We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we'll assume that you are happy to receive all cookies on the medicines.ie website. Find out more

Bristol-Myers Squibb Pharmaceutical Limited

Watery Lane, Swords, Co. Dublin,
Telephone: 1 800 749 749
Medical Information Direct Line: Freephone: 1 800 749 749
Medical Information e-mail: Medical.information@bms.com
Summary of Product Characteristics last updated on medicines.ie: 12/09/2017
SPC NULOJIX 250 mg powder for concentrate for solution for infusion

When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 12/09/2017 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01-Sep-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Update to the SmPC and PIL with information on the new important potential risk of venous thrombosis of the renal allograft when anti-thymocyte globulin (ATG) and belatacept are coadministered (at the same or nearly the same time) in patients with other predisposing risk factors for thrombosis are being proposed.

Updated on 06/04/2017 and displayed until 12/09/2017
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   24-Mar-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

In section 4.2 - Reference to no reports of anaphylaxis on belatacept was removed 

In section 4.4- Under Allergic reactions - reference to no reports of anaphylaxsis has been removed. The following sentence has been added - Anaphylaxis has been reported during post marketing surveillance (see section 4.8).

In section 4.8-Under infusion related reactions - reference to no reports of anaphylaxis or hypersensitivity was removed. The following sentence has been added - Anaphylaxis has ben reported post marketing (see section 4.4)

Under section 9 -The date of latest renewal has been added- 18th February 2016
 
Under section 10- The date of revision of text has been changed to the 24th March 2017
Updated on 06/03/2017 and displayed until 06/04/2017
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   23-Feb-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



In section 4.8 the following text  the following changes (highlighted) has been  made

Long-term extension in Study 1 and Study 2

Of the 1209 randomized and transplanted patients in the two Phase 3 studies (see section 5.1), 761 patients continued after Year 3 in a long-term extension period for up to an additional 4 years and continued to receive the study drug according to their original treatment assignment. As compared to the results from the initial 3 years, no new adverse reactions or increasing incidence of adverse reactions (listed above from the initial 3‑year period) were detected during the 4‑year long‑term open label extension.

 

Description of selected adverse reactions

 

Malignancies and post-transplant lymphoproliferative disease

Year 1 and 3 frequencies of malignancies are shown in Table 3, except for cases of PTLD which are presented at 1 year and > 3 years (median days of follow-up were 1,199 days for belatacept MI, 1,206 days for belatacept LI, and 1,139 days for ciclosporin). The Year 3 frequency of malignant neoplasms, excluding non-melanoma skin cancers, was similar in the belatacept LI and ciclosporin groups and higher in the belatacept MI group. PTLD occurred at a higher rate in both belatacept treatment groups versus ciclosporin (see section 4.4). Non-melanoma skin cancers occurred less frequently with the belatacept LI regimen than with the ciclosporin or belatacept MI regimens.

 

Table 3:           Malignancies occurring by treatment group (%)

 

Up to Year 1

Up to Year 3*,**

Belatacept MI
N= 477

Belatacept LI
N= 472

Ciclosporin
N= 476

Belatacept MI
N= 477

Belatacept LI
N= 472

Ciclosporin
N= 476

Any malignant neoplasm

3.4

1.9

3.4

8.6

5.7

7.1

Non-melanoma skin cancer

1.0

0.2

1.5

4.2

1.5

3.6

Malignant neoplasms excluding non-melanoma skin cancers

2.3

1.7

1.9

4.4

4.2

3.6

PTLD

0.8

0.8

0.2

1.7

1.3

0.6

Malignancies excluding non-melanoma skin cancer and PTLD

1.5

0.8

1.7

2.7

3.2

3.4

*Median follow-up excluding PTLD for pooled studies is 1,092 days for each treatment group.

**Median follow-up for PTLD for pooled studies is 1,199 days for MI, 1,206 days for LI, and 1,139 days for ciclosporin.

 

In the 3 studies (one phasePhase 2 and two phasePhase 3 studies, Study 1 and Study 2), the cumulative frequency of PTLD was higher in belatacept treated patients at the recommended dosing regimen (LI) (1.3%; 6/472) than in the ciclosporin group (0.6%; 3/476), and was highest in the belatacept MI group (1.7%; 8/477). Nine of 14 cases of PTLD in belatacept-treated patients were located in the CNS; within the observation period, 8 of 14 cases were fatal (6 of the fatal cases involved the CNS). Of the 6 PTLD cases in the LI regimen, 3 involved the CNS and were fatal.

 

EBV seronegative patients receiving immunosuppressants are at a particularly increased risk for PTLD. (see sections 4.3 and 4.4). In clinical studies, belatacept-treated transplant recipients with EBV seronegative status were at an increased risk for PTLD compared with those who were EBV positive (7.7%; 7/91 versus 0.7%; 6/810, respectively). At the recommended dosing regimen of belatacept there were 404 EBV positive recipients and 4 cases of PTLD occurred (1.0%); two2 of these presented in the CNS.

 

Table 3:           Malignancies occurring by treatment group (%)

 

Up to Year 1

Up to Year 3*

Belatacept MI
N= 477

Belatacept LI
N= 472

Ciclosporin
N= 476

Belatacept MI
N= 477

Belatacept LI
N= 472

Ciclosporin
N= 476

Any malignant neoplasm

3.4

1.9

3.4

8.6

5.7

7.1

Non-melanoma skin cancer

1.0

0.2

1.5

4.2

1.5

3.6

Malignant neoplasms excluding non-melanoma skin cancers

2.3

1.7

1.9

4.4

4.2

3.6

PTLD**

0.8

0.8

0.2

1.7

1.3

0.6

Malignancies excluding non-melanoma skin cancer and PTLD

1.5

0.8

1.7

2.7

3.2

3.4

*Median follow-up excluding PTLD for pooled studies is 1,092 days for each treatment group.

