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

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.

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).

5.1 Depression and Suicide

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. Serious neuropsychiatric reactions have been observed in 3% of patients treated with BESREMi during the clinical development program. Among the 178 patients in the clinical development program of BESREMi, 17 cases of depression, depressive symptoms, depressed mood, and listlessness occurred. Of these seventeen 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.

5.2 Endocrine Toxicity

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. Eight cases of hyperthyroidism (4.5%), seven cases of hypothyroidism (3.9%) and five cases (2.8%) of autoimmune thyroiditis/thyroiditis occurred in the development program of BESREMi.

Do not use BESREMi in patients with active serious or untreated endocrine disorders associated with autoimmune disease [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.

5.3 Cardiovascular Toxicity

Cardiovascular toxicity has occurred in patients receiving interferon alfa products, including BESREMi. Toxicities may include cardiomyopathy, myocardial infarction, atrial fibrillation and coronary artery ischemia [see Adverse Reactions (6.1)] . Patients with a history of cardiovascular disorders should be closely monitored for cardiovascular toxicity 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.

5.4 Decreased Peripheral Blood Counts

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). Thrombocytopenia of grade 3 (platelet counts <50,000 – 25,000/mm 3) or greater occurred in 2% of BESREMi-treated patients. Anemia of grade 3 (Hgb < 8 g/dL) or greater occurred in 1% of BESREMi-treated patients. Leukopenia of grade 3 (WBC counts <2,000 – 1,000/mm 3) or greater occurred in 2% of BESREMi-treated patients. Infection occurred in 48% of BESREMi treated patients, while serious infections occurred in 8% of BESREMi treated 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.

5.5 Hypersensitivity Reactions

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). If such reactions occur, discontinue BESREMi and institute appropriate medical therapy immediately. Transient rashes may not necessitate interruption of treatment.

5.6 Pancreatitis

Pancreatitis has occurred in patients receiving interferon alfa products, including BESREMi. Pancreatitis was reported in 2.2% of patients receiving BESREMi. 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.

5.7 Colitis

Fatal and serious 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.

5.8 Pulmonary Toxicity

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, and sarcoidosis. Some events have resulted in respiratory failure or death. Discontinue BESREMi in patients who develop pulmonary infiltrates or pulmonary function impairment.

5.9 Ophthalmologic Toxicity

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, 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.

5.10 Hyperlipidemia

Hyperlipidemia has occurred in patients treated with interferon alfa products, including BESREMi. Hyperlipidemia, hypertriglyceridemia, or dyslipidemia occurred in 3% of patients receiving BESREMi. 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.

5.11 Hepatotoxicity

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

In the clinical development program of BESREMi, 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. Reduce BESREMi dosage by 50 mcg for increased AST/ALT/GGT then monitor AST/ALT/GGT weekly until the values return to baseline or grade 1 (ALT and AST < 3 × ULN if baseline was normal; 1.5 - 3 × baseline if baseline was abnormal, and GGT < 2.5 × ULN if baseline was normal; 2 - 2.5 × baseline if baseline was abnormal) [see Dosage and Administration (2.3)]. If toxicity does not improve, continue decreasing the BESREMi dose at biweekly intervals until recovery to grade 1. Hold if AST/ALT/GGT > 20 × ULN and consider permanent discontinuation if increased liver enzyme levels persist after four dose-reductions. 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)] .

5.12 Renal Toxicity

Renal toxicity has occurred in patients receiving interferon alfa products, including BESREMi. During BESREMi therapy, <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)] .

5.13 Dental and Periodontal Toxicity

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.

5.14 Dermatologic Toxicity

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.

5.15 Driving and Operating Machinery

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.

5.16 Embryo-Fetal Toxicity

Based on the mechanism of action, BESREMi can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Use in Specific Populations (8.1)] . Pregnancy testing is recommended in females of reproductive potential prior to 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 (2.1) and Use in Specific Populations (8.1, 8.3)] .

6.1 Clinical Trials Experience

The following clinically significant adverse reactions are described elsewhere in the labeling.

• Depression and Suicide [see Warnings and Precautions (5.1)]
• Endocrine Toxicity [see Warnings and Precautions (5.2)]
• Cardiovascular Toxicity [see Warnings and Precautions (5.3)]
• Decreased Peripheral Blood Counts [see Warnings and Precautions (5.4)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
• Pancreatitis [see Warnings and Precautions (5.6)]
• Colitis [see Warnings and Precautions (5.7)]
• Pulmonary Toxicity [see Warnings and Precautions (5.8)]
• Ophthalmologic Toxicity [see Warnings and Precautions (5.9)]
• Hyperlipidemia [see Warnings and Precautions (5.10)]
• Hepatotoxicity [see Warnings and Precautions (5.11)]
• Renal Toxicity [see Warnings and Precautions (5.12)]
• Dental and Periodontal Toxicity [see Warnings and Precautions (5.13)]
• Dermatologic Toxicity [see Warnings and Precautions (5.14)]
• Driving and Operating Machinery [see Warnings and Precautions (5.15)]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.16)]

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.

