Raptiva - summary of medicine characteristics

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.

For a full list of excipients, see section 6.1.

4. CLINICAL PARTICULARS4.1 Therapeutic indications4.2 Posology and method of administration

ptiva 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:

Volume to be injected per 10 kg body weight 0.07 ml

Subsequent doses: 1 mg/kg

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.

4.3 Contraindications

4.4 Special warnings and precautions for

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).

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

Immune-mediated haemolytic anaemia

In post-marketing surveillance, isolated cases of severe haemolytic anaemia have been report 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. occur, efalizumab should be stopped immediately, a platelet count should be p appropriate symptomatic treatment should be instituted immediately (see section 4.8).

Platelet counts are recommended upon initiating and periodically while receiving Raptiva treatment. It is recommended that assessments be more frequent when initiating therapy (e.g., monthly) and may decrease in frequency with continued treatment (e.g., every 3 months).

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.

Hypersensitivity and allergic reactions

As with any recombinant product, Raptiva is potentially immunogenic. Consequently, if any serious hypersensitivity or allergic reaction occurs, Raptiva should be discontinued immediately and appropriate therapy initiated (see sections 4.3 and 4.8).

during treatment or after discontinuation of Raptiva. It is tiva if arthritis occurs during treatment.

iva, cases of exacerbation of psoriasis, including pustular, erythrodermic, ave been observed (see section 4.8). In such cases, it is recommended to

discontinment with Raptiva.

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

>ntinuation

gement 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.

4.5 Interaction with other medicinal products and other forms of interaction

Raptiva has been used in combination with top untoward effects nor with any observable signi above monotherapy with efalizumab.

Pregnancy

In general, immunoglobu the use of efalizumab in function of the offspring

ticosteroids in psoriasis patients without any eneficial effect of the combination therapy

Pregnant 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 d to be excreted in human milk. Moreover, an antibody analogue of efalizumab was shown to eted in milk of mice. Women should not breastfeed during treatment with Raptiva.

.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.

4.8 Undesirable 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

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:

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 an to 3 years, did not show any noteworthy differences in frequency of adverse events as compared weeks of exposure to Raptiva. Leucocytosis and lymphocytosis : in large placebo-controlled and 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 U Limit of Normal). Lymphocyte count returned to baseline after therapy discontinuation.

elevation in absolute neutrophil count and eosinophil count were observed but in a s of patients.

Thrombocytopenia :

In the combined safety database of 3291 Raptiva-treated patients at the ti nine occurrences (0.3%) of thrombocytopenia with less than 52,000 ce patients had clinical signs of thrombocytopenia. Based on available onset of platelet decline was between 8 and 12 weeks after the firs occurred later in the other patients. In one patient, thrombocytopen discontinuation. Over long term treatment up to 3 years, a counts within the normal range was observed. In the s thrombocytopenia (0.6%) of rapid onset were observed (S

Psoriasis :

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

iscontinuation of Raptiva, while 22 occurred during eatment, most of these events (16/22) occurred in patients ses occurring after discontinuation were observed both in g to Raptiva treatment.

Arthritis / Psoriatic arthritis :

In the first 12 weeks of placebo-controlled studies, arthritis and exacerbation or flare of arthritis were observed 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 placeb

Flu-like symptoms :

n large placebo-controlled clinical studies, approximately 20% of patients in excess of placebo eported flu-like symptoms including headaches, chills, fever, nausea and myalgia. The percentage of atients reporting flu-like symptoms was greatest with the first injection and decreased by more than 0% 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.

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.

Neoplasms benign and malignant :

A higher rate of malignancies has been ass placebo controlled clinical trials, the ov non-melanoma skin cancers) were simil In addition, the incidences of specific tu control psoriasis populations.

n increased risk of any particular malignancy over time with the exception er (0.3 vs. 0.9 per 100 patient-years, short term and long term treatment,.4).

during post-marketing surveillance. (See section 4.4).

ical study, where subjects were exposed to higher doses of efalizumab (up to 10 mg/kg venous), one subject receiving 3 mg/kg intravenous dose experienced hypertension, chills, and ver 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 PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: selective immunosuppressive agents, ATC code: L04AA21

Mechanism of action

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

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 IC 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 inhi stages in the immunologic cascade.

Pharmacodynamic effects

In studies using an initial dose of 0.7 mg/kg followed by 11 weekly doses of 1. maximally reduced expression of CD11a on circulating T lymphocytes to appr pre-dose baseline values and saturated CD11a to <5% of baseline available CDnding sites. The full effect was seen 24 to 48 hours after the first dose, and was maintained between weekly doses. Within 5 to 8 weeks following the 12th and final dose of efalizumab administered at 1.0 mg/kg/wk, CD11a levels returned to within a range of ±25% of baseline values.

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

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. p<0.001.

The efalizumab used in the study is the Genentech manufactured product _____________­_________________

Time to relapse (>50% loss of improvement) was evaluated in Study ACD2058g and IMP 2 patients who were classified as responders (>75% improvement on PASI) after 12 weeks of The median time to relapse among PASI responders ranged from 58 to 74 days following the Raptiva dose in the initial treatment period. In study IMP24011, approximately half of th (46.8%) who were partial responders (50% to 74% improvement on PASI, similar to 12 weeks of Raptiva treatment achieved a PASI 75 response at week 24.

Long-term treatment:

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 dropounsidered as non-responders).

5.2 Pharmacokinetic properties

Absorption :

After subcutaneous administration of efalizumab peak plasma concentrations are reached after 12 days. Comparison with intravenous data indicated an average bioavailability of about 50% at the recommended dose level of 1.0 mg/kg/wk subcutaneous.

k 4. At the 1 mg/kg/wk dose level (with an initial dose of 0.7 mg/kg lasma trough values were 11.1±7.9 pg/ml. Measurements of volume t after single intravenous doses were 110 ml/kg at dose g/kg.

Biotransforma­tion:

The metabolism of efaliz is through internalisation followed by intracellular degradation as a consequence of either binding to cell surface CD11a or through endocytosis. The expected degradation products 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.

is cleared by nonlinear saturable elimination (dose dependent). Mean steady state

s 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 pg/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

Efalizumab does not cross-react with CD11a from species other than humans and chimpanzees. 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 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 PARTICULARS6.1 List of excipients

Powder for solution for injection:

Polysorbate 20

Histidine

Histidine hydrochloride monohydrate

Sucrose

Solvent:

Water for injections

6 2 , 1W

6.2 Incompatibilities

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

6.3 Shelf life

• 4 years.

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.

6.5 Nature 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 1 needle for injection.

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

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

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Raptiva is for single use only.

One vial of Raptiva should be reconstituted with the solve use vial with 1.3 ml of the supplied water for injections yields deliver 100 mg per 1 ml of Raptiva. The maximum retrievable dose is 125 mg per 1.25 ml of Raptiva.

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.

be disposed of in accordance with local requirements.

Serono Europe 56 Marsh Wal London E Unite

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION