Therapy should be initiated by a physician experienced in the management of HIV infection. Posology ISENTRESS should be used in combination with other active anti-retroviral therapies (ARTs) (see sections 4.4 and 5.1).

The recommended dosage is 400 mg twice daily for adolescents 12 years of age and older, and children 6 through 11 years of age, weighing at least 25 kg. ISENTRESS is also available in a chewable tablet formulation for children 2 through 11 years of age. The maximum dose of the chewable tablet is 300 mg twice daily. Because the formulations are not bioequivalent, do not substitute the chewable tablets for the 400 mg tablet (see section 5.2). The chewable tablets have not been studied in HIV-infected adolescents or adults.

There is limited information regarding the use of raltegravir in older patients (see section 5.2). Therefore ISENTRESS should be used with caution in this population.

No dosage adjustment is required for patients with renal impairment (see section 5.2).

No dosage adjustment is required for patients with mild to moderate hepatic impairment. The safety and efficacy of raltegravir have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Safety and efficacy of raltegravir in children below 2 years of age have not yet been established. No data are available.

ISENTRESS 400 mg tablets can be administered with or without food. It is not recommended to chew, crush or split the 400 mg tablets.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Special warnings and precautions for use

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 (see sections 4.5 and 5.2). 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 (see section 5.1). In treatment naive 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).

The safety and efficacy of raltegravir have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.2 and 5.2). 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.

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.

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. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation: however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Co-administration of ISENTRESS with aluminium and magnesium antacids resulted in reduced raltegravir plasma levels. Co-administration of ISENTRESS with aluminium and/or magnesium antacids is not recommended (see section 4.5).

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 in adults. There are no data to guide co-administration of ISENTRESS with rifampicin in patients below 18 years of age (see section 4.5).

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 (see section 4.8).

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking ISENTRESS, in most cases concomitantly with other medicinal products 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 oedema, 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 ISENTRESS (see section 4.8). Depression, including suicidal ideation and behaviours, has been reported, particularly in patients with a pre-existing history of depression or psychiatric illness. Caution should be used in patients with a pre-existing history of depression or psychiatric illness.

ISENTRESS film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interaction with other medicinal products and other forms of interaction

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.

In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, midazolam or boceprevir. In some studies, co-administration of ISENTRESS with darunavir resulted in a modest decrease in darunavir plasma concentrations; the mechanism for this effect is unknown. However, the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically meaningful.

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 in adults. There are no data to guide co-administration of ISENTRESS with rifampicin in patients below 18 years of age (see section 4.4). 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. Co-administration of ISENTRESS with antacids containing divalent metal cations may reduce raltegravir absorption by chelation, resulting in a decrease of raltegravir plasma levels. Taking an aluminium and magnesium antacid within 2 hours of ISENTRESS administration significantly decreased raltegravir plasma levels. Therefore, co-administration of ISENTRESS with aluminium and/or magnesium containing antacids is not recommended. Co-administration of ISENTRESS with a calcium carbonate antacid decreased raltegravir plasma levels; however, this interaction is not considered clinically meaningful. Therefore, when ISENTRESS is co-administered with calcium carbonate containing antacids no dose adjustment is required. Co-administration of ISENTRESS with other agents that increase gastric pH (e.g., omeprazole and famotidine) may increase the rate of raltegravir absorption and result in increased plasma levels of raltegravir (see Table 1). Safety profiles in the subgroup of patients in Phase III trials taking proton pump inhibitors or H2 antagonists were comparable with those who were not taking these antacids. Therefore no dose adjustment is required with use of proton pump inhibitors or H2 antagonists. All interaction studies were performed in adults.

Table 1 Pharmacokinetic Interaction Data

Fertility, pregnancy and lactation

There are no adequate data from the use of raltegravir in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. ISENTRESS should not be used during pregnancy.

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. As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus.

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. As a general rule, it is recommended that mothers infected by HIV do not breast-feed their babies in order to avoid transmission of HIV.

No effect on fertility was seen in male and female rats at doses up to 600 mg/kg/day which resulted in 3-fold exposure above the exposure at the recommended human dose.

Effects on ability to drive and use machines

No studies have been performed on the effects of raltegravir on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing ISENTRESS, which may influence some patients' ability to drive and use machines (see section 4.8).

