LONQUEX 6mg injectible solution medication leaflet

Lonquex 6 mg solution for injection in pre-filled syringe

Lonquex 6 mg/0.6 ml solution for injection

Each pre-filled syringe contains 6 mg of lipegfilgrastim* in 0.6 ml solution.

Vial

Each vial contains 6 mg of lipegfilgrastim* in 0.6 ml solution.

Each ml of solution for injection contains 10 mg of lipegfilgrastim.

The active substance is a covalent conjugate of filgrastim** with methoxy polyethylene glycol (PEG)via a carbohydrate linker.

*This is based on protein content only. The concentration is 20.9 mg/ml (i.e. 12.6 mg per pre-filledsyringe or vial) if the PEG moiety and the carbohydrate linker are included.

**Filgrastim (recombinant methionyl human granulocyte-colony stimulating factor [G-CSF]) isproduced in Escherichia coli cells by recombinant DNA technology.

The potency of this medicinal product should not be compared to the potency of another pegylated ornon-pegylated protein of the same therapeutic class. For more information, see section 5.1.

Each pre-filled syringe or vial contains 30 mg sorbitol.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear, colourless solution

Lonquex is indicated in adults and in children 2 years of age and older for reduction in the duration ofneutropenia and the incidence of febrile neutropenia in patients treated with cytotoxic chemotherapyfor malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes).

Lonquex treatment should be initiated and supervised by physicians experienced in oncology orhaematology.

The recommended dose is 6 mg (0.6 ml solution in a single pre-filled syringe or vial) of Lonquex foreach chemotherapy cycle, given approximately 24 hours after cytotoxic chemotherapy.

Children 2 years of age and older

The recommended dose of Lonquex for paediatric patients is based on body weight according to thetable below:

Table 1: Recommended dose in children 2 years of age and older

Body weight (kg) Dose (for each chemotherapy cycle, given approximately 24 hoursafter cytotoxic chemotherapy)< 10 0.6 mg (0.06 ml)≥ 10 to < 20 1.5 mg (0.15 ml)≥ 20 to < 30 2.5 mg (0.25 ml)≥ 30 to < 45 4.0 mg (0.40 ml)≥ 45 6.0 mg (0.60 ml)

For children weighing 45 kg or more Lonquex can be used as vial or pre-filled syringe presentation.

In clinical studies with a limited number of elderly patients, there was no relevant age-relateddifference with regard to the efficacy or safety profiles of lipegfilgrastim. Therefore, no adjustment ofthe dose is necessary for elderly patients.

Currently available data are described in section 5.2, but no recommendation on a posology can bemade.

Currently available data are described in section 5.2, but no recommendation on a posology can bemade.

Paediatric patients (children less than 2 years)

The safety and efficacy of Lonquex in children below 2 years of age have not been established. Nodata are available.

The solution is to be injected subcutaneously (SC). The injection 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 underdirect medical supervision.

For instructions on handling of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

In order to improve the traceability of biological medicinal products, the trade name and batch numberof the administered medicinal product should be clearly recorded in the patient file.

The safety and efficacy of Lonquex have not been investigated in patients receiving high dosechemotherapy. Lonquex should not be used to increase the dose of cytotoxic chemotherapy beyondestablished dose regimens.

Allergic reactions and immunogenicity

Patients who are hypersensitive to G-CSF or derivatives are also at risk of hypersensitivity reactions tolipegfilgrastim due to possible cross-reactivity. No lipegfilgrastim therapy should be commenced inthese patients because of the risk of cross-reaction.

Most biological medicinal products elicit some level of anti-drug antibody response. This antibodyresponse can, in some cases, lead to undesirable effects or loss of efficacy. If a patient fails to respondto treatment, the patient should undergo further evaluation.

If a serious allergic reaction occurs, appropriate therapy with close patient follow-up over several daysshould be administered.

Haematopoietic system

Treatment with lipegfilgrastim does not preclude thrombocytopenia and anaemia caused bymyelosuppressive chemotherapy. Lipegfilgrastim may also cause reversible thrombocytopenia (seesection 4.8). Regular monitoring of the platelet count and haematocrit is recommended. Special careshould be taken when administering single or combination chemotherapeutic medicinal products thatare known to cause severe thrombocytopenia.