**Median follow-up for PTLD for pooled studies is 1,199 days for MI, 1,206 days for LI, and 1,139 days for ciclosporin.

 

During the long‑term extension period, malignancies (including PTLD) were reported in 10.3%, 8.4%, and 14.7% of patients in the belatacept MI, belatacept LI, and ciclosporin groups, respectively, in Study 1; and in 19.2%, 13.3% and 16.1% of patients in the belatacept MI, belatacept LI, and ciclosporin groups, respectively, in Study 2. Cases of PTLD varied by serostatus. In Study 1, one additional case of PTLD was reported in the ciclosporin group, in a patient who was EBV seropositive at the time of transplant. In Study 2, among patients who were EBV seropositive at the time of transplant, there was one case of PTLD in each of the three treatment groups. Among Study 2 patients who were EBV seronegative at the time of transplant (for whom use of belatacept is not recommended), there were three cases of PTLD in the belatacept LI group, and none in the belatacept MI and ciclosporin groups.

 

Infections

Year 1 and Year 3 frequencies of infections occurring by treatment group are shown in Table 4. The overall occurrence of tuberculosis infections and non-serious herpes infections were higher for belatacept regimens than for the ciclosporin regimen. The majority of cases of tuberculosis occurred in patients who currently live or previously lived in countries with a high prevalence of tuberculosis (see section 4.4). Overall occurrences of polyoma virus infections and fungal infections were numerically lower in the belatacept LI group compared with the belatacept MI and ciclosporin groups.

 

Within the belatacept clinical program, there were 2 patients diagnosed with PML. One fatal case of PML was reported in a renal transplant recipient treated with belatacept MI regimen, an IL-2 receptor antagonist, MMF, and corticosteroids for 2 years in a Phase 3 trial. The other case of PML was reported in a liver transplant recipient in a Phase 2 trial who received 6 months of treatment with an augmented belatacept MI regimen, MMF at doses higher than the recommended dose and corticosteroids (see section 4.4).

 

Infections involving the CNS were more frequent in the belatacept MI group (8 cases, including the PML case discussed above; 1.7%) than the belatacept LI (2 cases, 0.4%) and ciclosporin (one case; 0.2%) groups. The most common CNS infection was cryptococcal meningitis.

 

Table 4:           Infections occurring by treatment group (%)

 

Up to Year 1

Up to Year 3*

Belatacept MI
N= 477

Belatacept LI
N= 472

Ciclosporin N= 476

Belatacept MI
N= 477

Belatacept LI
N= 472

Ciclosporin N= 476

Infections and infestations

70.7

71.8

73.7

79.2

82.0

80.6

Serious infections

26.8

23.3

27.3

35.8

33.5

37.8

Viral infections

26.4

25.0

27.7

38.8

39.0

36.1

            CMV

11.1

11.9

13.7

13.8

13.8

14.7

            Polyomavirus

4.8

2.3

4.8

6.3

3.8

5.7

            Herpes

8.0

6.6

6.1

15.5

14.2

10.7

Fungal infections

13.8

11.0

15.1

22.9

16.7

20.6

Tuberculosis

0.4

0.4

0.2

1.3

1.3

0.2

*Median exposure for pooled studies is 1,092 days for each treatment group.

 

During the long-term extension period, serious infections occurred in 30.3% and 23.5% of patients in the belatacept MI and LI groups, respectively, and in 27.2% of patients in the ciclosporin group in Study 1; and in 35.6% and 38.1% of patients in the belatacept MI and LI groups, respectively, and in 37.9% of patients in the ciclosporin group in Study 2. There was one case of PML reported (Study 1) in the ciclosporin group at 82 months post-transplant (more than 56 days after discontinuing therapy).

 

Graft thrombosis

In a phasePhase 3 study in recipients of extended criteria donor (ECD) kidneys (Study 2), graft thrombosis occurred more frequently in the belatacept groups (4.3% and 5.1% for the MI and LI regimens respectively), versus 2.2% for ciclosporin. In another phasePhase 3 study in recipients of living donor and standard criteria deceased donor kidneys (Study 1), the incidence of graft thrombosis was 2.3% and 0.4% for the MI and LI regimens respectively, versus 1.8% for ciclosporin. In a phasePhase 2 study, there were 2 cases of graft thrombosis, 1 each in MI and LI (incidence of 1.4% for both) versus 0 in the ciclosporin group. In general, these events occurred early and the majority resulted in graft loss.

 

Infusion-related reactions

Up to Year 3, there were no reports of anaphylaxis or hypersensitivity related to the medicinal product.

 

Acute infusion-related reactions (reactions occurring within one hour of infusion) occurred in 5.5% of patients in the belatacept MI group and 4.4% of patients in the belatacept LI group up to Year 3. The most frequently reported acute infusion-related reactions in combined belatacept regimens were hypotension, hypertension, flushing and headache. Most events were not serious, were mild to moderate in intensity, and did not recur. When belatacept was compared to placebo infusions, there were no differences in event rates (placebo infusions were administered at Weeks 6 and 10 of the belatacept LI regimen to blind the MI and LI regimens).