Undesirable effects

Summary of the safety profile

The safety profile of ISENTRESS was based on the pooled safety data from two Phase III clinical studies in treatment-experienced adult patients and one Phase III clinical study in treatment-naive adult patients as described below. In treatment-experienced patients, the two randomised clinical studies used the recommended dose of 400 mg twice daily in combination with optimised background therapy (OBT) in 462 patients, in comparison to 237 patients taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 708 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 244 patient-years in the group receiving placebo. In treatment-naive patients, the multi-centre, randomised, double-blind, active-controlled clinical study used the recommended dose of 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 245 mg in 281 patients, in comparison to 282 patients taking efavirenz (EFV) 600 mg (at bedtime) in combination with emtricitabine (+) tenofovir. During double- blind treatment, the total follow-up was 1104 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 1036 patient-years in the group receiving efavirenz 600 mg at bedtime. In the pooled analysis of treatment-experienced patients, the rates of discontinuation of therapy due to adverse reactions were 3.9% in patients receiving ISENTRESS + OBT and 4.6% in patients receiving placebo + OBT. The rates of discontinuation of therapy in naive patients due to adverse reactions were 5.0% in patients receiving ISENTRESS + emtricitabine (+) tenofovir and 10.0% in patients receiving efavirenz + emtricitabine (+) tenofovir.

Tabulated summary of adverse reactions

Adverse reactions considered by investigators to be causally related to ISENTRESS (alone or in combination with other ART) are listed below by System Organ Class. 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 Class	Frequency	Adverse reactions ISENTRESS (alone or in combination with other ART)
Infections and infestations	uncommon	genital herpes, folliculitis, gastroenteritis, herpes simplex, herpes virus infection, herpes zoster, influenza, lymph node abscess, molluscum contagiosum, nasopharyngitis, upper respiratory tract infection
Neoplasms benign, malignant and unspecified (including cysts and polyps)	uncommon	skin papilloma
Blood and lymphatic system disorders	uncommon	anaemia, iron deficiency anaemia, lymph node pain, lymphadenopathy, neutropenia, thrombocytopenia
Immune system disorders	uncommon	immune reconstitution syndrome, drug hypersensitivity, hypersensitivity
Metabolism and nutrition disorders	common	decreased appetite
	uncommon	cachexia, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperphagia, increased appetite, polydipsia, body fat disorder
Psychiatric disorders	common	abnormal dreams, insomnia, nightmare, abnormal behaviour SS , depression
	uncommon	mental disorder, suicide attempt, anxiety, confusional state, depressed mood, major depression, middle insomnia, mood altered, panic attack, sleep disorder, suicidal ideation, suicidal behaviour (particularly in patients with a pre-existing history of psychiatric illness)
Nervous system disorders	common uncommon	dizziness, headache, psychomotor hyperactivity SS amnesia, carpal tunnel syndrome, cognitive disorder, disturbance in attention, dizziness postural, dysgeusia, hypersomnia, hypoaesthesia, lethargy, memory impairment, migraine, neuropathy peripheral, paraesthesia, somnolence, tension headache, tremor, poor quality sleep
Eye disorders	uncommon	visual impairment
Ear and labyrinth disorders	common uncommon	vertigo tinnitus
Cardiac disorders	uncommon	palpitations, sinus bradycardia, ventricular extrasystoles
Vascular disorders	uncommon	hot flush, hypertension
Respiratory, thoracic and mediastinal disorders	uncommon	dysphonia, epistaxis, nasal congestion
System Organ Class	Frequency	Adverse reactions ISENTRESS (alone or in combination with other ART)
Gastrointestinal disorders	common uncommon	abdominal distention, abdominal pain, diarrhoea, flatulence, nausea, vomiting, dyspepsia gastritis, abdominal discomfort, abdominal pain upper, abdominal tenderness, anorectal discomfort, constipation, dry mouth, epigastric discomfort, erosive duodenitis, eructation, gastrooesophageal reflux disease, gingivitis, glossitis, odynophagia, pancreatitis acute, peptic ulcer, rectal haemorrahage
Hepato-biliary disorders	uncommon	hepatitis, hepatic steatosis, hepatitis alcoholic, hepatic failure
Skin and subcutaneous tissue disorders	common uncommon	rash acne, alopecia, dermatitis acneiforme, dry skin, erythema, facial wasting, hyperhidrosis, lipoatrophy, lipodystrophy acquired, lipohypertrophy, night sweats, prurigo, pruritus, pruritus generalised, rash macular, rash maculo- papular, rash pruritic, skin lesion, urticaria, xeroderma, Stevens Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders	uncommon	arthralgia, arthritis, back pain, flank pain, musculoskeletal pain, myalgia, neck pain, osteopenia, pain in extremity, tendonitis, rhabdomyolysis
Renal and urinary disorders	uncommon	renal failure, nephritis, nephrolithiasis, nocturia, renal cyst, renal impairment, tubulointerstitial nephritis
Reproductive system and breast disorders	uncommon	erectile dysfunction, gynaecomastia, menopausal symptoms
General disorders and administration site conditions	common uncommon	asthenia, fatigue, pyrexia chest discomfort, chills, face oedema, fat tissue increased, feeling jittery, malaise, submandibular mass, oedema peripheral, pain
System Organ Class	Frequency	Adverse reactions ISENTRESS (alone or in combination with other ART)
Investigations	common uncommon	alanine aminotransferase increased, atypical lymphocytes, aspartate aminotransferase increased, blood triglycerides increased, lipase increased, blood pancreatic amylase increased absolute neutrophil count decreased, alkaline phosphatase increased, blood albumin decreased, blood amylase increased, blood bilirubin increased, blood cholesterol increased, blood creatinine increased, blood glucose increased, blood urea nitrogen increased, creatine phosphokinase increased, fasting blood glucose increased, glucose urine present, high density lipoprotein increased, international normalised ratio increased, low density lipoprotein increased, platelet count decreased, red blood cells urine positive, waist circumference increased, weight increased, white blood cell count decreased
Injury, poisoning and procedural complications	uncommon	accidental overdose
SS One paediatric patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity and abnormal behaviour, this patient also had insomnia.

