Lonquex 6 mg Solution

LONQUEX is indicated for the 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).

LONQUEX treatment should be initiated and supervised by medical practitioners experienced in oncology or haematology.

Posology: A single pre-filled syringe of LONQUEX (one 6 mg dose of lipegfilgrastim) is recommended for each chemotherapy cycle, given approximately 24 hours after cytotoxic chemotherapy.

Special populations:

• Elderly patients: In clinical studies with a limited number of elderly patients, there was no relevant age-related difference with regard to the efficacy or safety profiles of LONQUEX. Therefore, no adjustment of the dose is necessary for elderly patients.
• Patients with renal impairment: Currently available data are described in section 5.2, but no recommendation on a posology can be made.
• Patients with hepatic impairment: Currently available data are described in section 5.2, but no recommendation on a posology can be made.
• Paediatric population: The safety and efficacy of LONQUEX in children and adolescents aged up to 17 years have not yet been established. Currently available data are described in sections 4.8, 5.1 and 5.2.

Method of administration: The solution is injected subcutaneously (SC). The injections should be given into the abdomen, upper arm or thigh. Self-administration of LONQUEX should only be performed by patients who are well motivated, adequately trained and have access to expert advice. The first injection should be performed under direct medical supervision. For instructions on handling of the medicine before administration, see section 6.6.

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

Traceability: In order to improve traceability of biological medicines, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.

General: The safety and efficacy of LONQUEX have not been investigated in patients receiving high dose chemotherapy. LONQUEX should not be used to increase the dose of cytotoxic chemotherapy beyond established dose regimens.

Allergic reactions and immunogenicity: Patients who are hypersensitive to G-CSF or derivatives are also at risk of hypersensitivity reactions to LONQUEX due to possible cross-reactivity. No LONQUEX therapy should be commenced in these patients because of the risk of cross-reaction. Most biological medicines elicit some level of anti-drug antibody response. This antibody response can, in some cases, lead to undesirable effects or loss of efficacy. If a patient fails to respond to treatment, the patient should undergo further evaluation. If a serious allergic reaction occurs, appropriate therapy with close patient follow-up over several days should be administered.

Haematopoietic system: Treatment with LONQUEX does not preclude thrombocytopenia and anaemia caused by myelosuppressive chemotherapy. LONQUEX may also cause reversible thrombocytopenia (see section 4.8). Regular monitoring of the platelet count and haematocrit are recommended. Special care should be taken when administering single or combination chemotherapeutic medicine that are known to cause severe thrombocytopenia. Leukocytosis may occur (see section 4.8). No adverse events directly attributable to leukocytosis have been reported. Elevation in white blood cells (WBC) is consistent with the pharmacodynamic effects of LONQUEX. A WBC count should be performed at regular intervals during therapy owing to the clinical effects of lipegfilgrastim and the potential for leukocytosis. If WBC counts exceed 50 x 109/l after the expected nadir, LONQUEX should be discontinued immediately.

Increased haematopoietic 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.

Patients with myeloid leukaemia or myelodysplastic syndromes: Granulocyte-colony stimulating factor can promote growth of myeloid cells and some non-myeloid cells in vitro. The safety and efficacy of LONQUEX have not been investigated in patients with chronic myeloid leukaemia, myelodysplastic syndromes or secondary acute myeloid leukaemia; it should therefore not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from acute myeloid leukaemia (see section 4.3).

Myelodysplastic syndrome and acute myeloid leukaemia in breast and lung cancer patients: In an observational post-marketing study, myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) were associated with the use of pegfilgrastim, an alternative G-CSF medicine, in combination with chemotherapy and/or radiotherapy in breast and lung cancer patients. A similar association is not known between LONQUEX and MDS/AML. Nevertheless, patients with breast cancer and patients with lung cancer should be monitored for signs and symptoms of MDS/AML.

Splenic adverse reactions: Generally asymptomatic cases of splenomegaly have been reported after administration of LONQUEX (see section 4.8) and infrequent cases of splenic rupture, including fatal cases, have been reported after administration of G-CSF or derivatives (see section 4.8). Spleen size should therefore 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.

Pulmonary adverse reactions: Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after administration of LONQUEX (see section 4.8). Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk. The onset of pulmonary symptoms such as cough, fever and dyspnoea in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function together with an increased neutrophil count may be preliminary signs of Acute Respiratory Distress Syndrome (ARDS) (see section 4.8). In such circumstances LONQUEX should be discontinued at the discretion of the medical practitioner and appropriate treatment given.

Vascular adverse reactions: Capillary leak syndrome has been reported after administration of G-CSF or derivatives and is characterised by hypotension, hypo-albuminaemia, oedema 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).

Patients with sickle cell anaemia: Sickle cell crisis has been associated with the use of G-CSF or derivatives in patients with sickle cell anaemia (see section 4.8). Medical practitioners should therefore exercise caution when administering LONQUEX in patients with sickle cell anaemia, monitor appropriate clinical parameters and laboratory results and be attentive to the possible association of LONQUEX with splenic enlargement and vaso-occlusive crisis.

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.

Hypokalaemia: Hypokalaemia may occur (see section 4.8). For patients with increased risk on hypokalaemia due to underlying disease or co-medications, it is recommended to monitor the serum potassium level carefully and to substitute potassium if necessary.

Glomerulonephritis: Glomerulonephritis has been reported in patients receiving filgrastim, lenograstim or pegfilgrastim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim, lenograstim or pegfilgrastim. Urinalysis monitoring is recommended (see section 4.8).