Leukocytosis may occur (see section 4.8). No adverse events directly attributable to leukocytosis havebeen reported. Elevation in white blood cells (WBC) is consistent with the pharmacodynamic effectsof lipegfilgrastim. A WBC count should be performed at regular intervals during therapy owing to theclinical effects of lipegfilgrastim and the potential for leukocytosis. If WBC counts exceed 50 x 109/lafter the expected nadir, lipegfilgrastim should be discontinued immediately.

Increased haematopoietic activity of the bone marrow in response to growth factor therapy has beenassociated with transient positive bone-imaging findings. This should be considered when interpretingbone-imaging results.

Patients with myeloid leukaemia or myelodysplastic syndromes

Granulocyte-colony stimulating factor can promote growth of myeloid cells and some non-myeloidcells in vitro.

The safety and efficacy of Lonquex have not been investigated in patients with chronic myeloidleukaemia, myelodysplastic syndromes or secondary acute myeloid leukaemia; it should therefore notbe used in such patients. Particular care should be taken to distinguish the diagnosis of blasttransformation 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 myeloidleukaemia (AML) were associated with the use of pegfilgrastim, an alternative G-CSF, in combinationwith chemotherapy and/or radiotherapy in breast and lung cancer patients. A similar association is notknown between lipegfilgrastim and MDS/AML. Nevertheless, patients with breast cancer and patientswith 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 oflipegfilgrastim (see section 4.8) and infrequent cases of splenic rupture, including fatal cases, havebeen reported after administration of G-CSF or derivatives (see section 4.8). Spleen size shouldtherefore be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic ruptureshould 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 afteradministration of lipegfilgrastim (see section 4.8). Patients with a recent history of pulmonaryinfiltrates or pneumonia may be at higher risk.

The onset of pulmonary symptoms such as cough, fever and dyspnoea in association with radiologicalsigns of pulmonary infiltrates and deterioration in pulmonary function together with an increasedneutrophil count may be preliminary signs of Acute Respiratory Distress Syndrome (ARDS) (seesection 4.8). In such circumstances Lonquex should be discontinued at the discretion of the physicianand appropriate treatment given.

Vascular adverse reactions

Capillary leak syndrome has been reported after administration of G-CSF or derivatives and ischaracterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients whodevelop symptoms of capillary leak syndrome should be closely monitored and receive standardsymptomatic 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. Thesymptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatorymarkers (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 cellanaemia (see section 4.8). Physicians should therefore exercise caution when administering Lonquexin patients with sickle cell anaemia, monitor appropriate clinical parameters and laboratory results andbe attentive to the possible association of lipegfilgrastim with splenic enlargement and vaso-occlusivecrisis.

Hypokalaemia may occur (see section 4.8). For patients with increased risk on hypokalaemia due tounderling disease or co-medications, it is recommended to monitor the serum potassium level carefullyand 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).

This medicinal product contains sorbitol. The additive effect of concomitantly administered productscontaining sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken intoaccount.

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, Lonquexshould be administered approximately 24 hours after administration of cytotoxic chemotherapy.

Concomitant use of lipegfilgrastim with any chemotherapeutic medicinal product has not beenevaluated 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 chemotherapyassociated with delayed myelosuppression, e.g. nitrosoureas.

The potential for interaction with lithium, which also promotes the release of neutrophils, has not beenspecifically investigated. There is no evidence that such an interaction would be harmful.

There are very limited data (less than 300 pregnancy outcomes) on the use of lipegfilgrastim inpregnant women. Animal studies have shown reproductive toxicity (see section 5.3). As aprecautionary measure, it is preferable to avoid the use of Lonquex during pregnancy.

It is unknown whether lipegfilgrastim/metabolites are excreted in human milk. A risk to the breast-fedchild cannot be excluded. Breast-feeding should be discontinued during treatment with Lonquex.

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

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

The most frequent undesirable effects are musculoskeletal pain and nausea.

Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reportedmostly in cancer patients undergoing chemotherapy after administration of G-CSF or derivatives (seesection 4.4 and section 4.8).

The safety of lipegfilgrastim has been evaluated based on results from clinical studies including506 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. Frequencygroupings are defined according to the following convention: very common (≥1/10), common (≥1/100to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), notknown (cannot be estimated from the available data).

