Nulojix (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Bristol-Myers Squibb (France)

Manufactured By

Bristol-Myers Squibb Company (USA)

Labeled By

BRISTOL-MYERS SQUIBB Company (Italy)

ATC Code

L04AA28 (Belatacept)

Active Substance

Belatacept (Rec.INN registered by WHO)

Dosage Form

Nulojix

Lyophilizate for the preparation of solution for infusion 250 mg: fl. 1 or 2 pcs. in a set with a syringe

Dosage Form, Packaging, and Composition

250 mg – vials (1) in a set with a syringe (1) – cardboard boxes.
250 mg – vials (2) in a set with a syringe (2) – cardboard boxes.

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressive agent

Pharmacological Action

Selective T-lymphocyte co-stimulation blocker. It binds to CD80 and CD86 on antigen-presenting cells, thereby blocking CD28-mediated T-lymphocyte co-stimulation.

In vitro, Belatacept inhibits T-lymphocyte proliferation and the production of cytokines – interleukin-2, interferon beta, interleukin-4, and TNFα.

Activated T-lymphocytes play a major role in the process of immunological rejection.

In experimental studies in non-human primates, Belatacept, used as monotherapy, prolonged renal graft survival and reduced the production of antibodies to donor tissues.

Pharmacokinetics

Pharmacokinetic parameters of belatacept after IV infusion

* systemic clearance

Indications

Prophylaxis of transplant rejection after kidney transplantation (in combination with basiliximab induction, as well as in combination with mycophenolate mofetil and corticosteroids).

ICD codes

Dosage Regimen

Used only in patients with a seropositive reaction to the Epstein-Barr virus (EBV).

Administered intravenously as an infusion.

The dose is set individually based on the patient’s true body weight at the time of transplantation and should not be modified during the course of treatment, except when body weight changes by more than 10%.

In the initial phase of treatment, the dose is 10 mg/kg, in the maintenance phase – 5 mg/kg.

The dose is calculated individually according to a special scheme.

The duration of treatment is set individually.

Adverse Reactions

Neoplasms: post-transplant lymphoproliferative disorder (PTLD), predominantly affecting the CNS, non-melanoma skin cancer, other malignant diseases.

Infections: progressive multifocal leukoencephalopathy (PML) associated with JC virus, polyomavirus-associated nephropathy, fungal infection, herpes virus infections, tuberculosis, CNS infectious diseases, cytomegalovirus (CMV) infection.

Digestive system: ≥ 20% – diarrhea, constipation, nausea, vomiting; ≥ 10% – abdominal pain; < 10% – stomatitis (including aphthous).

Hematopoietic system: ≥ 20% – anemia, leukopenia; < 10% – neutropenia.

Urinary system: ≥ 20% – urinary tract infections; ≥ 10% – hematuria, proteinuria, dysuria, renal tubular necrosis, increased serum creatinine; < 10% – renal impairment, including renal artery stenosis, urinary incontinence, hydronephrosis.

Cardiovascular system: ≥ 20% – arterial hypertension; ≥ 10% – arterial hypotension; < 10% – hematoma, lymphocele, atrial fibrillation.

Respiratory system: ≥ 20% – cough; ≥ 10% – upper respiratory tract infections, nasopharyngitis, bronchitis, dyspnea.

CNS: ≥ 20% – headache; ≥ 10% – dizziness, tremor, anxiety, insomnia.

Metabolism: hypokalemia, hyperkalemia, diabetes mellitus; ≥ 10% – hypophosphatemia, dyslipidemia, hyperglycemia, hypocalcemia, hypercholesterolemia, hypomagnesemia, hyperuricemia.

Musculoskeletal system: ≥ 10% – arthralgia, back pain; < 10% – musculoskeletal pain.

Skin: ≥ 10% – acne; < 10% – alopecia, hyperhidrosis.

Immunological reactions: possible formation of antibodies to belatacept, including neutralizing ones (clinical significance not determined); < 10% – Guillain-Barré syndrome.

Transplant-related: ≥ 20% – dysfunction; < 10% – chronic allograft nephropathy, complications of the transplanted kidney, including wound dehiscence, arteriovenous fistula thrombosis.

General reactions: ≥ 20% – peripheral edema; infusion reactions.

Reasons for drug discontinuation: 1.5% – cytomegalovirus infection, complications after kidney transplantation.

Contraindications

Patients with seronegative or unknown status for EBV, hypersensitivity to belatacept.

Use in Pregnancy and Lactation

No clinical studies on use during pregnancy have been conducted. Should not be used during pregnancy, except when the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

It is not known whether Belatacept is excreted in human breast milk and whether it is absorbed by the infant with breast milk. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

In experimental studies, it was shown that Belatacept had no adverse effect on the fertility of male and female rats at a dose of 200 mg/kg/day (25 times higher than the average recommended human dose). Belatacept crosses the placental barrier in animals. It has no teratogenic effect in pregnant rats and rabbits at doses that are 16 and 19 times higher, respectively, than the average recommended human dose (10 mg/kg), administered during the first month of treatment, based on AUC value. It has been established that Belatacept is excreted in the breast milk of lactating rats.

Special Precautions

The use of belatacept is contraindicated in patients with seronegative or unknown EBV status, because the risk of developing PTLD, predominantly affecting the CNS, is higher in EBV-seronegative patients compared to EBV-seropositive patients.

Before starting belatacept, the patient’s serological status for EBV should be determined. Belatacept can only be used in EBV-seropositive patients.

Before starting belatacept, tests for tuberculosis status should be performed.

Since immunosuppression is a risk factor for the development of PTLD, PML, as well as serious infections, Belatacept should not be used in doses exceeding the recommended ones and more frequently than recommended.

Other risk factors for the development of PTLD are CMV infection and therapy with drugs that suppress T-cell activity.

Patients receiving Belatacept have an increased risk of developing PTLD predominantly involving the CNS, compared with patients receiving cyclosporine.

The physician should suspect the development of PTLD, PML upon the occurrence or worsening of neurological, cognitive symptoms, and behavioral disorders.

When treated with immunosuppressants, including Belatacept, the risk of malignant neoplasms, including skin cancer, is increased. Therefore, during treatment, patients should avoid exposure to sunlight and UV radiation.

Prophylaxis for cytomegalovirus infection is recommended within 3 months after transplantation.

Prophylaxis for Pneumocystis jiroveci infection is recommended after transplantation.

Patients should be monitored to detect symptoms of polyomavirus nephropathy, which can lead to serious consequences – impaired renal function and loss of the renal transplant.

During the use of belatacept, immunization with live vaccines should be avoided.

Drug Interactions

In renal transplant patients receiving Belatacept, symptoms of impaired efficacy or side effects were observed with the simultaneous administration of drugs metabolized by CYP450 isoenzymes. Such combinations should be used with caution.

In pharmacokinetic studies in patients receiving mycophenolate mofetil at doses of 500-1500 mg twice daily with belatacept at a dose of 5 mg/kg or with cyclosporine, it was found that the mean C_max and AUC_0-12 values of mycophenolic acid were 20% and 40% greater, respectively, when combined with belatacept than with cyclosporine. The possible change in the bioavailability of mycophenolic acid after switching from belatacept to cyclosporine or vice versa in patients receiving mycophenolate mofetil should be taken into account.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.