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Raptiva (efalizumab) – Summary of product characteristics - L04AA21

Updated on site: 09-Oct-2017

Medication nameRaptiva
ATC CodeL04AA21
Substanceefalizumab
ManufacturerSerono Europe Limited
For a full list of excipients, see section 6.1.

1.NAME OF THE MEDICINAL PRODUCT

Raptiva 100 mg/ml powder and solvent for solution for injection

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains a retrievable amount of 125 mg of efalizumab.

Reconstitution with the solvent yields a solution containing efalizumab at 100 mg/ml.

Efalizumab is a recombinant humanized monoclonal antibody produced in genetically engineered Chinese Hamster Ovary (CHO) cells. Efalizumab is an IgG1 kappa immunoglobulin, containing human constant region sequences and murine light- and heavy-chain complementary determining region sequences.

Excipients: 2.5 mg polysorbate 20, 3.55 mg histidine, 5.70 mg histidine hydrochloride monohydrate, 102.7 mg sucrose.

3.

PHARMACEUTICAL FORM

 

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Powder and solvent for solution for injection.

 

The powder is a white to off white cake.

 

The solvent is a clear, colourless liquid.

 

The pH of the reconstituted solution is 5.9 – 6.5.

4.

CLINICAL PARTICULARS

no

 

 

 

4.1

Therapeutic indications

 

 

 

product

 

 

authorised

Treatment of adult patients with moderate to severe chronic plaque psoriasis who have failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate and PUVA (see section 5.1 – Clinical Efficacy).

4.2 Posology and method of administration

Treatment with Raptiva should be initiated by a physician specialised in dermatology.

An initial single dose of 0.7 mg/kg body weight is given followed by weekly injections of 1.0 mg/kg body weight (maximum single dose should not exceed a total of 200 mg). The volume to be injected should be calculated as follows:

 

 

Dose

 

Volume to be injected per

 

 

 

 

10 kg body weight

 

Single initial dose:

0.7 mg/kg

0.07 ml

 

Subsequent doses:

1 mg/kg

0.1 ml

Medicinal

 

 

 

The duration of therapy is 12 weeks. Therapy may be continued only in patients who responded to treatment (PGA good or better). For discontinuation guidance see section 4.4.

Method of administration
Raptiva is for subcutaneous injection. Injection sites should be rotated. For instructions for use see section 6.6.

Children and adolescents (< 18 years)

Raptiva is not recommended for use in children below age 18 due to a lack of data on safety and efficacy.

Use in the elderly (≥ 65 years)

The dosage and administration schedule in the elderly should be the same as for adults (see also section 4.4).

Patients with renal or hepatic impairment

No studies have been conducted in patients with renal or hepatic impairment. Raptiva should be used with caution in this patient population.

After proper training in the reconstitution and injection technique, patients may self-inject with Raptiva, if their physician determines that this is appropriate.

authorised

4.3Contraindications

Hypersensitivity to efalizumab or to any of the excipients. Patients with history of malignancies.

Patients with active tuberculosis and other severe infections.

Patients with specific forms of psoriasis like guttate, erythrodermic or pustular psoriasis as sole or

predominant form of psoriasis.

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Patients with immunodeficiencies.

4.4Special warnings and precautions fornouseEffects on the immune system

a) Infections

product

 

Raptiva is a selective immunosuppressor that alters T-lymphocyte function and may affect host defences against infections. It has the potential to increase the risk or the severity of infections, e.g. tuberculous pneumonia, and reactivate latent, chronic infections e.g. JC virus infection.

Patients developing an infection during treatment with Raptiva should be monitored and according to severity Raptiva should be discontinued. In a patient with history of clinically significant recurring

infections, Raptiva should be used with caution.

MedicinalThe use of Raptiva may be associated with an increased risk of Progressive Multifocal Leukoencephalopathy (PML). One case of JC virus infection resulting in PML has been reported in

post-marketing surveillance in a patient with psoriasis receiving Raptiva (see section 4.8).

Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML (such as impaired cognition, visual disturbances, hemiparesis, altered mental state or behavioural changes). If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. If any doubt exists, further evaluation, including Magnetic Resonance Imaging (MRI) scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC viral DNA and repeat neurological assessment, should be considered. Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.