 

Immunogenicity

Antibodies directed against the belatacept molecule were assessed in 796 kidney transplant recipients (551 of these treated for at least 3 years) in the two Phase 3 studies. An additional 51 patients were treated for an average of 7 years in the long-term extension of a Phase 2 study. Anti-belatacept antibody development was not associated with altered clearance of belatacept.

 

A total of 45 of 847 patients (5.3%) developed antibodies during treatment with belatacept. In the individual studies, the percentage of patients with antibodies ranged from 4.5% and 5.2% in the Phase 3 studies to 11.8% in the long-term extension of the Phase 2 study. However, immunogenicity rate normalised for duration of exposure was consistent at 2.0 to 2.1 per 100 patient years among the three studies. In 153 patients assessed for antibodies at least 56 days (approximately 7 half-lives) after discontinuation of belatacept, an additional 10 (6.5%) developed antibodies. In general, antibody titers were low, not usually persistent, and often became undetectable with continued treatment.

 

To assess for the presence of neutralising antibodies, samples from 29 patients with confirmed binding activity to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) region of the molecule were assessed by an in vitro assay; 8 (27.6%) patients were shown to possess neutralising antibodies. The clinical relevance of such antibodies is unclear.

 

Autoimmunity

The occurrence of autoimmune events across the core clinical studies was infrequent, occurring at rates of 1.7%, 1.7%, and 1.9% by Year 3 for the MI, LI, and ciclosporin groups respectively. One patient on belatacept MI regimen developed Guillian-Barré syndrome which led to treatment discontinuation and subsequently resolved. Overall, the few reports across clinical studies suggest that prolonged exposure to belatacept does not predispose patients to an increased risk of development of autoimmune events.

 

During the long-term extension period, autoimmune events occurred in 2.6% and 3.0% of patients in the belatacept MI and LI groups, respectively, and in 3.7% of patients in the ciclosporin group in Study 1; and in 5.8% and 3.5% of patients in the belatacept MI and LI groups, respectively, and in 0% of patients in ciclosporin group in Study 2.

 


Under section 5.1 the following text has been added :



Long-term extension in Study 1 and Study 2

A total of 321 belatacept (MI: 155 and LI: 166) and 136 ciclosporin patients completed 3 years of treatment in Study 1 and entered the 4-year long-term open label extension period (up to 7 years in total). More patients discontinued in the ciclosporin group (32.4%) versus each belatacept group (17.4% and 18.1% in MI and LI groups, respectively) during the long-term extension period. A total of 217 belatacept (MI: 104 and LI: 113) and 87 ciclosporin patients completed 3 years of treatment in Study 2 and entered the 4-year long-term open label extension period (up to 7 years in total). More patients discontinued in the ciclosporin group (34.5%) versus each belatacept group (28.8% and 25.7% for MI and LI groups, respectively) during the long-term extension period.

 

As compared to ciclosporin and assessed by the hazard ratio (HR) estimates (for death or graft loss) from an ad hoc Cox regression analysis, overall patient and graft survival was higher for belatacept-treated patients in Study 1, HR 0.588 (95% CI: 0.356-0.972) for the MI group and HR 0.585 (95% CI: 0.356-0.961) for the LI group, and comparable across treatment groups in Study 2, HR 0.932 (95% CI: 0.635-1.367) for the MI group and HR 0.944 (95% CI: 0.644-1.383) for the LI group. The overall proportion of patients with death or graft loss was lower in belatacept-treated patients (MI: 11.4%, LI: 11.9%) as compared to ciclosporin-treated patients (17.6%) in Study 1. The overall proportion of patients with death or graft loss was comparable across treatment groups (29.3%, 30.9%, and 28.3% for MI, LI and ciclosporin, respectively) in Study 2. In Study 1, in the MI, LI, and ciclosporin groups, respectively, death occurred in 7.8%, 7.5%, and 11.3% of patients, and graft loss occurred in 4.6%, 4.9%, and 7.7% of patients. In Study 2, in the MI, LI, and ciclosporin groups, respectively, death occurred in 20.1%, 21.1%, and 15.8% of patients, and graft loss occurred in 11.4%, 13.1%, and 15.8% of patients. The higher proportion of deaths in the LI group in Study 2 was mainly due to neoplasms (MI: 3.8%, LI: 7.1%, ciclosporin: 2.3%).

 

The higher calculated GFR observed in belatacept-treated patients relative to ciclosporin‑treated patients during the first 3 years was maintained over the long-term extension period. In Study 1, mean calculated GFR at 7 years was 74.0, 77.9 and 50.7 mL/min/1.73 m2 in the belatacept MI, belatacept LI and ciclosporin groups, respectively. In Study 2, mean calculated GFR at 7 years was 57.6, 59.1 and 44.6 mL/min/1.73 m2, in the same groups, respectively. The time to death, graft loss, or GFR <30 mL/min/1.73 m2 was analyzed over the 7-year period: in Study 1, approximately 60% reduction in the risk of death, graft loss, or GFR <30 mL/min/1.73 m2 was observed among patients in the belatacept groups as compared with those assigned to ciclosporin. In Study 2, approximately 40% reduction in this risk was observed among patients in the belatacept groups as compared with those assigned to ciclosporin.

 

 

 

 

Updated on 14/03/2016 and displayed until 06/03/2017
Reasons for adding or updating:
  • Removal of black triangle
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.3 - Shelf life
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation
Date of revision of text on the SPC:   18-Feb-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company




Removal of black triangle and text

3.       PHARMACEUTICAL form

 

Powder for concentrate for solution for infusion (powder for sterile concentrate).

