi can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)]. Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with BESREMi. Advise females of reproductive potential to use an effective method of contraception during treatment with BESREMi and for at least 8 weeks after the final dose [see Dosage and Administration (2.2) and Use in Specific Populations (8.1, 8.3)].

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.

Essential Thrombocythemia

The pooled safety population described in the Warnings and Precautions section reflects exposure to BESREMi as monotherapy for the treatment of essential thrombocythemia dosed every 2 weeks in 182 patients in an open-label trial [P1101 ET, SURPASS ET] and a single-arm trial [A22-301, EXCEED ET]. The mean age was 56 years (range: 21 to 84 years). There were 104 (57%) women, 78 (43%) men, and 93 (51%) Asian, 76 (42%) Caucasian, 5 (2.7%) Black or African American, 5 (2.7%) Other, and 3 (1.6%) Hispanic patients were included in the studies. Among 182 patients who received BESREMi, 70 (39%) patients were exposed for >56 weeks (>14 months). The mean (SD) dose of BESREMi was 394.9 (98.4) mcg during the treatment period. In this pooled safety population, the most common adverse reactions in ≥10% of BESREMi-treated patients were aspartate aminotransferase increased (44%), alanine aminotransferase increased (43%), fatigue (31%), anemia (24%), white blood cell count decreased (23%), neutrophil count decreased (22%), pruritus (17%), gamma-glutamyltransferase increased (16%), alopecia (16%), headache (15%), diarrhea (13%), nausea (13%), beta 2 microglobulin urine increased (12%), influenza like illness (11%), and myalgia (11%).

The safety findings described below reflect exposure to BESREMi as monotherapy for the treatment of essential thrombocythemia in 91 patients in the SURPASS ET study [see Clinical Studies (14)]. Among the 91 patients receiving BESREMi, 55% were exposed for 9 to 13 months and 36% were exposed for more than 13 months.

Serious adverse reactions were reported in 2.2% of patients treated with BESREMi in the SURPASS ET study and included vascular headache and drug eruption.

Adverse reactions requiring permanent discontinuation of patients treated with BESREMi occurred in 1.1% patient each and included aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, pneumonitis, pulmonary hypertension, thyroiditis, dry eye, and erythema.

The most common adverse reactions reported in ≥10% of patients in the SURPASS ET study are listed in Table 4.

Polycythemia Vera

The pooled safety population described in the Warnings and Precautions section reflects exposure to BESREMi as monotherapy for the treatment of polycythemia vera dosed every two to four weeks in 178 patients in two open-label trials [PEGINVERA, PROUD-PV/CONTINUATION-PV]. The mean age at baseline was 58.6 years (range 30-85 years), 88 (49%) women, 90 (51%) men, 177 (99%) Caucasian and 1 (1%) Asian. Among 178 patients who received BESREMi, 80% were exposed for 12 months or longer. The mean dose of BESREMi was 334 mcg SD ± 121 during the treatment period. In this pooled safety population, the most common adverse reactions greater than 10%, were liver enzyme elevations (20%), leukopenia (20%), thrombocytopenia (19%), arthralgia (13%), fatigue (12%), myalgia (11%), and influenza-like illness (11%).

The safety findings described below reflect exposure to BESREMi as monotherapy for the treatment of polycythemia vera in 51 patients in the PEGINVERA study [see Clinical Studies (14)]. Among the 51 patients receiving BESREMi, 71% were exposed for 12 months or longer, 63% were exposed for three years or longer, and 53% were exposed for greater than five years.

Serious adverse reactions were reported in 16% of patients in the PEGINVERA study. The most common serious adverse reactions observed during the study (>4%) included urinary tract infection (8%), transient ischemic attack (6%) and depression (4%).

Adverse reactions requiring permanent discontinuation in >2% of patients who received BESREMi included depression (8%), arthralgia (4%), fatigue (4%), and general physical health deterioration (4%). In the PEGINVERA study, patients were not pre-screened for depression or anxiety disorders.

The most common adverse reactions reported in ≥10% of patients in the PEGINVERA study are listed in Table 5.

Certain proinflammatory cytokines, including interferons, can suppress CYP450 enzymes resulting in increased exposures of some CYP substrates [see Clinical Pharmacology (12.3)]. 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.

Concomitant use of BESREMi and myelosuppressive agents can produce additive myelosuppression. Avoid use and monitor patients receiving the combination for effects of excessive myelosuppression [see Warnings and Precautions (5.4)].

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)].

