Dyrupeg 6 mg solution for injection in a pre-filled syringe

4.1. Therapeutic indications

Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes).

4.2. Posology and method of administration

Dyrupeg therapy should be initiated and supervised by physicians experienced in oncology and/or hematology. Posology One 6 mg dose (a single pre-filled syringe) of Dyrupeg is recommended for each chemotherapy cycle, given at least 24 hours after cytotoxic chemotherapy. Special populations Paediatric population The safety and efficacy of Dyrupeg in children have not yet been established. Currently available data are described in sections 4.8, 5.1, and 5.2, but no recommendation on a posology can be made. Renal impairment No dose change is recommended in patients with renal impairment, including those with end-stage renal disease. Method of administration Dyrupeg is for subcutaneous use. The injection should be given into the thigh, abdomen, or upper arm. For instructions on handling the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs), the name and batch number of the administered medicinal product should be clearly recorded in the patient file. Patients with myeloid leukaemia or myelodysplastic syndromes Limited clinical data suggest a comparable effect on time to recovery of severe neutropenia for pegfilgrastim to filgrastim in patients with de novo acute myeloid leukaemia (AML) (see section 5.1). However, the long-term effects of pegfilgrastim have not been established in AML; therefore, it should be used with caution in this patient population. G-CSFs can promote the growth of myeloid cells in vitro, and similar effects may be seen on some non-myeloid cells in vitro . The safety and efficacy of pegfilgrastim have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukaemia, and in patients with secondary AML; therefore, it should not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from AML. The safety and efficacy of pegfilgrastim administration in de novo AML patients aged < 55 years with cytogenetics (15;17) have not been established. The safety and efficacy of pegfilgrastim have not been investigated in patients receiving high-dose chemotherapy. This medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dose regimens. Pulmonary adverse reactions Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk (see section 4.8). The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function along with increased neutrophil count may be preliminary signs of acute respiratory distress syndrome (ARDS). In such circumstances, pegfilgrastim should be discontinued at the discretion of the physician and the appropriate treatment given (see section 4.8). 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. Capillary leak syndrome Capillary leak syndrome has been reported after G-CSF administration and is characterized by hypotension, hypoalbuminemia, edema, and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care (see section 4.8). Splenomegaly and splenic rupture Generally, asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatal cases, have been reported following the administration of pegfilgrastim (see section 4.8). Therefore, spleen size should be carefully monitored (e.g., clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tip pain. Thrombocytopenia and anaemia Treatment with pegfilgrastim alone does not preclude thrombocytopenia and anaemia because full dose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of platelet count and hematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic agents, which are known to cause severe thrombocytopenia. Myelodysplastic syndrome and acute myeloid leukaemia in breast and lung cancer patients In the post-marketing observational study setting, pegfilgrastim in conjunction with chemotherapy and/or radiotherapy has been associated with the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) in breast and lung cancer patients (see section 4.8). Patients treated in these settings should be monitored for signs and symptoms of MDS/AML. Sickle cell anaemia Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease (see section 4.8). Therefore, physicians should use caution when prescribing pegfilgrastim in patients with sickle cell trait or sickle cell disease, should monitor appropriate clinical parameters and laboratory status, and be attentive to the possible association of this medicinal product with splenic enlargement and vaso-occlusive crisis. Leukocytosis White blood cell (WBC) counts of 100 × 10 9 /L or greater have been observed in less than 1% of patients receiving pegfilgrastim. Such elevation in white blood cells is transient, typically seen 24 to 48 hours after administration, and is consistent with the pharmacodynamic effects of this medicinal product . Consistent with the clinical effects and the potential for leukocytosis, a WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50 × 10 9 /L after the expected nadir, this medicinal product should be discontinued immediately. Hypersensitivity Hypersensitivity, including anaphylactic reactions occurring on initial or subsequent treatment, has been reported in patients treated with pegfilgrastim. Permanently discontinue pegfilgrastim in patients with clinically significant hypersensitivity. Do not administer pegfilgrastim to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in association with pegfilgrastim treatment. If the patient has developed SJS with the use of pegfilgrastim, treatment with pegfilgrastim must not be restarted in this patient at any time. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against pegfilgrastim are generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralizing activity at present. Aortitis Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). In most cases, aortitis was diagnosed by CT scan and generally resolved after withdrawal of G-CSF. See also section 4.8. Mobilization of PBPC (peripheral blood progenitor cell ) The safety and efficacy of Dyrupeg for the mobilization of blood progenitor cells in patients or healthy donors have not been adequately evaluated. Other special precautions The increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging findings. This should be considered when interpreting bone-imaging results. Excipients Sorbitol (E420) This medicinal product contains 30 mg of sorbitol in each pre-filled syringe, which is equivalent to 50 mg/mL. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per 6 mg dose, so it is essentially 'sodium-free.' Polysorbate 20 (E432) This medicinal product contains 0.02 mg of polysorbate 20 in each pre-filled syringe. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ pegfilgrastim should be administered at least 24 hours after administration of cytotoxic chemotherapy. In clinical trials, pegfilgrastim has been safely administered 14 days before chemotherapy. Concomitant use of pegfilgrastim with any chemotherapy agent has not been evaluated in patients. In animal models, concomitant administration of pegfilgrastim and 5-fluorouracil (5-FU) or other antimetabolites has been shown to potentiate myelosuppression. Possible interactions with other haematopoietic growth factors and cytokines have not been specifically investigated in clinical trials. The potential for interaction with lithium, which also promotes the release of neutrophils, has not been specifically investigated. There is no evidence that such an interaction would be harmful. The safety and efficacy of pegfilgrastim have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression, e.g., nitrosoureas. Specific interaction or metabolism studies have not been performed; however, clinical trials have not indicated an interaction of pegfilgrastim with any other medicinal products.