 

4.2     Posology and method of administration

 

Treatment should be prescribed and supervised by specialist physicians experienced in the management of immunosuppressive therapy and of renal transplant patients.

 

Belatacept has not been studied in patients with Panel Reactive Antibody (PRA) > 30% (who often require increased immunosuppression). Because of the risk of a high total burden of immunosuppression, belatacept should only be used in these patients after consideration of alternative therapy (see section 4.4).

 

Posology

Adults

The recommended dose is based on patient body weight (kg). The dose and treatment frequency is given below.

 

Table 1:               Dose of belatacept for renal transplant recipients

Dose for Initial Phasephase

Dose

Day of transplantation, prior to implantation (Day 1)

10 mg/kg

Day 5, Day 14 and Day 28

10 mg/kg

End of Week 8 and Week 12 after transplantation

10 mg/kg

Dose for Maintenance Phasephase

Dose

Every 4 weeks (± 3 days), starting at the end of week 16 after transplantation

5 mg/kg

 

For more details on the dose calculation, see section 6.6.

 

Patients do not require pre-medication prior to administration of belatacept.

 

NULOJIX should be administered in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids. Corticosteroid tapering in patients taking belatacept should be implemented cautiously, particularly in patients with 4 to 6 human leukocyte antigen (HLA) mismatches (see sections 4.4 and 5.1)

 

Infusion-related reactions have been reported with belatacept administration in clinical studies. There were no reports of anaphylaxis on belatacept. If any serious allergic or anaphylactic reaction occurs, belatacept therapy should be discontinued immediately and appropriate therapy initiated (see section 4.4).

 

Therapeutic monitoring of belatacept is not required.

 

During clinical studies, there was no dose modification of belatacept for a change in body weight of less than 10%.

 

Special populations

 

Elderly patients

No dose adjustment is required (see sections 5.1 and 5.2).

 

Renal impairment

No dose adjustment is recommended in patients with renal impairment or undergoing dialysis (see section 5.2).

 

Hepatic impairment

No patients with hepatic impairment were studied in renal transplant protocols, therefore dose modification of belatacept in hepatic impairment can not be recommended.

 

Paediatric population

The safety and efficacy of belatacept in children and adolescents 0 to 18 years of age have not yet been established. No data are available.

 

Method of administration

NULOJIX is for intravenous use only.

 

The diluted reconstituted solution must be administered as an intravenous infusion at a relatively constant rate over 30 minutes. Infusion of the first dose should be given in the immediate preoperative period or during surgery, but before completion of the transplant vascular anastomoses.

 

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

 

4.4     Special warnings and precautions for use

Infections

Use of immunosuppressants, including belatacept, can increase susceptibility to infection, including fatal infections, opportunistic infections, tuberculosis, and herpes (see Progressiveprogressive multifocal leukoencephalopathy (PML) warning below and also section 4.8).

Progressive multifocal leukoencephalopathy

PML is a rare, often rapidly progressive and fatal, opportunistic infection of the CNS that is caused by the John Cunningham (JC) virus.

4.6     Fertility, pregnancy and lactation

 

Women of child bearingchildbearing potential/Contraception in males and females

Women of child bearingchildbearing potential should use effective contraception during treatment with belatacept and up to 8 weeks after the last dose of treatment since the potential risk to embryonic/foetal development is unknown.




4.8     Undesirable effects

 

Summary of the safety profile

The adverse reaction profile associated with immunosuppressive agents is often difficult to establish due to the underlying disease and the concurrent use of multiple medicinal products.

 

The most common serious adverse reactions (≥ 2%) reported with belatacept in both regimens (more intensive [MI] and less intensive [LI]) cumulative up to Year 3 were urinary tract infection, CMV infection, pyrexia, increased blood creatinine, pyelonephritis, diarrhoea, gastroenteritis, graft dysfunction, leukopenia, pneumonia, basal cell carcinoma, anaemia, dehydration.

 

The most commonly reported adverse reactions (≥ 20%) among patients treated with both belatacept-based regimens (MI and LI) up to Year 3 are diarrhoea, anaemia, urinary tract infection, peripheral oedema, constipation, hypertension, pyrexia, nausea, graft dysfunction, cough, vomiting, leukopenia, hypophosphataemia, and headache.

 

Adverse reactions resulting in interruption or discontinuation of belatacept in ≥ 1% of patients up to Year 3 were renal vein thrombosis and CMV infection.

 

Tabulated list of adverse reactions

Presented in Table 2, by system organ classification and frequency categories, is the list of adverse reactions with at least a suspected causal relationship, reported in clinical trials cumulatively up to Year 3 and pooled for both belatacept regimens (MI and LI).