If a patient develops PML, the dosing of Raptiva must be permanently discontinued.

b) Vaccinations

Limited data are available on the effects of vaccination. Neo-vaccinations given during treatment with Raptiva may induce antibody levels lower than those observed in non-treated subjects, but the clinical

significance of this is unknown. Patients should not receive live and live-attenuated vaccines while on Raptiva therapy. Before vaccination, treatment with Raptiva should be withheld for 8 weeks and can resume 2 weeks after vaccination. (see section 4.5).

c) Malignancies and lymphoproliferative disorders

It is not yet known whether or not Raptiva can increase the risk of lymphoproliferative disorders or other malignancies in psoriasis patients. Raptiva should be discontinued if a malignancy develops

while the patient is on treatment (see sections 4.3 and 4.8).

Immune-mediated haemolytic anaemia

In post-marketing surveillance, isolated cases of severe haemolytic anaemia have been reported during treatment with Raptiva. In such circumstances, Raptiva should be discontinued.

Thrombocytopenia

Thrombocytopenia may occur during Raptiva treatment and may be associated with clinical signs such as echymoses, spontaneous bruising or bleeding from muco-cutaneous tissues. If these manifestations occur, efalizumab should be stopped immediately, a platelet count should be performed and appropriate symptomatic treatment should be instituted immediately (see section 4.8).

Raptiva has not been studied in combination with immunosuppressive systemicauthorisedantipsoriasis medicinal products. Therefore, combination therapies with these products are not recommended (see section 4.5).

is recommended that assessments be more frequent whenlongerinitiating therapy (e.g., monthly) and may decrease in frequency with continued treatment (e.g., every 3 months).

Platelet counts are recommended upon initiating and periodically while receiving Raptiva treatment. It

Inflammatory polyradiculoneuropathy

Cases of inflammatory polyradiculoneuropathy have been observed in post-marketing surveillance in patients receiving Raptiva (see section 4.8). Patients have recovered after discontinuation of Raptiva, therefore Raptiva should be stopped following the diagnosis of inflammatory polyradiculoneuropathy.

no As with any recombinantproductproduct, Raptiva is potentially immunogenic. Consequently, if any serious

Hypersensitivity and allergic reactions

hypersensitivity or allergic reaction occurs, Raptiva should be discontinued immediately and appropriate therapy initiated (see sections 4.3 and 4.8).

Arthritis

Cases of arthritis have been observed during treatment or after discontinuation of Raptiva. It is recommended to discontinue Raptiva if arthritis occurs during treatment.

Psoriasis

MedicinalDuring treatment with Raptiva, cases of exacerbation of psoriasis, including pustular, erythrodermic, and guttate subtypes, have been observed (see section 4.8). In such cases, it is recommended to discontinue treatment with Raptiva.

Discontinuation of treatment may cause a recurrence or exacerbation of plaque psoriasis including erythrodermic and pustular psoriasis, especially in patients not responding to treatment. Gradual reduction of dose or frequency does not appear to be beneficial.

Discontinuation

Management of patients discontinuing Raptiva includes close observation. In case of recurrence or exacerbation of disease, as well as in patients who discontinue Raptiva and are non-responders, the treating physician should institute the most appropriate psoriasis treatment as necessary.

In case re-treatment with Raptiva is indicated the same guidance should be followed as under Posology and method of administration. Re-treatment may be associated with lower or inadequate response to Raptiva than in the earlier treatment periods. Therapy may be continued only in those patients who respond adequately to treatment.

Special patient populations

No differences in safety or efficacy were observed between elderly (≥ 65 years) patients and younger patients. As there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.

Raptiva has not been studied in patients with renal or hepatic impairment and should therefore be used with caution in such patients. See section 4.8 regarding the effects on the hepatic function.

4.5 Interaction with other medicinal products and other forms of interaction

There have been no formal drug interaction studies performed with Raptiva.

Limited data are available on the effects of vaccination in patients receiving Raptiva.

