Armlupeg Product Monograph

1 INDICATIONS

Indications have been granted on the basis of similarity between Armlupeg and the reference biologic drug Neulasta.

Armlupeg (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-neoplastic drugs.

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

2 CONTRAINDICATIONS

Armlupeg (pegfilgrastim) is contraindicated in patients with known hypersensitivity to E. coli- derived products, pegfilgrastim, filgrastim, or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

• Splenic rupture, including fatal cases, has been reported following the administration of pegfilgrastim and its parent compound, filgrastim (see 7 WARNINGS AND PRECAUTIONS: General).
• Severe sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease. Severe sickle cell crises, in some cases resulting in death, have also been associated with filgrastim, the parent compound of pegfilgrastim (see 7 WARNINGS AND PRECAUTIONS: Hematologic).

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Armlupeg (pegfilgrastim) should be administered no sooner than 24 hours after the administration of cytotoxic chemotherapy (see 7 WARNINGS AND PRECAUTIONS).

Renal impairment, including end-stage renal disease, appears to have no effect on the pharmacokinetics of pegfilgrastim and no dosage adjustment is required.

4.2 Recommended Dose and Dosage Adjustment

The recommended dosage of Armlupeg is a single subcutaneous injection of 6 mg, administered once per cycle of chemotherapy. Armlupeg should be administered no sooner than 24 hours after the administration of cytotoxic chemotherapy (see 7 WARNINGS AND PRECAUTIONS).

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. (see 1.1 Pediatrics).

4.3 Reconstitution

Not applicable. Product does not need to be reconstituted.

4.4 Administration

Armlupeg is intended for subcutaneous injection only and should not be given by any other route of administration. Armlupeg should not be mixed with any diluents.

Armlupeg should not be vigorously shaken.

Following administration of Armlupeg from the single-use prefilled syringe, the patient should activate the UltraSafe^® Plus Passive Needle Guard by placing their hands behind the needle, grasping the guard with one hand, and sliding the guard forward until the needle is completely covered and the guard clicks into place. NOTE: If an audible click is not heard, the needle guard may not be completely activated.

4.5 Missed Dose

If a scheduled dose is missed, Armlupeg should not be administered less than 14 days before subsequent administration of cytotoxic chemotherapy.

5 OVERDOSAGE

The maximum tolerated dose of Armlupeg (pegfilgrastim) has not been determined in humans. Pegfilgrastim administered at a dose of 300 mcg/kg (n = 12), approximately three times the recommended dose, exhibited an adverse event profile similar to that observed at the recommended dose.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of biologic products, including biosimilars, health professionals should recognize the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 1. Dosage Forms, Strengths, Composition and Packaging

Armlupeg is a sterile‚ clear‚ colourless‚ preservative-free solution for subcutaneous administration, presented as single-dose prefilled syringe (PFS) which contains 6 mg of pegfilgrastim (based on protein mass only) in 0.6 mL solution for injection. The pH of the product is pH 4.00 ± 0.20.

Availability of Dosage Forms

Armlupeg is supplied as a preservative-free solution (0.6 mL) containing 6 mg of pegfilgrastim (10 mg/mL) in a single-dose syringe with a 27 gauge, ½ inch needle, with an UltraSafe^® Plus Passive Needle Guard.

The needle cover on the single-use prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions and should not be handled by individuals who are sensitive to latex.

To reduce the risk of accidental needle sticks to users, each single-use prefilled syringe is equipped with an UltraSafe^® Plus Passive Needle Guard that is manually activated to cover the needle during disposal.

Armlupeg is provided in a dispensing pack containing one syringe.

Description

Armlupeg (pegfilgrastim) is a biosimilar biological drug that is a long-acting form of recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) or filgrastim. Armlupeg is composed of filgrastim with a 20,000 dalton polyethylene glycol (PEG) molecule covalently bound to the N-terminal methionine residue. Filgrastim is a 175 amino acid protein with a molecular weight of 18,800 daltons; Armlupeg has a total molecular weight of 39,000 daltons.

For management of a suspected drug overdose, contact your regional poison control centre.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Armlupeg (pegfilgrastim) has not been evaluated for PBPC (peripheral blood progenitor cell) mobilization. Therefore, it should not be used in that setting.

Splenic Rupture

Splenic rupture, including fatal cases, has been reported following the administration of pegfilgrastim and its parent compound, filgrastim. Patients receiving Armlupeg who report left upper abdominal and/or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture.