 

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

 

 

Infections and infestations

Very Common

urinary tract infection, upper respiratory infection, cytomegalovirus infection*, bronchitis

Common

sepsis, pneumonia, influenza, gastroenteritis, herpes zoster, sinusitis, herpes simplex, oral candidiasis, pyelonephritis, onychomycosis, BK virus infection, respiratory tract infection, candidiasis, rhinitis, cellulitis, wound infection, localised infection, herpes virus infection, fungal infection, fungal skin infection

Uncommon

progressive multifocal leukoencephalopathy*, cerebral fungal infection, cytomegalovirus (CMV) colitis, polyomavirus-associated nephropathy, genital herpes, staphylococcal infection, endocarditis, tuberculosis*, bronchiectasis, osteomyelitis, strongyloidiasis, blastocystis infection, giardiasis, lymphangitis

 

Neoplasms, benign, malignant and unspecified (incl cysts and polyps)*

Common

squamous cell carcinoma of skin, basal cell carcinoma, skin papilloma

Uncommon

EBV associated lymphoproliferative disorder**,lung cancer, rectal cancer, breast cancer, sarcoma, kaposi's sarcoma, prostate cancer, cervix carcinoma, laryngeal cancer, lymphoma, multiple myeloma, transitional cell carcinoma

 

Blood and lymphatic system disorders

Very Common

anaemia, leukopenia

Common

thrombocytopenia, neutropenia, leukocytosis, polycythaemia, lymphopenia

Uncommon

monocytopenia, pure red cell aplasia, agranulocytosis, haemolysis, hypercoagulation

 

Immune system disorders

Common

 

 

blood immunoglobulin G decreased, blood immunoglobulin M decreased,

 

 

Uncommon

hypogammaglobulinaemia, seasonal allergy

 

Endocrine disorders

Common

cushingoid

Uncommon

adrenal insufficiency

 

Metabolism and nutrition disorders

Very Common

hypophosphataemia, hypokalaemia, dyslipidaemia, hyperkalaemia, hyperglycaemia, hypocalcaemia

Common

weight increase, diabetes mellitus, dehydration, weight decrease, acidosis, fluid retention, hypercalcaemia, hypoproteinaemia

Uncommon

diabetic ketoacidosis, diabetic foot, alkalosis, decreased appetite, vitamin D deficiency

 

Psychiatric disorders

Very Common

insomnia, anxiety

Common

depression

Uncommon

abnormal dreams, mood swings, attention deficit/hyperactivity disorder, libido increased

 

Nervous system disorders

Very Common

headache

Common

tremor, paraesthesia, cerebrovascular accident, dizziness, syncope, lethargy, neuropathy peripheral

Uncommon

encephalitis, Guillain-Barré syndrome*, brain oedema, intracranial pressure increased, encephalopathy, convulsion, hemiparesis, demyelination, facial palsy, dysgeusia, cognitive disorder, memory impairment, migraine, burning sensation, diabetic neuropathy, restless leg syndrome

 

Eye disorders

Common

cataract, ocular hyperaemia, vision blurred

Uncommon

retinitis, conjunctivitis, eye inflammation, keratitis, photophobia, eyelid oedema

 

Ear and labyrinth disorders

Common

vertigo, ear pain, tinnitus

Uncommon

hypoacusis

 

Cardiac disorders

Common

tachycardia, bradycardia, atrial fibrillation, cardiac failure, angina pectoris, left ventricular hypertrophy

Uncommon

acute coronary syndrome, atrioventricular block second degree, aortic valve disease, arrhythmia supraventricular

 

Vascular disorders

Very Common

hypertension, hypotension

Common

shock, infarction, haematoma, lymphocele, angiopathy, arterial fibrosis

Uncommon

venous thrombosis, arterial thrombosis, thrombophlebitis, arterial stenosis, intermittent claudication, flushing

 

Respiratory, thoracic and mediastinal disorders

Very Common

dyspnoea, cough

Common

pulmonary oedema, wheezing, hypocapnea, orthopnoea, epistaxis, oropharyngeal pain

Uncommon

acute respiratory distress syndrome, pulmonary hypertension, pneumonitis, haemoptysis, bronchopneumopathy, painful respiration, pleural effusion, sleep apnoea syndrome, dysphonia, oropharyngeal blistering

 

Gastrointestinal disorders

Very Common

diarrhoea, constipation, nausea, vomiting, abdominal pain

Common

dyspepsia, aphthous stomatitis, abdominal hernia

Uncommon

gastrointestinal disorder, pancreatitis, large intestinal ulcer, melaena, gastroduodenal ulcer, rectal haemorrhage, small intestinal obstruction, cheilitis, gingival hyperplasia, salivary gland pain, faeces discoloured

 

Hepatobiliary disorders

Common

cytolytic hepatitis, liver function test abnormal

Uncommon

cholelithiasis, hepatic cyst, hepatic steatosis

 

Skin and subcutaneous tissue disorders

Common

acne, pruritis, alopecia, skin lesion, rash, night sweats, hyperhidrosis

Uncommon

psoriasis, hair growth abnormal, onychoclasis, penile ulceration, swelling face, trichorrhexis

 

Musculoskeletal and connective tissue disorders

Very Common

arthralgia, back pain, pain in extremity

Common

myalgia, muscular weakness, bone pain, joint swelling, intervertebral disc disorder, joint lock, muscle spasms, osteoarthritis

Uncommon

bone metabolism disorder, osteitis, osteolysis, synovitis

 

Renal and urinary disorders

Very Common

proteinuria, blood creatinine increased, dysuria, haematuria

Common

renal tubular necrosis, renal vein thrombosis*, renal artery stenosis, glycosuria, hydronephrosis, vesicoureteric reflux, urinary incontinence, urinary retention, nocturia

Uncommon

renal artery thrombosis*, nephritis, nephrosclerosis, renal tubular atrophy, cystitis haemorrhagic, kidney fibrosis

 

Reproductive system and breast disorders

Uncommon

epididymitis, priapism, cervical dysplasia, breast mass, testicular pain, vulval ulceration, atrophic vulvovaginitis, infertility, scrotal oedema

 

Congenital, familial and genetic disorders

Common

hydrocele

Uncommon

hypophosphatasia

 