Excipients with known effect: LONQUEX contains sorbitol. Patients with hereditary fructose intolerance (HFI) should not use LONQUEX. LONQUEX contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. essentially sodium-free.

Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, LONQUEX should be administered approximately 24 hours after administration of cytotoxic chemotherapy. Concomitant use of LONQUEX with any chemotherapeutic medicine has not been evaluated in patients. In animal models, concomitant administration of G-CSF and 5-fluorouracil (5-FU) or other antimetabolites has been shown to potentiate myelosuppression.

The safety and efficacy of LONQUEX have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression, e.g. nitrosoureas. 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.

Pregnancy: There are very limited data (less than 300 pregnancy outcomes) on the use of LONQUEX in pregnant women. Safety and efficacy in pregnant women have therefore not been established. The use of LONQUEX should be avoided during pregnancy.

Breastfeeding: It is unknown whether the active ingredient, lipegfilgrastim, or its metabolites are excreted in human milk. A risk to the breastfed child cannot be excluded. Breastfeeding should be discontinued during treatment with LONQUEX.

Fertility: No data are available. Animal studies with G-CSF and derivatives do not indicate harmful effects with respect to fertility (see section 5.3).

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

a. Summary of the safety profile: The most frequent undesirable effects are musculoskeletal pain and nausea. Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported mostly in cancer patients undergoing chemotherapy after administration of G-CSF or derivatives (see section 4.4 and section 4.8).

b. Tabulated summary of adverse reactions: The safety of LONQUEX has been evaluated based on results from clinical studies including 506 patients and 76 healthy volunteers treated at least once with lipegfilgrastim. The adverse reactions listed below in table 1 are classified according to system organ class. Frequency groupings are defined according to the following convention: very common (u22651/10), common (u22651/100 to <1/10), uncommon (u22651/1 000 to <1/100), rare (u22651/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Adverse reactions:

System organ class Frequency Adverse reaction

Blood and lymphatic system disorders Common Thrombocytopenia* Uncommon Leukocytosis*, splenomegaly*

Immune system disorders Uncommon Hypersensitivity reactions*

Metabolism and nutrition disorders Common Hypokalaemia*

Nervous system disorders Common Headache

Vascular disorders Not known Capillary leak syndrome*, aortitis*

Respiratory, thoracic and mediastinal disorders Common Haemoptysis Uncommon Pulmonary adverse reactions*, Pulmonary haemorrhage

Gastrointestinal disorders Very common Nausea*

Skin and subcutaneous tissue disorders Common Skin reactions* Uncommon Injection site reactions*

Musculoskeletal and connective tissue disorders Very common Musculoskeletal pain*

General disorders and administration site conditions Common Chest pain

Investigations Uncommon Increased blood alkaline phosphatase*, increased blood lactate dehydrogenase*

*See section u201cDescription of selected adverse reactionsu201d below

c. Description of selected adverse events: Thrombocytopenia and leukocytosis have been reported (see section 4.4). Splenomegaly, generally asymptomatic, has been reported (see section 4.4). Hypersensitivity reactions such as allergic skin reactions, urticaria, angioedema and serious allergic reactions may occur. Hypokalaemia has been reported (see section 4.4). Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported (see section 4.4). These pulmonary adverse reactions may also include pulmonary oedema, pulmonary infiltrates, pulmonary fibrosis, respiratory failure or ARDS (see section 4.4). Nausea was very commonly observed in patients receiving chemotherapy. Skin reactions such as erythema and rash may occur. Injection site reactions such as injection site induration and injection site pain may occur. The most frequent adverse reactions include musculoskeletal pains such as bone pain and myalgia. Musculoskeletal pain is generally of mild to moderate severity, transient and can be controlled in most patients with standard analgesics. However, cases of severe musculoskeletal pain (mainly bone pain and back pain) have been reported, including cases that led to hospitalisation. Reversible, mild to moderate elevations in alkaline phosphatase and lactate dehydrogenase may occur, with no associated clinical effects. Elevations in alkaline phosphatase and lactate dehydrogenase most likely originate from the increase in neutrophils. Certain adverse reactions have not yet been observed with LONQUEX, but are generally accepted as being attributable to G-CSF and derivatives:

Blood and lymphatic system disorders:

• Splenic rupture including some fatal cases (see section 4.4)
• Sickle cell crisis in patients with sickle cell anaemia (see section 4.4)

Vascular disorders:

• Capillary leak syndrome

Cases of capillary leak syndrome have been reported in post-marketing experience after administration of G-CSF or derivatives. These have generally occurred in patients suffering from advanced malignant diseases, having sepsis, taking multiple chemotherapy medicines or undergoing apheresis (see section 4.4).

Aortitis (see section 4.4)

Skin and subcutaneous tissue disorders:

• Acute febrile neutrophilic dermatosis (Sweet's syndrome)
• Cutaneous vasculitis

Renal and urinary disorders:

• Glomerulonephritis (see section 4.4)

d. Paediatric population: The experience in children is limited to a single-dose phase 1 study in 21 paediatric patients aged 2 to <18 years (see section 5.1), which did not indicate a difference in the safety profile of LONQUEX in children compared to that in adults. Treatment-related adverse events were back pain, bone pain and increased neutrophil count (1 event each).

There is no experience with overdose of LONQUEX. In the case of overdose, whole blood count and platelet count should be performed regularly and spleen size should be carefully monitored (e.g. clinical examination, ultrasound).