Lipegfilgrastim

Lipegfilgrastim is a covalent conjugate of filgrastim, an unglycosylated recombinant methionyl human G-CSF made in Escherichia coli cells, with a single methoxy polyethylene glycol (PEG) molecule attached through a carbohydrate linker of glycine, N-acetylneuraminic acid and N-acetylgalactosamine. Its average molecular mass is about 39 kDa, of which the protein part is roughly 48%. It is a sustained-duration form of filgrastim because its renal clearance is reduced. The SmPC states that its potency should not be compared with that of another pegylated or non-pegylated protein of the same class.

Mechanism of Action

• Receptor binding: lipegfilgrastim binds the human G-CSF receptor, as filgrastim does. Human G-CSF is the glycoprotein that regulates the production of functional neutrophils in the bone marrow and their release into the blood.
• Neutrophil production: it stimulates the proliferation of haematopoietic progenitor cells, their differentiation into mature cells and their release into the peripheral blood. The effect includes the neutrophil lineage and extends to other single-lineage and multilineage progenitors and to pluripotent haematopoietic stem cells.
• Pharmacodynamic effect: neutrophil counts rise markedly within 24 hours, with minor increases in monocytes and/or lymphocytes. G-CSF also increases the antibacterial activity of neutrophils, including phagocytosis.
• Long action: attaching PEG lowers clearance, so a single dose per chemotherapy cycle is enough.

Pharmacokinetics

• Absorption: after a single 6 mg subcutaneous dose in healthy volunteers, the peak blood concentration was reached after a median of 30–36 hours. Bioavailability (peak concentration and area under the curve) was lower after injection into the thigh than into the abdomen or upper arm, with larger differences in men than in women; pharmacodynamic effects were similar regardless of injection site and sex. In patients on chemotherapy, mean peak concentrations in the first cycle were 227 and 262 ng/mL (breast cancer, doxorubicin and docetaxel; median time to peak 44 and 48 hours) and 317 ng/mL (non-small cell lung cancer, cisplatin and etoposide; median 24 hours). In the fourth cycle the peaks were lower (77 and 111 ng/mL; 149 ng/mL) and came earlier (median 8 hours).
• Distribution: DrugBank gives a weight-dependent volume of distribution of about 70 mL/kg, indicating little distribution beyond the vascular and lymphatic system.
• Metabolism: degraded by proteolytic enzymes. The non-linear pathway is uptake by neutrophils followed by breakdown inside the cell; the linear pathway is extracellular breakdown by neutrophil elastase and other plasma proteases. In vitro data show little or no effect on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4/5, so an effect on cytochrome P450 metabolism is unlikely.
• Elimination: mainly neutrophil-mediated clearance, which becomes saturated at higher doses. Because of this self-regulating mechanism, the serum concentration falls slowly during the chemotherapy-induced neutrophil nadir and rapidly once neutrophils recover. The mean terminal half-life was about 32–62 hours in healthy volunteers and about 28–42 hours in patients.
• Special populations: kidney or liver impairment is not expected to change the pharmacokinetics. Patients aged 65–74 years had exposure similar to younger patients; there are no data in those aged 75 or over. In children given 100 µg/kg (maximum 6 mg), geometric mean peak concentrations were 243, 255 and 224 ng/mL in the 2 to under 6, 6 to under 12 and 12 to under 18 year groups; modelling supports exposures comparable to adults and the dosing by weight band. Exposure tends to fall as body weight rises, so a lower response in patients above 95 kg cannot be excluded.

Lipegfilgrastim (Lonquex) is indicated in adults and in children aged 2 years and older:

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

• Hypersensitivity to the active substance or to any of the excipients.

The safety of lipegfilgrastim was evaluated in clinical studies including 506 patients and 76 healthy volunteers. The most frequent undesirable effects are musculoskeletal pain and nausea.

Very common (≥1/10): nausea, musculoskeletal pain.

Common (≥1/100 to <1/10): thrombocytopenia, hypokalaemia, headache, haemoptysis, skin reactions, chest pain.

Uncommon (≥1/1,000 to <1/100): leukocytosis, splenomegaly, hypersensitivity reactions, pulmonary adverse reactions, pulmonary haemorrhage, injection site reactions, raised blood alkaline phosphatase and lactate dehydrogenase.

