Isentress

/ MSD

Adults: The recommended dosage is 400 mg administered twice daily with or without food. The effect of food on absorption of raltegravir is uncertain. It is not recommended to chew, crush or split the tablets.
Elderly: There is limited information regarding the use in the elderly. Therefore this product should be used with caution in this population.
Children & adolescents: Safety and efficacy have not been established in patients below 16 years of age.
Renal impairment: No dosage adjustment is required for patients with renal impairment.
Hepatic impairment: No dosage adjustment is required for patients with mild to moderate hepatic impairment. The safety and efficacy  have not been established in patients with severe underlying liver disorders. Therefore this product should be used with caution in patients with severe hepatic impairment.
For full details see prescribing information.

In combination with other anti-retroviral medicdbinal products, for the treatment of human immunodeficiency virus (HIV 1) infection in treatment-experienced adult patients with evidence of HIV 1 replication despite ongoing anti-retroviral therapy.

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

Patients should be advised that current anti-retroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed. Overall, considerable inter- and intra-subject variability was observed in the pharmacokinetics of raltegravir. Raltegravir has a relatively low genetic barrier to resistance. Therefore, whenever possible, raltegravir should be administered with two other active ARTs to minimise the potential for virological failure and the development of resistance. In treatment naïve patients, the clinical study data on use of raltegravir are limited to use in combination with two nucleotide reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovir disoproxil fumarate).
Hepatic impairment: The safety and efficacy of ISENTRESS have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment. Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination anti-retroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.
Patients with chronic hepatitis B or C and treated with combination anti-retroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events.
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination anti-retroviral therapy. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Immune reactivation syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination anti-retroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Caution should be used when co-administering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered.
Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions.
USevere skin and hypersensitivity reactions: Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking ISENTRESS, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction. Rash occurred more commonly in treatment-experienced patients receiving regimens containing ISENTRESS + darunavir compared to patients receiving ISENTRESS without darunavir or darunavir without ISENTRES. Depression, including suicidal ideation and behaviors, has been reported, particularly in patients with a pre-existing history of depression or psychiatric illness. Caution should be used in patients with a preexisting history of depression or psychiatric illness. ISENTRESS contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
See prescribing information for full details.

Cancers were reported in treatment-experienced and treatment-naïve patients who initiated ISENTRESS in conjunction with other antiretroviral agents. The types and rates of specific cancers were those expected in a highly immunodeficient population. The risk of developing cancer in these studies was similar in the groups receiving ISENTRESS and in the groups receiving comparators. Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions. Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown. Patients co-infected with hepatitis B and/or hepatitis C virus In Phase III studies, treatment-experienced patients (N = 114/699 or 16 %; HBV=6 %, HCV=9 %, HBV+HCV=1 %) and treatment-naïve patients (N = 34/563 or 6 %; HBV=4 %, HCV=2 %, HBV+HCV=0.2 %) with chronic (but not acute) active hepatitis B and/or hepatitis C co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal. In general the safety profile of ISENTRESS in patients with hepatitis B and/or hepatitis C virus co-infection was similar to that in patients without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were somewhat higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. At 96-weeks, in treatment-experienced patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29 %, 34 % and 13 %, respectively, of co-infected subjects treated with ISENTRESS as compared to 11 %, 10 % and 9 % of all other subjects treated with ISENTRESS. At 156-weeks, in treatment-naïve patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 17 %, 33 % and 17 %, respectively, of co-infected subjects treated with ISENTRESS as compared to 8 %, 10 % and 5% of all other subjects treated with ISENTRESS.
Paediatric population: The safety and efficacy of ISENTRESS have not been established in pediatric patients.
See prescribing information for full details.

In vitro studies indicate that raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not induce CYP3A4 and does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.
Based on in vitro and in vivo studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway. Although in vitro studies indicated that raltegravir is not an inhibitor of the UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, one clinical study has suggested that some inhibition of UGT1A1 may occur in vivo based on effects observed on bilirubin glucuronidation. However, the magnitude of the effect seems unlikely to result in clinically important drug-drug interactions. Considerable inter- and intra-individual variability was observed in the pharmacokinetics of raltegravir. The following drug interaction information is based on Geometric Mean values; the effect for an individual patient cannot be predicted precisely. Effect of raltegravir on the pharmacokinetics of other medicinal products In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, or midazolam. Effect of other agents on the pharmacokinetics of raltegravir Given that raltegravir is metabolised primarily via UGT1A1, caution should be used when co-administering ISENTRESS with strong inducers of UGT1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered. The impact of other strong inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, glucocorticoids, St. John’s wort, pioglitazone) may be used with the recommended dose of ISENTRESS. Co-administration of ISENTRESS with medicinal products that are known to be potent UGT1A1 inhibitors (e.g., atazanavir) may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors (e.g., indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extent compared with atazanavir. In addition, tenofovir may increase plasma levels of raltegravir, however, the mechanism for this effect is unknown (see Table 1). From the clinical trials, a large proportion of patients used atazanavir and / or tenofovir, both agents that result in increases in raltegravir plasma levels, in the optimised background regimens. The safety profile observed in patients who used atazanavir and / or tenofovir was generally similar to the safety profile of patients who did not use these agents. Therefore no dose adjustment is required. In healthy subjects, co-administration with omeprazole increases raltegravir plasma levels. As the effects of increasing gastric pH on the absorption of raltegravir in HIV-infected patients are uncertain, use ISENTRESS with medicinal products that increase gastric pH (e.g., proton pump inhibitors and H2 antagonists) only if unavoidable.
See prescribing information for full details.

Pregnancy: There are no adequate data from the use of raltegravir in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. ISENTRESS should not be used during pregnancy.
Anti-retroviral Pregnancy Registry: To monitor maternal-foetal outcomes in patients inadvertently administered ISENTRESS while pregnant, an Anti-retroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry.
Lactation: It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. In rats, at a maternal dose of 600 mg/kg/day, mean active substance concentrations in milk were approximately 3-fold greater than in maternal plasma. Breastfeeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-infected mothers should not breastfeed their infants to avoid risking postnatal transmission of HIV.

No specific information is available on the treatment of overdose with ISENTRESS.
In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. It should be taken into account that raltegravir is presented for clinical use as the potassium salt. The extent to which ISENTRESS may be dialysable is unknown.