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

Table 2: Adverse reactions

System organ class Frequency Adverse reaction

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

Immune system disorders Uncommon Hypersensitivity reactions*

Metabolism and nutrition Common Hypokalaemia*disorders

Nervous system disorders Common Headache

Vascular disorders Not known Capillary leak syndrome*,

Aortitis*

Respiratory, thoracic and Common Haemoptysismediastinal disorders Uncommon Pulmonary adverse reactions*,

Pulmonary Haemorrhage

Gastrointestinal disorders Very common Nausea*

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

Musculoskeletal and Very common Musculoskeletal pains*connective tissue disorders

General disorders and Common Chest painadministration site conditions

Investigations Uncommon Blood alkaline phosphataseincreased*, Blood lactatedehydrogenase increased*

*See section “Description of selected adverse reactions” below

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 allergicreactions 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 mostpatients with standard analgesics. However cases of severe musculoskeletal pain (mainly bone painand 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 mostlikely originate from the increase in neutrophils.

Certain adverse reactions have not yet been observed with lipegfilgrastim, but are generally acceptedas being attributable to G-CSF and derivatives:

- Splenic rupture including some fatal cases (see section 4.4)

- Sickle cell crisis in patients with sickle cell anaemia (see section 4.4)

- Capillary leak syndrome

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

- Aortitis (see section 4.4)

- Acute febrile neutrophilic dermatosis (Sweet’s syndrome)

- Cutaneous vasculitis

- Glomerulonephritis (see section 4.4)

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

- a phase I study with 21 paediatric patients aged 2 to 16 years with Ewing family of tumours orrhabdomyosarcoma receiving lipegfilgrastim after a single cycle of chemotherapy (see alsosection 5.1)

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

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no experience with overdose of lipegfilgrastim. In the case of overdose, WBC and plateletcount should be performed regularly and spleen size should be carefully monitored (e.g. clinicalexamination, ultrasound).

Pharmacotherapeutic group: Immunostimulants, colony stimulating factors, ATC code: L03AA14

Lipegfilgrastim is a covalent conjugate of filgrastim with a single methoxy polyethylene glycol (PEG)molecule via a carbohydrate linker consisting of glycine, N-acetylneuraminic acid and

N-acetylgalactosamine. The average molecular mass is approximately 39 kDa of which the proteinmoiety constitutes approximately 48 %. Human G-CSF is a glycoprotein that regulates the productionand release of functional neutrophils from the bone marrow. Filgrastim is an un-glycosylatedrecombinant methionyl human G-CSF. Lipegfilgrastim is a sustained duration form of filgrastim dueto decreased renal clearance. Lipegfilgrastim binds to human the G-CSF receptor like filgrastim andpegfilgrastim.

Lipegfilgrastim and filgrastim induced a marked increase in peripheral blood neutrophil counts within24 hours, with minor increases in monocytes and/or lymphocytes. These results suggest that the

G-CSF moiety of lipegfilgrastim confers the expected activity of this growth factor: stimulation ofproliferation of haematopoietic progenitor cells, differentiation into mature cells and release into theperipheral blood. This effect includes not only the neutrophil lineage but extends to other singlelineage and multilineage progenitors and pluripotent haematopoietic stem cells. G-CSF also increasesthe antibacterial activities of neutrophils including the phagocytosis.

Once-per-cycle dosing of lipegfilgrastim was investigated in two pivotal randomised, double-blindclinical studies in patients undergoing myelosuppressive chemotherapy.

The first pivotal (phase III) clinical study XM22-03 was an active-controlled study in 202 patientswith stage II-IV breast cancer receiving up to 4 cycles of chemotherapy consisting of doxorubicin anddocetaxel. Patients were randomised 1:1 to receive 6 mg lipegfilgrastim or 6 mg pegfilgrastim. Thestudy showed non-inferiority of 6 mg lipegfilgrastim to 6 mg pegfilgrastim for the primary endpoint,duration of severe neutropenia (DSN) in the first cycle of chemotherapy (see table 3).

