BESREMi

2 DOSAGE AND ADMINISTRATION 2.1 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)]. 2.2 Recommended Dosage 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 (hematocrit less than 45%, platelets less than 400 x 109/L, and leukocytes less than 10 x 109/L). 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 x 109/L, and leukocytes less than 10 x 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)]. 2.3 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 (Table 1). 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. Table 1 Dose Modifications for BESREMi Adverse Reactions Adverse Reaction a Severity Dosage Modification 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 x the upper limit of normal (ULN) but ≤20 x 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 20 x ULN Interrupt treatment until ALT and AST recover to 10.0 g/dL, platelets >75,000/mm3, and WBC >3,000/mm3 If the interrupted dose is 50 mcg, refrain from treatment until recovery. Anemia: Hemoglobin levels are life threatening, or urgent intervention needed Thrombocytopenia: platelet count 10.0 g/dL, platelets >75,000/mm3, and WBC >3,000/mm3. Consider permanent discontinuation if toxicity persists after four dose-modifications. Depression Mild, without suicidal ideation Moderate, without suicidal ideation Severe, or any severity with suicidal ideation Consider psychiatric consultation if persistent (>8 weeks). Consider dose reduction and psychiatric consultation. Discontinue therapy, recommend psychiatric consultation. a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 2.4 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 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 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 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. 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 ( 2.1 ) Interrupt or discontinue dosing if certain adverse reactions occur ( 2.3 , 5 ) 2.1 Pre-Treatment Testing Pregnancy testing is recommended prior to BESREMi treatment in females of reproductive potential [see Use in Specific Populations (8.3) ] . 2.2 Recommended Dosage 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 (hematocrit less than 45%, platelets less than 400 × 10 9 /L, and leukocytes less than 10 × 10 9 /L). 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 × 10 9 /L, and leukocytes less than 10 × 10 9 /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) ] . 2.3 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 (Table 1). 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. Table 1 Dose Modifications for BESREMi Adverse Reactions Adverse Reaction National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 Severity Dosage Modification 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 20 × ULN Interrupt treatment until ALT and AST recover to 10.0 g/dL, platelets >75,000/mm 3 , and WBC >3,000/mm 3 Thrombocytopenia: platelet count 10.0 g/dL, platelets >75,000/mm 3 , and WBC >3,000/mm 3 . Thrombocytopenia: platelet count 8 weeks). Moderate, without suicidal ideation Consider dose reduction and psychiatric consultation. Severe, or any severity with suicidal ideation Discontinue therapy, recommend psychiatric consultation. 2.4 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 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 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 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.

See official label

1 INDICATIONS AND USAGE BESREMi is indicated for the treatment of adults with polycythemia vera.