In a study of 66 patients with moderate plaque psoriasis, immune responses during and after Raptiva treatment were investigated. Following booster vaccination with tetanus toxoid (recall antigen), the ability to mount an immune response to the tetanus toxoid was preserved in those patients undergoing Raptiva therapy. After 35 days of treatment with Raptiva, the proportion of subjects treated with efalizumab with positive skin test reactions to Candida was significantly reduced compared with the

placebo group. Antibody response to an experimental neo-antigen ( X174) was reduced during

Raptiva therapy, but began to normalize 6 weeks after discontinuation of Raptiva therapy and did not

demonstrate tolerance induction. A pneumococcal vaccine administered 6 weeks after discontinuation

 

 

 

authorised

of Raptiva yielded normal results. Neo-vaccinations given during treatment with Raptiva may induce

antibody levels lower than non-treated subjects, but the clinical significance of this is unknown.

Patients should not receive live and live-attenuated vaccines during Raptiva treatment. (See section

4.4).

 

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Given the mechanism of action of efalizumab, its effects on the immune system may be potentiated by

systemic immunosuppressives commonly used for the treatment of psoriasis (see section 4.4).

 

no

 

 

Raptiva has been used in combination with topical corticosteroids in psoriasis patients without any

untoward effects nor with any observable significant beneficial effect of the combination therapy

product

 

 

 

above monotherapy with efalizumab.

 

 

 

4.6 Pregnancy and lactation

Pregnancy

In general, immunoglobulins are known to cross the placental barrier. There are no adequate data from the use of efalizumab in pregnant women. Animal studies indicate an impairment of the immune function of the offspring (see section 5.3).

MedicinalPregnant women should not be treated with Raptiva.

Women of childbearing potential have to use appropriate contraception during treatment.

Lactation

Excretion of efalizumab in human milk has not been investigated, however immunoglobulins are expected to be excreted in human milk. Moreover, an antibody analogue of efalizumab was shown to be excreted in milk of mice. Women should not breastfeed during treatment with Raptiva.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Based on the pharmacological mechanism of action of efalizumab, the use of Raptiva is not expected to affect patient’s ability to drive and use machines.

4.8Undesirable effects

The most frequent symptomatic adverse drug reactions (ADRs) observed during Raptiva therapy were mild to moderate dose-related acute flu-like symptoms including headache, fever, chills, nausea and

6

myalgia. In large placebo-controlled clinical studies, these reactions were observed in approximately 41% of Raptiva-treated patients and 24% in placebo-treated patients over 12 weeks of treatment. After initiation of therapy, these reactions were generally less frequent and occurred at similar rates to that seen in the placebo group from the third and subsequent weekly injections.

Antibodies to efalizumab were detected in only 6% of patients. In this small number of patients no differences were observed in pharmacokinetics, pharmacodynamics, clinically noteworthy adverse events or clinical efficacy.

Adverse events (Preferred Terms) in the overall population studied clinically with Raptiva are listed below by frequency of occurrence and by MedDRA System Organ Class. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Very

Common

Uncommon

Rare

Very rare

Not known

 

common

(>1/100<1/10)

(>1/1,000,

(>1/10,000,

(<1/10,000)

 

 

(>1/10)

 

<1/100)

<1/1,000)

 

 

Infections and

 

 

 

 

 

 

 

Aseptic meningitis*,

infestations

 

 

 

 

 

 

 

Severe infections*,

 

 

 

 

 

 

 

 

JC virus infection

 

 

 

 

 

 

 

 

resulting in

 

 

 

 

 

 

 

 

progressive multifocal

 

 

 

 

 

 

 

 

leukoencephalopathy*

 

 

 

 

 

 

 

authorised

Blood and the

Leuko-

 

Thrombo-

 

 

Immune mediated

lymphatic system

cytosis and

 

cytopenia

 

 

haemolytic anaemia*

disorders

lympho-

 

 

 

 

 

 

 

cytosis

 

 

 

 

 

 

Immune system

 

 

Hyper-

 

longer

 

 

disorders

 

 

sensitivity

 

 

 

 

 

 

reactions

 

 

 

Nervous system

 

 

 

Facial palsy

 

 

Inflammatory

disorders

 

 

 

(Bell’s

 

 

 

polyradiculo-

 

 

 

 

palsy)

 

 

 

neuropathy*

 

 

 

 

no

 

 

 

 

Respiratory,

 

 

 

 

 

 

 

Interstitial

thoracic and

 

 

 

 

 

 

 

pneumonitis*

mediastinal

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

Skin and

 

 

Psoriasis

Urticaria

 

 

 

Erythema

subcutaneous tissue

 

 

 

 

 

 