Simultaneous Use with Chemotherapy and Radiation Therapy

The safety and efficacy of Armlupeg administered concurrently with cytotoxic chemotherapy have not been established. Because of the potential for an increase in sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ Armlupeg should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see 4 DOSAGE AND ADMINISTRATION).

The safety and efficacy of Armlupeg have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas), mitomycin C, or myelosuppressive doses of anti-metabolites such as 5-fluorouracil (5-FU). Concomitant use of Armlupeg with 5-FU or other anti-metabolites has not been evaluated in humans, although it has been studied and shown to potentiate myelosuppression in animal models (see 16 NON-CLINICAL TOXICOLOGY).

The safety and efficacy of Armlupeg have not been evaluated in patients receiving radiation therapy, except for patients with breast or lung cancer.

Carcinogenesis and Mutagenesis

No carcinogenesis or mutagenesis studies were conducted with Armlupeg.

Potential Effect on Malignant Cells

Armlupeg (pegfilgrastim) and filgrastim are growth factors that primarily stimulate production of neutrophils and neutrophil precursors by binding to the G-CSF receptor. Overall, the possibility that Armlupeg can act as a growth factor for any tumour type cannot be excluded. The use of pegfilgrastim in chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS) has not been studied.

MDS and AML in Breast and Lung Cancer Patients

In the post-marketing observational study setting, findings showed that pegfilgrastim is associated with an increased risk of MDS and AML in breast and lung cancer patients when used in conjunction with chemotherapy and/or radiotherapy. Monitor patients for signs and symptoms of MDS/AML in these settings.

Cardiovascular

Aortitis

Aortitis has been reported in patients receiving pegfilgrastim and may present with generalized signs and symptoms such as fever and increased inflammatory markers. Consider aortitis in patients who develop these signs and symptoms without known etiology.

Capillary Leak Syndrome

Capillary leak syndrome (CLS) has been reported after the administration of pegfilgrastim or filgrastim. CLS can cause circulatory shock and may be fatal, and is characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive treatment, which may include a need for intensive care.

Hematologic

Sickle Cell Crises

Severe sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease. Severe sickle cell crises, in some cases resulting in death, have also been associated with filgrastim, the parent compound of pegfilgrastim. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell trait and sickle cell disease should prescribe Armlupeg for such patients, and only after careful consideration of the potential risks and benefits.

Leukocytosis

In clinical studies with pegfilgrastim, white blood cell counts of 100 x 10⁹/L or greater have been reported in less than 1% of patients with cancer receiving myelosuppressive chemotherapy (n = 930), and were not associated with any reported adverse clinical effects (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

In studies of pegfilgrastim administration after chemotherapy‚ most reported side effects were consistent with those usually seen as a result of cytotoxic chemotherapy (see 8 ADVERSE REACTIONS). Because of the potential for patients to receive full doses of chemotherapy on the prescribed schedule‚ patients may be at greater risk of thrombocytopenia‚ anemia‚ and non- hematologic consequences of increased chemotherapy doses (please refer to the prescribing information for specific chemotherapy agents). Regular monitoring of hematocrit value and platelet count is recommended. Furthermore‚ care should be exercised in the administration of Armlupeg in conjunction with drugs known to lower platelet count.

Thrombocytopenia

Thrombocytopenia, including serious events, has been reported in patients receiving pegfilgrastim. Platelet counts should be monitored regularly as clinically indicated.

Immune

Hypersensitivity/Allergic Reactions

Hypersensitivity including serious allergic reactions and anaphylactic reactions, skin rash, urticaria and erythema/flushing occurring on initial or subsequent treatment have been reported both with pegfilgrastim and filgrastim. In some cases, symptoms have recurred with rechallenge, suggesting a causal relationship. In rare cases, allergic reactions, including anaphylactic reactions, recurred within days after initial anti-allergic treatment was discontinued. If a serious allergic reaction or an anaphylactic reaction occurs, appropriate therapy should be administered and further use of Armlupeg should be discontinued. Antibodies to filgrastim or pegfilgrastim have been reported, although no neutralizing antibodies have been reported (see 8 ADVERSE REACTIONS: Immunogenicity). Do not administer filgrastim to patients with a history of hypersensitivity to filgrastim or pegfilgrastim.

