Kevzara 150 mg solution for injection in pre-filled syringe

Kevzara 150 mg solution for injection in pre-filled pen

Kevzara 200 mg solution for injection in pre-filled syringe

Kevzara 200 mg solution for injection in pre-filled pen

150 mg solution for injection

Each single-dose pre-filled syringe contains 150 mg sarilumab in 1.14 ml solution (131.6 mg/ml).

Each single-dose pre-filled pen contains 150 mg sarilumab in 1.14 ml solution (131.6 mg/ml).

200 mg solution for injection

Each single-dose pre-filled syringe contains 200 mg sarilumab in 1.14 ml solution (175 mg/ml).

Each single-dose pre-filled pen contains 200 mg sarilumab in 1.14 ml solution (175 mg/ml).

Sarilumab is a human monoclonal antibody selective for the interleukin-6 (IL-6) receptor, produced in Chinese Hamster Ovary cells by recombinant DNA technology.

For the full list of excipients see section 6.1.

Solution for injection (injection)

Clear, colourless to pale yellow sterile solution of approximately pH 6.0.

Kevzara in combination with methotrexate (MTX) is indicated for the treatment of moderately to severely active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease modifying anti rheumatic drugs (DMARDs). Kevzara can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate (see section 5.1).

Treatment should be initiated and supervised by healthcare professionals experienced in the diagnosis and treatment of rheumatoid arthritis. Patients treated with Kevzara should be given the patient alert card.

Posology

The recommended dose of Kevzara is 200 mg once every 2 weeks administered as a subcutaneous injection.

Reduction of dose from 200 mg once every 2 weeks to 150 mg once every 2 weeks is recommended for management of neutropenia, thrombocytopenia, and liver enzyme elevations.

Dose modification:

Treatment with Kevzara should be withheld in patients who develop a serious infection until the infection is controlled.

Initiating treatment with Kevzara is not recommended in patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2 x 10⁹/L.

Initiating treatment with Kevzara is not recommended in patients with a platelet count below 150 x 10³/µL.

Recommended dose modifications in case of neutropenia, thrombocytopenia, or liver enzyme elevations (see sections 4.4 and 4.8):

Missed dose

If a dose of Kevzara is missed and it has been 3 days or less since the missed dose, the next dose should be administered as soon as possible. The subsequent dose should be administered at the regularly scheduled time. If it has been 4 days or more since the missed dose, the subsequent dose should be administered at the next regularly scheduled time, the dose should not be doubled.

Special Populations

Renal impairment:

No dose adjustment is required in patients with mild to moderate renal impairment. Kevzara has not been studied in patients with severe renal impairment (see section 5.2).

Hepatic impairment:

The safety and efficacy of Kevzara have not been studied in patients with hepatic impairment, including patients with positive hepatitis B virus (HBV) or hepatitis C virus (HCV) serology (see section 4.4).

Elderly:

No dose adjustment is required in patients over 65 years of age (see section 4.4).

Paediatric population:

The safety and efficacy of Kevzara in children up to 18 years of age have not been established. No data are available.

Method of Administration

Subcutaneous use.

The total content (1.14 ml) of the pre-filled syringe/pre-filled pen should be administered as a subcutaneous injection. Injection sites (abdomen, thigh and upper arm) should be rotated with each injection. Kevzara should not be injected into skin that is tender, damaged, or has bruises or scars.

A patient may self-inject Kevzara or the patient's caregiver may administer Kevzara if their healthcare professional determines that it is appropriate. Proper training should be provided to patients and/or caregivers on the preparation and administration of Kevzara prior to use.

For further details on administration of this medicinal product see section 6.6.

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

Active, severe infections (see section 4.4).

Traceability of Kevzara

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

Serious infections

Patients should be closely monitored for the development of signs and symptoms of infection during treatment with Kevzara (see sections 4.2 and 4.8). As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Kevzara should not be administered in patients with an active infection, including localised infections. Consider the risks and benefits of treatment prior to initiating Kevzara in patients who have:

• chronic or recurrent infection;

• a history of serious or opportunistic infections;

• HIV infection;

• underlying conditions that may predispose them to infection;

• been exposed to tuberculosis; or

• lived in or travelled to areas of endemic tuberculosis or endemic mycoses.

Treatment with Kevzara should be withheld if a patient develops a serious infection or an opportunistic infection.

A patient who develops an infection during treatment with Kevzara should also undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including Kevzara for RA. The most frequently observed serious infections with Kevzara included pneumonia and cellulitis (see section 4.8). Among opportunistic infections, tuberculosis, candidiasis, and pneumocystis were reported with Kevzara. In isolated cases, disseminated rather than localised infections were observed in patients often taking concomitant immunosuppressants such as MTX or corticosteroids, which in addition to RA may predispose them to infections.

Tuberculosis

Patients should be eva luated for tuberculosis risk factors and tested for latent infection prior to initiating treatment with Kevzara. Patients with latent or active tuberculosis should be treated with standard antimycobacterial therapy before initiating Kevzara. Consider anti-tuberculosis therapy prior to initiation of Kevzara in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. When considering anti-tuberculosis therapy, consultation with a physician with expertise in tuberculosis may be appropriate.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Viral reactivation

Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with Kevzara. No cases of Hepatitis B reactivation were reported in the clinical studies; however patients who were at risk for reactivation were excluded.

Laboratory parameters

Neutrophil count

Treatment with Kevzara was associated with a higher incidence of decrease in ANC. Decrease in ANC was not associated with higher incidence of infections, including serious infections.

• Initiating treatment with Kevzara is not recommended in patients with a low neutrophil count, i.e., ANC less than 2 x 10⁹/L. In patients who develop an ANC less than 0.5 x 10⁹/L, treatment with Kevzara should be discontinued.

