Special Warning : אזהרת שימוש

5        WARNINGS AND PRECAUTIONS
5.1      Hepatotoxicity
Hepatotoxicity with allergic features including life-threatening events has been reported in clinical trials and postmarketing. Severe rash or evidence of systemic allergic reaction including drug-related rash with fever, eosinophilia, elevated IgE, or other systemic symptoms have been reported in conjunction with hepatotoxicity [see Warnings and Precautions (5.2)]. These events occurred approximately 1 month after starting treatment. Among reported cases of hepatitis, some were observed in the absence of allergic features or with no pre-existing hepatic disease.
Appropriate laboratory testing including ALT, AST, and bilirubin should be conducted prior to initiating therapy with CELSENTRI and at other time points during treatment as clinically indicated. Hepatic laboratory parameters should be obtained in any patient who develops rash, or signs or symptoms of hepatitis, or allergic reaction. Discontinuation of CELSENTRI should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.

When administering CELSENTRI to patients with pre-existing liver dysfunction or who are co- infected with hepatitis B and/or C virus, additional monitoring may be warranted. The safety and efficacy of CELSENTRI have not been specifically studied in patients with significant underlying liver disorders.
5.2    Severe Skin and Hypersensitivity Reactions
Severe, potentially life-threatening skin and hypersensitivity reactions have been reported in patients taking CELSENTRI, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) [see Adverse Reactions (6.2)]. The cases were characterized by features including rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Discontinue CELSENTRI and other suspected agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, lip swelling, eosinophilia). Delay in stopping treatment with CELSENTRI or other suspect drugs after the onset of rash may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated.
5.3    Cardiovascular Events
Eleven subjects (1.3%) who received CELSENTRI had cardiovascular events, including myocardial ischemia and/or infarction, during the Phase 3 trials in treatment-experienced subjects (total exposure 609 patient-years [300 on CELSENTRI once daily + 309 on CELSENTRI twice daily]), while no subjects who received placebo had such events (total exposure 111 patient-years). These subjects generally had cardiac disease or cardiac risk factors prior to use of CELSENTRI, and the relative contribution of CELSENTRI to these events is not known.
In the Phase 2b/3 trial in treatment-naive adult subjects, 3 subjects (0.8%) who received CELSENTRI had events related to ischemic heart disease and 5 subjects (1.4%) who received efavirenz had such events (total exposure 506 and 508 patient-years for CELSENTRI and efavirenz, respectively).
When CELSENTRI was administered to healthy volunteers at doses higher than the recommended dose, symptomatic postural hypotension was seen at a greater frequency than in placebo. However, when CELSENTRI was given at the recommended dose in HIV-1–infected adult subjects in Phase 3 trials, postural hypotension was seen at a rate similar to placebo (approximately 0.5%).
Patients with cardiovascular comorbidities, risk factors for postural hypotension, or receiving concomitant medication known to lower blood pressure, could be at increased risk of 

