Celsentri

/ GSK

Dose Recommendations for Patients With Normal Renal Function: The recommended dose differs based on concomitant medications due to drug interactions. This product can be taken with or without food. it must be given in combination with other antiretroviral medications.
For full details see prescribing information.

In combination with other antiretroviral medicdbinal products, for treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable.

Hypersensitivity to the active substance or to peanut or soy or to any of the excipients.

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. 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  and at other timepoints 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 should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms. Caution should be used when administering to patients with pre-existing liver dysfunction or who are co-infected with viral hepatitis B or C. The safety and efficacy  have not been specifically studied in patients with significant underlying liver disorders. In trials of treatment-experienced HIV-1-infected subjects, approximately 6% of subjects were co-infected with hepatitis B and approximately 6% were co-infected with hepatitis C. Due to the small number of co-infected subjects studied, no conclusions can be drawn regarding whether they are at an increased risk for hepatic adverse events with administration of CELSENTRI.
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). 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.
Cardiovascular Events: Use with caution in patients at increased risk for 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 once daily + 309 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, and the relative contribution of CELSENTRI to these events is not known. In the Phase 2b/3 trial in treatment-naive subjects, 3 subjects (0.8%) who received this product had events related to ischemic heart diseases and 5 subjects (1.4%) who received
efavirenz had such events (total exposure 506 and 508 patient-years and efavirenz, respectively). When it 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 it was given at the recommended dose in HIV-1-infected subjects in Phase 3 trials, postural hypotension was seen at a rate similar to placebo (approximately 0.5%). Caution should be used when administering in patients with a history of or risk factors for postural hypotension, cardiovascular comorbidities, or on concomitant medication known to lower blood pressure. Patients with cardiovascular comorbidities could be at increased risk of cardiovascular adverse events triggered by postural hypotension.
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  in these patients should only be considered when no alternative treatment options are available. If 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.
Immune reconstitution syndrome: has been reported in patients treated with combination antiretroviral therapy, including this product. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as infection with Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis, or reactivation of Herpes simplex and Herpes zoster), which may necessitate further evaluation and treatment. Autoimmune disorders (such as 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.
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 treatment-experienced trials of CELSENTRI. While there was a higher rate of certain upper respiratory tract infections reported in the arm receiving compared with placebo (23% versus 13%), there was a lower rate of pneumonia (2% versus 5%) reported in subjects receiving. A higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the arm receiving CELSENTRI when adjusted for exposure compared with placebo (8 per 100 patient-years). In the Phase 2b/3 trial in treatment-naive 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 it.
Potential Risk of Malignancy: While no increase in malignancy has been observed with it, 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 treatment-experienced trials was 4.6 forthis product compared with 9.3 on placebo. In treatment-naive 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.
Soya lecithin: This product contains soya lecithin. If a patient is hypersensitive to peanut or soya,it should not be used. .
Pregnancy and lactation: Should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Mothers should be instructed not to breastfeed if they are receiving therapy because of the potential for HIV transmission as well as any possible undesirable effects in breastfed infants.

Folliculitis, hypertriglyceridemia. Insomnia, abnormal dreams. Neuropathy peripheral, syncope, hypoesthesia, paresthesia, dysgeusia, somnolence. Eye irritation, dry eye. Hot flush. Cough, dysphonea, nasal congestion. Abdominal pain, dyspepsia, gastroesophageal reflux disease, constipation. Rash, lipodystrophy acquired, lipohypertrophy, erythema, alopecia. Muscle spasms, back pain, pain in extremity. Erectile dysfunction. Nocturia. Asthenia. Alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, blood creatine phosphokinase increased, blood triglycerides increased, weight decreased.

Efavirenz, nevirapine, atazanavir, lopinavir, ritonavir, darunavir, saquinavir, darunavir, nelfinavir, indinavir, rifampicin, rifabutin, clarithromycin, telithromycin, antifungals, St. John’s Wort.
See prescribing information for full details.

Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with maraviroc in rats at exposures (AUC) approximately 20-fold higher and in rabbits at approximately 5-fold higher than human exposures at the recommended daily dose (up to 1,000 mg/kg/day in rats and 75 mg/kg/day in rabbits). During the pre- and postnatal development studies in the offspring, development of the offspring, including fertility and reproductive performance, was not affected by the maternal administration of maraviroc.

The highest single dose administered in clinical trials was 1,200 mg. The dose-limiting adverse event was postural hypotension, which was observed at 600 mg. While the recommended dose for CELSENTRI in patients receiving a CYP3A inducer without a CYP3A inhibitor is 600 mg twice daily, this dose is appropriate due to enhanced metabolism.  Prolongation of the QT interval was seen in dogs and monkeys at plasma concentrations 6 and 12 times, respectively, those expected in humans at the intended exposure of 300 mg equivalents twice daily. However, no significant QT prolongation was seen in the trials in treatment-experienced subjects with HIV using the recommended doses of maraviroc or in a specific pharmacokinetic trial to evaluate the potential of maraviroc to prolong the QT interval [see Clinical Pharmacology (12.3)].  There is no specific antidote for overdose with maraviroc. Treatment of overdose should consist of general supportive measures including keeping the patient in a supine position, careful assessment of patient vital signs, blood pressure, and ECG.  If indicated, elimination of unabsorbed active maraviroc should be achieved by emesis. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug.  Hemodialysis had a minimal effect on maraviroc clearance and exposure in a trial in subjects with ESRD.