 

multiforme*

disorders

 

 

 

 

 

 

 

 

Musculoskeletal and

 

 

Arthralgia

 

 

 

 

 

connective tissue

 

 

Arthritis /

 

 

 

 

 

disorders

 

product

 

 

 

 

 

 

 

Psoriatic

 

 

 

 

 

 

 

 

arthritis

 

 

 

 

 

 

 

 

(exacerbation/

 

 

 

 

 

 

 

 

flare)

 

 

 

 

 

General disorders

Flu-like

Back pain,

Injection site

 

 

 

and administration

symptoms

Asthenia

reactions

 

 

 

 

site conditions

including

 

 

 

 

 

 

Medicinal

fever,

 

 

 

 

 

 

 

headaches,

 

 

 

 

 

 

chills,

 

 

 

 

 

 

nausea and

 

 

 

 

 

 

myalgia

 

 

 

 

 

 

 

 

 

 

 

 

 

Investigations

 

 

Elevation of

 

 

 

 

 

 

 

 

alkaline

 

 

 

 

 

 

 

 

Phosphatase,

 

 

 

 

 

 

 

 

Elevation of

 

 

 

 

 

 

 

 

ALT

 

 

 

 

 

* Events identified during postmarketing surveillance

The safety profile in the target population as defined in section 4.1 is similar to the safety profile in the overall population treated during clinical development of Raptiva as presented above.

Additional Information

Long-term exposure:

Thrombocytopenia:authorised In the combined safety database of 3291 Raptiva-treated patients at the time of approval, there were

Analysis following long-term use in a cohort of 339 patients with moderate to severe psoriasis receiving Raptiva 1 mg/kg/week, of which 166 patients have been treated for more than 2 years and up

to 3 years, did not show any noteworthy differences in frequency of adverse events as compared to 12

weeks of exposure to Raptiva. Leucocytosis and lymphocytosis: in large placebo-controlled and in long-term clinical studies, between 40 and 50% of patients developed sustained asymptomatic lymphocytosis during Raptiva therapy. All values were between 2.5 fold and 3.5 fold the ULN (Upper

Limit of Normal). Lymphocyte count returned to baseline after therapy discontinuation. Slight elevation in absolute neutrophil count and eosinophil count were observed but in a smaller proportion of patients.

nine occurrences (0.3%) of thrombocytopenia with less than 52,000 cells per μl reported. Four of these patients had clinical signs of thrombocytopenia. Based on available platelet count measurements, the onset of platelet decline was between 8 and 12 weeks after the first dose of Raptiva in 5 patients, but

occurred later in the other patients. In one patient, thrombocytopenia occurred 3 weeks after treatment

discontinuation. Over long term treatment up to 3 years, a small and gradual decrease in mean platelet

counts within the normal range was observed. In the same population two cases of severe

thrombocytopenia (0.6%) of rapid onset were observed (See section 4.4).

Psoriasis:

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treatment. In the cases occurring during treatment, most of these events (16/22) occurred in patients presenting no response to Raptiva. Cases occurring after discontinuation were observed both in patients responding or not responding to Raptiva treatment.

In the first 12 weeks of placebo-controlled studies, the rate of psoriasis adverse events was 3.2% in the

Raptiva-treated patients and 1.4% in the placebo-treated patients. Among 3291 patients in the

 

no

combined safety database, 39 patients presented an erythrodermic or pustular psoriasis (1.2%).

Seventeen of these events occurred after discontinuation of Raptiva, while 22 occurred during

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Arthritis / Psoriatic arthritis:

In the first 12 weeks of placebo-controlled studies, arthritis and exacerbation or flare of arthritis were Medicinalobserved in 1.8% of Raptiva-treated patients and placebo-treated patients. In these studies, the

incidence of other types of arthritis-related adverse events were similar between the Raptiva and placebo groups.

Flu-like symptoms:

In large placebo-controlled clinical studies, approximately 20% of patients in excess of placebo reported flu-like symptoms including headaches, chills, fever, nausea and myalgia. The percentage of patients reporting flu-like symptoms was greatest with the first injection and decreased by more than 50% with the second injection. These symptoms diminished thereafter to a percentage comparable to that of patients treated with placebo. Headache was the most frequent of the flu-like symptoms. None of those events was serious and less than 5% were considered severe. Overall less than 1% of patients discontinued therapy because of acute flu-like symptoms.

