Efbemalenograstim Alfa

Efbemalenograstim alfa is a recombinant fusion protein of human granulocyte colony-stimulating factor (G-CSF), a 16-amino-acid linker and the Fc portion of human IgG2. In solution it forms covalently linked dimers (disulfide bonds between the Fc parts) with an immunoglobulin-like structure. It belongs to the colony-stimulating factors (immunostimulants) and is a sustained-duration form of G-CSF because its renal clearance is reduced.

Mechanism of Action

• Neutrophil production: G-CSF is a glycoprotein that regulates the production and release of neutrophils from the bone marrow. Efbemalenograstim alfa binds specific receptors on the surface of haematopoietic cells and stimulates their proliferation, differentiation and functional activation.
• Same mode of action as other G-CSFs: blood neutrophil counts rise markedly within 24 hours, with minor rises in monocytes and/or lymphocytes. The neutrophils formed show normal or enhanced chemotactic and phagocytic function.
• Other cells: in vitro, G-CSF stimulates human endothelial cells and can promote the growth of myeloid cells, including malignant cells, and of some non-myeloid cells.
• Clinical study: in a randomised, double-blind, placebo-controlled study, 122 patients with breast cancer receiving docetaxel and doxorubicin every 3 weeks (4 cycles) were given either a single 20 mg dose about 24 hours after chemotherapy in cycle 1, or placebo. The efficacy results are in section 5.1 of the SmPC.

Pharmacokinetics

• Absorption: after subcutaneous injection the peak serum concentration occurs about 36 hours after the dose (range 6–96 hours), and serum levels are maintained through the period of neutropenia that follows myelosuppressive chemotherapy.
• Distribution: the apparent volume of distribution ranges from 395 to 5,679 mL/kg.
• Metabolism: expected to be broken down into small peptides by catabolic pathways.
• Elimination: mainly neutrophil-mediated clearance, which becomes saturated at higher doses, so the serum concentration falls quickly once neutrophils recover. The half-life ranges from 19 to 84 hours after subcutaneous injection. Pharmacokinetics are non-linear and time-dependent over 30–360 µg/kg.
• Special populations: because clearance is neutrophil-mediated, the pharmacokinetics are not expected to be affected by renal or hepatic impairment. Limited data show similar exposure in people over 65 years. There are no data in children.

• Neutropenia during chemotherapy: reduction in the duration of neutropenia and in the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy, with the exception of chronic myeloid leukaemia and myelodysplastic syndromes.

It is authorised for adults only; no data are available in children.

• Hypersensitivity to the active substance or to any of the excipients (sodium acetate trihydrate, glacial acetic acid, sorbitol, polysorbate 20, edetic acid, water for injections).

Bone pain is the most frequently reported reaction (very common). Musculoskeletal pain is generally mild to moderate and transient, and standard analgesics control it in most patients. The frequencies below were estimated from 488 patients in four clinical trials. Several of the common events (nausea, vomiting, diarrhoea, asthenia, fatigue, pyrexia, vertigo, headache) are also typical of the chemotherapy these patients receive.

Very common (≥1/10): bone pain.

Common (≥1/100 to <1/10): headache, vertigo, nausea, vomiting, diarrhoea, back pain, arthralgia, pain in extremity, asthenia, fatigue, pyrexia, increased white blood cell count, increased alanine aminotransferase, increased aspartate aminotransferase.

Uncommon (≥1/1,000 to <1/100): herpes infection; leukopenia, neutropenia, thrombocytopenia, anaemia, splenomegaly; hyperglycaemia, decreased appetite; dizziness, taste disorder, muscle spasticity, peripheral neuropathy, somnolence; increased lacrimation; tachycardia, palpitations; vasculitis, hot flush; pulmonary oedema, epistaxis, oropharyngeal pain, cough, dyspnoea, nasal dryness; stomatitis, dry mouth, dyspepsia, abdominal pain, dysphagia; alopecia, urticaria, allergic dermatitis, rash, dermatitis, erythema, toxic skin eruption, maculopapular rash, pruritus, eczema, dry skin, skin disorder, angioedema, cold sweat, night sweats, onychalgia (nail pain); myalgia, osteoarthropathy, musculoskeletal discomfort, neck pain; injection site reactions, peripheral swelling, chills, thirst; increased neutrophil count, increased blood creatinine, increased gamma-glutamyltransferase, weight increased.

