LONQUEX Solution for injection in pre-filled syringe Ref.[8545] Active ingredients: Lipegfilgrastim

Traceability

In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered medicinal product should be clearly recorded 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 lipegfilgrastim due to possible cross-reactivity. No lipegfilgrastim therapy should be commenced in these patients because of the risk of cross-reaction.

Most biological medicinal products 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 lipegfilgrastim does not preclude thrombocytopenia and anaemia caused by myelosuppressive chemotherapy. Lipegfilgrastim may also cause reversible thrombocytopenia (see section 4.8). Regular monitoring of the platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic medicinal products 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 lipegfilgrastim. 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, lipegfilgrastim 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.

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, in combination with chemotherapy and/or radiotherapy in breast and lung cancer patients. A similar association is not known between lipegfilgrastim 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 lipegfilgrastim (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 lipegfilgrastim (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 physician 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, hypoalbuminaemia, 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).

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.

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). Physicians 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 lipegfilgrastim with splenic enlargement and vaso-occlusive crisis.

Hypokalaemia

Hypokalaemia may occur (see section 4.8). For patients with increased risk on hypokalaemia due to underling 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

This medicinal product contains sorbitol. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe or vial, 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 lipegfilgrastim with any chemotherapeutic medicinal product 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 lipegfilgrastim in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Lonquex during pregnancy.

Breast-feeding

It is unknown whether lipegfilgrastim/metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded. Breast-feeding 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.

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).

Tabulated list of adverse reactions

The safety of lipegfilgrastim 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 2 are classified according to system organ class. Frequency groupings are defined according to the following convention: 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), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2. Adverse reactions:

^* See section "Description of selected adverse reactions" below

Description of selected adverse reactions

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 lipegfilgrastim, 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 postmarketing experience after administration of G-CSF or derivatives. These have generally occurred in patients suffering from advanced malignant diseases, having sepsis, taking multiple chemotherapy medicinal products 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)

Paediatric population

The safety assessment in paediatric patients is limited to the clinical study data from the following studies:

• a phase I study with 21 paediatric patients aged 2 to 16 years with Ewing family of tumours or rhabdomyosarcoma receiving lipegfilgrastim after a single cycle of chemotherapy (see also section 5.1)
• a phase II study with 21 paediatric patients aged 2 to 18 years with Ewing family of tumours or rhabdomyosarcoma receiving one dose of lipegfilgrastim per chemotherapy cycle, for 4 consecutive cycles (see also section 5.1).

Overall, the safety profile in paediatric patients appeared similar to that observed in adult clinical studies. Some blood and lymphatic system disorders (anaemia, lymphopenia, thrombocytopenia) and gastrointestinal disorders (vomiting) were observed with a higher frequency in paediatric patients than those in adult clinical studies (see also section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.