Hypersensitivity and allergic disorders:

In large placebo-controlled clinical studies, the percentage of patients experiencing an adverse event suggestive of hypersensitivity, including urticaria, rash and allergic reactions was slightly higher in the Raptiva group (8%) than in the placebo group (7%). (See section 4.4). Over long term treatment, the frequency of hypersensitivity-related adverse events did not increase.

Class adverse reactions

Elevation of alkaline phosphatase:

In large placebo-controlled clinical studies approximately 4.5% of patients developed sustained elevation of alkaline phosphatase throughout Raptiva therapy compared to 1% in placebo patients. All values were between 1.5 fold and 3 fold the ULN, and returned to baseline levels after therapy discontinuation.

Elevation of ALT:

in the Raptiva group than in the placebo group. All values returned to baseline levels upon therapy discontinuation.

About 5.7% of patients developed elevation in ALT during Raptiva therapy comparedauthorisedto 3.5% in placebo. All occurrences were asymptomatic and values above 2.5 fold ULN were not more frequent

Infections:

Other therapies that alter T-lymphocyte function have been associated with increased risk of

developing serious infections. In placebo controlled clinical trials, infection rates in Raptiva-treated patients was approximately 27.3% versus 24.0% in placebo-treated patients. In the target population studied in study IMP24011, the infection rate in Raptiva-treated patients was approximately 25.7% versus 22.3% in placebo-treated patients.

As regards serious infections, the overall incidence in both controlled and uncontrolled studies of up to

100 patient-years for placebo-treated patients. The most longerfrequent serious infections were pneumonia, cellulitis, infections not otherwise specified and sepsis. Over long term treatment, the incidence of

12 weeks was 2.8 per 100 patient-years for Raptiva-treated patients compared with 1.4 per

serious infection was 1.8 per 100 patient years (see section 4.).

JC virus infection resulting in PML has been reported in post-marketing surveillance in a patient with psoriasis receiving Raptiva (see section 4.4).

no A higher rate of malignanciesproducthas been associated with therapies affecting the immune system. In placebo controlled clinical trials, the overall incidences of malignancy (the majority of which were

Neoplasms benign and malignant:

non-melanoma skin cancers) were similar in Raptiva-treated patients and in placebo-treated patients. In addition, the incidences of specific tumours in Raptiva patients were in line with those observed in control psoriasis populations.

There was no evidence of an increased risk of any particular malignancy over time with the exception of non-melanoma skin cancer (0.3 vs. 0.9 per 100 patient-years, short term and long term treatment, respectively) (See section 4.4).

MedicinalInflammatory polyradiculoneuropathy:

Isolated cases have been observed during post-marketing surveillance. (See section 4.4).

4.9 Overdose

In a clinical study, where subjects were exposed to higher doses of efalizumab (up to 10 mg/kg intravenous), one subject receiving 3 mg/kg intravenous dose experienced hypertension, chills, and fever on the day of study drug dosing, which required hospitalization. Another subject who received 10 mg/kg intravenous dose experienced severe vomiting following administration of efalizumab, which also required hospitalization. Both occurrences fully resolved without any sequelae. Doses up to 4 mg/kg/week subcutaneously for 10 weeks have been administered without any toxic effect.

There is no known antidote to Raptiva or any specific treatment for Raptiva overdose other than withholding treatment and patient observation. In case of overdose, it is recommended that the patient be monitored under close medical care and appropriate symptomatic treatment instituted immediately.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: selective immunosuppressive agents, ATC code: L04AA21

Mechanism of action

By this mechanism, efalizumab inhibits the binding of LFA-1 to ICAM-1, which interferes with T lymphocytes adhesion to other cell types. LFA-1 is present on activated T lymphocytes, and ICAM-1 is up-regulated on endothelial cells and keratinocytes in psoriasis plaques. By preventing LFA-1/ICAM binding, efalizumab may alleviate signs and symptoms of psoriasis by inhibiting several stages in the immunologic cascade.

Efalizumab is a recombinant humanized monoclonal antibody that binds specificallyauthorisedto the CD11a subunit of LFA-1 (lymphocyte function-associated antigen-1), a leukocyte cell surface protein.