Not known: capillary leak syndrome, aortitis.

Capillary leak syndrome can be life-threatening if treatment is delayed; it has been reported mostly in cancer patients on chemotherapy after G-CSF or its derivatives. The warnings also cover splenic rupture (reported with G-CSFs), acute respiratory distress syndrome, sickle cell crisis, glomerulonephritis and serious allergic reactions.

• Cytotoxic chemotherapy: rapidly dividing myeloid cells are sensitive to cytotoxic chemotherapy, so lipegfilgrastim is given about 24 hours after it. Concomitant use with any chemotherapeutic medicine has not been evaluated in patients.
• 5-Fluorouracil and other antimetabolites: in animal models, giving G-CSF together with 5-fluorouracil or other antimetabolites potentiated myelosuppression.
• Chemotherapy with delayed myelosuppression: safety and efficacy have not been evaluated in patients receiving such chemotherapy, for example nitrosoureas.
• Lithium: lithium also promotes the release of neutrophils. A possible interaction has not been specifically investigated, and there is no evidence that it would be harmful.
• Cytochrome P450: in vitro data indicate little or no effect on the main CYP enzymes, so lipegfilgrastim is not likely to affect metabolism through human cytochrome P450.

Treatment should be started and supervised by physicians experienced in oncology or haematology. The solution is injected subcutaneously into the abdomen, upper arm or thigh. Instructions for handling the medicine before use are in section 6.6 of the SmPC.

Adults

• 6 mg (0.6 mL, one pre-filled syringe or vial) for each chemotherapy cycle, given approximately 24 hours after the cytotoxic chemotherapy.

Children Aged 2 Years and Older

The dose depends on body weight, for each chemotherapy cycle, again given approximately 24 hours after the cytotoxic chemotherapy:

• below 10 kg: 0.6 mg (0.06 mL)
• 10 kg to below 20 kg: 1.5 mg (0.15 mL)
• 20 kg to below 30 kg: 2.5 mg (0.25 mL)
• 30 kg to below 45 kg: 4.0 mg (0.40 mL)
• 45 kg or more: 6.0 mg (0.60 mL)

For children weighing 45 kg or more, the vial or the pre-filled syringe can be used.

Self-Administration of the Pre-Filled Syringe

The SmPC says that 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.

Special Populations

• Elderly: no dose adjustment is necessary. Studies included a limited number of elderly patients and showed no relevant age-related difference in efficacy or safety.
• Renal and hepatic impairment: available data are described in the pharmacokinetic section of the SmPC, but no recommendation on a dose can be made.
• Children below 2 years: safety and efficacy have not been established; no data are available.

Traceability

Lonquex is a biological medicinal product, so the trade name and batch number of each administered dose should be recorded in the patient file.

High-Dose Chemotherapy

Safety and efficacy have not been investigated in patients receiving high-dose chemotherapy. Lipegfilgrastim must not be used to raise the dose of cytotoxic chemotherapy beyond established regimens.

Allergic Reactions and Immunogenicity

Patients who are hypersensitive to G-CSF or its derivatives may react to lipegfilgrastim through cross-reactivity and should not start it. Most biological medicines provoke some anti-drug antibodies, which can in some cases cause undesirable effects or loss of efficacy; a patient who does not respond should be evaluated further. A serious allergic reaction needs appropriate treatment and close follow-up over several days.

Blood Counts

Lipegfilgrastim does not prevent the thrombocytopenia and anaemia caused by myelosuppressive chemotherapy and may itself cause reversible thrombocytopenia, so platelet count and haematocrit should be monitored regularly. Particular care is needed with chemotherapy known to cause severe thrombocytopenia. Leukocytosis may occur; a rise in white cells is consistent with the drug’s pharmacodynamic effect and no adverse events directly attributable to it have been reported. White cell counts should be checked at regular intervals, and treatment stopped immediately if the count exceeds 50 × 10⁹/L after the expected nadir. Increased bone-marrow activity can cause transient positive bone-imaging findings, which should be kept in mind when scans are interpreted.

