Drug Class Description
Antiviral for systemic use

Generic Name
Raltegravir

Drug Description
Each film-coated tablet contains 400 mg of raltegravir (as potassium). Excipient: Each tablet contains 26.06 mg lactose monohydrate.

Presentation
Film-coated tablet.Pink, oval tablet, marked with "227" on one side.

Indications
ISENTRESS is indicated in combination with other anti-retroviral medicinal 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.This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials of 48 weeks duration in treatment-experienced patients

Adult Dosage
Therapy should be initiated by a physician experienced in the management of HIV infection. ISENTRESS should be used in combination with other active anti-retroviral therapies (ARTs).PosologyAdultsThe recommended dosage of ISENTRESS 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.ElderlyThere is limited information regarding the use of ISENTRESS in the elderly. Therefore ISENTRESS should be used with caution in this population.Children and adolescentsSafety and efficacy have not been established in patients below 16 years of age.Renal impairmentNo dosage adjustment is required for patients with renal impairment.Hepatic impairmentNo dosage adjustment is required for patients with mild to moderate 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.Method of administrationOral

Child Dosage
Safety and efficacy have not been established in patients below 16 years of age.

Elderly Dosage
There is limited information regarding the use of ISENTRESS in the elderly. Therefore ISENTRESS should be used with caution in this population.

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

Special Precautions
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.Higher response rates were observed in patients with Genotypic Sensitivity Score (GSS)>0. Patients with GSS or Phenotypic Sensitivity Score (PSS)=0 had a higher risk of developing resistance to raltegravir. Raltegravir should be used in combination with at least one other active agent to enhance benefit and to reduce the risk of virologic failure and development of resistance to raltegravir.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 preexisting 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.There are very limited data on the use of raltegravir in patients co-infected with HIV and hepatitis B virus (HBV) or hepatitis C virus (HCV). 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.OsteonecrosisAlthough 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 longterm 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 syndromeIn 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 eva luated 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; however, the relationship of ISENTRESS to these events is not known. 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.During the clinical studies in treatment-experienced HIV-infected patients there was a slightly higher rate of cancer in the raltegravir group compared to the group that received only optimised background therapy. At present there are insufficient data to be able to exclude the possibility that raltegravir might be associated with a risk of cancer.ISENTRESS contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interactions
Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, and does not induce CYP3A4. Raltegravir is not an inhibitor of the UDP-glucuronosyltransferases (UGTs) 1A1 and 2B7, and raltegravir 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.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 tenofovir, hormonal contraceptives, or midazolam.Effect of other agents on the pharmacokinetics of raltegravirGiven 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 metabolising enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, 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 of ISENTRESS 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.Table 1Pharmacokinetic Interaction DataMedicinal products by therapeutic areaInteraction(mechanism, if known)Recommendations concerningco-administrationANTI-RETROVIRAL Protease inhibitors (PI)atazanavir /ritonavir(raltegravir 400 mg BID)raltegravir AUC ↑41%raltegravir C12hr↑77%raltegravir Cmax↑24%(UGT1A1 inhibition)No dose adjustment required for ISENTRESS.tipranavir /ritonavir(raltegravir 400 mg BID)raltegravir AUC 24%raltegravir C12hr55%raltegravir Cmax18%(UGT1A1 induction)No dose adjustment required for ISENTRESS.Non-nucleoside reverse transcriptase inhibitors (NNRTIs)efavirenz(raltegravir 400 mg SD)raltegravir AUC 36%raltegravir C12hr21%raltegravir Cmax36%(UGT1A1 induction)No dose adjustment required for ISENTRESSNucleoside/tide reverse transcriptase inhibitorstenofovir(raltegravir 400 mg BID)raltegravir AUC ↑49%raltegravir C12hr↑3%raltegravir Cmax↑64%(mechanism of interaction unknown)tenofovir AUC 10%tenofovir C12hr13%tenofovir Cmax23%No dose adjustment required for ISENTRESS or tenofovir disoproxil fumarate.ANTIMICROBIALSAntimycobacterialrifampicin(raltegravir 400 mg SD)raltegravir AUC 40%raltegravir C12hr61%raltegravir Cmax38%(UGT1A1 induction)Rifampicin reduces plasma levels of ISENTRESS. If co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered.SEDATIVEmidazolam(raltegravir 400 mg BID)midazolam AUC 8%midazolam Cmax↑3%No dosage adjustment required for ISENTRESS or midazolam.These results indicate that raltegravir is not an inducer or inhibitor of CYP3A4, and raltegravir is thus not anticipated to affect the pharmacokinetics of medicinal products which are CYP3A4 substrates.ANTI-ULCERomeprazole(raltegravir 400 mg SD)raltegravir AUC ↑ 212%raltegravir C12 hr↑ 46%raltegravir Cmax↑ 315%Co-administration of proton pump inhibitors or other antiulcer medicinal products may increase plasma levels of raltegravir.Do not use ISENTRESS with medicinal products that increase gastric pH unless this is unavoidable.HORMONAL CONTRACEPTIVESEthinyl EstradiolNorelgestromin(raltegravir 400 mg BID)Ethinyl Estradiol AUC 2 %Ethinyl Estradiol Cmax↑ 1 %Norelgestromin AUC ↑ 14 %Norelgestromin Cmax↑ 29 %No dosage adjustment required for ISENTRESS or hormonal contraceptives (estrogen- and/or progesterone-based)