4.6. Fertility, pregnancy and lactation

Pregnancy There is no or limited amount of data on the use of pegfilgrastim in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Pegfilgrastim is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding There is insufficient information on the excretion of pegfilgrastim/metabolites in human breast milk; a risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from pegfilgrastim therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 6 to 9 times higher than the recommended human dose (based on body surface area) (see section 5.3).

4.7. Effects on ability to drive and use machines

Pegfilgrastim has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile The most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) and musculoskeletal pain (common [≥ 1/100 to < 1/10]). Bone pain was generally of mild to moderate severity, transient, and could be controlled in most patients with standard analgesics. Hypersensitivity-type reactions, including skin rash, urticaria, angioedema, dyspnoea, erythema, flushing, and hypotension, occurred on initial or subsequent treatment with pegfilgrastim (uncommon [≥ 1/1 000 to < 1/100]). Serious allergic reactions, including anaphylaxis, can occur in patients receiving pegfilgrastim (uncommon) (see section 4.4). Capillary Leak Syndrome, which can be life-threatening if treatment is delayed, has been reported as uncommon (≥ 1/1 000 to < 1/100) in cancer patients undergoing chemotherapy following administration of G-CSFs; see section 4.4 and section “Description of selected adverse reactions” below. Splenomegaly, generally asymptomatic, is uncommon. Splenic rupture, including some fatal cases, is uncommonly reported following administration of pegfilgrastim (see section 4.4). Uncommon pulmonary adverse reactions, including interstitial pneumonia, pulmonary edema, pulmonary infiltrates, and pulmonary fibrosis, have been reported. Uncommonly, cases have resulted in respiratory failure or ARDS, which may be fatal (see section 4.4). Isolated cases of sickle cell crises have been reported in patients with sickle cell trait or sickle cell disease (uncommon in sickle cell patients) (see section 4.4). Tabulated list of adverse reactions The data in the table below describe adverse reactions reported from clinical trials and spontaneous reporting. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table: List of adverse reactions MedDRA system organ class Adverse reactions Very common (≥ 1/10) Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1 000 to < 1/100) Rare (≥ 1/10 000 to < 1/1 000) Neoplasms benign, malignant, and unspecified (including cysts and polyps) Myelodysplastic syndrome 1 Acute myeloid leukaemia 1 Blood and lymphatic system disorders Thrombocytopenia 1 Leukocytosis 1 Sickle cell anaemia with crisis 2 Splenomegaly 2 Splenic rupture 2 Immune system disorders Hypersensitivity reactions Anaphylaxis Metabolism and nutrition disorders Elevations in uric acid Nervous system disorders Headache 1 Vascular disorders Capillary leak syndrome 1 Aortitis Respiratory, thoracic, and mediastinal disorders Acute Respiratory Distress Syndrome 2 ; Pulmonary adverse reactions (interstitial pneumonia, pulmonary edema, pulmonary infiltrates, and pulmonary fibrosis); Haemoptysis Pulmonary haemorrhage Gastrointestinal disorders Nausea 1 Skin and subcutaneous tissue disorders Sweet's syndrome (acute febrile neutrophilic dermatosis) 1,2 ; Cutaneous vasculitis 1,2 Steven-Johnson syndrome Musculoskeletal and connective tissue disorders Bone pain Musculoskeletal pain (myalgia, arthralgia, pain in extremity, back pain, musculoskeletal pain, neck pain) Renal and urinary disorders Glomerulonephritis 2 General disorders and administration site conditions Injection site pain 1 Non-cardiac chest pain Injection site reactions 2 Investigations Elevations in lactate dehydrogenase and alkaline phosphatase 1 Transient elevations in LFTs for ALT or AST 1 1 See section “Description of selected adverse reactions” below. 2 This adverse reaction was identified through post-marketing surveillance but not observed in randomized, controlled clinical trials in adults. The frequency category was estimated from a statistical calculation based on 1 576 patients receiving pegfilgrastim in nine randomized clinical trials. Description of selected adverse reactions Uncommon cases of Sweet's syndrome have been reported, although in some cases underlying haematological malignancies may play a role. Uncommon events of cutaneous vasculitis have been reported in patients treated with pegfilgrastim. The mechanism of vasculitis in patients receiving pegfilgrastim is unknown. Injection site reactions, including injection site erythema (uncommon), as well as injection site pain (common), have occurred on initial or subsequent treatment with pegfilgrastim. Common cases of leukocytosis (White Blood Count [WBC] > 100 × 10 9 /L) have been reported (see section 4.4). Reversible, mild to moderate elevations in uric acid and alkaline phosphatase, with no associated clinical effects, were uncommon; reversible, mild to moderate elevations in lactate dehydrogenase, with no associated clinical effects, were uncommon in patients receiving pegfilgrastim following cytotoxic chemotherapy. Nausea and headaches were very commonly observed in patients receiving chemotherapy. Uncommon elevations in liver function tests (LFTs) for alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have been observed in patients after receiving pegfilgrastim following cytotoxic chemotherapy. These elevations are transient and return to baseline. Common cases of thrombocytopenia have been reported. An increased risk of MDS/AML following treatment with pegfilgrastim in conjunction with chemotherapy and/or radiotherapy has been observed in an epidemiological study in breast and lung cancer patients (see section 4.4). Cases of capillary leak syndrome have been reported in the post-marketing setting with G-CSF use. These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple chemotherapy, medicinal products, or undergoing apheresis (see section 4.4). Paediatric population The experience in children and adolescents is limited. A higher frequency of serious adverse reactions in younger children aged 0-5 years (92 %) has been observed compared to older children aged 6-11 and 12-21 years, respectively (80 % and 67 %) and adults. The most common adverse reaction reported was bone pain (see section 5.1 and 5.2). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below). 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4.9. Overdose

Single doses of 300 mcg/kg have been administered subcutaneously to a limited number of healthy volunteers and patients with non-small cell lung cancer without serious adverse reactions. The adverse reactions were similar to those in subjects receiving lower doses of pegfilgrastim.