Description of selected adverse reactions

Cancers were reported in treatment-experienced and treatment-naive 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 (see section 4.4). 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 (see section 4.4). In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4). For each of the following clinical adverse reactions there was at least one serious occurrence: genital herpes, anaemia, immune reconstitution syndrome, depression, mental disorder, suicide attempt, gastritis, hepatitis, renal failure, accidental overdose. In clinical studies of treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing ISENTRESS + darunavir compared to those containing ISENTRESS without darunavir or darunavir without ISENTRESS. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4).

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-naive 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 enrol 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 240-weeks, in treatment-naive patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 22 %, 44 % and 17 %, respectively, of co-infected subjects treated with ISENTRESS as compared to 13 %, 13 % and 5 % of all other subjects treated with ISENTRESS. The following adverse reactions were identified through post-marketing surveillance but not reported as drug-related in randomised controlled Phase III clinical trials (Protocols 018, 019, and 021): thrombocytopenia, suicidal ideation, suicidal behaviour (particularly in patients with a pre-existing history of psychiatric illness), hepatic failure, Stevens Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), rhabdomyolysis.

Paediatric population

Raltegravir has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 through 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066 (see sections 5.1 and 5.2). Of the 126 patients, 96 received the recommended dose of ISENTRESS. In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through Week 48 were comparable to those observed in adults. One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behaviour and insomnia; one patient experienced a Grade 2 serious drug related allergic rash. One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious.

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 the national reporting system listed in Appendix V.

Overdose

No specific information is available on the treatment of overdosage 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 raltegravir may be dialysable is unknown.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, other antivirals, ATC code: J05AX08. Mechanism of action Raltegravir is an integrase strand transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1). Raltegravir inhibits the catalytic activity of integrase, an HIV-encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of the HIV genome into the host cell genome. HIV genomes that fail to integrate cannot direct the production of new infectious viral particles, so inhibiting integration prevents propagation of the viral infection.

Raltegravir at concentrations of 31 +- 20 nM resulted in 95 % inhibition (IC95) of HIV-1 replication (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir inhibited viral replication in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates from 5 non-B subtypes, and isolates resistant to reverse transcriptase inhibitors and protease inhibitors. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV isolates representing 5 non-B subtypes and 5 circulating recombinant forms with IC50 values ranging from 5 to 12 nM.

