Source: European Medicines Agency (EU) Revision Year: 2009 Publisher: Serono Europe Ltd., 56 Marsh Wall, London E14 9TP, United Kingdom
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.
Patients with immunodeficiencies.
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.
The 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.
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).
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).
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 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). 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).
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.
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).
Cases of arthritis have been observed during treatment or after discontinuation of Raptiva. It is recommended to discontinue Raptiva if arthritis occurs during treatment.
During 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.
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.
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.
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 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).
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).
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 above monotherapy with efalizumab.
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).
Pregnant women should not be treated with Raptiva.
Women of childbearing potential have to use appropriate contraception during treatment.
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.
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.
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 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 (>1/10) | Common (>1/100, <1/10) | Uncommon (>1/1,000, <1/100) | Rare (>1/10,000, <1/1,000) | Very rare (<1/10,000) | Not known |
|---|---|---|---|---|---|---|
| Infections and infestations | Aseptic meningitis*, Severe infections*, JC virus infection resulting in progressive multifocal leukoencephalopathy* | |||||
| Blood and the lymphatic system disorders | Leukocytosis and lymphocytosis | Thrombocytopenia | Immune mediated haemolytic anaemia* | |||
| Immune system disorders | Hypersensitivity reactions | |||||
| Nervous system disorders | Facial palsy (Bell’s palsy) | Inflammatory polyradiculo- neuropathy* | ||||
| Respiratory, thoracic and mediastinal disorders | Interstitial pneumonitis* | |||||
| Skin and subcutaneous tissue disorders | Psoriasis | Urticaria | Erythema multiforme* | |||
| Musculoskeletal and connective tissue disorders | Arthralgia Arthritis / Psoriatic arthritis (exacerbation/ flare) | |||||
| General disorders and administration site conditions | Flu-like symptoms including fever, headaches, chills, nausea and myalgia | Back pain, Asthenia | Injection site reactions | |||
| 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.
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.
In the combined safety database of 3291 Raptiva-treated patients at the time of approval, there were 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).
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%). Seventeen of these events occurred after discontinuation of Raptiva, while 22 occurred during 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, 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 placebo groups.
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.
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.
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.
About 5.7% of patients developed elevation in ALT during Raptiva therapy compared to 3.5% in placebo. All occurrences were asymptomatic and values above 2.5 fold ULN were not more frequent in the Raptiva group than in the placebo group. All values returned to baseline levels upon therapy discontinuation.
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 12 weeks was 2.8 per 100 patient-years for Raptiva-treated patients compared with 1.4 per 100 patient-years for placebo-treated patients. The most frequent 3 serious infections were pneumonia, cellulitis, infections not otherwise specified and sepsis. Over long term treatment, the incidence of serious infection was 1.8 per 100 patient years (see section 4.4).
JC virus infection resulting in PML has been reported in post-marketing surveillance in a patient with psoriasis receiving Raptiva (see section 4.4).
A higher rate of malignancies has been associated with therapies affecting the immune system. In placebo controlled clinical trials, the overall incidences of malignancy (the majority of which were 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).
Isolated cases have been observed during post-marketing surveillance. (See section 4.4).
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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