Table 3: DSN, severe neutropenia (SN) and febrile neutropenia (FN) in cycle 1 ofstudy XM22-03 (ITT)

Pegfilgrastim 6 mg Lipegfilgrastim 6 mg(n = 101) (n = 101)

DSN

Mean ± SD (d) 0.9 ± 0.9 0.7 ± 1.0

Δ LS mean -0.18695 % CI -0.461 to 0.089

SN

Incidence (%) 51.5 43.6

FN

Incidence (%) 3.0 1.0

ITT = Intent-to-treat population (all randomised patients)

SD = standard deviationd = days

CI = confidence interval

Δ LS mean (least square mean difference lipegfilgrastim - pegfilgrastim) and CI out of multivariate

Poisson regression analysis

The second pivotal (phase III) clinical study XM22-04 was a placebo-controlled study in 375 patientswith non-small cell lung cancer receiving up to 4 cycles of chemotherapy consisting of cisplatin andetoposide. Patients were randomised 2:1 to receive either 6 mg lipegfilgrastim or placebo. The resultsof the study are presented in table 4. When the main study was finalised, the incidence of death was7.2 % (placebo) and 12.5 % (6 mg lipegfilgrastim) although after the 360-day follow-up period theoverall incidence of death was similar between placebo and lipegfilgrastim (44.8 % and 44.0 %; safetypopulation).

Table 4: DSN, SN and FN in cycle 1 of study XM22-04 (ITT)

Placebo Lipegfilgrastim 6 mg(n = 125) (n = 250)

FN

Incidence (%) 5.6 2.495 % CI 0.121 to 1.260p-value 0.1151

DSN

Mean ± SD (d) 2.3 ± 2.5 0.6 ± 1.1

Δ LS mean -1.66195 % CI -2.089 to -1.232p-value < 0.0001

SN

Incidence (%) 59.2 32.1

Odds ratio 0.32595 % CI 0.206 to 0.512p-value < 0.0001

Δ LS mean (least square mean difference lipegfilgrastim - placebo), CI and p-value out ofmultivariate Poisson regression analysis

Odds ratio (lipegfilgrastim/placebo), CI and p-value out of multivariate logistic regression analysis

A post-authorisation safety study XM22-ONC-40041 was conducted to collect data of diseaseprogression and mortality in patients with advanced squamous or non-squamous cell lung cancerreceiving lipegfilgrastim in addition to the platinum-based chemotherapy. Increased risk of diseaseprogression or death was not observed with lipegfilgrastim.

An analysis of anti-drug antibodies of 579 patients and healthy volunteers treated with lipegfilgrastim,188 patients and healthy volunteers treated with pegfilgrastim and 121 patients treated with placebowas performed. Drug-specific antibodies emerging after start of treatment were detected in 0.86 % ofthe subjects receiving lipegfilgrastim, in 1.06 % of the subjects receiving pegfilgrastim and in 1.65 %of the subjects receiving placebo. No neutralising antibodies against lipegfilgrastim were observed.

Two clinical studies (XM22-07 and XM22-08) were conducted in paediatric populations usinglipegfilgrastim for the treatment of chemotherapy-induced neutropenia and the prevention ofchemotherapy-induced febrile neutropenia. In both studies, lipegfilgrastim was supplied in glass vialscontaining 10 mg of lipegfilgrastim in a 1 ml solution for subcutaneous injection.

In the phase I study (XM22-07), 21 children aged between 2 and 16 years with Ewing family oftumours or rhabdomyosarcoma received lipegfilgrastim as a single subcutaneous dose of 100 μg/kg(up to a maximum of 6 mg, which is the fixed dose for adults) 24 hours after the end of the lastchemotherapy treatment in week 1 of the regimen. The chemotherapy regimens consisted of:vincristine, ifosfamide, doxorubicin and etoposide (VIDE); vincristine, actinomycin D andcyclophosphamide (VAC); or ifosfamide, vincristine, and actinomycin D (IVA). The incidence of FNvaried according to age (from 14.3 % to 71.4 %), with the highest frequency in the oldest age group.

The use of three different chemotherapy regimens, with varying myelosuppressive effects and agedistributions, complicated the comparison of efficacy across age groups.