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. An abortifacient effect was reported in cynomolgus monkeys receiving ropeginterferon alfa-2b (see Data ). Based on mechanism of action and the role of interferon alfa in pregnancy and fetal development, BESREMi can cause fetal harm and should be assumed to have abortifacient potential when administered to a pregnant woman. There are adverse effects on maternal and fetal outcomes associated with polycythemia vera in pregnancy (see Clinical Considerations). 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.

Data

Animal Data

In an embryo-fetal development study, pregnant cynomolgus monkeys received subcutaneous injection of ropeginterferon alfa-2b twice weekly during the period of organogenesis (Gestation Days 20-48). Maternal toxicity, characterized by a significant decline in food consumption and transient body weight loss, occurred at all dose levels and ropeginterferon alfa-2b was abortifacient and caused embryonic death at exposures 275-times (C_max) and 64-times (AUC) the human exposure at the maximum recommended human dose of 500 mcg. There were no effects on fetal developmental parameters or abnormalities in the surviving fetuses (GD 100) where the ropeginterferon alfa-2b exposures achieved in pregnant cynomolgus monkeys during the first trimester were 961-times (C_max) and 224-times (AUC) the human exposure at the maximum recommended human dose of 500 mcg.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Untreated polycythemia vera during pregnancy is associated with adverse maternal outcomes such as thrombosis and hemorrhage. Adverse pregnancy outcomes associated with polycythemia vera include increased risk for miscarriage.

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.

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

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.

Safety and effectiveness in pediatric patients have not been established.

Of the total number of BESREMi-treated patients in the essential thrombocythemia studies, 65 (36%) were 65 years of age and older, while 15 (8%) were 75 years of age and older [see Clinical Studies (14)]. Of the total number of BESREMi-treated patients in the polycythemia studies, 17 (33%) were 65 years of age and older, while 5 (10%) were 75 years of age and older. 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.

No dose adjustment is necessary in patients with estimated glomerular filtration rate (eGFR) ≥30 mL/min [see Clinical Pharmacology (12.3)]. Avoid use of BESREMi in patients with eGFR <30 mL/min [see Warnings and Precautions (5.12)].

BESREMi is contraindicated in patients with hepatic impairment (Child-Pugh B or C) [see Contraindications (4)].

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 [see Dosage and Administration (2.3) and Warnings and Precautions (5.11)].

Interferon alfa belongs to the class of type I interferons, which exhibit their cellular effects in polycythemia vera and essential thrombocythemia in the bone marrow by binding to a transmembrane receptor termed interferon alfa receptor (IFNAR). Binding to IFNAR initiates a downstream signaling cascade through the activation of kinases, in particular Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) and activator of transcription (STAT) proteins. Nuclear translocation of STAT proteins controls distinct gene-expression programs and exhibits various cellular effects. The actions involved in the therapeutic effects of interferon alfa in polycythemia vera and essential thrombocythemia are not fully elucidated.

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-2b-njft concentrations. Complete hematological response (CHR, defined as a patient achieving hematocrit <45% without phlebotomy [at least 2 months since last phlebotomy], platelets ≤400 × 10⁹/L and leukocytes ≤10 × 10⁹/L) increased with increasing ropeginterferon alfa-2b-njft concentration over time. Based on the exposure-response (E-R) analyses using data from the PEGINVERA study in patients with polycythemia vera, the predicted probability of CHR (95% Prediction Intervals) was 22% (11% – 34%) before treatment, 50% (38% – 62%) at week 20 (end of titration), 64% (47% – 78%) at week 52, and 70% (55% – 88%) at week 104. The E-R analyses show that the maximum probability of CHR is reached after 2 years of continuous treatment.

In patients with essential thrombocythemia, following subcutaneous administration of BESREMi, peak serum concentrations (Cmax) were reached between 62 to 123 hours post-dose (T_max). Exposure appeared generally dose‑proportional following repeated subcutaneous doses of 250 to 500 mcg at Week 12.

In patients with polycythemia vera, the estimated steady state C_max, C_min and area under the curve (AUC) after a two-week 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 1,011 – 7,809 ng × h/mL, respectively. The estimated steady state C_max 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 of BESREMi is approximately 7 days and the clearance is approximately 1.7-2.5 L/h in patients with polycythemia vera over a dose range of 100 mcg to 500 mcg, respectively.

In patients with essential thrombocythemia, the median terminal phase half-life (t_1/2,λz) is 122 hours following a single subcutaneous dose. Following repeated subcutaneous dosing, the median t_1/2,λz ranged from 210 to 251 hours across doses of 250 mcg to 500 mcg at Week 12.