Myeloid Leukaemia and Myelodysplastic Syndromes

G-CSF can promote the growth of myeloid cells and some non-myeloid cells in vitro. Lipegfilgrastim has not been investigated in chronic myeloid leukaemia, myelodysplastic syndromes or secondary acute myeloid leukaemia and should not be used in these patients; care is needed to distinguish blast transformation of chronic myeloid leukaemia from acute myeloid leukaemia. An observational study linked another G-CSF, pegfilgrastim, with myelodysplastic syndrome and acute myeloid leukaemia in breast and lung cancer patients given chemotherapy and/or radiotherapy. A similar link is not known for lipegfilgrastim, but patients with breast or lung cancer should be monitored for signs and symptoms.

Spleen

Mostly asymptomatic splenomegaly has been reported with lipegfilgrastim, and infrequent cases of splenic rupture, including fatal ones, after G-CSFs. Spleen size should be monitored (clinical examination, ultrasound), and splenic rupture considered in patients with pain in the left upper abdomen or at the shoulder tip.

Lungs

Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported; a recent history of pulmonary infiltrates or pneumonia may raise the risk. Cough, fever and breathlessness with radiological pulmonary infiltrates, worse lung function and a rising neutrophil count may be early signs of acute respiratory distress syndrome. Lipegfilgrastim should then be stopped at the physician’s discretion and appropriate treatment given.

Capillary Leak Syndrome and Aortitis

Capillary leak syndrome (hypotension, hypoalbuminaemia, oedema and haemoconcentration) has been reported with G-CSFs. Patients who develop symptoms need close monitoring and standard symptomatic treatment, which may include intensive care. Aortitis has been reported after G-CSF in healthy subjects and cancer patients, with fever, abdominal pain, malaise, back pain and raised inflammatory markers such as C-reactive protein and white cell count; it was usually diagnosed by CT scan and generally resolved after the G-CSF was stopped.

Sickle Cell Anaemia

Sickle cell crisis has been associated with G-CSFs in patients with sickle cell anaemia. Caution is needed: appropriate clinical and laboratory parameters should be monitored, with attention to splenic enlargement and vaso-occlusive crisis.

Hypokalaemia

In patients at higher risk of hypokalaemia because of their disease or co-medication, serum potassium should be monitored carefully and replaced if necessary.

Glomerulonephritis

Glomerulonephritis has been reported with filgrastim, lenograstim and pegfilgrastim and generally resolved after dose reduction or withdrawal. Urinalysis monitoring is recommended.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: data are very limited (fewer than 300 pregnancy outcomes) and animal studies have shown reproductive toxicity. As a precaution it is preferable to avoid Lonquex during pregnancy.
• Breastfeeding: it is unknown whether lipegfilgrastim or its metabolites pass into human milk, and a risk to the breast-fed child cannot be excluded. Breastfeeding should be discontinued during treatment.
• Fertility: there are no human data; animal studies with G-CSF and derivatives do not indicate harmful effects on fertility.

Sorbitol and Sodium

Each pre-filled syringe or vial contains 30 mg of sorbitol. The additive effect of other sorbitol- (or fructose-) containing products taken at the same time and of sorbitol (or fructose) in the diet should be taken into account. The medicine contains less than 1 mmol (23 mg) sodium per dose, so it is essentially sodium-free.

Effect on Driving

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

Store in a refrigerator at 2–8 °C. Do not freeze. Keep the pre-filled syringe or vial in the outer carton to protect it from light. Lonquex may be taken out of the refrigerator and stored below 25 °C for a single period of up to 7 days; once removed, it must be used within that period or disposed of. As a refrigerated product, it should be transported and stored in an unbroken cold chain. Pre-filled syringes (type I glass with a fixed needle) come in packs of 1 or 4 with a safety device, or 1 without; vials come in packs of 1 or 6. Not all pack sizes may be marketed.

3 years. Once taken out of the refrigerator for storage below 25 °C, use within 7 days.

Prescription only (Rx), under restricted medical prescription (Annex II B of the marketing authorisation); treatment is started and supervised by a physician experienced in oncology or haematology. The SmPC allows self-injection of the pre-filled syringe by well-motivated, adequately trained patients with access to expert advice, after a first injection under direct medical supervision. Lonquex is supplied to the patient or to the treating clinic on prescription, with cold-chain delivery at 2–8 °C.