Most viruses isolated from patients failing raltegravir had high-level raltegravir resistance resulting from the appearance of two or more mutations. Most had a signature mutation at amino acid 155 (N155 changed to H), amino acid 148 (Q148 changed to H, K, or R), or amino acid 143 (Y143 changed to H, C, or R), along with one or more additional integrase mutations (e.g., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, S230R). The signature mutations decrease viral susceptibility to raltegravir and addition of other mutations results in a further decrease in raltegravir susceptibility. Factors that reduced the likelihood of developing resistance included lower baseline viral load and use of other active anti-retroviral agents. Preliminary data indicate that there is potential for at least some degree of cross-resistance to occur between raltegravir and other integrase inhibitors.

The evidence of efficacy of ISENTRESS is based on the analyses of 96-week data from two ongoing, randomised, double-blind, placebo-controlled trials, (BENCHMRK 1 and BENCHMRK 2, Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult patients and the analysis of 240-week data from an ongoing, randomised, double-blind, active-control trial, (STARTMRK, Protocol 021) in antiretroviral treatment-naive HIV-1 infected adult patients.

BENCHMRK 1 and BENCHMRK 2 (ongoing multi-centre, randomised, double-blind, placebo- controlled trials) evaluate the safety and anti-retroviral activity of ISENTRESS 400 mg twice daily vs. placebo in a combination with optimized background therapy (OBT), in HIV-infected patients, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NRTIs, NNRTIs, PIs) of anti-retroviral therapies. Prior to randomization, OBT were selected by the investigator based on the patient's prior treatment history, as well as baseline genotypic and phenotypic viral resistance testing. Patient demographics (gender, age and race) and baseline characteristics were comparable between the groups receiving ISENTRESS 400 mg twice daily and placebo. Patients had prior exposure to a median of 12 anti-retrovirals for a median of 10 years. A median of 4 ARTs was used in OBT.

Durable outcomes (Week 48 and Week 96) for patients on the recommended dose ISENTRESS 400 mg twice daily from the pooled studies BENCHMRK 1 and BENCHMRK 2 are shown in Table 2.

Table 2

Efficacy Outcome at Weeks 48 and 96

Raltegravir achieved virologic responses (using Not Completer=Failure approach) of HIV RNA < 50 copies/ml in 61.7 % of patients at Week 16, in 62.1 % at Week 48 and in 57.0 % at Week 96. Some patients experienced viral rebound between Week 16 and Week 96. Factors associated with failure include high baseline viral load and OBT that did not include at least one potent active agent.

The SWITCHMRK 1 & 2 (Protocols 032 & 033) studies evaluated HIV-infected patients receiving suppressive (screening HIV RNA < 50 copies/ml; stable regimen > 3 months) therapy with lopinavir 200 mg (+) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors and randomized them 1:1 to continue lopinavir (+) ritonavir 2 tablets twice daily (n=174 and n=178, respectively) or replace lopinavir (+) ritonavir with raltegravir 400 mg twice daily (n=174 and n=176, respectively). Patients with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited. These studies were terminated after the primary efficacy analysis at Week 24 because they failed to demonstrate non-inferiority of raltegravir versus lopinavir (+) ritonavir. In both studies at Week 24, suppression of HIV RNA to less than 50 copies/ml was maintained in 84.4 % of the raltegravir group versus 90.6 % of the lopinavir (+) ritonavir group, (Non-completers = Failure). See section 4.4 regarding the need to administer raltegravir with two other active agents.

STARTMRK (ongoing multi-centre, randomised, double-blind, active-control trial) evaluates the safety and anti-retroviral activity of ISENTRESS 400 mg twice daily vs. efavirenz 600 mg at bedtime, in a combination with emtricitabine (+) tenofovir, in treatment-naive HIV-infected patients with HIV RNA > 5,000 copies/ml. Randomization was stratified by screening HIV RNA level (<=50,000 copies/ml; and > 50,000 copies/ml) and by hepatitis B or C status (positive or negative). Patient demographics (gender, age and race) and baseline characteristics were comparable between the group receiving ISENTRESS 400 mg twice daily and the group receiving efavirenz 600 mg at bedtime.