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/CONTINUATION PV]. The mean age at baseline was 58.6 years (range 30-85 years), 88 (49.4%) women, 90 (50.6%) 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 2.

Clinically relevant adverse reactions in < 10% of patients include:

Cardiovascular System: Atrial fibrillation

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other interferon alfa-2b products may be misleading.

The incidence of binding antibodies to ropeginterferon alfa-2b-njft was 1.4% (2/146) and they were observed as early as 8 weeks post-dosing. Among the patients who tested positive for binding antibodies, none developed neutralizing antibodies.

7.1 Drugs Metabolized by Cytochrome P450

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.

7.2 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 [see Warnings and Precautions (5.4)] .

7.3 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)] .

8.1 Pregnancy

8.2 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.

8.3 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)] .

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 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.

8.6 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)].

8.7 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)] .

12.1 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). 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 are not fully elucidated.

12.2 Pharmacodynamics

The efficacy of ropeginterferon alfa-2b-njft is dependent on the stabilization of hematological parameters (hematocrit <45%, platelets <400 × 10 9/L and leukocytes <10 × 10 9/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 × 10 9/L and leukocytes ≤10 × 10 9/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, 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.

12.3 Pharmacokinetics

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 1011 – 7809 ng×h/mL, respectively. The estimated steady state C max occurs between 2 to 5 days.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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)] .

16.1 How Supplied

BESREMi (ropeginterferon alfa-2b-njft) injection is a sterile, preservative-free, clear and colorless to slightly yellowish solution for subcutaneous administration in a single-dose prefilled syringe. Each carton contains one 500 mcg/mL prefilled syringe with a 30 gauge, ½ inch safety hypodermic needle (NDC 73536-500-01).

16.2 Storage and Handling

Store in a refrigerator at 36 °F to 46 °F (2 °C to 8 °C) in the original carton to protect from light.

Do not freeze.

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 [see Warnings and Precautions (5.1)] .

Endocrine Toxicity

Advise patients to report any signs or symptoms of diabetes or thyroid dysfunction [see Warnings and Precautions (5.2)] .

Cardiovascular Toxicity

Advise patients to report signs or symptoms of cardiovascular toxicity to their healthcare provider [see Warnings and Precautions (5.3)].

Decreased Peripheral Blood Counts

Advise patients to seek prompt medical attention if they experience weakness/fatigue, fever, easy bruising, or frequent nose bleeds [see Warnings and Precautions (5.4)].

Hypersensitivity

Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.5) and Drug Interactions (7)].

Pancreatitis

Advise patients to report signs or symptoms of pancreatitis [see Warnings and Precautions (5.6)] .

Colitis

Advise patients to report signs or symptoms of colitis [see Warnings and Precautions (5.7)] .

Pulmonary Toxicity

Advise patients to report signs or symptoms of pulmonary toxicity [see Warnings and Precautions (5.8)] .

Ophthalmologic Toxicity

Advise patients to report visual changes and to have eye examinations before and during treatment [see Warnings and Precautions (5.9)] .

Hyperlipidemia

Advise patients that BESREMi may increase blood triglycerides and that they will need blood testing to monitor for this toxicity [see Warnings and Precautions (5.10)] .

Hepatotoxicity

Advise patients to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions (5.11) and Use in Specific Populations (8.7)] .

Renal Toxicity

Advise patients to report signs or symptoms of kidney disease [see Warnings and Precautions (5.12) and Use in Specific Populations (8.6)] .

Dental and Periodontal Toxicity

Advise patients to maintain good oral hygiene and to have regular dental examinations [see Warnings and Precautions (5.13)] .

Dermatologic Toxicity

Advise patients to seek medical attention if significant pruritus, alopecia, rash and/or other dermatological toxicities occur [see Warnings and Precautions (5.14)] .

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 [see Warnings and Precautions (5.15)] .

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 [see Use in Specific Populations (8.1, 8.3)] .

Lactation

Advise women not to breastfeed during treatment and for 8 weeks after the final dose [see Use in Specific Populations (8.2)] .

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 [see Dosage and Administration (2.4)] .