UDENYCA Solution for injection Ref.[28054] Active ingredients: Pegfilgrastim

In order to improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded.

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 (see section 5.1). However, the long-term effects of pegfilgrastim have not been established in acute myeloid leukaemia; therefore, it should be used with caution in this patient population.

G-CSF can promote 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 Acute Myeloid Leukaemia (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 acute myeloid leukaemia.

The safety and efficacy of pegfilgrastim administration in de novo AML patients aged <55 years with cytogenetics t(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 dosage regimens.

The safety and efficacy of pegfilgrastim for the mobilisation of blood progenitor cells in patients or healthy donors has not been adequately evaluated.

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.

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 characterised by hypotension, hypoalbuminaemia, oedema and hemoconcentration. 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

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).

Splenomegaly and splenic rupture

Uncommon but generally asymptomatic cases of splenomegaly and uncommon cases of splenic rupture, including some fatal cases, have been reported following 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 haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic agents which are known to cause severe thrombocytopenia.

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 medicine with splenic enlargement and vaso-occlusive crisis.

Leukocytosis

White blood cell (WBC) counts of 100 × 10⁹/l or greater have been observed in less than 1% of patients receiving pegfilgrastim. No adverse events directly attributable to this degree of leukocytosis have been reported. 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 medicine. 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 × 10⁹/l after the expected nadir, this medicine should be discontinued immediately.

Hypersensitivity

Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have 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 is generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralising activity at present.

Pegfilgrastim contains sorbitol. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

Pegfilgrastim contains less than 1 mmol (23 mg) sodium per 6 mg dose, that is to say, essentially ‘sodium-free’.

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.

Pregnancy

There are no or limited amount of data from the use of pegfilgrastim in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). UDENYCA 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 milk, a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from UDENYCA 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).

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

Summary of the safety profile

The most frequently reported adverse reactions were bone pain (very common) and musculoskeletal pain (common). 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, erythaema, flushing, and hypotension occurred on initial or subsequent treatment with pegfilgrastim (uncommon). 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 in cancer patients undergoing chemotherapy following administration of G-CSFs; see section 4.4 and section “Description of selected adverse reactions” below.

Aortitis [rare frequency] (see section 4.4).

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 oedema, pulmonary infiltrates and pulmonary fibrosis have been reported. Uncommonly, cases have resulted in respiratory failure or Acute Respiratory Distress Syndrome (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. The adverse reactions are ranked under heading of frequency using 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) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

¹ See section “Description of selected adverse reactions” below.
² This adverse reaction was identified through post-marketing surveillance but not observed in randomised, controlled clinical trials in adults. The frequency category was estimated from a statistical calculation based upon 1,576 patients receiving pegfilgrastim in nine randomised 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 erythaema (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 × 10⁹/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 ALT (alanine aminotransferase) or AST (aspartate aminotransferase), 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.

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 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 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.

This medicinal product must not be mixed with other medicinal products, particularly with sodium chloride solutions.