• Neutrophil count should be monitored 4 to 8 weeks after start of therapy and according to clinical judgment thereafter. For recommended dose modifications based on ANC results see section 4.2.

• Based on the pharmacodynamics of the changes in ANC, use results obtained at the end of the dosing interval when considering dose modification (see section 5.1).

Platelet count

Treatment with Kevzara was associated with a reduction in platelet counts in clinical studies. Reduction in platelets was not associated with bleeding events (see section 4.8).

• Initiating treatment with Kevzara is not recommended in patients with a platelet count below 150 x10³/µL. In patients who develop a platelet count less than 50 x 10³/ µL, treatment with Kevzara should be discontinued.

• Platelet count should be monitored 4 to 8 weeks after start of therapy and according to clinical judgment thereafter. For recommended dose modifications based on platelet counts see section 4.2.

Liver enzymes

Treatment with Kevzara was associated with a higher incidence of transaminase elevations. These elevations were transient and did not result in any clinically evident hepatic injury in clinical studies (see section 4.8). Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic medicinal products (e.g., MTX) were used in combination with Kevzara.

Initiating treatment with Kevzara is not recommended in patients with elevated transaminases, ALT or AST greater than 1.5 x ULN. In patients who develop elevated ALT greater than 5 x ULN, treatment with Kevzara should be discontinued (see section 4.2).

ALT and AST levels should be monitored 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, consider other liver function tests such as bilirubin. For recommended dose modifications based on transaminase elevations see section 4.2.

Lipid abnormalities

Lipid levels may be reduced in patients with chronic inflammation. Treatment with Kevzara was associated with increases in lipid parameters such as LDL cholesterol, HDL cholesterol, and/or triglycerides (see section 4.8).

Lipid parameters should be assessed approximately 4 to 8 weeks following initiation of treatment with Kevzara, then at approximately 6 month intervals.

Patients should be managed according to clinical guidelines for the management of hyperlipidaemia.

Gastrointestinal perforation

Events of gastrointestinal perforation have been reported in clinical studies, primarily as complications of diverticulitis. Use Kevzara with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with new onset abdominal symptoms such as persistent pain with fever should be eva luated promptly (see section 4.8).

Malignancies

Treatment with immunosuppressants may result in an increased risk of malignancies. The impact of treatment with Kevzara on the development of malignancies is not known but malignancies were reported in clinical studies (see section 4.8).

Hypersensitivity reactions

Hypersensitivity reactions have been reported in association with Kevzara (see section 4.8). Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Patients should be advised to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, administration of Kevzara should be stopped immediately. Kevzara should not be administered to patients with known hypersensitivity to sarilumab (see section 4.3).

Hepatic impairment

Treatment with Kevzara is not recommended in patients with active hepatic disease or hepatic impairment (see sections 4.2 and 4.8).

Vaccinations

Avoid concurrent use of live vaccines as well as live attenuated vaccines during treatment with Kevzara as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Kevzara. Prior to initiating Kevzara, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines. The interval between live vaccinations and initiation of Kevzara therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents (see section 4.5).

Cardiovascular risk

RA patients have an increased risk for cardiovascular disorders and risk factors (e.g. hypertension, hyperlipidaemia) should be managed as part of usual standard of care.

Sarilumab exposure was not affected when coadministered with MTX based on the population pharmacokinetic analyses and across study comparisons. MTX exposure is not expected to be changed by sarilumab coadministration; however, no clinical data was collected. Kevzara has not been investigated in combination with Janus kinase (JAK) inhibitors or biological DMARDs such as Tumor Necrosis Factor (TNF) antagonists.

Various in vitro and limited in vivo human studies have shown that cytokines and cytokine modulators can influence the expression and activity of specific cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C9, CYP2C19, and CYP3A4) and therefore have the potential to alter the pharmacokinetics of concomitantly administered medicinal products that are substrates of these enzymes. Elevated levels of interleukin-6 (IL-6) may down-regulate CYP activity such as in patients with RA and hence increase drug levels compared to subjects without RA. Blockade of IL-6 signalling by IL-6Rα antagonists such as sarilumab might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered medicinal products concentrations.

The modulation of IL-6 effect on CYP enzymes by sarilumab may be clinically relevant for CYP substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Kevzara in patients being treated with CYP substrate medicinal products, therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., theophylline) should be performed and the individual dose of the medicinal product should be adjusted as needed.

Caution should be exercised in patients who start Kevzara treatment while on therapy with CYP3A4 substrates (e.g., oral contraceptives or statins), as Kevzara may reverse the inhibitory effect of IL-6 and restore CYP3A4 activity, leading to decreased exposure and activity of CYP3A4 substrate. (see section 5.2).Interaction of sarilumab with substrates of other CYPs (CYP2C9, CYP 2C19, CYP2D6) has not been studied.

Women of childbearing potential

Women of childbearing potential should use effective contraception during and up to 3 months after treatment.

Pregnancy

There are no or limited amount of data from the use of sarilumab in pregnant women.

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

Kevzara should not be used during pregnancy unless the clinical condition of the woman requires treatment with sarilumab.

Breast-feeding

It is unknown whether sarilumab is excreted in human milk or absorbed systemically after ingestion. The excretion of sarilumab in milk has not been studied in animals (see section 5.3).

Because IgG1 are excreted in human milk, a decision should be made whether to discontinue breast-feeding or to discontinue sarilumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No data are available on the effect of sarilumab on human fertility. Animal studies showed no impairment of male or female fertility (see section 5.3).

Kevzara has no or negligible influence on the ability to drive or operate machinery.