Cutaneous Vasculitis

Uncommon (≥ 1/1,000 to < 1/100) events of cutaneous vasculitis have been reported in patients treated with pegfilgrastim. The mechanism of vasculitis in patients receiving pegfilgrastim is unknown.

Monitoring and Laboratory Tests

To assess a patient's hematologic status and ability to tolerate myelosuppressive chemotherapy, a complete blood count (CBC) and platelet count should be obtained before chemotherapy is administered. Pegfilgrastim produced ANC (absolute neutrophil count) profiles similar to daily filgrastim, including earlier ANC nadir, shorter duration of severe neutropenia, and accelerated ANC recovery, compared with ANC profiles observed without growth factor support. Regular monitoring of hematocrit value, white blood cell count and platelet count, as clinically indicated, is recommended.

Renal

Glomerulonephritis

Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended.

Respiratory

Acute Respiratory Distress Syndrome (ARDS)

Acute respiratory distress syndrome (ARDS) has been reported following administration of pegfilgrastim and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Neutropenic patients receiving Armlupeg who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, Armlupeg should be discontinued and/or withheld until resolution of ARDS and patients should receive appropriate medical management for this condition.

Sexual Function/Reproduction

No studies evaluating sexual function or reproduction in humans were conducted with Armlupeg.

7.1 Special Populations

7.1.1 Pregnant Women

There were no pregnant women exposed to pegfilgrastim in clinical trials. Armlupeg should be used during pregnancy only if the potential benefit outweighs the risk to the fetus (see 16 NON-CLINICAL TOXICOLOGY).

7.1.2 Breast-feeding

It is not known whether pegfilgrastim is excreted in human milk. Because many drugs are excreted in human milk‚ Armlupeg is not recommended for women who are breast feeding. Armlupeg should only be administered to a nursing woman if the potential benefit outweighs the risk.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): The safety and effectiveness of Armlupeg in pediatric patients have not been established.

7.1.4 Geriatrics

Geriatrics (> 65 years of age): Of the total number of subjects with cancer who received pegfilgrastim in clinical studies (n = 930), 139 subjects (15%) were 65 years or older and

18 subjects (2%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients; however, due to the small number of elderly subjects, small but clinically relevant differences cannot be excluded.

8 ADVERSE REACTIONS

The adverse drug reaction profiles reported in clinical studies that compared Armlupeg to the reference biologic drug were comparable. The description of adverse reactions in this section is based on clinical experience with the reference biologic drug.

8.1 Adverse Reaction Overview

The most frequently reported study drug-related adverse event was bone pain, for which the incidence in patients treated with pegfilgrastim was similar to that in patients treated with filgrastim. Bone pain was generally reported as mild-to-moderate, could be controlled in most patients with non-narcotic analgesia.

See 7 WARNINGS AND PRECAUTIONS regarding Splenic Rupture, ARDS, Hypersensitivity/Allergic Reactions, and Sickle Cell Crises.

8.2 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Safety data are based on 7 randomized clinical trials involving 932 patients with lymphoma and solid tumours (breast and thoracic) who received pegfilgrastim after non-myeloablative cytotoxic chemotherapy. Common adverse events occurred at similar rates between the treatment arms in both the filgrastim-controlled trials (pegfilgrastim, n = 465; filgrastim, n = 331) and the placebo-controlled trial (pegfilgrastim, n = 467; placebo, n = 461). Most adverse experiences were attributed by the investigator as the sequelae of the underlying malignancy or cytotoxic chemotherapy. In the filgrastim-controlled trials, these adverse experiences occurred at rates between 15% and 72% and included: nausea, fatigue, alopecia, diarrhea, vomiting, constipation, fever, anorexia, skeletal pain, headache, taste perversion, dyspepsia, myalgia, insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema, dizziness, granulocytopenia, stomatitis, mucositis and neutropenic fever. A summary of the most frequently reported adverse reactions in these randomized clinical trials can be found in Table 1 and 2.

In clinical trials comparing pegfilgrastim to filgrastim, medullary bone pain was reported in 26% of pegfilgrastim-treated patients, which was comparable to the incidence in filgrastim-treated patients. In the study comparing pegfilgrastim to placebo, the incidence of bone pain was 23% vs. 16%, respectively. This bone pain was generally reported to be of mild-to-moderate severity.

Approximately 17% (for all bone pain type AEs; 10% for specifically “bone pain”) of all subjects utilized non-narcotic analgesics and less than 6% utilized narcotic analgesics in association with bone pain. No patient withdrew from study due to bone pain.