Not known: reactions not yet seen in efbemalenograstim alfa studies but generally accepted as attributable to G-CSFs: myelodysplastic syndrome and acute myeloid leukaemia (seen in an epidemiological study with some G-CSFs given with chemotherapy and/or radiotherapy in breast and lung cancer), hypersensitivity reactions, capillary leak syndrome, aortitis, Stevens-Johnson syndrome, Sweet’s syndrome (acute febrile neutrophilic dermatosis) and glomerulonephritis.

Serious angioedema occurred on repeat treatment, and one case of serious urticaria was reported. Splenomegaly was generally asymptomatic, but splenic rupture, including fatal cases, has been reported with G-CSFs. Pulmonary oedema was uncommon; interstitial pneumonia, pulmonary infiltrates, pulmonary fibrosis, respiratory failure and acute respiratory distress syndrome (ARDS), which may be fatal, have been reported with G-CSFs. Isolated cases of sickle cell crisis have been linked to G-CSFs in patients with sickle cell trait or sickle cell disease. Capillary leak syndrome can be life-threatening if treatment is delayed. The rise in white blood cell count and the increases in liver enzymes are transient.

• Cytotoxic chemotherapy (timing): rapidly dividing myeloid cells are sensitive to cytotoxic chemotherapy, so efbemalenograstim alfa is given at least 24 hours after chemotherapy and at least 14 days before the next chemotherapy dose. Giving it on the same day as chemotherapy has been shown to potentiate myelosuppression.
• Chemotherapy with delayed myelosuppression (for example nitrosoureas): safety and efficacy have not been evaluated.
• Other haematopoietic growth factors and cytokines: possible interactions have not been specifically investigated in clinical trials.
• Lithium: it also promotes the release of neutrophils. An interaction has not been specifically investigated, and there is no evidence that it would be harmful.

Efbemalenograstim alfa is given by subcutaneous injection from a pre-filled syringe containing 20 mg in 1 mL.

Who Starts and Gives the Treatment

Therapy should be initiated and supervised by physicians experienced in oncology and/or haematology. The SmPC describes the syringe as provided for manual administration; section 4.2 does not name who gives the injection, so the prescriber’s instructions and the package leaflet apply.

Recommended Dose

• One 20 mg dose (one pre-filled syringe) for each chemotherapy cycle, given at least 24 hours after the cytotoxic chemotherapy and at least 14 days before the next chemotherapy dose. It is not given on the same day as chemotherapy.
• Injection site: the thigh, abdomen, buttock or upper arm.
• Instructions for handling the medicinal product before administration are in section 6.6 of the SmPC.

Special Populations

• Renal impairment: no dose change, including in end-stage renal disease.
• Hepatic impairment: pharmacokinetics are not expected to be affected.
• Elderly: limited data show pharmacokinetics similar to those in younger adults.
• Children: safety and efficacy have not been established; no data are available.

Traceability

Because this is a biological medicinal product, the name and batch number of the administered product should be clearly recorded.

Malignant Cell Growth

G-CSF can promote the growth of myeloid cells, and of some non-myeloid cells, in vitro. Safety and efficacy have not been investigated in myelodysplastic syndrome, chronic myeloid leukaemia or acute myeloid leukaemia, so it should not be used in these patients. It has not been studied with high-dose chemotherapy and must not be used to raise the dose of cytotoxic chemotherapy above established regimens. Myelodysplastic syndrome and acute myeloid leukaemia have been seen after some G-CSFs (for example pegfilgrastim) given with chemotherapy and/or radiotherapy in patients with breast and lung cancer, so these patients should be monitored for signs and symptoms.

Pulmonary Reactions

Interstitial pneumonia and other pulmonary reactions have been reported after G-CSFs, and people with a recent history of pulmonary infiltrates or pneumonia may be at higher risk. Cough, fever and dyspnoea with radiological signs of pulmonary infiltrates, worsening lung function and a rising neutrophil count may be early signs of ARDS. In that case the physician may stop efbemalenograstim alfa and give appropriate treatment.

Splenomegaly and Splenic Rupture

Generally asymptomatic splenomegaly has been reported with efbemalenograstim alfa, and splenic rupture, including fatal cases, with G-CSFs. Spleen size should be monitored carefully (for example by clinical examination or ultrasound). Splenic rupture should be considered in anyone reporting left upper abdominal pain or shoulder tip pain.