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.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ropeginterferon alfa-2b-njft or of other ropeginterferon alfa-2b products.

The immunogenicity of BESREMi was evaluated in adult patients with essential thrombocythemia in two clinical studies (SURPASS ET and EXCEED ET). In the SURPASS ET study, among 91 evaluable patients treated with BESREMi, 7% (6/91) developed treatment-induced anti-ropeginterferon alfa-2b antibodies. In the EXCEED ET study, among 88 evaluable patients, 13% (11/88) developed treatment-induced anti-ropeginterferon alfa-2b antibodies. These antibody responses were transient and of low titer. No neutralizing antibodies against ropeginterferon alfa-2b were detected in patients from either study. The presence of anti-ropeginterferon alfa-2b-njft antibodies was not associated with a clinically meaningful impact on the pharmacokinetics, safety, or efficacy of BESREMi.

In three studies in patients with polycythemia vera (PEGINVERA, PROUD-PV/CONTINUATION-PV), from a total of 146 subjects who have been followed up to 362 weeks, the incidence of confirmed anti-drug antibodies was 1.4% (2/146). No neutralizing antibodies were detected.

Ropeginterferon alfa-2b-njft has not been tested for its carcinogenic potential. Neither ropeginterferon alfa-2b-njft nor its components, interferon or methoxypolyethylene glycol, caused damage to DNA when tested in the standard battery of mutagenesis assays. Ropeginterferon alfa-2b-njft effects on fertility have not been assessed [see Use in Specific Populations (8.1, 8.2, 8.3)].

SURPASS ET:

The SURPASS ET study was a randomized, open-label, multicenter, active-controlled study to assess pharmacokinetics, efficacy, safety, and tolerability of BESREMi compared to anagrelide as second line therapy after 12 months of treatment. The study included 174 adults with essential thrombocythemia and documented resistance/intolerance to hydroxyurea, of which, 91 patients received BESREMi and 83 patients received anagrelide. The median age at baseline was 62.5 years (range 20-83 years), with 52% females and 48% males, and 96% Asian and 4% Caucasian patients. There were 79% of patients with an ECOG Grade 0 and patients had a mean (SD) TSS of 12.5 (14) at baseline. Hydroxyurea was previously used by all patients, with an overall mean (SD) duration of use of 27.9 (59.7) months; the mean (SD) prior duration of use was 22 (39.9) months for patients who received BESREMi and 35.2 (80) months for patients who received anagrelide. There were 82% of patients with a JAK2V617F mutation at baseline, with a mean (SD) allelic burden of 44 (30)%. There were 12% of patients with a CALR mutation at baseline, with a mean (SD) allelic burden of 25 (18)%. One percent of patients had an MPL mutation at baseline, with a mean (SD) allelic burden of 29 (4.1)%. At baseline, mean (SD) platelets and white blood cells were 1,024.5 × 10⁹/L (439.1) and 14.2 × 10⁹/L (7.7), respectively. The spleen was palpable in 14% of patients at baseline, with a median spleen size of 13.9 cm. Two percent of patients had splenomegaly at baseline (defined as a longitudinal diameter of >17 cm). There were 35% of patients with a history of thrombosis, 35% of patients with a history of hemorrhage, 85% of patients with a JAK-2 mutation history, 9% of patients with a CALR mutation history, and 2% of patients with an MPL mutation history.

BESREMi was administered subcutaneously every 2 weeks at the starting dose of 250 mcg (Week 0), then 350 mcg (Week 2), and 500 mcg (Week 4), and then remained fixed at 500 mcg for the remaining Treatment Period. Anagrelide was administered orally; the starting dose, maintenance dose, and any dose adjustment was according to the local country product label and treatment practices. Low-dose aspirin (75 to 150 mg/day per local practice) was given to subjects in both arms during the 12 months of study treatment, unless contraindicated.

The median duration of treatment exposure was 11.9 months; 55% of patients completed at least 12 months of treatment and 36% of patients completed more than 12 months of treatment. Overall, 74% of patients completed the study, with 10% of patients discontinuing due to a study drug related treatment-emergent adverse event. The mean (SD) dose of BESREMi was 10,174.2 (3,120.3) mcg during the treatment period.