Across all studies, no life-threatening or fatal adverse events were attributed to pegfilgrastim. There was only one serious adverse event (dyspnea) reported as possibly related to pegfilgrastim in a single patient. No events of pleuritis, pericarditis, or other major systemic reactions to pegfilgrastim were reported.

No clinically significant changes in vital signs were observed. No evidence of interaction of pegfilgrastim with other drugs was observed in the course of clinical trials (see 7 WARNINGS AND PRECAUTIONS).

Table 2. Most Frequently* Reported Adverse Reactions in Randomized Clinical Trials with Filgrastim as Comparator

* Most frequently reported events were considered to be those events reported in ≥ 1% of the patients in the pegfilgrastim group.

Table 3. Most Frequently* Reported Adverse Reactions in Randomized Clinical Trials with Placebo Control

* Most frequently reported events were considered to be those events reported in ≥ 1% of the patients in the pegfilgrastim group.

8.3 Less Common Clinical Trial Adverse Reactions

The following adverse drug reactions were reported at an incidence of < 1% in controlled clinical studies (occurring in more than 1 patient, with higher frequency than filgrastim):

General Disorders and Administration Site Conditions: injection site bruising;

Infections and Infestations: rhinitis;

Nervous System Disorders: hypertonia;

Skin and Subcutaneous Tissue Disorders: periorbital edema.

The following adverse drug reactions were reported at an incidence of < 1% in controlled clinical studies (occurring in more than 1 patient, with higher frequency than placebo):

General Disorders and Administration Site Conditions: chest pain, pain.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Spontaneously reversible elevations in LDH, alkaline phosphatase, and uric acid of mild-to- moderate severity were observed. Most changes have been attributed to post-cytokine bone marrow expansion as well as to chemotherapy and metastatic disease. The incidences of these changes, presented for pegfilgrastim versus filgrastim and placebo, were: LDH (18% versus 29% and 18%), alkaline phosphatase (11% versus 16% and 12%), and uric acid [10% versus 9% and 13% (1% of uric acid reported cases for filgrastim and pegfilgrastim treatment groups were classified as severe)].

In clinical studies with pegfilgrastim, white blood cell counts of 100 x 10⁹/L or greater have been reported in less than 1% of patients with cancer receiving myelosuppressive chemotherapy (n = 930), and were not associated with any reported adverse clinical effects.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving pegfilgrastim has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to filgrastim or pegfilgrastim, the nature and specificity of these antibodies has not been adequately studied. No neutralizing antibodies have been detected using a cell-based bioassay in 46 (9%, n = 534) patients who apparently developed binding antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to pegfilgrastim with the incidence of antibodies to other products may be misleading.

Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against pegfilgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia, but this has not been observed in clinical studies.

For detailed immunogenicity information for Armlupeg, see 14.3 CLINICAL TRIALS: Immunogenicity.

8.5 Post-Market Adverse Reactions

In addition to the events listed above, reports of adverse reactions have been identified post- market in patients receiving pegfilgrastim, including:

• Splenomegaly (enlarged spleen) and Splenic rupture (see 7 WARNINGS AND PRECAUTIONS, General, Splenic Rupture)
• Aortitis (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular)
• Capillary Leak Syndrome (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular)
• Sickle cell crisis (see 7 WARNINGS AND PRECAUTIONS, Hematologic)
• Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukaemia (AML) in Breast and Lung Cancer Patients (see 7 WARNINGS AND PRECAUTIONS, Hematologic)

• Allergic reactions (see 7 WARNINGS AND PRECAUTIONS, Immune,

  Hypersensitivity/Allergic Reactions)

• Cutaneous Vasculitis (see 7 WARNINGS AND PRECAUTIONS, Immune)
• Glomerulonephritis (see 7 WARNINGS AND PRECAUTIONS, Renal)
• Acute respiratory distress syndrome (ARDS) (see 7 WARNINGS AND PRECAUTIONS, Respiratory)
• Injection site reactions (pain, induration, and local erythema)
• Generalized erythema and flushing
• Sweet’s syndrome (acute febrile neutrophilic dermatosis)

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

No serious drug interactions have been identified.

9.2 Drug Interactions Overview

Drug interactions between pegfilgrastim and other drugs have not been studied. Drugs such as lithium that may potentiate the release of neutrophils should be used with caution; such patients should have more frequent monitoring of their neutrophil counts.