cardiovascular adverse events triggered by postural hypotension. Additional monitoring may be warranted.
Postural Hypotension in Patients with Renal Impairment
An increased risk of postural hypotension may occur in patients with severe renal insufficiency or in those with ESRD due to increased maraviroc exposure in some patients. CELSENTRI should be used in patients with severe renal impairment or ESRD only if they are not receiving a concomitant potent CYP3A inhibitor or inducer. However, the use of CELSENTRI in these patients should only be considered when no alternative treatment options are available. If adult patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking 300 mg twice daily, the dose should be reduced to 150 mg twice daily [see Dosage and Administration (2.4)].
5.4    Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including CELSENTRI. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as infection with Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], tuberculosis, or reactivation of Herpes simplex and Herpes zoster), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as autoimmune hepatitis, Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.5    Potential Risk of Infection
CELSENTRI antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infection, as well as AIDS-defining category C infections, were comparable in the treatment groups during the Phase 3 adult treatment-experienced trials of CELSENTRI. While there was a higher rate of certain upper respiratory tract infections reported in the treatment arm receiving CELSENTRI compared with placebo (23% versus 13%), there was a lower rate of pneumonia (2% versus 5%) reported in subjects receiving CELSENTRI. A higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the treatment arm receiving CELSENTRI when adjusted for exposure compared with placebo (8 per 100 patient-years).
In the Phase 2b/3 trial in treatment-naive adult subjects, the incidence of AIDS-defining Category C events when adjusted for exposure was 1.8 for CELSENTRI compared with 2.4 for efavirenz per 100 patient-years of exposure.
Patients should be monitored closely for evidence of infections while receiving CELSENTRI.
5.6      Potential Risk of Malignancy
While no increase in malignancy has been observed with CELSENTRI, due to this drug’s mechanism of action, it could affect immune surveillance and lead to an increased risk of malignancy.
The exposure-adjusted rate for malignancies per 100 patient-years of exposure in adult treatment-experienced trials was 4.6 for CELSENTRI compared with 9.3 on placebo. In treatment-naive adult subjects, the rates were 1.0 and 2.4 per 100 patient-years of exposure for CELSENTRI and efavirenz, respectively.
Long-term follow-up is needed to more fully assess this risk.
5.7      Excipients
CELSENTRI contains soya lecithin.
Each CELSENTRI 150 mg film-coated tablet contains 0.84 mg of soya lecithin.
Each CELSENTRI 300 mg film-coated tablet contains 1.68 mg of soya lecithin.


If a patient is hypersensitive to peanut or soya, CELSENTRI should not be used.
CELSENTRI contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium free’.


6        ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
•     Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)]
•     Severe Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.2)]
•     Cardiovascular Events [see Warnings and Precautions (5.3)]
•     Immune Reconstitution Syndrome [see Warnings and Precautions (5.4)] 6.1      Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience in Adult Subjects
Treatment-Experienced Subjects: The safety profile of CELSENTRI is primarily based on 840 HIV-1–infected subjects who received at least 1 dose of CELSENTRI during two Phase 3 trials. A total of 426 of these subjects received the indicated twice-daily dosing regimen.


Assessment of treatment-emergent adverse events is based on the pooled data from 2 trials in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with CELSENTRI for subjects in these trials was 48 weeks, with the total exposure on CELSENTRI twice daily at 309 patient-years versus 111 patient-years on placebo each administered with optimized background therapy (OBT). The population was 89% male and 84% white, with mean age of 46 years (range: 17 to 75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily.
The most common adverse events reported with twice-daily therapy with CELSENTRI with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash, and dizziness. In these 2 trials, the rate of discontinuation due to adverse events was 5% for subjects who received SELZENTRY twice daily + OBT as well as those who received placebo + OBT. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with twice-daily dosing of SELZENTRY.
The total numbers of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving SELZENTRY twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on SELZENTRY compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both SELZENTRY twice daily and placebo.
Dizziness or postural dizziness occurred in 8% of subjects on either SELZENTRY or placebo, with 2 subjects (0.5%) on SELZENTRY permanently discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 subject on placebo (0.5%) permanently discontinuing therapy due to dizziness.
Treatment-emergent adverse events, regardless of causality, from Trials A4001027 and A4001028 are summarized in Table 3. Selected events occurring at greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with CELSENTRI are included; events that occurred at the same or higher rate on placebo are not displayed.


