SAPHNELO Concentrate for solution for infusion Ref.[50047] Active ingredients: Anifrolumab

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Patient groups excluded from clinical studies

Anifrolumab has not been studied in combination with other biologic therapies, including B-cell-targeted therapies. Therefore, treatment with anifrolumab is not recommended in combination with biologic therapies.

Anifrolumab has not been studied in patients with severe active central nervous system lupus or severe active lupus nephritis (see section 5.1).

Hypersensitivity

Serious hypersensitivity reactions including anaphylaxis have been reported following administration of anifrolumab (see section 4.8).

In the intravenous and subcutaneous clinical trials of 52-week treatment duration, serious hypersensitivity reactions (including angioedema) were reported for 0.5% of patients receiving anifrolumab.

In patients with a history of infusion-related reactions and/or hypersensitivity, premedication (e.g., an antihistamine) may be administered before the infusion of anifrolumab (see section 4.2).

If a serious infusion-related or hypersensitivity reaction (e.g., anaphylaxis) occurs, administration of anifrolumab should be interrupted immediately, and appropriate therapy initiated.

Infections

Anifrolumab increases the risk of respiratory infections and herpes zoster (disseminated herpes zoster events have been observed), see section 4.8. SLE patients also taking immunosuppressants may be at higher risk of herpes zoster infections.

In controlled-clinical trials serious and sometimes fatal infections (including pneumonia) occurred, including in patients receiving anifrolumab.

Due to the mechanism of action, anifrolumab should be used with caution in patients with a chronic infection, a history of recurrent infections, or known risk factors for infection. Treatment with anifrolumab should not be initiated in patients with any clinically significant active infection until the infection resolves or is adequately treated. Patients should be instructed to seek medical advice if signs or symptoms of clinically significant infection occur. If a patient develops an infection, or is not responding to standard therapy, they should be closely monitored and careful consideration given to interrupting anifrolumab therapy until the infection resolves.

Studies in patients with a history of primary immunodeficiency have not been conducted.

The placebo-controlled clinical trials excluded patients with a history of active TB or latent TB in whom an adequate course of treatment could not be confirmed. Anti-tuberculosis (anti-TB) therapy should be considered prior to initiation of anifrolumab in patients with untreated latent TB. Anifrolumab should not be administered to patients with active TB.

Immunisations

Prior to initiating therapy, completion of all appropriate immunisations should be considered according to current immunisation guidelines. Concurrent use of live or attenuated vaccines should be avoided in patients treated with anifrolumab.

Immune responses to non-live vaccines have been assessed in a small number of patients (see section 4.5).

Malignancy

The impact of treatment with anifrolumab on the potential development of malignancies is not known. Studies in patients with a history of malignancy have not been conducted; however, patients with squamous or basal cell skin cancers and uterine cervical cancer that had been fully excised or adequately treated were eligible for enrolment in the SLE clinical trials.

In the intravenous and subcutaneous clinical trials of 52-week treatment duration, malignant neoplasm (including non-melanoma skin cancers) was reported for 1.1% of patients receiving anifrolumab compared to 0.5% patients receiving placebo (exposure-adjusted incidence rate [EAIR]: 1.1 and 0.5 events per 100 patient years [PY], respectively). Malignancies excluding non-melanoma skin cancers were observed in 0.5% and 0.5% of patients receiving anifrolumab and placebo, respectively. In patients receiving anifrolumab, breast and squamous cell carcinoma were the malignancies observed in more than one patient.

Individual benefit-risk should be considered in patients with known risk factors for the development or reoccurrence of malignancy. Caution should be exercised when considering continuing therapy for patients who develop malignancy.

Excipient with known effect

This medicinal product contains 1 mg of polysorbate 80 (E 433) in each vial, which is equivalent to 0.5 mg/ml. Polysorbates may cause allergic reactions.

No interaction studies have been performed.

Anifrolumab is not expected to undergo metabolism by hepatic enzymes or renal elimination.

The formation of some CYP450 enzymes is suppressed by increased levels of certain cytokines during chronic inflammation. Anifrolumab modestly suppresses the levels of some cytokines; the impact on CYP450 activity is unknown. In patients who are being treated with other medicines that are CYP substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin), therapeutic monitoring is recommended.

Immune response

Non-live vaccines

Immune response to non-live seasonal influenza vaccine was assessed in a small number of adult patients with moderate to severe SLE in an exploratory study. Humoral antibody responses induced by seasonal influenza virus vaccination were numerically comparable between patients receiving anifrolumab in addition to standard of care and those receiving standard of care alone.

Live vaccines

The concurrent use of anifrolumab with live and live-attenuated vaccines has not been studied (see section 4.4).

