4.1. Therapeutic indications

CINQAERO is indicated as add-on therapy in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus another medicinal product for maintenance treatment (see section 5.

4.2. Posology and method of administration

CINQAERO should be prescribed by physicians experienced in the diagnosis and treatment of the above-mentioned indication (see section 4.1).

Posology

CINQAERO is given as intravenous infusion once every four weeks.

Patients below 35 kg or above 199 kg

The recommended dose is 3 mg/kg body weight. The volume (in mL) required from the vial(s) should be calculated as follows: 0.3 x patient body weight (in kg).

Patients between 35 kg and 199 kg

The recommended dose is achieved using the vial-based dosing scheme in Table 1 below. The recommended dose is based on patient body weight and should only be adjusted for significant changes in body weight.

Table 1: Vial-based dosing scheme* for patients with body weight between 35 kg and 199 kg

Body weight (kg)

Reslizumab total dose (mg)

Numbers of each vial**

Vials with 10 mL concentrate

(100 mg reslizumab)

Vials with 2.5 mL concentrate

(25 mg reslizumab)

35-41

100

1

0

42-49

125

1

1

50-58

150

1

2

59-66

175

1

3

67-74

200

2

0

75-83

225

2

1

84-91

250

2

2

92-99

275

2

3

100-108

300

3

0

109-116

325

3

1

117-124

350

3

2

125-133

375

3

3

134-141

400

4

0

142-149

425

4

1

150-158

450

4

2

159-166

475

4

3

167-174

500

5

0

175-183

525

5

1

184-191***

550

5

2

192-199***

575

5

3

* This dosing scheme is based on a maximum dose of 3 mg/kg.

** The nominal volume of the vials (10 mL or 2.5 mL for each vial) has to be used.

*** Patients weighing more than 188 kg were not studied.

Treatment duration

CINQAERO is intended for long-term treatment.

A decision to continue the therapy should be made at least annually based on disease severity and level of exacerbation control.

Missed dose

If a reslizumab infusion is missed on the planned date, dosing should resume as soon as possible on the indicated dose and regimen. A double dose must not be administered to make up for a missed dose.

Special populations

Elderly

There are limited data available on the use of reslizumab in patients older than 75 years of age. Based on the similar reslizumab exposure observed in patients older than 65 years of age as compared to patients 18 to <65 years of age, no dose adjustment is recommended (see section 5.2).

Renal impairment

No dose adjustment is required in patients with renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment is required in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of CINQAERO in children and adolescents aged up to 17 years have not been established.

No data are available for children aged up to 11 years. Currently available data in adolescents from 12 to 17 years are described in sections 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

Intravenous use.

This medicinal product is for intravenous infusion only. It must not be administered by the subcutaneous, oral or intramuscular route.

The appropriate volume of concentrate should be dispensed into an infusion bag containing 50 mL sodium chloride 9 mg/mL (0.9%) solution for infusion.

This medicinal product must not be administered as a bolus injection or as undiluted concentrate.

The infusion must be discontinued immediately if the patient experiences a hypersensitivity reaction to reslizumab or to any of the excipients (see section 4.4).

Instructions for administration

1. CINQAERO should be administered by a healthcare professional prepared to manage hypersensitivity reactions including anaphylaxis (see section 4.4). The patient has to be observed over the duration of the infusion and for an appropriate period afterwards. Patients should be instructed on how to recognise symptoms of serious allergic reactions.

2. If the solution for infusion has been stored in a refrigerator, allow it to reach room temperature (15 °C-25 °C).

3. The solution for infusion should be infused intravenously over 20 – 50 minutes. Infusion time may vary depending on the total volume to be infused.

4. The solution for infusion should not be infused concomitantly in the same intravenous line with other medicinal products. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of reslizumab with other medicinal products.

5. An infusion set with an in-line, sterile, non-pyrogenic, single-use, low-protein-binding filter (pore size of 0.2 µm) should be used for infusion. CINQAERO is compatible with polyethersulfone (PES), polyvinylidene fluoride (PVDF), nylon, cellulose acetate (CA) low protein binding in-line infusion filters.

6. Upon completion of the infusion, flush the infusion set with sterile sodium chloride 9 mg/mL (0.9%) solution for infusion to ensure that all of the CINQAERO solution for infusion has been administered.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Reslizumab should not be used to treat acute asthma exacerbations.

Asthma-related symptoms or exacerbations may occur during treatment. Patients should be instructed to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment.

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.