General disorders and administration site conditions

Very Common

oedema peripheral, pyrexia

Common

chest pain, fatigue, malaise, impaired healing

Uncommon

infusion related reaction*, irritability, fibrosis, inflammation, disease recurrence, feeling hot, ulcer

 

Investigations

Common

c-reactive protein increased, blood parathyroid hormone increased

Uncommon

pancreatic enzymes increased, troponin increased, electrolyte imbalance, prostate-specific antigen increased, blood uric acid increased, urine output decreased, blood glucose decreased, CD4 lymphocytes decreased

 

Injury, poisoning and procedural complications

Very Common

graft dysfunction

Common

chronic allograft nephropathy (CAN), incisional hernia

Uncommon

transplant failure, transfusion reaction, wound dehiscence, fracture, tendon rupture, procedural hypotension, procedural hypertension, post-procedural haematoma, procedural pain, procedural headache, contusion



Table 3:           Malignancies Occuring by Treatment Group occurring by treatment group (%)

Table 4:           Infections Occuring by Treatment Group occurring by treatment group (%)

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 (see details below).

 

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie


 

5.1     Pharmacodynamic properties

Study 1: Recipients of Living Donor and Standard Criteria Deceased Donor Kidneys

Standard criteria donor organs were defined as organs from a living donor, or a deceased donor with anticipated cold ischemia time of < 24 hours and not meeting the definition of extended criteria donor organs. Study 1 excluded (1) recipients undergoing a first transplant whose current PRA were ≥50%; (2) recipients undergoing a retransplantation whose current PRA were ≥30%; (3) recipients when previous graft loss was due to acute rejection and in case of a positive T-cell lymphocytotoxic cross match.

 

In this study, 666 patients were enrolled, randomized randomised, and transplanted; 219 to belatacept MI, 226 to belatacept LI, and 221 to ciclosporin. The median age was 45 years; 58% of donor organs were from living patients;  3% were re-transplanted; 69% of the study population was male; 61% of patients were white, 8% were black/African-American, 31% were categorisedcategorised as of other races; 16% had PRA ³ 10%; and 41% had 4 to 6 HLA mismatches.

 

The dose of corticosteroids used in all treatment groups was tapered during the first 6 months following transplantation. The median corticosteroid doses administered with the belatacept recommended regimen up to months 1, 3, and 6 were 20 mg, 12 mg and 10 mg, respectively.

 

Study  2: Recipients of Extended Criteria Donor Kidneys

Extended criteria donors were defined as deceased donors with at least one of the following: (1) donor age ≥ 60 years; (2) donor age ≥ 50 years and other donor comorbidities (≥ 2 of the following: stroke, hypertension, serum creatinine > 1.5 mg/dl); (3) donation after cardiac death or (4) anticipated cold ischemia time of ≥ 24 hours. Study 2 excluded recipients with a current PRA ≥ 30%, re-transplanted patients, and in case of a positive T-cell lymphocytotoxic cross match.

 

In this study, 543 patients were enrolled, randomised, and transplanted; 184 to belatacept MI, 175 to belatacept LI, and 184 to ciclosporin. The median age was 58 years; 67% of the study population was male; 75% of patients were white, 13% were black/African-American, 12% were categorised as of other races; 3% had PRA ³ 10%; and 53% had 4 to 6 HLA mismatches.



Table 5:           Key Efficay Outcomes at years efficacy outcomes at years 1 and 3 

New Onset Diabetes Mellitus and Blood Pressure

In a prespecified pooled analysis of Studies 1 and 2 at Year 1, the incidence of new onset diabetes mellitus (NODM), defined as use of an antidiabetic agent for ≥ 30 days or ≥ 2 fasting plasma glucose values > 126 mg/dl (7.0 mmol/l) post-transplantation, was 5% with belatacept and 10% with ciclosporin. At Year 3, the incidence of NODM was 8% with belatacept and 10% with ciclosporin.

 

For Studies 1 and 2 at Years 1 and 3, belatacept was associated with 6 to 9 mmHg lower mean systolic blood pressure, approximately 2 to 4 mmHg lower mean diastolic blood pressure, and less use of antihypertensive medicines medicinal products than ciclosporin.

 

Phase 2 liver transplant study

A single, randomized randomised, multi-center, controlled phase 2 trial of belatacept in de novo orthotopic liver transplant recipients was conducted. A total of 250 subjects were randomized randomised to 1 of 5 treatment groups (3 belatacept and 2 tacrolimus groups). The belatacept dosing used in this liver study was higher in all 3 belatacept arms than the belatacept dosing used in the Phase 2 and 3 renal transplant studies.

 

An excess in mortality and graft loss was observed in the belatatacept LI + MMF group and an excess in mortality was observed in the belatacept MI + MMF group. No pattern was identified in the causes of death. There was an increase in viral and fungal infections in the belatacept groups versus the tacrolimus groups, however overall frequency of serious infections was not different among all treatment groups (see Section section 4.4).

 

Elderly

Two hundred seventeen (217) patients 65 years and older received belatacept across one Phase 2 and two Phase 3 renal studies.

Elderly patients demonstrated consistency with the overall study population for safety and efficacy as assessed by patient and graft survival, renal function, and acute rejection.



6.3     Shelf life

 

Unopened vials

3 years

 

After reconstitution

The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately.