Table 3 Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on CELSENTRI (and at a Higher Rate Compared with Placebo) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)
Body System/              CELSENTRI
Adverse Event              Twice Dailya                Placebo
Exposure-
Adjusted                 Exposure-
Rate                Adjusted Rate
(per 100 pt- (n = 209    (per 100 pt-
(n = 426)       yrs)         )           yrs)
%        PYE = 309  b    %        PYE = 111b
Eye Disorders
Conjunctivitis                    2             3          1             3 Ocular infections,                2             3          1             2 inflammations, and associated manifestations
Gastrointestinal Disorders
Constipation                      6             9          3             6 General Disorders and
Administration Site
Conditions
Pyrexia                          13            20          9            17 Pain and discomfort               4             5          3             5 Infections and Infestations
Upper respiratory tract          23            37         13            27 infection
Herpes infection                  8            11          4             8 Sinusitis                         7            10          3             6 Bronchitis                        7             9          5             9 Folliculitis                      4             5          2             4 Anogenital warts                  2             3          1             3 Influenza                         2             3         0.5            1 Otitis media                      2             3         0.5            1 Metabolism and Nutrition
Disorders
Appetite disorders                8            11          7            13 Musculoskeletal and
Connective Tissue Disorders
Joint-related signs and           7            10          3             5 symptoms
Muscle pains                     3        4    0.5   1
Neoplasms Benign,
Malignant, and Unspecified
Skin neoplasms benign            3        4    1     3
Nervous System Disorders
Dizziness/postural dizziness     9        13   8     17
Paresthesias and dysesthesias    5         7   3      6
Sensory abnormalities            4         6   1      3
Disturbances in consciousness    4         5   3      6
Peripheral neuropathies          4         5   3      6
Psychiatric Disorders
Disturbances in initiating and   8        11   5     10 maintaining sleep
Depressive disorders             4        6    3     5
Anxiety symptoms                 4        5    3     7
Renal and Urinary
Disorders
Bladder and urethral             5        7    1     3 symptoms
Urinary tract signs and          3        4    1     3 symptoms
Respiratory, Thoracic, and
Mediastinal Disorders
Coughing and associated          14       21   5     10 symptoms
Upper respiratory tract signs    6        9    3     6 and symptoms
Nasal congestion and             4        6    3     5 inflammations
Breathing abnormalities          4        5     2    5
Paranasal sinus disorders        3        4    0.5   1
Skin and Subcutaneous
Tissue Disorders
Rash                             11       16   5     11
Apocrine and eccrine gland        5        7   4     7.5 disorders
Pruritus                         4        5     2    4
Lipodystrophies                  3        5    0.5   1
Erythema                         2        3     1    2
Vascular Disorders
Vascular hypertensive               3             4            2             4 disorders a
300-mg dose equivalent.
b
PYE = Patient-years of exposure.
Laboratory Abnormalities: Table 4 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in greater than 2% of subjects receiving CELSENTRI.

Table 4. Maximum Shift in Laboratory Test Values (without Regard to Baseline) ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)
CELSENTRI
Twice Daily + OBT         Placebo + OBT
Laboratory Parameter                                  (n = 421)a             (n = 207)a Preferred Term                Limit                   %                      % Aspartate aminotransferase        >5.0 x ULN                 4.8                    2.9 Alanine aminotransferase          >5.0 x ULN                 2.6                    3.4 Total bilirubin                   >2.5 x ULN                 5.5                    5.3 Amylase                           >2.0 x ULN                 5.7                    5.8 Lipase                            >2.0 x ULN                 4.9                    6.3 3
Absolute neutrophil count          <750/mm                   4.3                    2.4 ULN = Upper limit of normal.
a
Percentages based on total subjects evaluated for each laboratory parameter.
Treatment-Naive Subjects: Treatment-Emergent Adverse Events: Treatment-emergent adverse events, regardless of causality, from Trial A4001026, a double-blind, comparative, controlled trial in which 721 treatment-naive subjects received CELSENTRI 300 mg twice daily (n = 360) or efavirenz 600 mg once daily (n = 361) in combination with lamivudine/zidovudine (COMBIVIR) for 96 weeks, are summarized in Table 5. Selected events occurring in greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with CELSENTRI are included; events that occurred at the same or higher rate on efavirenz are not displayed.