9.3 Drug-Behavioural Interactions

No drug-behavioural interactions have been established.

9.4 Drug-Drug Interactions

Interactions with other drugs have not been established.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes. This should be considered when interpreting bone-imaging results.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Both pegfilgrastim and filgrastim are colony-stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors thereby stimulating proliferation, differentiation, commitment, and end cell functional activation. Studies on cellular proliferation, receptor binding, and neutrophil function demonstrate that filgrastim and pegfilgrastim have the same mechanism of action. Pegfilgrastim has reduced renal clearance and prolonged persistence in vivo as compared to filgrastim.

10.2 Pharmacodynamics

See information in 10.3 below.

10.3 Pharmacokinetics

The pharmacokinetics and pharmacodynamics of pegfilgrastim were studied in patients with cancer. The pharmacokinetics of pegfilgrastim were nonlinear in cancer patients and clearance decreased with increases in dose. Neutrophil-mediated clearance is an important component of the clearance of pegfilgrastim, and serum clearance is related to the number of neutrophils (neutrophil-mediated, self-regulating clearance). Consistent with a self-regulating clearance mechanism, the serum concentration of pegfilgrastim declined rapidly at the onset of neutrophil recovery, following myelosuppressive chemotherapy. In addition to numbers of neutrophils, body weight appeared to be a factor. Patients with higher body weights experienced higher systemic exposure to pegfilgrastim after receiving a dose normalized for body weight. A large variability in the pharmacokinetics of pegfilgrastim was observed in cancer patients. The half-life of pegfilgrastim ranged from 25 to 49 hours after SC injection.

Table 4. Summary of Pharmacokinetic Parameters of pegfilgrastim in Cancer Patients After SC Administration

* Doses of 100 mcg/kg and 6 mg

Figure 1. Median pegfilgrastim Serum Concentration and Absolute Neutrophil Count Profiles in Patients With Non-Small Cell Lung Cancer (n = 3) After a Single Injection of pegfilgrastim 100 mcg/kg Administered Before and After Chemotherapy

Special Populations and Conditions

• Pediatrics: The pharmacokinetic profile in pediatric populations has not been assessed. Health Canada has not authorized an indication for pediatric use.
• Geriatrics: No differences were observed in the pharmacokinetics of geriatric patients with cancer (≥ 65 years of age) compared to younger patients (< 65 years of age) (see 7.1.4 Geriatrics).
• Sex: No gender-related differences were observed in the pharmacokinetics of pegfilgrastim.
• Ethnic Origin: The effect of race on pharmacokinetics has not been adequately assessed.
• Hepatic Insufficiency: The pharmacokinetic profile in patients with hepatic insufficiency has not been assessed.
• Renal Insufficiency: Renal impairment, including end-stage renal disease, appears to have no effects on the pharmacokinetics of pegfilgrastim.

11 STORAGE, STABILITY AND DISPOSAL

Armlupeg (pegfilgrastim) should be stored refrigerated at 2° to 8°C (36° to 46°F). Keep the container in the outer carton to protect from light. Before injection‚ Armlupeg may be allowed to reach room temperature for a maximum of 48 hours. Armlupeg left at room temperature for more than 48 hours should be discarded. Freezing should be avoided; however, if accidentally frozen Armlupeg should be allowed to thaw in the refrigerator before administration. If frozen a second time, Armlupeg should be discarded.

Armlupeg should be visually inspected for discolouration and particulate matter before administration. Armlupeg should not be administered if discolouration or particulates are observed.

12 SPECIAL HANDLING INSTRUCTIONS

Armlupeg (pegfilgrastim) should not be vigorously shaken.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Product Characteristics

Armlupeg (pegfilgrastim) is a sterile, clear, colourless liquid.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Clinical studies conducted to support similarity between Armlupeg and the reference biologic drug included:

• A randomized, double-blind, two-way cross over comparative pharmacokinetic (PK)/ pharmacodynamic (PD) study in healthy adult, volunteers (ALR/18/360/LBC-19-146)
• An open-label, randomized, comparative clinical study to assess immunogenicity in patients with breast cancer receiving myelosuppressive chemotherapy (LRP/PegGCSF/2016/004)

An overview of the study design and demographic characteristics of subjects enrolled in each clinical study is presented in Table 5.