With respect to the primary efficacy endpoint, the proportion (%) of patients achieving HIV RNA < 50 copies/ml at Week 48 was 241/280 (86.1 %) in the group receiving ISENTRESS and 230/281 (81.9 %) in the group receiving efavirenz. The treatment difference (ISENTRESS - efavirenz) was 4.2 % with an associated 95 % CI of (-1.9, 10.3) establishing that ISENTRESS is non-inferior to efavirenz (p-value for non-inferiority < 0.001). At Week 240, the treatment difference (ISENTRESS - efavirenz) was 9.5 % with an associated 95 % CI of (1.7, 17.3). Week 48 and Week 240 outcomes for patients on the recommended dose of ISENTRESS 400 mg twice daily from STARTMRK are shown in Table 3.

Table 3

Efficacy Outcome at Weeks 48 and 240

IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled 126 treatment experienced children and adolescents 2 through 18 years of age. Patients were stratified by age, enrolling adolescents first and then successively younger children. Patients received either the 400 mg tablet formulation (6 through 18 years of age) or the chewable tablet formulation (2 through 11 years of age). Raltegravir was administered with an optimized background regimen. The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based upon achieving similar raltegravir plasma exposure and trough concentration as seen in adults, and acceptable short term safety. After dose selection, additional patients were enrolled for evaluation of long term safety, tolerability and efficacy. Of the 126 patients, 96 received the recommended dose of ISENTRESS (see section 4.2).

Table 4

Baseline Characteristics and Efficacy Outcomes at Weeks 24 and 48 from IMPAACT P1066

The European Medicines Agency has deferred the obligation to submit the results of studies with ISENTRESS in one or more subsets of the paediatric population in Human Immunodeficiency virus infection (see section 4.2 for information on paediatric use).

Pharmacokinetic properties

As demonstrated in healthy volunteers administered single oral doses of raltegravir in the fasted state, raltegravir is rapidly absorbed with a tmax of approximately 3 hours postdose. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1,600 mg. Raltegravir C12 hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1,600 mg. Dose proportionality has not been established in patients. With twice-daily dosing, pharmacokinetic steady state is achieved rapidly, within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax and evidence of slight accumulation in C12 hr. The absolute bioavailability of raltegravir has not been established. ISENTRESS may be administered with or without food. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-infected patients. Administration of multiple doses of raltegravir following a moderate-fat meal did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13 % relative to fasting. Raltegravir C12 hr was 66 % higher and Cmax was 5 % higher following a moderate-fat meal compared to fasting. Administration of raltegravir following a high-fat meal increased AUC and Cmax by approximately 2-fold and increased C12 hr by 4.1-fold. Administration of raltegravir following a low-fat meal decreased AUC and Cmax by 46 % and 52 %, respectively; C12 hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting. Overall, considerable variability was observed in the pharmacokinetics of raltegravir. For observed C12 hr in BENCHMRK 1 and 2 the coefficient of variation (CV) for inter-subject variability = 212 % and the CV for intra-subject variability = 122 %. Sources of variability may include differences in co-administration with food and concomitant medications.

Raltegravir is approximately 83 % bound to human plasma protein over the concentration range of 2 to 10 uM. Raltegravir readily crossed the placenta in rats, but did not penetrate the brain to any appreciable extent. In two studies of HIV-1 infected patients who received raltegravir 400 mg twice daily, raltegravir was readily detected in the cerebrospinal fluid. In the first study (n=18), the median cerebrospinal fluid concentration was 5.8 % (range 1 to 53.5 %) of the corresponding plasma concentration. In the second study (n=16), the median cerebrospinal fluid concentration was 3 % (range 1 to 61 %) of the corresponding plasma concentration. These median proportions are approximately 3- to 6-fold lower than the free fraction of raltegravir in plasma.

The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter a-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32 % of the dose was excreted in faeces and urine, respectively. In faeces, only raltegravir was present, most of which is likely to be derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23 % of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70 % of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.

In a comparison of 30 subjects with *28/ *28 genotype to 27 subjects with wild-type genotype, the geometric mean ratio (90 % CI) of AUC was 1.41 (0.96, 2.09) and the geometric mean ratio of C12 hr was 1.91 (1.43, 2.55). Dose adjustment is not considered necessary in subjects with reduced UGT1A1 activity due to genetic polymorphism.