Pharmacodynamic effects

In studies using an initial dose of 0.7 mg/kg followed by 11 weekly doses of 1.0 mg/kg, efalizumab maximally reduced expression of CD11a on circulating T lymphocytes to approximately 15-30% of

pre-dose baseline values and saturated CD11a to <5% of baseline available CD11a binding sites. The Within 5 to 8 weeks following the 12th and final dose oflongerefalizumab administered at 1.0 mg/kg/wk, CD11a levels returned to within a range of ±25% of baseline values.

full effect was seen 24 to 48 hours after the first dose, and was maintained between weekly doses.

Another pharmacodynamic marker, consistent with the mechanism of action of efalizumab, was the

absolute count of circulating lymphocytes. In clinical trials, mean lymphocyte counts approximately doubled relative to baseline in subjects receiving 1.0 mg/kg/wk of Raptiva. The increase included

increase in the absolute counts of circulating leukocytes observed during efalizumab treatment. Increased absolute counts were apparent within 24 hours of the first dose, remained elevated with weekly dosing, and returned to baseline after treatmentno cessation. The largest increase occurred in the

CD4 T-lymphocytes,productCD8 T-lymphocytes, B-lymphocytes, and natural killer (NK) cells, although NK

cells and CD4 cells increased less relative to other cell types. At a dose of 1.0 mg/kg/wk subcutaneous efalizumab, lymphocyte levels returned to within 10% of baseline by 8 weeks post last dose.

Clinical efficacy

The efficacy of Raptiva versus other systemic therapies in patients with moderate to severe psoriasis has not been evaluated in studies directly comparing Raptiva with other systemic therapies. The present results of Raptiva versus placebo over 12 weeks of treatment with different populations

indicate a PASI 75 response to Raptiva in 22% to 39% of patients (see Table 2). Based on the clinical Medicinaldevelopment data generated (see Table 1) and long-term experience, Raptiva is recommended for use

in patients as defined in section 4.1.

Failure on prior systemic therapies is defined as insufficient response (PASI < 50 or PGA less than good), or worsening of disease in patients while on treatment, and who were adequately dosed for a sufficiently long duration to assess response with at least each of the 3 major systemic therapies as available.

The safety and efficacy of Raptiva in moderate to severe plaque psoriasis patients has been demonstrated in five randomized, double-blind, placebo-controlled trials at the recommended dose (n=1742). There are no comparative data with Raptiva versus other systemic psoriasis therapies. The largest study IMP24011 (n=793) included patients (n=526) who were not controlled by, contraindicated to, or intolerant to two or more systemic therapies as judged from the patients’ histories of psoriasis treatment. In all studies, the primary endpoint was the proportion of patients with a 75% improvement in the Psoriasis Area and Severity Index score (a PASI 75 response) relative to baseline when assessed one week after a 12-week treatment course. Secondary endpoints included the proportion of subjects who achieved a rating of Minimal or Clear on a static global assessment by the physician, the Overall Lesion Severity (OLS), the proportion of patients with a 50% improvement in

PASI score (a PASI 50 response) relative to baseline after 12 weeks of treatment, the time-course of mean PASI percentage improvement from baseline, improvement in the Dermatology Life Quality Index (DLQI), Psoriasis Symptom Assessment (PSA), the Physician’s Global Assessment (PGA) of change, change in the PASI thickness component, and change in the body surface area affected.

In all five studies, patients randomized to the Raptiva group achieved statistically significantly better responses than placebo on the primary endpoint. The same results were confirmed in patients that were unsuitable for other systemic therapies (see Table 1 below).

 

Table 1

 

 

 

Primary Endpoint: Proportion of Subjects with ≥75% improvement in PASI after 12 weeks of

 

Treatment (PASI 75)

 

 

 

 

 

 

Efalizumab a

 

 

Patient population IMP24011

Placebo

1.0 mg/kg/wk

Treatment

 

 

 

 

 

Effect

 

 

 

 

[95% CI]

 

All patients

4%

31%

27%

 

 

 

(n=264)

(n=529) b

[22%, 32%]

 

 

Patients who are not controlled by,

3%

30%

27%

 

 

contraindicated to, or intolerant to two or

(n=184)

(n=342) b

[21%, 32%]

 

 

more systemic therapies *

 

 

authorised

 

 

 

 

 

a

p-values compared efalizumab with placebo using logistic regression including baseline

 

b

PASI score, prior treatment for psoriasis and geographical region as covariates.

p<0.001.