Table 5 – Summary of Trial Design and Patient Demographics

PK: Pharmacokinetics, PD: Pharmacodynamics, US = United States

Comparative Safety

In an open-label immunogenicity study (LRP/PegGCSF/2016/004), female patients with breast cancer receiving myelosuppressive chemotherapy were randomized 1:1 to receive either Armlupeg or US-Neulasta administered on Day 2/3 of each chemotherapy cycle of 21 days for up to 4 cycles. No differences in the safety between Armlupeg and US-Neulasta were observed in the breast cancer patients under the study conditions.

14.3 Comparative Bioavailability Studies

PK and PD comparability of Armlupeg and Neulasta was evaluated in a single-dose, two-way cross over comparative study (ALR/18/360/LBC-19-146) in healthy adult subjects with a single subcutaneous administration of Armlupeg and the reference biologic drug (US-licensed Neulasta).

Pharmacokinetics

The results of the PK comparisons are shown in Table 6.

Table 6 – Study ALR/18/360/LBC-19-146: Analysis of Primary PK Parameters

1. 1. Armlupeg (Pegfilgrastim) by Lupin Pharma
2. 2. US-Neulasta (Pegfilgrastim) by Amgen Inc

AUC_0-t = Area under the serum concentration-time curve measured from the time of dosing to the last measurable concentration

AUC_0-∞ = Area under the serum concentration-time curve measured from the time of dosing and extrapolated to infinity

Cmax = maximum concentration

Tmax = time to Cmax. Tmax is expressed as the arithmetic mean (CV%).

T1/2 = half-life. T1/2 is expressed as the arithmetic mean (CV%).

Pharmacodynamics

The results of the pharmacodynamics comparisons are shown in Table 7.

Table 7 – Study ALR/18/360LBC-19-146: Analysis of Primary Pharmacodynamic Parameters [absolute neutrophil count (ANC)]

1. 1. Armlupeg (Pegfilgrastim) by Lupin Pharma
2. 2. US-Neulasta (Pegfilgrastim) by Amgen Inc

ANC_AUEC_0-t = area under the effect ANC-time curve from time zero to the last measurable time point

ANC_C_max = maximum effect in ANC

Comparative Safety

Similar safety profiles between Armlupeg and Neulasta were observed in the PK-PD study in healthy volunteers (ALR/18/360/LBC-19-146).

14.4 Immunogenicity

A tiered approach was used for anti-drug (pegfilgrastim) antibody (ADA) testing. Immunogenicity was assessed using a validated electrochemiluminescence (ECL) assay against ADA. A cell-based assay was used to detect neutralizing antibodies.

ALR/18/360/LBC-19-146 (single dose cross-over study in healthy subjects)

In study ALR/18/360/LBC-19-146, ADA were assessed from blood samples collected at pre-dose and 336 hours post dose in each period. In the sequence group receiving Armlupeg in the first period, 36 out of 114 (31.6%) subjects were positive for treatment-emergent ADA. In sequence group receiving Neulasta in the first period, 23 out of 111 (20.7%) subjects were positive for treatment-emergent ADA. Among them, 3 out of 36 (8.3%) subjects were positive for neutralizing antibody in subjects receiving Armlupeg in the first period, and 5 out of 23 (21.7%) positive for neutralizing antibody in subjects receiving Neulasta in the first period.

LRP/PegGCSF/2016/004 (immunogenicity study in breast cancer patients)

In the immunogenicity study (LRP/PegGCSF/2016/004) in breast cancer patients receiving myelosuppressive chemotherapy, one (1.7%) patient in the Armlupeg and 3 (5.4%) patients in the Neulasta group had treatment-emergent ADA (defined as a shift from negative at baseline to positive post-treatment) which developed 1 to 9 weeks after study drug administration. No patients had positive ADA detected at the end of the study (Day 84). None of the binding antibodies were neutralizing.

14.5 Clinical Trials- Reference biologic drug

Table 8. Summary of patient demographics for clinical trials in specific indication

Study Results

Clinical Experience: Response to pegfilgrastim

Pegfilgrastim administered as a single SC injection, after each cycle of chemotherapy, has been shown to be safe and effective in reducing neutropenia and associated clinical sequelae in a variety of chemotherapy settings.