Based on a formulation comparison study in healthy adult volunteers, the chewable tablet has higher oral bioavailability compared to the 400 mg tablet. In this study, administration of the chewable tablet with a high fat meal led to an average 6 % decrease in AUC, 62 % decrease in Cmax, and 188 % increase in C12hr compared to administration in the fasted state. Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food. Table 5 displays pharmacokinetic parameters in the 400 mg tablet (6 through 18 years of age) and the chewable tablet (2 through 11 years of age).

Table 5: Raltegravir Pharmacokinetic Parameters IMPAACT P1066 Following Administration of Doses in Section 4.2

The pharmacokinetics of raltegravir in children under 2 years of age has not been established.

There was no clinically meaningful effect of age on raltegravir pharmacokinetics over the age range studied (19 to 71 years, with few (8) subjects over the age of 65).

There were no clinically important pharmacokinetic differences due to gender, race or body mass index (BMI) in adults.

Renal clearance of unchanged medicinal product is a minor pathway of elimination. In adults, there were no clinically important pharmacokinetic differences between patients with severe renal insufficiency and healthy subjects (see section 4.2). Because the extent to which raltegravir may be dialysable is unknown, dosing before a dialysis session should be avoided.

Raltegravir is eliminated primarily by glucuronidation in the liver. In adults, there were no clinically important pharmacokinetic differences between patients with moderate hepatic insufficiency and healthy subjects. The effect of severe hepatic insufficiency on the pharmacokinetics of raltegravir has not been studied (see sections 4.2 and 4.4).

Preclinical safety data

Non-clinical toxicology studies, including conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, developmental toxicity and juvenile toxicity, have been conducted with raltegravir, in mice, rats, dogs and rabbits. Effects at exposure levels sufficiently in excess of clinical exposure levels indicate no special hazard for humans.

No evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage and in vitro and in vivo chromosomal aberration studies.

A carcinogenicity study of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was similar to that at the clinical dose of 400 mg twice daily. In rats, tumours (squamous cell carcinoma) of the nose/nasopharynx were identified at 300 and 600 mg/kg/day in females and at 300 mg/kg/day in males. These neoplasia could result from local deposition and/or aspiration of drug on the mucosa of the nose/nasopharynx during oral gavage dosing and subsequent chronic irritation and inflammation; it is likely that they are of limited relevance for the intended clinical use. At the NOAEL, systemic exposure was similar to that at the clinical dose of 400 mg twice daily. Standard genotoxicity studies to evaluate mutagenicity and clastogenicity were negative.

Raltegravir was not teratogenic in developmental toxicity studies in rats and rabbits. A slight increase in incidence of supernumerary ribs was observed in rat pups of dams exposed to raltegravir at approximately 4.4-fold human exposure at 400 mg twice daily based on AUC0-24 hr. No development effects were seen at 3.4-fold human exposure at 400 mg twice daily based on AUC0-24 hr (see section 4.6). Similar findings were not observed in rabbits.

PHARMACEUTICAL PARTICULARS

List of excipients

Polyvinyl alcohol Titanium dioxide (E171) Polyethylene glycol 3350 Talc Red iron oxide (E172) Black iron oxide (E172)

Incompatibilities

Shelf life

Special precautions for storage

Nature and contents of container

High density polyethylene (HDPE) bottle with a child-resistant polypropylene closure. Two pack sizes are available: 1 bottle with 60 tablets, and 3 bottles of 60 tablets. Not all pack sizes may be marketed.