 

 

 

 

 

 

 

 

 

*

As judged from the patients’ histories of psoriasis treatments

 

 

In all five studies, patients randomized to the Raptiva doselongergroup achieved statistically significantly better responses than placebo on the primary endpoint (PASI 75 response) (see Table 2 below) and on all the secondary efficacy endpoints.

 

 

 

Table 2

 

 

 

 

no

 

 

Primary Endpoint: Proportion of Subjects with ≥75%

 

improvement in PASI after 12 weeks of Treatment (PASI 75)

 

 

 

 

 

 

 

 

 

 

Efalizumab a

 

Study

Placebo

 

1.0 mg/kg/wk

Treatment Effect

 

 

 

 

 

[95% CI]

 

ACD2390g *

4%

 

27%

22%

Medicinal

product(n=187)

 

(n=369) b

[16%, 29%]

ACD2058g

2%

 

39%

37%

 

(n=170)

 

(n=162) b

[28%, 46%]

ACD2059g *

5%

 

22%

17%

 

(n=122)

 

(n=232) b

[9%, 27%]

ACD2600g *

3%

 

24%

21%

 

(n=236)

 

(n=450) b

[15%, 27%]

IMP24011 *

4%

 

31%

27%

 

(n=264)

 

(n=529) b

[22%, 32%]

 

 

 

 

 

a

IMP24011: p-values compared efalizumab with placebo using logistic regression including baseline PASI score, prior treatment for psoriasis and geographical region as covariates.

Other studies: p-values compared each efalizumab group with placebo using Fisher’s exact test within each study.

b

p<0.001.

 

*

The efalizumab used in the study is the Genentech

 

manufactured product

patients who were classified as responders (≥75% improvement on PASI) after 12 weeks of treatment. The median time to relapse among PASI responders ranged from 58 to 74 days following the last Raptiva dose in the initial treatment period. In study IMP24011, approximately half of the patients (46.8%) who were partial responders (50% to 74% improvement on PASI, similar to PGA good) after 12 weeks of Raptiva treatment achieved a PASI 75 response at week 24.

Long-term treatment:

Time to relapse (≥50% loss of improvement) was evaluated in Study ACD2058gauthorisedand IMP 24011 for

Data from extended treatment (more than 12 weeks) have been obtained from 4311 patients in open label uncontrolled studies. Over 600 patients have been treated for more than 1 year including

166 patients treated for more than 2 years and up to 3 years. Approximately half of the patients treated for more than 1 year were PASI 75 responders (when all dropouts were considered as non-responders).

5.2Pharmacokinetic properties

Absorption:

 

 

After subcutaneous administration of efalizumab peak plasma concentrations are reached after 1-

 

 

no

2 days. Comparison with intravenous data indicated an averagelongerbioavailability of about 50% at the

recommended dose level of 1.0 mg/kg/wk subcutaneous.

Distribution:

product

 

 

 

Steady state was achieved at week 4. At the 1 mg/kg/wk dose level (with an initial dose of 0.7 mg/kg the first week), mean efalizumab plasma trough values were 11.1±7.9 µg/ml. Measurements of volume of distribution of the central compartment after single intravenous doses were 110 ml/kg at dose

0.03 mg/kg and 58 ml/kg at dose 10 mg/kg.

Biotransformation:

The metabolism of efalizumab is through internalisation followed by intracellular degradation as a

consequence of either binding to cell surface CD11a or through endocytosis. The expected degradation Medicinalproducts are small peptides and individual amino acids which are eliminated by glomerular filtration.

Cytochrome P450 enzymes as well as conjugation reactions are not involved in the metabolism of efalizumab.

Elimination:

Efalizumab is cleared by nonlinear saturable elimination (dose dependent). Mean steady state clearance is 24 ml/kg/day (range 5-76 ml/kg/day) at 1 mg/kg/ week subcutaneous.

The elimination half-life was about 5.5-10.5 days at 1 mg/kg/ week subcutaneous. Tend at steady state is 25 days (range 13-35 days). Weight is the most significant covariate affecting efalizumab clearance.