Table 5 Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on CELSENTRI (and at a Higher Rate Compared with Efavirenz) in Trial A4001026 (96 Weeks)
CELSENTRI                     Efavirenz
300 mg Twice Daily +         600 mg Once Daily +
Lamivudine/Zidovudine        Lamivudine/Zidovudine
Body System/                    (n = 360)                    (n = 361) Adverse Event                       %                             %
Blood and Lymphatic System
Disorders
Anemias NEC                                    8                          5 Neutropenias                                   4                          3 Ear and Labyrinth Disorders
Ear disorders NEC                              3                          2 Gastrointestinal Disorders
Flatulence, bloating, and distention          10                          7 Gastrointestinal atonic and                    9                          5 hypomotility disorders NEC
Gastrointestinal signs and                     3                          2 symptoms NEC
General Disorders and
Administration Site Conditions
Body temperature perception                    3                          1 Infections and Infestations
Upper respiratory tract infection             32                         30 Bronchitis                                    13                          9 Herpes infection                               7                          6 Bacterial infections NEC                       6                          3 Herpes zoster/varicella                        5                          4 Tinea infections                               4                          3 Lower respiratory tract and lung               3                          2 infections
Neisseria infections                           3                          0 Viral infections NEC                           3                          2 Musculoskeletal and Connective
Tissue Disorders
Joint-related signs and symptoms               6                          5 Nervous System Disorders
Paresthesias and dysesthesias                  4                          3 
Memory loss (excluding dementia)                3                           1 Renal and Urinary Disorders
Bladder and urethral symptoms                   4                           3 Reproductive System and Breast
Disorders
Erection and ejaculation conditions             3                           2 and disorders
Respiratory, Thoracic, and
Mediastinal Disorders
Upper respiratory tract signs and               9                           5 symptoms
Skin and Subcutaneous Disorders
Nail and nail bed conditions                    6                           2 (excluding infections and infestations)
Lipodystrophies                                 4                           3 Acnes                                           3                           2 Alopecias                                       2                           1 
Laboratory Abnormalities:

Table 6. Maximum Shift in Laboratory Test Values (without Regard to Baseline) ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) in Trial A4001026 (96 Weeks) CELSENTRI 300 mg                 Efavirenz
Twice Daily +           600 mg Once Daily+
Laboratory                         Lamivudine/Zidovudine Lamivudine/Zidovudine Parameter                                 (n = 353)a                 (n = 350)a Preferred Term          Limit                    %                          % Aspartate              >5.0 x ULN                  4.0                        4.0 aminotransferase
Alanine                >5.0 x ULN                  3.9                        4.0 aminotransferase
Creatine kinase       >10.0 x ULN                  3.9                        4.8 Amylase                >2.0 x ULN                  4.3                        6.0 3
Absolute neutrophil     <750/mm                    5.7                        4.9 count
Hemoglobin              <7.0 g/dL                  2.9                        2.3 ULN = Upper limit of normal.
a n = Total number of subjects evaluable for laboratory abnormalities.

Percentages based on total subjects evaluated for each laboratory parameter. If the same subject in a given treatment group had greater than 1 occurrence of the same abnormality, only the most severe is counted.
Less Common Adverse Events in Clinical Trials: The following adverse events occurred in less than 2% of subjects treated with CELSENTRI or at a rate similar to the comparator. These events have been included because of their seriousness and either increased frequency on CELSENTRI or are potential risks due to the mechanism of action. Events attributed to the subjects’ underlying HIV-1 infection are not listed.
Blood and Lymphatic System: Marrow depression and hypoplastic anemia.
Cardiac Disorders: Unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, myocardial ischemia.
Hepatobiliary Disorders: Hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein thrombosis, jaundice.
Infections and Infestations: Endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis.
Musculoskeletal and Connective Tissue Disorders: Myositis, osteonecrosis, rhabdomyolysis, blood CK increased.
Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps): Abdominal neoplasm, anal cancer, basal cell carcinoma, Bowen’s disease, cholangiocarcinoma, diffuse large B-cell lymphoma, lymphoma, metastases to liver, esophageal carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (malignant stage unspecified), anaplastic large cell lymphomas T- and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified.
Nervous System Disorders: Cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital), facial palsy, hemianopia, loss of consciousness, visual field defect.
6.2    Postmarketing Experience
The following adverse events have been identified during post-approval use of CELSENTRI Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and Subcutaneous Tissue Disorders
Stevens-Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il

Additionally, you should also report to GSK Israel (il.safety@gsk.com) 

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