Ristempa - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

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).

Ristempa 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 Ristempa is recommended for each chemotherapy cycle, given at least 24 hours after cytotoxic chemotherapy.

Method of administration

Ristempa 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.

Paediatric population

The safety and efficacy of Ristempa 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 st renal disease.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Limited clinical data suggest a comparable effect on time to recovery for

pegfilgrastim to filgrastim in patients with de novo acute myeloid leuk           sec­tion 5.1).

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

Granulocyte-colony stimulating factor can prom may be seen on some non-myeloid cells in vitro.

The safety and efficacy of Ristempa 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 Ristempa administration in de novo AML patients aged < 55 years with cytogenetics t(15;17) have not been established.

empa have not been investigated in patients receiving high dose product should not be used to increase the dose of cytotoxic blished dosage regimens.

>1/1,000 to < 1/100) pulmonary adverse reactions, in particular interstitial pneumonia, reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates monia 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 Ristempa 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

Uncommon but generally asymptomatic cases of splenomegaly and uncommon cases rupture, including some fatal cases, have been reported following administration of section 4.8). Therefore, spleen size should be carefully monitored (e.g. clinical ultrasound). A diagnosis of splenic rupture should be considered in abdominal pain or shoulder tip pain.

Thrombocytopenia and anaemia

Treatment with Ristempa alone does not preclude thromboc myelosuppressive chemotherapy is maintained on the prescri platelet count and haematocrit is recommended. Special c single or combination chemotherapeutic agents which a

Sickle cell anaemia

h the use of pegfilgrastim in patients with sickle cell trait or fore, physicians should use caution when prescribing t sickle cell disease, should monitor appropriate clinical ;entive to the possible association of this medicine with

White blood cell (WBC) counts of 100 × 109/l or greater have been observed in less than 1% of patients receiving Ristempa. 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 administra and is consistent with the pharmacodynamic effects of this medicine. Consistent with the clinica cts 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.

lersensitivity

Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have been reported in patients treated with Ristempa. Permanently discontinue Ristempa in patients with clinically significant hypersensitivity. Do not administer Ristempa 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.

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.

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

The needle cap of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may

cause allergic reactions.

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

Ristempa contains sorbitol. Patients with rare hereditary problems of fructose intol take this medicine.

Ristempa contains less than 1 mmol (23 mg) sodium per 6 mg dose, i.e. es

In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs), the trade name of the administered product should be clearly recorded in the patient file.

4.5 Interaction with other medicinal products and othf interaction

Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, Ristempa should be administered at least 24 hours after administration of cytotoxic chemotherapy. In clinical trials, Ristempa has been safely administered 14 days before chemotherapy. Concomitant use of Ristempa with any chemotherapy agent has not been evaluated in patients. In animal models concomitant administration of Ristempa 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 clini

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 Ristempa have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression e.g., nitrosoureas.

tion or metabolism studies have not been performed, however, clinical trials have not nteraction of Ristempa with any other medicinal products.

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). Ristempa is not recommended during pregnancy and in women of childbearing potential not using contraception.

Women who become pregnant during Ristempa treatment are encouraged to enrol in Amgen’s Pregnancy Surveillance Programme. Contact details are provided in section 6 of the Package leaflet.

Breast-feeding

There is insufficient information on the excretion of Ristempa / 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 Ristempa therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women who are breast-feeding during Ristempa treatment are encouraged to enrol in Amgen’s Lactation Surveillance programme. Contact details are provided in section 6 of the Package leaflet.

Fertility

Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumu weekly doses approximately 6 to 9 times higher than the recommended human dose (based on b surface area) (see section 5.3).

4.7 Effects on ability to drive and use machines

Ristempa 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 (     ommon [> 1/10]) 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 Ristempa (uncommon [> 1/1,000 to < 1/100]). Serious allergic reactions, including anaphylaxis can occur in patients receiving Ristempa (uncommon) (see section 4.4).

e-threatening if treatment is delayed, has been reported as r patients undergoing chemotherapy following

-stimulating factors; see section 4.4 and section “Description of

Splenomegaly, generally asymptomatic, is uncommon.

ing some fatal cases is uncommonly reported following administration of tion 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 summary 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 Ristempa in nine randomized clinical trials.

Description of selected adverse reactions

Uncommon cases of Sweet’s syndrome have been reported, although in some cases underlyin haematological malignancies may play a role.

Uncommon events of cutaneous vasculitis have been reported in patients treated with Ristempa. The mechanism of vasculitis in patients receiving Ristempa is unknown.

Injection site reactions, including injection site erythaema (uncommon (> 1/1000 to < 1/100)) as well as injection site pain (common events > 1/100 to < 1/10) have occurred on initial or subsequent treatment with Ristempa.

Common (> 1/100 to < 1/10) cases of leukocytosis (White 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 Ristempa following cytotoxic chemotherapy.

y observed in patients receiving chemotherapy.

Uncommon elevations in liver function tests (LFTs) for ALT (alanine aminotransferase) or AST (aspartate aminotransferas     ve been observed in patients after receiving pegfilgrastim following

cytotoxic chemotherapy. T     elevations are transient and return to baseline.

Common cases of thrombocytopenia have been reported.

y leak syndrome have been reported in the post marketing setting with granulocyte ng factor use. These have generally occurred in patients with advanced malignant taking multiple chemotherapy medications or undergoing apheresis (see section 4.4).

ric 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.

4.9 Overdose

Single doses of 300 ^g/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. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: immunostimulants, colony stimulating factor; ATC Code

Human granulocyte colony stimulating factor (G-CSF) is a glycoprotein, which regula 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 ^g /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 hospitalisations 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 ^g/kg pegfilgrastim following cycle 1 of vincristine, doxorubicin and cyclophosphamide (VAdriaC/IE) chemotherapy, a longer duration of severe neutropenia (neutrophils < 0.5 × 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).

-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is not affected by renal or hepatic impairment. In an open label, single dose study (n = 31) s of renal impairment, including end-stage renal disease, had no impact on the kinetics of pegfilgrastim.

Elderly people

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 pg/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 pgJir/ml) than older children aged 6–11 years and 12–21 years (22.0 ± 13.1 pgJir/ml and 29.3 ± 23.2 pg-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 pg/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. PHARMACEUTICAL PARTICULARS6.1 List of excipients