Capillary Leak Syndrome and Glomerulonephritis

Capillary leak syndrome (hypotension, hypoalbuminaemia, oedema and haemoconcentration) has been reported after G-CSFs. Affected patients need close monitoring and standard symptomatic treatment, possibly intensive care. Glomerulonephritis has been reported with G-CSFs and generally resolved after dose reduction or withdrawal; urinalysis monitoring is recommended.

Leukocytosis

White blood cell counts of 100 × 10⁹/L or more have been seen with G-CSFs. The rise is transient, typically 24 to 48 hours after the dose, and no adverse events directly attributable to it have been reported. A white blood cell count should be done at regular intervals during therapy. If the count exceeds 50 × 10⁹/L after the expected nadir, the medicinal product should be discontinued immediately.

Thrombocytopenia and Anaemia

Efbemalenograstim alfa does not prevent thrombocytopenia and anaemia, because full-dose myelosuppressive chemotherapy continues on schedule. Regular monitoring of platelet count and haematocrit is recommended, with special care for chemotherapy known to cause severe thrombocytopenia.

Sickle Cell Disease

Sickle cell crises have been associated with G-CSFs in patients with sickle cell trait or disease. Physicians should take care when prescribing it in these patients and monitor clinical and laboratory parameters for splenic enlargement and vaso-occlusive crisis.

Hypersensitivity and Severe Skin Reactions

Serious allergic reactions have been reported with G-CSFs on first or later treatment. Efbemalenograstim alfa should be permanently discontinued in patients with clinically significant hypersensitivity and should not be given to anyone with a history of hypersensitivity to it. Caution applies in patients with serious allergic reactions to other G-CSF products, because cross-reactivity cannot be excluded. Stevens-Johnson syndrome has been reported rarely with G-CSFs; if it occurs with this medicinal product, treatment must never be restarted.

Aortitis

Aortitis has been reported after G-CSFs in healthy subjects and cancer patients, with fever, abdominal pain, malaise, back pain and raised inflammatory markers. It was usually diagnosed by CT scan and generally resolved after the G-CSF was withdrawn.

Immunogenicity and Other Warnings

• Antibodies against efbemalenograstim alfa are generated at a generally low rate; binding antibodies have not been associated with neutralising activity so far.
• Safety and efficacy for mobilising blood progenitor cells in patients or healthy donors have not been adequately evaluated.
• Increased bone-marrow activity during growth-factor therapy has been associated with transient positive bone-imaging findings, which should be considered when interpreting bone scans.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data in pregnant women. Animal studies showed no reproductive toxicity, but it is not recommended during pregnancy or in women of childbearing potential who are not using contraception.
• Breastfeeding: information on excretion in human milk is insufficient, and a risk to the infant cannot be excluded. A decision must be made whether to stop breastfeeding or to abstain from the therapy, weighing the benefit of breastfeeding against the benefit of treatment.
• Fertility: reproductive performance and fertility of male and female rats were unaffected at cumulative weekly doses about 2.2 times the recommended human dose (by body surface area).

Excipients and Latex

• Sorbitol: each syringe contains 50 mg; the additive effect of other sorbitol- or fructose-containing products and of dietary intake should be taken into account.
• Sodium: less than 1 mmol (23 mg) per 20 mg dose, so essentially sodium-free.
• Latex: the needle cap of the pre-filled syringe contains dry natural rubber (latex), which may cause allergic reactions.

Effect on Driving

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

Store in a refrigerator at 2–8 °C, in the outer carton to protect from light. Keep the cold chain intact during transport and storage. Do not freeze; accidental exposure to freezing temperatures for a single period of less than 24 hours does not adversely affect stability. The syringe may be exposed to room temperature (not above 30 °C) for one single period of up to 48 hours at most; a syringe left at room temperature for longer than 48 hours must be discarded.

The syringe is made of Type I glass with a rubber stopper, stainless steel needle and needle cap. Each pack holds one 1 mL pre-filled syringe.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx), under restricted medical prescription (Annex II B of the marketing authorisation). Treatment is started and supervised by physicians experienced in oncology and/or haematology. The SmPC does not name who gives the injection, so the pre-filled syringe is supplied on prescription to the treating clinic or hospital, or to the patient, as the supervising physician directs, with cold-chain delivery until use.