In the phase II study (XM22-08), 42 children aged between 2 and < 18 years with Ewing family oftumours or rhabdomyosarcoma received for 4 consecutive chemotherapy cycles in a randomised1:1 ratio either lipegfilgrastim at a dose of 100 μg/kg (up to a maximum of 6 mg, 1 dose per cycle) orfilgrastim at a dose of 5 μg/kg (once daily for at least 5 consecutive days per cycle [maximum of14 days]). The chemotherapy regimens consisted of: VIDE; VAC; IVA; vincristine, doxorubicin, andcyclophosphamide alternating with ifosfamide and etoposide (VDC/IE); or ifosfamide, vincristine,actinomycin D and doxorubicin (IVADo). The primary endpoint was the duration of severeneutropenia (DSN) in cycle 1. DSN (mean [standard deviation]) in cycle 1 was 2.7 (2.25) days in thelipegfilgrastim group and 2.5 (2.09) days in the filgrastim group (Per Protocol [PP] Analysis set). Theoverall incidence of febrile neutropenia was 35 % in the lipegfilgrastim group and 42% in thefilgrastim group (PP Analysis Set). The study was not powered for formal hypothesis testing.

Therefore, results from this study should be interpreted with caution.

Healthy volunteers

In 3 studies (XM22-01, XM22-05, XM22-06) in healthy volunteers, the maximum bloodconcentration was reached after a median of 30 to 36 hours and the average terminal half-life rangedfrom approximately 32 to 62 hours after a single subcutaneous injection of 6 mg lipegfilgrastim.

After subcutaneous injection of 6 mg lipegfilgrastim at three different sites (upper arm, abdomen andthigh) in healthy volunteers, the bioavailability (peak concentration and area under the curve [AUC])was lower after subcutaneous injection in the thigh compared to subcutaneous injection in theabdomen and in the upper arm. In this limited study XM22-06, bioavailability of lipegfilgrastim andobserved differences among the injection sites were higher in male subjects compared to femalesubjects. Nevertheless, pharmacodynamic effects were similar and independent from gender andinjection site.

Lipegfilgrastim is metabolised via intra- or extracellular degradation by proteolytic enzymes.

Lipegfilgrastim is internalised by neutrophils (non-linear process), then degraded within the cell byendogenous proteolytic enzymes. The linear pathway is likely due to extracellular protein degradationby neutrophil elastase and other plasma proteases.

In vitro data indicate that lipegfilgrastim is has little or no direct or immune system-mediated effects on

CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 activity. Therefore, lipegfilgrastimis not likely to affect metabolism via human cytochrome P450 enzymes.

Cancer patients

In 2 studies (XM22-02 and XM22-03) in patients with breast cancer receiving chemotherapyconsisting of doxorubicin and docetaxel, mean maximum blood concentrations of 227 and 262 ng/mlwere reached after median times to maximum concentration (tmax) of 44 and 48 hours. The meanterminal half-lives were approximately 29 and 31 hours after a single subcutaneous injection of 6 mglipegfilgrastim during the first cycle of chemotherapy. After a single subcutaneous injection of 6 mglipegfilgrastim during the fourth cycle, the maximum blood concentrations were lower than observedin the first cycle (mean values 77 and 111 ng/ml) and were reached after median tmax of 8 hours. Themean terminal half-lives in the fourth cycle were approximately 39 and 42 hours.

In a study (XM22-04) in patients with non-small cell lung cancer receiving chemotherapy consistingof cisplatin and etoposide, the mean maximum blood concentration of 317 ng/ml was reached after amedian tmax of 24 hours and the mean terminal half-life was approximately 28 hours after a singlesubcutaneous injection of 6 mg lipegfilgrastim during the first cycle of chemotherapy. After a singlesubcutaneous injection of 6 mg lipegfilgrastim during the fourth cycle, the mean maximum bloodconcentration of 149 ng/ml was reached after a median tmax of 8 hours and the mean terminal half-lifewas approximately 34 hours.

Lipegfilgrastim appears to be mainly eliminated by neutrophil-mediated clearance, which becomessaturated at higher doses. Consistent with a self-regulating clearance mechanism, the serumconcentration of lipegfilgrastim declines slowly during the chemotherapy-induced transient neutrophilnadir and rapidly at the following onset of neutrophil recovery (see figure 1).

Figure 1: Profile of median serum concentration of lipegfilgrastim and median ANC inchemotherapy-treated patients after a single 6 mg injection of lipegfilgrastim

Lipegfilgrastim

ANC

Study days, injection of lipegfilgrastim at day 0

Due to the neutrophil-mediated clearance mechanism, the pharmacokinetics of lipegfilgrastim is notexpected to be affected by renal or hepatic impairment.