 

After dilution

After dilution Chemical and physical in-use stability of the solution for infusion has been demonstrated for 24 hours when stored in a refrigerator (2° (2°C - 8°C). From a microbiological point of view, the product should be used immediately. If not used immediately, the solution for infusion may be stored in a refrigerator (2°C - 8°C) for up to 24 hours. The Out of these 24 hours, the solution for infusion may be stored below 25°C for a maximum of 4 hours of the total 24 hours below 25°C. Do not freeze.

The NULOJIX infusion must be completed within 24 hours of reconstitution of the powder.



6.6          Special precautions for disposal and other handling

 

§  Use aseptic technique to reconstitute the vials and dilute the solution for administration.

§  Use the silicone-free disposable syringe provided to make up the vials and to add the solution to the infusion. This will avoid aggregate formation (see section 6.2).

§  Do not shake the vials. This will avoid foam formation (see section 6.2).

§  The solution for infusion is to be used in conjunction with a sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 µm to 1.2 µm).

 

Dose selection and reconstitution of the vials

Calculate the dose and number of NULOJIX vials required. Each NULOJIX vial provides 250 mg of belatacept.

§  Total dose of belatacept in mg equals the patient weight in kg times the belatacept dose in mg/kg (5 or 10 mg/kg, see section 4.2).

§  Dose modification of NULOJIX is not recommended for a change in body weight of less than 10%.

§  Number of vials required equals the belatacept dose in mg divided by 250 rounded up to the next full number of vials.

§  Make up each vial with 10.5 ml reconstitution solution.

§  Volume of the reconstituted solution required (ml) equals total belatacept dose in mg divided by 25.

 

Practical details on the reconstitution of vials

Using aseptic technique, make up each vial with 10.5 ml of one of the following solvents (sterile water for injections, sodium chloride 9 mg/ml (0.9%) solution for injection or 5% dextrose glucose solution for injection), using the co-packed silicone free disposable syringe (necessary to avoid aggregate formation) and an 18-21 gauge needle. Syringes are marked in units of 0.5 ml; therefore, the calculated dose should be rounded to the nearest 0.5 ml.

 

Remove the flip off seal from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the centre of the rubber stopper. Direct the stream of fluid to the glass wall of the vial and not into the powder. Remove the syringe and needle after 10.5 ml of reconstitution fluid has been added to the vial.

 

To minimize foam formation, gently swirl and invert the vial for at least 30 seconds or until the powder is completely dissolved. do not shake. Although some foam may remain on the surface of the reconstituted solution, a sufficient excess of belatacept is included in each vial to account for withdrawal losses. Thus, 10 ml of a 25 mg/ml belatacept solution can be withdrawn from each vial.

 

The reconstituted solution should be clear to slightly opalescent and colourless to pale yellow. Do not use if opaque particles, discolouration or other foreign particles are present. It is recommended to tranfer the reconstituted solution from the vial to the infusion bag or bottle immediately.

 

Practical details on the preparation of the solution for infusion

After reconstitution, dilute the product to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% dextrose glucose solution for injection. From a 100 ml infusion bag or bottle (typically, an infusion volume of 100 ml will be appropriate for most patients and doses, but total infusion volume ranging from 50 ml to 250 ml may be used), withdraw a volume of sodium chloride 9 mg/ml (0.9%) solution for injection or 5% dextrose glucose solution for injection equal to the volume (ml equals total dose in mg divided by 25) of the reconstituted belatacept solution required to provide the dose and discard it. Slowly add the required amount of reconstituted belatacept solution from each vial to the infusion bag or bottle using the same silicone free disposable syringe used for reconstitution of the powder. Gently mix the infusion container. The concentration of belatacept in the infusion should be between 2 mg and 10 mg belatacept per ml solution.

 

Any unused portion in the vials must be discarded in accordance with local requirements.

 

Administration

When reconstitution and dilution are performed under aseptic conditions, the NULOJIX infusion should be started immediately or must be completed within 24 hours of reconstitution of the powder. If not used immediately, the solution for infusion may be stored in the refrigerator (2°C - 8°C) for up to 24 hours. Do not freeze. The solution for infusion may be stored for a maximum of 4 hours of the total 24 hours below 25°C. Infusion must be completed within 24 hours of reconstitution of the powder. Prior to administration, the NULOJIX solution for infusion should be inspected visually for particulate matter or discolouration. Discard the solution if any particulate matter or discolouration is observed. The entire, fully diluted NULOJIX infusion should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 μm to 1.2 μm). Following administration, it is recommended that the intravenous line be flushed with infusion fluid to ensure administration of the complete dose.

Do not store any unused portion of the solution for infusion for reuse.

 

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.



9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 17 June 2011

Date of latest renewal:   18 February 2016




10.     DATE OF REVISION OF THE TEXT

 

18 February 2016

 

Updated on 22/01/2015 and displayed until 14/03/2016
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Date of revision of text on the SPC:   18-Dec-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

To update Section 4.5 of the SmPC with pharmacokinetic and pharmacodynamic data from the drug-drug interaction study,  IM103151 (An open-label, single-sequence study of the effect of belatacept on the pharmacokinetics of caffeine, losarten, omeprazole, dextromethorphan, and midazolam administered as “Inje Cocktail” in healthy subjects). This study supports the recommendation that no dose adjustment is needed for drugs metabolized by cytochrome (CYP) P450 enzymes when co-administered with Nulojix (belatacept).
Updated on 21/05/2014 and displayed until 22/01/2015
Reasons for adding or updating:
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
Date of revision of text on the SPC:   17-Dec-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Update to ADR reporting statement.
Updated on 19/03/2013 and displayed until 21/05/2014
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.4 - Special precautions for storage
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   26-Feb-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



4.2     Posology and method of administration

NULOJIX should be administered in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids. Corticosteroid tapering in patients taking belatacept should be implemented cautiously, particularly in patients with 4 to 6 human leukocyte antigen (HLA) mismatches (see sections 4.4 and 5.1)

4.4       Special warnings and precautions for use

 

Concomitant use with other immunosuppressive agents

Belatacept has been administered with the following immunosuppressive agents in clinical studies: basiliximab, an MPA and corticosteroids.


