4.1 Therapeutic indications

Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients

treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia

and myelodysplastic syndromes).

4.2 Posology and method of administration

Pegfilgrastim therapy should be initiated and supervised by physicians experienced in oncology and/or

haematology.

Posology

One 6 mg dose (a single pre-filled syringe) of pegfilgrastim is recommended for each chemotherapy

cycle, given at least 24 hours after cytotoxic chemotherapy.

Special populations

 Paediatric population

The safety and efficacy of pegfilgrastim in children has not yet been established. Currently available

data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Patients with renal impairment

No dose change is recommended in patients with renal impairment, including those with end stage

renal disease.

Method of administration

Fulphila is injected subcutaneously. The injections should be given into the thigh, abdomen or upper arm.

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

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number

of the administered product should be clearly recorded.

Patients with myeloid leukaemia or myelodysplastic syndromes

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 (AML) (see section 5.1).

However, the long-term effects of pegfilgrastim have not been established in AML; therefore, it should

be used with caution in this patient population.

Granulocyte-colony stimulating factor 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.

General

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.

Pulmonary adverse events

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 granulocyte-colony stimulating factor 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).

Splenomegaly and splenic rupture

Generally asymptomatic cases of splenomegaly and 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 x 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 x 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.

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.

Other warnings

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.

This medicinal product contains 30 mg sorbitol in each pre-filled syringe which is equivalent to 50

mg/mL. 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 (23 mg) sodium per 6 mg dose, that is to say

essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

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.

4.6 Fertility, pregnancy and lactation

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). Pegfilgrastim 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 Fulphila 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).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) and

musculoskeletal pain (common [≥ 1/100 to < 1/10]). 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, erythema,

flushing, and hypotension occurred on initial or subsequent treatment with pegfilgrastim (uncommon

[≥ 1/1,000 to < 1/100]). 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 (≥ 1/1,000 to < 1/100) in cancer patients undergoing chemotherapy following

administration of granulocyte colony-stimulating factors; see section 4.4 and section “Description of selected adverse reactions” below.

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. 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 1576 patients receiving pegfilgrastim in nine randomized 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 erythema (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 x 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 granulocyte

colony-stimulating factor 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 and adolescents 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.

To report any side effect(s):

Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

o  Toll free phone: 8002490000

o  E-mail: npc.drug@sfda.gov.sa

o  Website: www.sfda.gov.sa/npc

Other GCC States

Please contact the relevant competent authority. 

4.9 Overdose

Single doses of 300 μg/kg have been administered subcutaneously to a limited number of healthy

volunteers and patients with non-small cell lung cancer without serious adverse reactions. The adverse

events were similar to those in subjects receiving lower doses of pegfilgrastim.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: immunostimulants, colony stimulating factor; ATC Code: L03AA13

Fulphila is a biosimilar medicinal product.

Human granulocyte colony stimulating factor (G-CSF) is a glycoprotein, which regulates the

production and release of neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate of

recombinant human G-CSF (r-metHuG-CSF) with a single 20 kd polyethylene glycol (PEG) molecule.

Pegfilgrastim is a sustained duration form of filgrastim due to decreased renal clearance. Pegfilgrastim

and filgrastim have been shown to have identical modes of action, causing a marked increase in

peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/or

lymphocytes. Similarly, to filgrastim, neutrophils produced in response to pegfilgrastim show normal

or enhanced function as demonstrated by tests of chemotactic and phagocytic function. As with other

haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial

cells. G-CSF can promote growth of myeloid cells, including malignant cells, in vitro and similar

effects may be seen on some non-myeloid cells in vitro.

In two randomised, double-blind, pivotal studies in patients with high risk stage II-IV breast cancer

undergoing myelosuppressive chemotherapy consisting of doxorubicin and docetaxel, use of

pegfilgrastim, as a single once per cycle dose, reduced the duration of neutropenia and the incidence of

febrile neutropenia similarly to that observed with daily administrations of filgrastim (a median of

11 daily administrations). In the absence of growth factor support, this regimen has been reported to

result in a mean duration of grade 4 neutropenia of 5 to7 days, and a 30-40 % incidence of febrile

neutropenia. In one study (n = 157), which used a 6mg fixed dose of pegfilgrastim the mean duration

of grade 4 neutropenia for the pegfilgrastim group was 1.8 days compared with 1.6 days in the

filgrastim group (difference 0.23 days, 95 % CI -0.15, 0.63). Over the entire study, the rate of febrile

neutropenia was 13 % of pegfilgrastim-treated patients compared with 20 % of filgrastim-treated

patients (difference 7 %, 95 % CI of -19 %, 5 %). In a second study (n = 310), which used a

weight-adjusted dose (100 μg /kg), the mean duration of grade 4 neutropenia for the pegfilgrastim

group was 1.7 days, compared with 1.8 days in the filgrastim group (difference 0.03 days, 95 %

CI -0.36, 0.30). The overall rate of febrile neutropenia was 9 % of patients treated with pegfilgrastim

and 18 % of patients treated with filgrastim (difference 9 %, 95 % CI of -16.8 %,-1.1 %).

In a placebo-controlled, double blind study in patients with breast cancer the effect of pegfilgrastim on

the incidence of febrile neutropenia was evaluated following administration of a chemotherapy

regimen associated with a febrile neutropenia rate of 10-20 % (docetaxel 100 mg/m² every 3 weeks for

4 cycles). Nine hundred and twenty-eight patients were randomised to receive either a single dose of

pegfilgrastim or placebo approximately 24 hours (Day 2) after chemotherapy in each cycle. The

incidence of febrile neutropenia was lower for patients randomised to receive pegfilgrastim compared

with placebo (1 % versus 17 %, p < 0.001). The incidence of hospitalizations and IV anti-infective use

associated with a clinical diagnosis of febrile neutropenia was lower in the pegfilgrastim group

compared with placebo (1 % versus 14 %, p < 0.001; and 2 % versus 10 %, p < 0.001).