Non-linearity:

Efalizumab shows dose-dependent nonlinear pharmacokinetics which can be explained by its saturable specific binding to cell surface receptors CD11a. It appeared that the receptor mediated clearance of efalizumab was saturated when plasma efalizumab concentrations were above 1 μg/ml.

Through population pharmacokinetic analysis, weight was found to affect efalizumab clearance. Covariates as baseline PASI, baseline lymphocyte count and age had modest effects on clearance;

gender and ethnic origin had no effect. The pharmacokinetics of efalizumab in paediatric patients have not been studied. The effect of renal or hepatic impairment on the pharmacokinetics of efalizumab has not been studied.

Antibodies to efalizumab were detected in only 6% of patients evaluated. In this small number of patients no differences were observed in either pharmacodynamic or pharmacokinetic parameters.

5.3 Preclinical safety data

Therefore, conventional non-clinical safety data with the medicinal product are limited and do not allow for a comprehensive safety assessment. Inhibitory effects were observed on the humoral and T-cell dependent immune responses. In pups of mice treated with an antibody analogue of efalizumab, a decrease in T-cell dependent immunity was observed up to at least 11 weeks of age. Only at

Efalizumab does not cross-react with CD11a from species other than humans andauthorisedchimpanzees.

25 weeks of age was this decrease no longer significant.

Otherwise, the effects observed in non-clinical studies could be related to the pharmacology of efalizumab.

No lymphomas were observed following 6 months treatment with an antibody analogue of efalizumab in a 6 months study with p53 +/+ wild type mice.

No teratogenic effects were seen in mice during organogenesis.

6.

PHARMACEUTICAL PARTICULARS

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6.1

List of excipients

 

 

 

Powder for solution for injection:

no

 

Polysorbate 20

 

 

 

 

 

Histidine

 

 

 

Histidine hydrochloride monohydrate

 

 

Sucrose

product

 

 

 

 

 

Solvent:

 

 

 

Water for injections

 

 

 

6.2

Incompatibilities

 

 

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

products.

 

 

 

Medicinal

 

 

 

6.3

Shelf life

 

 

 

4 years.

After reconstitution, an immediate use is recommended (see also section 6.4).

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze.

Store in the original package in order to protect from light.

From a microbiological point of view, the product should be used immediately after first opening and reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions. Physico-chemical stability of the reconstituted product has been shown for 24 hours at 2°C to 8°C.

6.5Nature and contents of container

Powder:

Colourless type I glass vial with a butyl rubber stopper, and aluminium seal fitted with a flip-off plastic cap.

Solvent:

Type I glass pre-filled syringe.

Raptiva is available in:

Packs of 1 vial of powder, 1 pre-filled syringe of solvent, 1 EasyMIX adapter for reconstitution and 1 needle for injection.

Packs of 4 vials of powder, 4 pre-filled syringes of solvent, 4 EasyMIX adapters for reconstitution and 4 needles for injection.

Packs of 12 vials of powder, 12 pre-filled syringes of solvent, 12 EasyMIX adapters for reconstitution and 12 needles for injection.

Not all pack sizes may be marketed.

authorised

6.6 Special precautions for disposal and other handling

Raptiva is for single use only.

 

One vial of Raptiva should be reconstituted with the solvent before use. Reconstitution of the single-

use vial with 1.3 ml of the supplied water for injections yields approximately 1.5 ml of solution to

deliver 100 mg per 1 ml of Raptiva. The maximum retrievable dose is 125 mg per 1.25 ml of Raptiva.

 

 

 

 

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The solution should reconstitute in not more than 5 minutes. The reconstituted solution is a clear to

slightly opalescent, colourless to pale yellow solution, and should not be administered if it contains

particles or is not clear.

no

 

 

 

 

 

Detailed instructions for use are provided in the package leaflet.

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

7.

MARKETING AUTHORISATION HOLDER

 

Serono Europe Ltd.

product

 

 

56 Marsh Wall

 

 

 

 

 

London E14 9TP

 

 

 

United Kingdom

 

 

 

8.

MARKETING AUTHORISATION NUMBERS

Medicinal

 

 

 

EU/1/04/291/001

EU/1/04/291/002

EU/1/04/291/003

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 September 2004

10.DATE OF REVISION OF THE TEXT

 

 

 

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authorised

 

 

no

 

 

product

 

 

Medicinal

 

 

 

 

 

 

 

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