The efficacy of BESREMi was evaluated in the SURPASS ET study by assessing durable Modified European Leukemia Net (ELN) response rates at Months 9 and 12. The modified ELN response criteria involved the following: peripheral blood count remission (platelets ≤400 × 10⁹ and white blood cells <9.5 × 10⁹/L) AND improvement or non-progression in disease-related signs (splenomegaly) AND absence of hemorrhagic or thrombotic events. The modified ELN response differs from the 2013 ELN response criteria as it excludes components for bone marrow histological remission and the requirement for durable resolution of disease-related signs and large symptoms improvement, and uses a lower white blood cell threshold. Additional evaluations for efficacy included durable response at Months 3 and 6, longitudinal rate of change in the ELN response rates over 12 months, change from baseline in JAK2V617F allelic burden from baseline over time (by 2013 ELN criteria), and thromboembolic events. Other evaluations for efficacy included response rates based on peripheral blood count remission, no signs of progressive disease, and absence of any hemorrhagic or thrombotic events at 3, 6, 9, and 12 months, and time to first peripheral blood count remission response.

In the SURPASS ET study, the BESREMi treatment demonstrated a statistically significantly higher response rate compared with anagrelide for the durable modified ELN response rate at both Months 9 and 12. Table 6 summarizes the efficacy results for SURPASS ET.

The efficacy and safety of BESREMi were evaluated in the PEGINVERA study, a prospective, multicenter, single-arm trial of 7.5 years duration. The study included 51 adults with polycythemia vera. The mean age at baseline was 56 years (range 35-82 years) with 20 (39%) women and 31 (61%) men. All patients had the JAK2V617F mutation with 16% of subjects being newly diagnosed; 84% had known disease with a median duration of 2.2 years. One-third (33%) of patients were undergoing treatment with hydroxyurea (HU) upon study entry. At baseline, the mean ± SD hematocrit, platelets, and leukocytes were 45% ± 4.0%, 457 × 10⁹/L ± 187 × 10⁹/L and 11.8 × 10⁹/L ± 5.2 × 10⁹/L, respectively. Median spleen size was 13.2 cm with 16 (31%) having splenomegaly (defined as a longitudinal diameter of >12 cm for women and >13 cm for men). Eleven patients (22%) had a prior history of a major cardiovascular event including pulmonary embolism (6), stroke (2), myocardial infarction (2) and portal vein thrombosis (1).

In stage I, the maximum tolerated dose, defined as the highest administered dose without dose-limiting toxicities was determined to be 540 mcg. In stage II, an intra-patient dose escalation began at 150 mcg, or 100 mcg if titrating from hydroxyurea, or at the highest dose achieved in those patients enrolled during stage I. Titration with BESREMi occurred every two-weeks at doses of 225 mcg, 300 mcg, 400 mcg, and 450 mcg with dose escalation stopping when hematological parameters were stabilized. For patients transitioning from hydroxyurea, the hydroxyurea dose was tapered off over the first 12 weeks of treatment to avoid toxicity. After at least one year on therapy and at a median time of 21.5 months, 28 eligible patients in the PEGINVERA study increased the dosing interval to once every 4 weeks. Because of formulation changes, the recommended starting dose, titration amounts, and maximum dose of BESREMi differ slightly from those used in the trial [see Dosage and Administration (2)].

The median duration of treatment exposure was 61 months and 53% of patients completed at least 60 months of treatment. Thirty-six patients completed one year of treatment with eleven patients discontinuing after one year of treatment mainly due to treatment emergent adverse events. The mean dose of BESREMi was 237 mcg (± 110) during the treatment period.

The efficacy of BESREMi was evaluated in the PEGINVERA study by assessing complete hematological response (CHR) defined as hematocrit <45% and no phlebotomy in the preceding 2 months, platelets ≤400 × 10⁹/L and leukocytes ≤10 × 10⁹/L, normal spleen size (longitudinal diameter ≤12 cm for females and ≤13 cm for males) assessed by ultrasound and absence of thromboembolic events.

The CHR in the treated population during the treatment period was 61% (31/51) (95% CI: 46, 74). The median duration of response was 14.3 months (95% CI: 5.5, 30.1).

Among the patients in the treated population who achieved a CHR, the median time to response was 7.8 months of treatment with BESREMi. It required 1.2 years of treatment with BESREMi for 50% of patients (hydroxyurea-naïve) to achieve a CHR and 1.4 years for 50% of patients with prior hydroxyurea use to achieve a CHR.

A hematological response based only on hematocrit, platelets, and leukocytes was achieved among 80% of patients treated with BESREMi (41/51) (95% CI: 67, 90). The median duration of this response was 20.8 months (95% CI: 13.0, 43.8).