Dosage & Administration
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Besremi Prescribing Information
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.
BESREMi is indicated for the treatment of adults with polycythemia vera.
Pre-Treatment Testing
Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with BESREMi [see Use in Specific Populations (8.3)].
Recommended Dosage
Patients Not Already on Hydroxyurea:
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- The recommended BESREMi starting dosage for patients not on hydroxyurea is 100 mcg by subcutaneous injection every two weeks.
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- Increase the dose 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).
Patients Transitioning from Hydroxyurea:
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- When transitioning to BESREMi from hydroxyurea, start BESREMi at 50 mcg by subcutaneous injection every two weeks in combination with hydroxyurea.
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- Gradually taper off the hydroxyurea by reducing the total biweekly dose by 20-40% every two weeks during Weeks 3-12.
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- 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).
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- 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)].
Dose Modifications
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 . 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.
| Adverse Reactiona | Severity | Dosage Modification |
|---|---|---|
| aNational Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 | ||
Liver enzyme elevation with concomitant bilirubin elevation, or other evidence of hepatic decompensation | Any increase above baseline | Interrupt treatment until recovery, restart at dose 50 mcg lower than the interrupted dose. If the interrupted dose is 50 mcg, refrain from treatment until recovery. Consider permanent discontinuation if toxicity persists after four dose-modifications. |
Liver enzyme elevation | >5 × the upper limit of normal (ULN) but ≤20 × ULN | Decrease dose by 50 mcg; if toxicity does not improve, continue decreasing at biweekly intervals until alanine aminotransferase (ALT) and aspartate aminotransferase (AST) recover < 3 × ULN if baseline was normal; 3 × baseline if baseline was abnormal, and gamma-glutamyltransferase (GGT) recovers to < 2.5 × ULN if baseline was normal; 2.5 × baseline if baseline was abnormal. |
If the interrupted dose is 50 mcg, refrain from treatment until recovery. | ||
>20 × ULN | Interrupt treatment until ALT and AST recover to < 3 × ULN if baseline was normal; 1.5 × baseline if baseline was abnormal, and gamma-glutamyltransferase (GGT) recovers to < 2.5 × ULN if baseline was normal; 2 × baseline if baseline was abnormal. Consider permanent discontinuation if toxicity persists after four dose-modifications. | |
Cytopenia | Anemia: Hemoglobin (Hgb) < 8 g/dL | Decrease dose by 50 mcg; if toxicity does not improve, continue decreasing at biweekly intervals until recovery of Hgb >10.0 g/dL, platelets >75,000/mm3, and WBC >3,000/mm3 |
Thrombocytopenia: platelet count < 50,000/mm3 but ≥25,000/mm3 | ||
Leukopenia: white blood cell count (WBC) <2000/mm3 but ≥1,000/mm3 | ||
If the interrupted dose is 50 mcg, refrain from treatment until recovery. | ||
Anemia: Hemoglobin levels are life threatening, or urgent intervention needed | Interrupt treatment until recovery of Hgb >10.0 g/dL, platelets >75,000/mm3, and WBC >3,000/mm3. | |
Thrombocytopenia: platelet count <25,000/mm 3 | Consider permanent discontinuation if toxicity persists after four dose-modifications. | |
Leukopenia: WBC <1000/mm3 | ||
Depression | Mild, without suicidal ideation | Consider psychiatric consultation if persistent (>8 weeks). |
Moderate, without suicidal ideation | Consider dose reduction and psychiatric consultation. | |
Severe, or any severity with suicidal ideation | Discontinue therapy, recommend psychiatric consultation. | |
Preparation and Administration
Read the INSTRUCTIONS FOR USE before administering the single-dose BESREMi prefilled syringe. 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 from the refrigerator. Keep the prefilled syringe in the carton and lay it flat on a clean work surface for 15-30 minutes to allow the prefilled syringe to reach room temperature [59 ˚F to 77 ˚F (15 ˚C to 25 ˚C)].
Before injection, visually inspect BESREMi in the prefilled syringe for particulate matter and discoloration before administration (do not use if the solution in the syringe is cloudy, discolored, contains particulate matter or if the syringe shows any sign of damage).
Syringe Preparation
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- Remove the prefilled syringe cap by unscrewing it counterclockwise.
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- 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.
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- 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.
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- 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
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- Depending on the prescribed dose, the amount of dose in the syringe may need to be adjusted by discarding some of the medication.
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- 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.
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- 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
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- 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.
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- 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 Syringe
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- 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.
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- Throw away the used prefilled syringe with the needle still attached, into an FDA-cleared sharps disposal container.
Injection: 500 mcg/mL clear and colorless to slightly yellowish solution in a single-dose prefilled syringe.
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. 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 may 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 (Cmax) and 64-times (AUC) the human exposure at the maximum recommended human dose of 500 µg. 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 (Cmax) and 224-times (AUC) the human exposure at the maximum recommended human dose of 500 µg.
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.
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.
Females and Males of Reproductive Potential
BESREMi may 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.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
There were 17 patients 65 years of age and older in the clinical study in polycythemia vera [see Clinical Studies (14)]. Of the total number of BESREMi-treated patients in this study, 17 (33%) were 65 years of age and older, while 5 (9.8%) 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.
Renal Impairment
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)].
Hepatic Impairment
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 (2.2) and Warnings and Precautions (5.11)].
BESREMi is contraindicated in patients with:
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- Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt.
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- Hypersensitivity to interferons including interferon alfa-2b or any of the inactive ingredients of BESREMi.
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- Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.
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- History or presence of active serious or untreated autoimmune disease.
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- History of transplantation and receiving immunosuppressant agents.