Hypersensitivity and administration-related reactions

Acute systemic reactions, including anaphylactic reactions, have been reported in association with reslizumab (see section 4.8). These adverse reactions were observed during or within 20 minutes after completion of the infusion. Patients should be monitored during and for an appropriate time after administration of reslizumab. If an anaphylactic reaction occurs, administration of reslizumab should be stopped immediately and appropriate medical treatment should be provided; reslizumab must be discontinued permanently (see section 4.3).

Parasitic (helminth) infections

Eosinophils may be involved in the immunological response to some helminth infections. Patients with pre-existing helminth infections should be treated before starting reslizumab therapy. If patients become infected whilst receiving treatment with reslizumab and do not respond to anti-helminth treatment, temporary discontinuation of therapy should be considered.

Sodium content

This medicinal product contains 4.6 mg sodium per vial of 10 mL (1.15 mg sodium per vial of 2.5 mL), equivalent to 0.23% (0.06%) of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

No formal clinical interaction studies have been performed with reslizumab. In vitro data indicate that IL-5 and reslizumab are unlikely to affect CYP1A2, 3A4 or 2B6 activity. Based on the characteristics of reslizumab, interactions are not expected. Results of population pharmacokinetic analysis confirm that concomitant use of either leukotriene antagonists or systemic corticosteroids does not affect the pharmacokinetics of reslizumab (see section 5.2).

Reslizumab has not been studied in patients concurrently taking immunosuppressant medicinal products other than oral corticosteroids (OCS); therefore, the safety and efficacy profile of reslizumab in these patients is unknown.

Reslizumab has not been studied in patients receiving live vaccines. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving reslizumab or the response to new immunisations in patients receiving reslizumab.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of reslizumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of CINQAERO during pregnancy. Reslizumab has a long half-life (see section 5.2). This should be taken into consideration.

Breast-feeding

It is unknown whether reslizumab is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of reslizumab in milk.

In humans, during the first few days after birth antibodies may be transferred to the newborns through milk. In this short period, a risk to the suckling child cannot be excluded. Afterwards, CINQAERO could be used during breast-feeding if appropriate.

Fertility

There are no fertility data in humans. Available non-clinical data do not suggest an effect on fertility.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions are increased blood creatine phosphokinase (approximately 2% of patients) and anaphylactic reaction (see section 4.4) less than 1% of patients).

During controlled clinical studies, the proportion of patients who discontinued due to any adverse reaction was 1% for both the 3 mg/kg reslizumab and placebo groups.

Tabulated list of adverse reactions

.The following adverse reactions have been reported with reslizumab during placebo-controlled asthma studies for up to 52 weeks of treatment with a 3 mg/kg dose given intravenously. Adverse reactions are listed below in Table 2 by system organ class and frequency (frequencies 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), not known (cannot be estimated from the available data).

Table 2: Adverse reactions

System organ class

Frequency

Adverse reaction

Immune system disorders

Uncommon

Anaphylactic reaction*

Musculoskeletal and connective tissue disorders

Uncommon

Myalgia*

Investigations

Common

Blood creatine phosphokinase increased*

*See subsection “Description of selected adverse reactions” below

Description of selected adverse reactions

Anaphylactic reaction

The serious adverse reaction of anaphylactic reaction was reported and considered related to reslizumab in 3 patients (0.19%) during placebo-controlled and open-label asthma studies. These reactions were observed during or within 20 minutes after completion of the reslizumab infusion and were reported as early as the second dose of reslizumab. They were fully resolved with standard treatment with no residual effect. Manifestations included skin or mucosal involvement, dyspnoea, wheezing, gastrointestinal symptoms and chills. These cases resulted in the discontinuation of treatment. Due to an overlap in signs and symptoms, it was not possible to distinguish between an anaphylactic reaction, another hypersensitivity reaction and an infusion-related reaction in all cases (see section 4.4).

Myalgia

Myalgia was reported in 0.97% of patients (10 out of 1,028) in the 3 mg/kg reslizumab group of the placebo-controlled asthma studies compared with 0.55% of patients (4 out of 730) in the placebo group.

Blood creatine phosphokinase increased

Blood creatine phosphokinase elevations were transient and asymptomatic, and did not lead to treatment discontinuation.

Malignancies

In placebo-controlled clinical studies, 6 out of 1,028 patients (0.6%) receiving 3 mg/kg reslizumab had at least one malignant neoplasm reported compared to 2 out of 730 patients (0.3%) in the placebo group. The malignancies observed in reslizumab-treated patients were diverse in nature and without clustering of any particular tissue type.

Paediatric population

Experience in paediatric patients is limited (see section 5.1). The data did not indicate a difference in the safety profile of reslizumab in paediatric patients compared with that in adult patients.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The highest single dose administered intravenously was reported at 12.1 mg/kg and had no clinical consequences for the patient. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse effects and given appropriate symptomatic treatment.