Lymphocyte Depleting Therapies and MPA:
As the total burden of immunosuppression is a risk factor for malignancies and opportunistic infections, higher than the recommended doses of concomitant immunosuppressive agents should be avoided.

Lymphocyte depleting therapies to treat acute rejection should be used cautiously.

Patients with high PRA often require increased immunosuppression. Belatacept has not been studied in patients with PRA > 30% (see section 4.2).

 

Corticosteroid Taper: Corticosteroid tapering in patients taking belatacept should be implemented cautiously, particularly in patients at high immunologic risk, such as those with 4 to 6 human leukocyte antigen (HLA) mismatches. In postmarketing experience, use of belatacept in conjunction with basiliximab induction, mycophenolate mofetil and corticosteroid taper to 5 mg/day by Week 6 post-transplant was associated with an increased rate of acute rejection, particularly Grade III rejection. These Grade III rejections occurred in patients with 4 to 6 HLA mismatches (See sections 4.2 and 5.1).

Corticosteroid Taper: Corticosteroid tapering in patients taking belatacept should be implemented cautiously, particularly in patients at high immunologic risk, such as those with 4 to 6 human leukocyte antigen (HLA) mismatches. In postmarketing experience, use of belatacept in conjunction with basiliximab induction, mycophenolate mofetil and corticosteroid taper to 5 mg/day by Week 6 post-transplant was associated with an increased rate of acute rejection, particularly Grade III rejection. These Grade III rejections occurred in patients with 4 to 6 HLA mismatches (See sections 4.2 and 5.1).

 

Breast-feeding

Studies in rats have shown excretion of belatacept in milk. It is unknown whether belatacept is excreted in human milk (see section 5.3). Women should not breast-feed while on treatment with a belatacept‑based regimen.

5.1       Pharmacodynamic properties

Study 1: Recipients of Living Donor and Standard Criteria Deceased Donor Kidneys

Standard criteria donor organs were defined as organs from a living donor, or a deceased donor with anticipated cold ischemia time of < 24 hours and not meeting the definition of extended criteria donor organs. Study 1 excluded (1) recipients undergoing a first transplant whose current PRA were ≥50%; (2) recipients undergoing a retransplantation whose current PRA were ≥30%; (3) recipients when previous graft loss was due to acute rejection and in case of a positive T-cell lymphocytotoxic cross match.

 

In this study, 666 patients were enrolled, randomized, and transplanted; 219 to belatacept MI, 226 to belatacept LI, and 221 to ciclosporin. The median age was 45 years; 58% of donor organs were from living patients;  3% were re-transplanted; 69% of the study population was male; 61% of patients were white, 8% were black/African-American, 31% were categorized as of other races; 16% had PRA ³ 10%; and 41% had 4 to 6 HLA mismatches.

 

The dose of corticosteroids used in all treatment groups was tapered during the first 6 months following transplantation. The median corticosteroid doses administered with the belatacept recommended regimen up to months 1, 3, and 6 were 20 mg, 12 mg and 10 mg, respectively.

 

 

 

Study  2: Recipients of Extended Criteria Donor Kidneys

Extended criteria donors were defined as deceased donors with at least one of the following: (1) donor age ≥ 60 years; (2) donor age ≥ 50 years and other donor comorbidities (≥ 2 of the following: stroke, hypertension, serum creatinine > 1.5 mg/dl); (3) donation after cardiac death or (4) anticipated cold ischemia time of ≥ 24 hours. Study 2 excluded recipients with a current PRA ≥ 30%, re-transplanted patients, and in case of a positive T-cell lymphocytotoxic cross match.

 

In this study, 543 patients were enrolled, randomized, and transplanted; 184 to belatacept MI, 175 to belatacept LI, and 184 to ciclosporin. The median age was 58 years; 67% of the study population was male; 75% of patients were white, 13% were black/African-American, 12% were categorized as of other races; 3% had PRA ³ 10%; and 53% had 4 to 6 HLA mismatches.

 

The dose of corticosteroids used in all treatment groups was tapered during the first 6 months following transplantation. The median corticosteroid doses administered with the belatacept recommended regimen up to months 1, 3, and 6 were 21 mg, 13 mg and 10 mg, respectively.

5.2       Pharmacokinetic properties

Addition of the following text:

Absorption, Distribution and Elimination


6.4     Special precautions for storage

 

Store in a refrigerator (2°C - 8°C).

Store in the original package in order to protect from light.

For storage conditions after reconstitution or dilution of the medicinal product see section 6.3.

10.       DATE OF REVISION OF THE TEXT

February 2013

 

 

 

Updated on 07/02/2012 and displayed until 19/03/2013
Reasons for adding or updating:
  • New SPC for new product
  • New SPC for medicines.ie
Date of revision of text on the SPC:  
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

None provided

Document Links

 
  View all medicines
from this company
View Document
Bookmark and Share

Active Ingredients

 
   Belatacept