Pregnancy

There are limited data (less than 300 pregnancy outcomes) from the use of Saphnelo in pregnant women.

Animal studies are inconclusive with respect to reproductive toxicity (see section 5.3).

Saphnelo is not recommended during pregnancy and in women of childbearing potential not using contraception, unless the possible benefit justifies the potential risk.

Breast-feeding

It is not known whether anifrolumab is excreted in human milk. Anifrolumab was detected in the milk of female cynomolgus monkeys (see section 5.3).

A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue from Saphnelo therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no fertility data in humans.

Animal studies show no adverse effects of anifrolumab on indirect measures of fertility (see section 5.3).

Saphnelo has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most commonly reported adverse reactions during anifrolumab treatment were upper respiratory tract infection (31%), bronchitis (10%), infusion-related reaction (9.4%) and herpes zoster (6.0%). The most common serious adverse reaction was herpes zoster (0.4%).

Tabulated list of adverse reactions

Adverse reactions reported from controlled clinical trials and post-marketing data are classified by MedDRA System Organ Class (SOC), see Table 1. Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000) and not known (cannot be estimated from available data).

Table 1. Adverse reactions:

^* Grouped terms: Upper respiratory tract infection (including Upper respiratory tract infection, Nasopharyngitis, Pharyngitis); Bronchitis (including Bronchitis, Bronchitis viral, Tracheobronchitis); Respiratory tract infection (including Respiratory tract infection, Respiratory tract infection viral, Respiratory tract infection bacterial).
^§ See 'Description of selected adverse reactions' below and section 4.4.
^‡ Applies to intravenous infusion route of administration only.

Long-term safety

Patients who completed Trials 1 and 2 (Phase III intravenous trials) through Week 52 were eligible to continue on treatment in a randomised, double-blind, placebo-controlled long-term extension (LTE) for an additional 3 years (see section 5.1). The overall long-term safety profile of intravenous anifrolumab was consistent with the 52-week trials.

Description of selected adverse reactions

Hypersensitivity

In controlled intravenous and subcutaneous clinical trials of 52-week treatment duration, the incidence of hypersensitivity reactions was 2.5% in the anifrolumab group and 0.5% in the placebo group. Hypersensitivity reactions were predominantly mild to moderate in intensity. One event of hypersensitivity in the subcutaneous trial led to discontinuation of anifrolumab.

In the intravenous clinical trials of 52-week treatment duration, all hypersensitivity reactions were reported within the first 6 infusions. One serious adverse reaction of hypersensitivity was reported during the patient's first infusion; the patient continued to receive anifrolumab with premedication given for subsequent infusions.

In the SLE development program, anaphylactic reaction was reported in one patient, which occurred following the intravenous administration of 150 mg anifrolumab, the patient was treated and recovered (see section 4.4).

Infusion-related reactions

In the controlled intravenous clinical trials of 52-week treatment duration, the incidence of infusion-related reactions was 9.4% in the anifrolumab group and 7.1% in the placebo group. Infusion-related reactions were mild or moderate in intensity (the most common symptoms were headache, nausea, vomiting, fatigue, and dizziness); none were serious, and none led to discontinuation of anifrolumab. Infusion-related reactions were most commonly reported at the start of treatment, on the first and second infusions, with fewer reports on subsequent infusions.

Respiratory infections

In the controlled intravenous and subcutaneous clinical trials of 52-week treatment duration, the incidence rates for anifrolumab compared to placebo were: upper respiratory tract infection (30.9% vs 20.3%), bronchitis (10.2% vs 5.2%) and respiratory tract infection (3.0% vs 1.4%). Infections were predominantly non-serious, mild or moderate in intensity and resolved without discontinuation of anifrolumab therapy (see section 4.4).

Herpes zoster

In the controlled intravenous and subcutaneous clinical trials of 52-week treatment duration, the incidence of herpes zoster infections was 6.0% in the anifrolumab group and 1.4% in the placebo group (see section 4.4). The mean time to onset in patients receiving anifrolumab was 129 days (range 2-351 days).

In the LTE (intravenous administration), incidence rates decreased over time.

Herpes zoster infections were predominantly of localised cutaneous presentation, mild or moderate in intensity and resolved without discontinuation of anifrolumab therapy. Cases with multidermatomal involvement and cases of disseminated disease (including central nervous system involvement) have been reported (see section 4.4).

Immunogenicity

In the intravenous Phase III trials, treatment-emergent anti-drug antibodies were detected in 6 out of 352 patients (1.7%) treated with anifrolumab at the recommended dosing regimen during the 60-week study period.

In the LTE (years 2 through 4 on treatment), treatment-emergent anti-drug antibodies were detected in an additional 5 patients treated with anifrolumab.

Due to methodological limitations, the clinical relevance of these findings is not known.

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.

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