NYXTHRACIS Concentrate for solution for infusion Ref.[50576] Active ingredients: Obiltoxaximab

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.

Infusion-related reactions, hypersensitivity and anaphylaxis

Infusion-related/hypersensitivity reactions were commonly observed during clinical trials with obiltoxaximab in healthy subjects. Due to the risk of severe reactions or anaphylaxis, obiltoxaximab should be administered in monitored settings by personnel trained and equipped to manage anaphylaxis. Patients should be monitored closely throughout the infusion period and for at least one hour after administration.

Since the clinical trials were conducted in healthy volunteers, obiltoxaximab infusions were stopped at the onset of any reaction. Based on experience with other monoclonal antibodies used in the treatment of serious medical conditions, infusions can generally be completed if managed appropriately. Infusion-related reactions should be managed as outlined in table 1.

Premedication with an antihistamine, e.g. diphenhydramine, is recommended prior to administration of obiltoxaximab (see section 4.2). Diphenhydramine was administered 30 minutes prior to treatment with obiltoxaximab in clinical trials conducted with obiltoxaximab. Premedication with an antihistamine does not prevent anaphylaxis and may mask or delay onset of symptoms of hypersensitivity.

Anthrax meningitis

Obiltoxaximab does not cross the blood-brain barrier and does not prevent or treat anthrax meningitis.

Paediatric population

There have been no studies of safety or PK of obiltoxaximab in the paediatric population (see section 5.2).

Laboratory test interactions

Exposure to NYXTHRACIS may interfere with serological tests for anthrax.

Sorbitol

Each mL of NYXTHRACIS contains 36 mg of sorbitol (see sections 2 and 6.1). Medicinal products containing sorbitol may be fatal if given intravenously to subjects with hereditary fructose intolerance (HFI). Obiltotoxaximab should not be used in subjects with HFI unless there is an overwhelming clinical need and no alternatives are available. A detailed history with regard to HFI symptoms should be taken from each patient prior to being given this medicinal product.

Infants and toddlers (below 2 years of age) are at particular risk since they may not yet be diagnosed with HFI.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per each 6 mL vial, that is to say essentially ‘sodium-free’.

Ciprofloxacin

In an interaction study, a single dose of obiltoxaximab was given alone or co-administered with ciprofloxacin in 40 subjects. Twenty subjects received obiltoxaximab alone and 20 subjects received obiltoxaximab plus ciprofloxacin for 9 days. The administration of 16 mg/kg obiltoxaximab intravenous infusion prior to ciprofloxacin intravenous infusion or ciprofloxacin twice daily oral tablet ingestion did not alter the pharmacokinetics of obiltoxaximab. Likewise, obiltoxaximab did not alter the pharmacokinetics of ciprofloxacin administered orally or intravenously.

No other interaction studies have been performed. Since obiltoxaximab is a monoclonal antibody, the risk of interaction is low.

Pregnancy

There are no data from the use of obiltoxaximab in pregnant women, however, human IgG is known to cross the placental barrier.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of NYXTHRACIS during pregnancy.

Breast-feeding

It is unknown whether obiltoxaximab is excreted in human milk. Human IgG is known to be excreted in breast milk during the first days after birth and is decreasing to low concentrations soon afterwards. Consequently, a risk to breast-fed infants cannot be excluded during this short period. Afterwards, use of obiltoxaximab could be considered during breast-feeding, only if clinically needed.

Fertility

Fertility studies have not been conducted with obiltoxaximab.

Obiltoxaximab may have a minor influence on the ability to drive and use machines since headache, dizziness, fatigue and vomiting may occur following administration of NYXTHRACIS (see section 4.8).

Summary of the safety profile

The safety of obiltoxaximab has been studied only in healthy adult subjects.

The safety of obiltoxaximab was evaluated in 320 healthy subjects (aged 18 to 79 years old) treated with one or two 16 mg/kg intravenous doses in three clinical studies.

Overall 250 of the 320 subjects received a single dose of 16 mg/kg obiltoxaximab. Hypersensitivity related adverse reactions (including rash) occurred in 9% (22/250) of these subjects, with one case of anaphylaxis that occurred during the infusion. The infusion was discontinued in 3% (8/250) due to hypersensitivity or anaphylaxis.

The most frequently reported adverse reactions were headache (4%, 9/250), pruritus (4%, 9/250), and urticaria (2%, 6/250).

Most commonly observed adverse reactions within the first three hours after start of infusion were pruritus (n=7; 2.8%), urticaria (n=6; 2.4%), headache (n=4; 1.6%), rash (n=3; 1.2%), cough (n=3; 1.2%), dizziness (n=3; 1.2%) (includes dizziness and dizziness postural).

The following severe adverse reactions occurred within the first three hours following the infusion: urticaria (n=1, 0.4%), pruritus (n=1, 0.4%) and back pain (n=1, 0.4%).

The most commonly observed adverse reaction within 3 to 24 hours after start of infusion was headache (n=3; 1.2%).

Tabulated list of adverse reactions

Table 4 presents adverse reactions observed with obiltoxaximab in the 250 healthy human subjects that received a single intravenous dose of 16 mg/kg obiltoxaximab, by System Organ Class and frequency.

The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 4. Adverse reactions reported in healthy adult subjects:

Description of selected adverse reactions

Hypersensitivity and anaphylaxis

The adverse reactions reported in the 8 subjects in whom the obiltoxaximab infusion was discontinued for possible hypersensitivity included urticaria, rash, cough, pruritus, dizziness, throat irritation, dysphonia, dyspnoea and chest discomfort. The remaining subjects with hypersensitivity had predominantly skin-related symptoms such as pruritus and rash, and 6 subjects reported cough. The anaphylaxis event was characterised by a diffuse pruritic urticarial rash over most of the body, including neck, chest, back, abdomen, arms, and legs, shortness of breath, and coughing.

There was no evidence that the hypersensitivity reactions and rashes have been triggered by cytokine release; no clinically significant changes in cytokines have been observed.

Immunogenicity

The development of anti-obiltoxaximab antibodies was evaluated in all subjects receiving single and double doses of obiltoxaximab in three clinical studies. Eight subjects (2.5% (8/320)) who received at least one intravenous dose of obiltoxaximab were positive for a treatment-emergent anti-therapeutic antibody (ATA) response. Quantitative titres were low ranging from 1:20 to 1:320. There was no evidence of altered pharmacokinetics or toxicity profile in subjects with an ATA response.

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.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.