Efalizumab

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

Efalizumab has not been studied in combination with immunosuppressive systemic antipsoriasis medicinal products. Therefore, combination therapies with these products are not recommended. 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.

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.

Pregnant women should not be treated with efalizumab.

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 efalizumab.

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 is not expected to affect patient’s ability to drive and use machines.

The most frequent symptomatic adverse drug reactions (ADRs) observed during efalizumab 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 efalizumab-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 efalizumab 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.

* Events identified during postmarketing surveillance

The safety profile in the target population is similar to the safety profile in the overall population treated during clinical development of efalizumab 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 efalizumab 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 efalizumab. Leucocytosis and lymphocytosis: in large placebo-controlled and in long-term clinical studies, between 40 and 50% of patients developed sustained asymptomatic lymphocytosis during efalizumab 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.

Thrombocytopenia

In the combined safety database of 3,291 efalizumab-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 efalizumab 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.

Psoriasis

In the first 12 weeks of placebo-controlled studies, the rate of psoriasis adverse events was 3.2% in the efalizumab-treated patients and 1.4% in the placebo-treated patients. Among 3,291 patients in the combined safety database, 39 patients presented an erythrodermic or pustular psoriasis (1.2%). Seventeen of these events occurred after discontinuation of efalizumab, while 22 occurred during treatment. In the cases occurring during treatment, most of these events (16/22) occurred in patients presenting no response to efalizumab. Cases occurring after discontinuation were observed both in patients responding or not responding to efalizumab 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 efalizumab-treated patients and placebo-treated patients. In these studies, the incidence of other types of arthritis-related adverse events were similar between the efalizumab 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 efalizumab group (8%) than in the placebo group (7%). 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 efalizumab 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

About 5.7% of patients developed elevation in ALT during efalizumab therapy compared to 3.5% in placebo. All occurrences were asymptomatic and values above 2.5 fold ULN were not more frequent in the efalizumab group than in the placebo group. All values returned to baseline levels upon therapy discontinuation.

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 efalizumab-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 efalizumab-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 efalizumab-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.

JC virus infection resulting in PML has been reported in post-marketing surveillance in a patient with psoriasis receiving efalizumab.

Class adverse reactions

Neoplasms benign and malignant

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 efalizumab-treated patients and in placebo-treated patients. In addition, the incidences of specific tumours in efalizumab 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).

Inflammatory polyradiculoneuropathy

Isolated cases have been observed during post-marketing surveillance.