Pegfilgrastim has been evaluated in three Phase 3, randomized, double-blind, controlled studies. Results from two active controlled studies (n = 467) conducted in patients with breast cancer undergoing up to 4 cycles of chemotherapy with doxorubicin and docetaxel demonstrated non- inferiority of pegfilgrastim to filgrastim. A clinically and statistically similar reduction in the duration of severe neutropenia (absolute neutrophil count [ANC] < 0.5 x 10⁹/L; WHO grade 4) was seen in patients who received a single injection of pegfilgrastim, either 6 mg fixed dose or 100 mcg/kg, compared with patients who received a mean of 11 daily injections (cycle 1) of filgrastim 5 mcg/kg/day.

The mean (std dev) duration of severe neutropenia in cycle 1 in patients who received a single fixed-dose (6 mg) SC injection of pegfilgrastim (n = 68) was 1.8 (1.4) days compared with 1.6 (1.1) days in patients who received daily injections (range: 7-14 injections) of filgrastim (n = 62). The difference in means was 0.18 days (95% CI of -0.23 to 0.61). Durations of severe neutropenia were also comparable between treatment groups in all subsequent cycles. The rate of febrile neutropenia (temperature ≥ 38.2°C with an ANC < 0.5 x 10⁹/L) across all cycles was lower for patients receiving pegfilgrastim (13%) compared to patients receiving filgrastim (20%) (-7% difference; 95% CI of -19% to +5%). A single SC injection of pegfilgrastim per chemotherapy cycle was safe and well tolerated (see 8 ADVERSE REACTIONS).

The third study employed a placebo control and evaluated the effect of pegfilgrastim on the incidence of febrile neutropenia when administered in first and all subsequent cycles of a moderately myelosuppressive chemotherapy regimen, docetaxel administered at 100 mg/m² Q3W for 4 cycles, which has been reported to be associated with a febrile neutropenia rate of 10% to 20%.

In this study, 928 patients with metastatic or non-metastatic breast cancer were treated with docetaxel. On day 2 of cycle 1, patients were randomized to receive either a single SC dose of 6 mg of pegfilgrastim or placebo. Patients who received pegfilgrastim in cycle 1 were scheduled to receive pegfilgrastim in all subsequent cycles. Patients who received placebo in cycle 1 were scheduled to receive placebo in all subsequent cycles; however, patients who experienced febrile neutropenia would receive open-label pegfilgrastim.

The incidence of febrile neutropenia was statistically significantly lower for patients randomized to receive pegfilgrastim versus placebo (1% versus 17%, p ≤ 0.001). The incidence of hospitalizations and IV anti-infective use associated with a clinical diagnosis of febrile neutropenia was significantly lower in the pegfilgrastim group compared with placebo [1% versus 14%, p ≤ 0.001; and 2% versus 10%, p ≤ 0.001, respectively (see Figure 2)].

Figure 2. Percentage of Subjects With Febrile Neutropenia (FN), Who Were Hospitalized, and Who Received IV Anti-infectives for FN

Data from Phase 2 studies in patients with various malignancies undergoing a variety of chemotherapy regimens further support the safety and efficacy of pegfilgrastim. Dose-finding studies in patients with breast cancer (n = 152), thoracic tumours (n = 92), and non-Hodgkin's lymphoma (NHL) (n = 49) demonstrated that the efficacy of a single injection of pegfilgrastim

100 mcg/kg was similar to daily injections of filgrastim 5 mcg/kg/day, and superior to pegfilgrastim doses of 30 or 60 mcg/kg, at reducing the duration of severe neutropenia and the rate of febrile neutropenia. A randomized phase II study of patients with NHL or Hodgkin's lymphoma (n = 60) further supports the safety and efficacy of pegfilgrastim.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Preclinical Studies

The preclinical toxicology of pegfilgrastim was studied in Sprague-Dawley^® rats and cynomolgus monkeys. A single-dose IV study was conducted in rats. Pegfilgrastim caused no clinical signs or mortality at single IV doses up to 10,000 mcg/kg in rats.

Repeat-dose studies included 2-week SC (every-other-day dosing) and 6-month SC/IV (weekly dosing) studies in rats and a 1-month SC (weekly dosing) study in monkeys. Dosing was intermittent to mimic intended human use of pegfilgrastim. Pegfilgrastim was well tolerated for 6 months at once-weekly doses up to 1000 mcg/kg SC or 300 mcg/kg IV in rats, and for 1 month at once-weekly doses up to 750 mcg/kg SC in cynomolgus monkeys. No effects on body weight, food consumption, or survival were observed. Pegfilgrastim caused an increase in leukocyte counts, primarily segmented neutrophils, but also some increases in band neutrophils, monocytes, and lymphocytes. Pegfilgrastim also modestly decreased erythrocyte counts, hemoglobin and hematocrit levels, decreased serum cholesterol, slightly decreased serum potassium, and increased serum alkaline phosphatase. Splenomegaly was the principal gross pathological finding. Histopathological examination revealed increased neutrophilic granulopoiesis in bone marrow and extramedullary hematopoiesis in spleen, liver, and/or lymph nodes. Leukocytosis in spleen, liver, and lymph nodes, and mild inflammation and mononuclear cell infiltrate at the injection site were additionally observed in monkeys treated with pegfilgrastim. Observed changes tended to reverse upon cessation of treatment. Changes specific to every-other-day dosing in rats (≥ 500 mcg/kg only) included slightly increased serum ALT and/or AST, mild myelofibrosis in bone marrow, and increased osteoblastic/osteoclastic activity in bone. Little or no seroreactivity to pegfilgrastim was evident in rats, whereas a dose- and time-dependent increase in seroreactivity was observed in monkeys; however, pegfilgrastim-induced neutrophil increases were maintained.

Pegfilgrastim has been shown to have adverse effects in pregnant rabbits when given every- other-day at doses as low as 50 mcg/kg. Nonclinical data in pregnant rats indicate that very low levels of pegfilgrastim may cross the placenta.

Pegfilgrastim administered SC to pregnant rabbits at doses of 200 and 250 mcg/kg every-other- day during the period of organogenesis was associated with an increased incidence of abortions. Increased postimplantation loss due to early resorptions and decreased numbers of live fetuses were observed at pegfilgrastim doses of 200 to 1000 mcg/kg every other day.

Decreased maternal food consumption and/or weight gain and decreased fetal weight were observed at doses of 50 to 1000 mcg/kg every other day. Pegfilgrastim did not cause visceral or skeletal malformations in rabbit fetuses at doses as high as 200 mcg/kg every-other-day and did not cause external malformations in rabbit fetuses at doses as high as 1000 mcg/kg every other day.

Pegfilgrastim was not associated with an increase in external, visceral, or skeletal malformations in fetuses when administered by SC injection to pregnant rats during the period of organogenesis at dose levels up to 1000 mcg/kg every other day. However, an increased incidence of wavy ribs, generally regarded as a reversible pathological finding, was observed in rat fetuses at dose levels of 300 and 1000 mcg/kg every other day. No maternal or neonatal toxicities were observed in female rats administered once-weekly SC injections of pegfilgrastim up to 1000 mcg/kg in a pre- and postnatal developmental study.

Filgrastim is known to be negative in bacterial mutagenesis assays (Ames assay). Pegfilgrastim did not cause precancerous or cancerous lesions in Sprague-Dawley^® rats after once-weekly SC injections of up to 1000 mcg/kg for 6 months. Given the similar biochemical activity to filgrastim, the chemical nature of the PEG moiety, and extensive clinical experience with filgrastim, it is considered unlikely that pegfilgrastim would be carcinogenic when used as directed.

Pegfilgrastim is a growth factor that primarily stimulates production of neutrophils and neutrophil precursors; however, the G-CSF receptor through which pegfilgrastim and filgrastim act has been found on tumour cell lines, including some myeloid, T-lymphoid, lung, head and neck, and bladder tumour cell lines. In vitro proliferation has been observed in response to filgrastim in some of these cell lines, particularly acute myeloid leukemia (AML) cell lines.

Indices of mating or fertility in male and female Sprague-Dawley^® rats were not adversely affected by once-weekly SC injections of pegfilgrastim of up to 1000 mcg/kg for 2 to 4 weeks before and during cohabitation.

16.1 Comparative Non-Clinical Pharmacology and Toxicology

16.1.1 Comparative Non-Clinical Pharmacodynamics

In vitro studies

The biological characteristic of Armlupeg and US-Neulasta was evaluated using a cell-based proliferation assay and a receptor binding assay, as outlined in Table 9.

Table 9 – Overview of Studies Comparing In vitro activity between Armlupeg and Neulasta.

17 SUPPORTING PRODUCT MONOGRAPHS

NEULASTA (Pegfilgrastim Injection, Sterile Solution, 6 mg (10 mg/mL)), Submission Control No.: 242732, Product Monograph, Amgen Canada Inc. (JAN 08, 2021)