Limited patient data indicate that the pharmacokinetics of lipegfilgrastim in elderly patients(65 - 74 years) is similar to that in younger patients. No pharmacokinetic data are available in patients≥ 75 years.

In a phase I study (see section 5.1) the geometric mean maximum blood concentrations (Cmax) were243 ng/ml in the 2 to < 6-year group, 255 ng/ml in the 6 to < 12-year group and 224 ng/ml in the 12 to< 18-year group after a single subcutaneous injection of 100 μg/kg (maximum 6 mg) lipegfilgrastimwith the first cycle of chemotherapy. The maximum blood concentrations were reached after a mediantime (tmax) of 23.9 hours, 30.0 hours and 95.8 hours, respectively.

Pharmacokinetic and pharmacodynamic (PK-PD) modelling of paediatric data (aged 2 to < 18 yearswith administered doses of 100 µg/kg), including additional data from the phase II study (see section5.1) and combined with previous adult PK data, support that comparable lipegfilgrastim serumexposures were achieved in paediatric patients as compared to adult patients, and that PK and PDparameters were comparable across the paediatric weight bands studied and support the doserecommendation by body weight ranges for paediatric patients.

Overweight patients

A trend towards a decrease in lipegfilgrastim exposure was observed with increase in weight. Thismay result in lowered pharmacodynamic responses in heavy patients (> 95 kg). Consequent decreasein efficacy in these patients cannot be excluded on current data.

Median serum concentration of lipegfilgrastim (ng/ml)

Median ANC (x 109 cells/l)

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, single and repeated dose toxicity and local tolerance.

In a study of toxicity to reproduction and development in rabbits, an increased incidence ofpost-implantation loss and abortion has been observed at high doses of lipegfilgrastim, likely owing toan exaggerated pharmacodynamic effect specific for rabbits. There is no evidence that lipegfilgrastimis teratogenic. These findings are consistent with results from G-CSF and derivatives. Publishedinformation on G-CSF and derivatives reveal no evidence of adverse effects on fertility andembryo-foetal development in rats or pre-/postnatal effects other than those related to maternaltoxicity as well. There is evidence that filgrastim and pegfilgrastim may be transported at low levelsover the placenta in rats, although no information is available for lipegfilgrastim. The relevance ofthese findings for humans is not known.

Glacial acetic acid

Sodium hydroxide (for pH-adjustment)

Sorbitol (E420)

Polysorbate 20

Water for injections

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

3 years

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Keep the pre-filled syringe or vial in the outer carton in order to protect from light.

Lonquex may be removed from the refrigerator and stored below 25 °C for a maximum single periodof up to 7 days. Once removed from the refrigerator, the medicinal product must be used within thisperiod or disposed of.

Pre-filled syringe (type I glass) with a plunger stopper [poly(ethylene-co-tetrafluoroethylene)-coatedbromobutyl rubber] and a fixed injection needle (stainless steel, 29G [0.34 mm] or 27G [0.4 mm] x0.5 inch [12.7 mm]).

Each pre-filled syringe contains 0.6 ml of solution.

Pack sizes of 1 and 4 pre-filled syringes with safety device (which prevents needle stick injury andre-use) or 1 pre-filled syringe without safety device.

Not all pack sizes may be marketed.

Vial

Type I clear, borosilicate glass vial with a bromobutyl rubber stopper and an aluminium crimp sealwith polypropylene flip-off cap.

Each vial contains 0.6 ml of solution.

Pack sizes of 1 or 6 vials.

Not all pack sizes may be marketed.

The solution should be visually inspected before use. Only clear, colourless solutions without particlesshould be used.

The solution should be allowed to reach a comfortable temperature (15 °C - 25 °C) for injection.

Vigorous shaking should be avoided. Excessive shaking may aggregate lipegfilgrastim, rendering itbiologically inactive.

Lonquex does not contain any preservative. In view of the possible risk of microbial contamination,

Lonquex syringes or vials are for single use only. Any unused portions of each vial must be discardedproperly. Do not save any unused portions for later administrations.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Teva B.V.

Swensweg 52031 GA Haarlem

Netherlands

EU/1/13/856/001

EU/1/13/856/002

EU/1/13/856/003

Vial

EU/1/13/856/004

EU/1/13/856/005

Date of first authorisation: 25 July 2013

Date of latest renewal: 19 April 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.