Adverse Reactions
Treatment-experienced The safety assessment of ISENTRESS in treatment-experienced patients is based on the pooled safety data from three randomised clinical studies. These studies used the recommended dose of 400mg twice daily in combination with optimised background therapy (OBT) in 507 patients, in comparison to 282 patients taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 504.1 patient-years in the ISENTRESS 400 mg b.i.d. group and 202.5 patient-years in the placebo group.For patients in the ISENTRESS 400 mg twice daily + OBT arm and the comparator placebo + OBT arm, the most commonly reported adverse reactions (>10 % in either group), of all intensities and regardless of causality were: diarrhoea in 17.6 % and 20.6 %, nausea in 11.2 % and 15.2 %, headache in 10.1 % and 12.4 %, pyrexia in 6.3 % and 11.0 % of patients, respectively. In this pooled analysis, the rates of discontinuation of therapy due to adverse reactions were 2.4 % in patients receiving ISENTRESS + OBT and 2.8 % in patients receiving placebo + OBT.Adverse reactions considered by investigators to be causally related to ISENTRESS (alone or in combination with OBT) are listed below by System Organ Class. Any term that includes at least one serious adverse reaction is identified with a dagger (†). Adverse reactions identified from post-marketing experience are included in italics.Frequencies are defined as common ( 1/100 to <1/10), uncommon ( 1/1,000 to <1/100), and not known (cannot be estimated from the available data).System Organ ClassFrequencyAdverse reactionsISENTRESS (alone or in combination with OBT)Infections and infestationsuncommongenital herpes† , folliculitis, herpes simplex, herpes virus infection, herpes zoster, influenza, molluscum contagiosumBlood and lymphatic system disordersuncommoniron deficiency anaemiaImmune system disordersuncommondrug hypersensitivity†Metabolism and nutrition disordersuncommoncentral obesity, decreased appetite, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, increased appetitePsychiatric disorderscommoninsomniauncommonabnormal dreams, anxiety, depression, middle insomnia, sleep disordernot knownsuicidal ideation, suicidal behaviour (particularly in patients with a pre-existing history of psychiatric illness)Nervous system disorderscommondizziness, headacheuncommoncarpal tunnel syndrome, disturbance in attention, dizziness postural, dysgeusia, hypersomnia, hypoaesthesia, lethargy, neuropathy, neuropathy peripheral, paraesthesia, somnolence, tension headache, tremorEye disordersuncommonvisual disturbanceEar and labyrinth disordersuncommonvertigoCardiac disordersuncommonpalpitations, ventricular extrasystolesRespiratory, thoracic and mediastinal disordersuncommondysphonia, epistaxis, nasal congestion, pharyngeal erythemaGastrointestinal disorderscommonabdominal distention, abdominal pain, constipation, diarrhoea, flatulence, nausea, vomitinguncommongastritis† , abdominal discomfort, abdominal pain upper, anal discomfort, dry mouth, dyspepsia, eructation, gastro-oesophageal reflux disease, glossitis, odynophagia, oral pain, pancreatitis acute, peptic ulcer, rectal haemorrhage, stomach discomfortHepato-biliary disordersuncommonhepatitis†Skin and subcutaneous tissue disorderscommonhyperhidrosis, night sweats, pruritus, rashuncommonacne, dermatitis acneiforme, dry skin, erythema, facial wasting, lipoatrophy, lipodystrophy acquired, lipohypertrophy, prurigo, pruritis generalised, rash macular, rash maculo-papular, rash pruritic, xerodermanot knownStevens Johnson syndromeMusculoskeletal and connective tissue disorderscommonarthralgiauncommonback pain, muscle atrophy, musculoskeletal pain, myalgia, myositis, pain in extremity, tendonitisRenal and urinary disordersuncommonrenal failure† , nephritis interstitial, nephrolithiasis, nocturia, pollakiuriaReproductive system and breast disordersuncommonerectile dysfunction, gynaecomastia, menopausal symptomsGeneral disorders and administration site conditionscommonasthenia, fatigueuncommonchest discomfort, chills, face oedema, fat tissue increased, feeling hot, feeling jittery, pyrexia, xerosisInvestigationscommonalanine aminotransferase increased, aspartate aminotransferase increased, blood triglycerides increased, serum creatinine kinase increased, lipase increaseduncommonabsolute neutrophil count decreased, blood amylase increased, blood cholesterol increased, blood creatinine increased, blood glucose increased, blood urea nitrogen increased, fasting blood glucose increased, glucose urine present, high density lipoprotein increased, low density lipoprotein increased, platelet count decreased, red blood cells urine positive, weight increased, white blood cell count decreasedInjury, poisoning and procedural complicationsuncommonaccidental overdose†† includes at least one serious adverse reactionCancers were reported in treatmentexperienced patients who initiated ISENTRESS with OBT; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4 cell counts below 50 cells/mm3 and most had prior AIDS diagnoses). The cancers included Kaposi's sarcoma, lymphoma, squamous cell carcinoma, hepatocellular carcinoma and anal cancer. Most patients had other risk factors for cancer including tobacco use, papillomavirus and active hepatitis B virus infection. It is unknown if these cancer diagnoses were related to ISENTRESS use.Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. 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.-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, patients with chronic active hepatitis B and/or hepatitis C co-infection (N = 113/699 or 16.2%; HBV=6 %, HCV=9 %, HBV+HCV=1%) were permitted to enrol provided that AST, ALT, and alkaline phosphatase 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. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 31%, 31% and 16%, respectively, of raltegravir-treated co-infected subjects as compared to 9%, 8% and 8% of all other raltegravir-treated subjects.

Manufacturer
Merck Sharp & Dohme

Drug Availability
(POM)

Updated
12 August 2009