A small (n = 83), Phase II, randomised, double-blind study in patients receiving chemotherapy for de

novo acute myeloid leukaemia compared pegfilgrastim (single dose of 6 mg) with filgrastim,

administered during induction chemotherapy. Median time to recovery from severe neutropenia was

estimated as 22 days in both treatment groups. Long term outcome was not studied (see section 4.4).

In a phase II (n = 37) multicentre, randomised, open-label study of paediatric sarcoma patients

receiving 100 mcg/kg pegfilgrastim following cycle 1 of vincristine, doxorubicin and

cyclophosphamide (VAdriaC/IE) chemotherapy, a longer duration of severe neutropenia (neutrophils

< 0.5 x 109) was observed in younger children aged 0-5 yrs (8.9 days) compared to older children aged

6-11 years and 12-21 years (6 days and 3.7 days, respectively) and adults. Additionally, a higher

incidence of febrile neutropenia was observed in younger children aged 0-5 yrs (75 %) compared to

older children aged 6-11 years and 12-21 years (70 % and 33 %, respectively) and adults (see sections

4.8 and 5.2).

5.2 Pharmacokinetic properties

After a single subcutaneous dose of pegfilgrastim, the peak serum concentration of pegfilgrastim

occurs at 16 to 120 hours after dosing and serum concentrations of pegfilgrastim are maintained during

the period of neutropenia after myelosuppressive chemotherapy. The elimination of pegfilgrastim is

non-linear with respect to dose; serum clearance of pegfilgrastim decreases with increasing dose.

Pegfilgrastim appears to be mainly eliminated by neutrophil mediated clearance, which becomes

saturated at higher doses. Consistent with a self-regulating clearance mechanism, the serum

concentration of pegfilgrastim declines rapidly at the onset of neutrophil recovery (see figure 1).

Figure 1. Profile of median pegfilgrastim serum concentration and Absolute Neutrophil Count

(ANC) in chemotherapy treated patients after a single 6 mg injection

Due to the neutrophil-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is not

expected to be affected by renal or hepatic impairment. In an open label, single dose study (n = 31)

various stages of renal impairment, including end-stage renal disease, had no impact on the

pharmacokinetics of pegfilgrastim.

Elderly

Limited data indicate that the pharmacokinetics of pegfilgrastim in elderly subjects (> 65 years) is

similar to that in adults.

Paediatric population

The pharmacokinetics of pegfilgrastim were studied in 37 paediatric patients with sarcoma, who

received 100 mcg/kg pegfilgrastim after the completion of VAdriaC/IE chemotherapy. The youngest

age group (0-5 years) had a higher mean exposure to pegfilgrastim (AUC) (± Standard Deviation)

(47.9 ± 22.5 μg·hr/ml) than older children aged 6-11 years and 12-21 years (22.0 ± 13.1 mcg·hr/ml

and 29.3 ± 23.2 mcg·hr/ml, respectively) (see section 5.1). With the exception of the youngest age

group (0-5 years), the mean AUC in paediatric subjects appeared similar to that for adult patients with

high-risk stage II-IV breast cancer and receiving 100 mcg/kg pegfilgrastim after the completion of

doxorubicin/docetaxel (see sections 4.8 and 5.1).

5.3 Preclinical safety data

Preclinical data from conventional studies of repeated dose toxicity revealed the expected

pharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow,

extramedullary haematopoiesis and splenic enlargement.

There were no adverse effects observed in offspring from pregnant rats given pegfilgrastim

subcutaneously, but in rabbits pegfilgrastim has been shown to cause embryo/foetal toxicity (embryo

loss) at cumulative doses approximately 4 times the recommended human dose, which were not seen

when pregnant rabbits were exposed to the recommended human dose. In rat studies, it was shown that

pegfilgrastim may cross the placenta. Studies in rats indicated that reproductive performance, fertility,

oestrous cycling, days between pairing and coitus, and intrauterine survival were unaffected by

pegfilgrastim given subcutaneously. The relevance of these findings for humans is not known.

6.1 List of excipients

Sodium acetate*

Sorbitol (E420)

Polysorbate 20

Water for injections

*Sodium acetate is formed by titrating glacial acetic acid with sodium hydroxide.

6.2 Incompatibilities

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

chloride solutions.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Fulphila may be exposed to room temperature (not above 30°C) for a maximum single period of up to

72 hours. Fulphila left at room temperature for more than 72 hours should be discarded.

Do not freeze. Accidental exposure to freezing temperatures for a single period of less than 24 hours

does not adversely affect the stability of Fulphila.

Keep the container in the outer carton in order to protect from light.

6.5 Nature and contents of container

Pre-filled syringe (Type I glass), with a bromobutyl rubber stopper and a stainless steel needle with or

without an automatic needle guard.

Pack size of one pre-filled syringe, in blistered packaging.

6.6 Special precautions for disposal and other handling

Before administration, Fulphila solution should be inspected visually for particulate matter. Only a

solution that is clear and colourless should be injected.

Excessive shaking may aggregate pegfilgrastim, rendering it biologically inactive.

The pre-filled syringe should be allowed to reach room temperature before injecting.

Any unused product or waste material should be disposed of in accordance with local requirements.