Special precautions for disposal

MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited Hertford Road, Hoddesdon Hertfordshire EN11 9BU United Kingdom

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 December 2007 Date of latest renewal: 20 December 2008

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Medicinal products by therapeutic area	Interaction (mechanism, if known)	Recommendations concerning co-administration
ANTI-RETROVIRAL
Protease inhibitors (PI)
atazanavir /ritonavir (raltegravir 400 mg Twice Daily)	raltegravir AUC \| 41 % raltegravir C 1 2hr \| 77 % raltegravir C m ax \| 24 % (UGT1A1 inhibition)	No dose adjustment required for ISENTRESS.
tipranavir /ritonavir (raltegravir 400 mg Twice Daily)	raltegravir AUC \| 24 % raltegravir C 1 2hr \| 55 % raltegravir C m ax \| 18 % (UGT1A1 induction)	No dose adjustment required for ISENTRESS.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
efavirenz (raltegravir 400 mg Single Dose)	raltegravir AUC \| 36 % raltegravir C 1 2hr \| 21 % raltegravir C m ax \| 36 % (UGT1A1 induction)	No dose adjustment required for ISENTRESS.
etravirine (raltegravir 400 mg Twice Daily)	raltegravir AUC \| 10 % raltegravir C 1 2hr \| 34 % raltegravir C m ax \| 11 % (UGT1A1 induction) etravirine AUC \| 10 % etravirine C 12 hr \| 17 % etravirine C m ax \| 4 %	No dose adjustment required for ISENTRESS or etravirine.
Nucleoside/tide reverse transcriptase inhibitors
tenofovir (raltegravir 400 mg Twice Daily)	raltegravir AUC \| 49 % raltegravir C 1 2hr \| 3 % raltegravir C m ax \| 64 % (mechanism of interaction unknown) tenofovir AUC \| 10 % tenofovir C 2 4hr \| 13 % tenofovir C m ax \| 23 %	No dose adjustment required for ISENTRESS or tenofovir disoproxil fumarate.
Medicinal products by therapeutic area	Interaction (mechanism, if known)	Recommendations concerning co-administration
CCR5 inhibitors
maraviroc (raltegravir 400 mg Twice Daily)	raltegravir AUC \| 37 % raltegravir C 1 2hr \| 28 % raltegravir C m ax \| 33 % (mechanism of interaction unknown) maraviroc AUC \| 14 % maraviroc C 12hr \| 10 % maraviroc C m ax \| 21 %	No dose adjustment required for ISENTRESS or maraviroc.
HCV ANTIVIRALS
NS3/4A protease inhibitors (PI)
boceprevir (raltegravir 400 mg Single Dose)	raltegravir AUC \| 4 % raltegravir C 1 2hr \| 25 % raltegravir C m ax \| 11 % (mechanism of interaction unknown)	No dose adjustment required for ISENTRESS or boceprevir.
ANTIMICROBIALS
Antimycobacterial
rifampicin (raltegravir 400 mg Single Dose)	raltegravir AUC \| 40 % raltegravir C 1 2hr \| 61 % raltegravir C m ax \| 38 % (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 (see section 4.4).
SEDATIVE
midazolam ( raltegravir 400 mg Twice Daily)	midazolam AUC \| 8 % midazolam C m ax \| 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.
Medicinal products by therapeutic area	Interaction (mechanism, if known)	Recommendations concerning co-administration
METAL CATION ANTACIDS
aluminium and magnesium hydroxide antacid (raltegravir 400 mg Twice Daily)	raltegravir AUC \| 49 % raltegravir C 12 hr \| 63 % raltegravir C m ax \| 44 % 2 hours before raltegravir raltegravir AUC \| 51 % raltegravir C 12 hr \| 56 % raltegravir C m ax \| 51 % 2 hours after raltegravir raltegravir AUC \| 30 % raltegravir C 12 hr \| 57 % raltegravir C m ax \| 24 % (chelation of metal cations)	Aluminium and magnesium containing antacids reduce raltegravir plasma levels. Co- administration of ISENTRESS with aluminium and/or magnesium containing antacids is not recommended.
calcium carbonate antacid (raltegravir 400 mg Twice Daily)	raltegravir AUC \| 55 % raltegravir C 12 hr \| 32 % raltegravir C m ax \| 52 % (chelation of metal cations)	No dose adjustment required for ISENTRESS.
H2 BLOCKERS AND PROTON PUMP INHIBITORS
omeprazole (raltegravir 400 mg Twice Daily)	raltegravir AUC \| 37 % raltegravir C 12 hr \| 24 % raltegravir C m ax \| 51 % (increased solubility)	No dose adjustment required for ISENTRESS.
famotidine (raltegravir 400 mg Twice Daily)	raltegravir AUC \| 44 % raltegravir C 12 hr \| 6 % raltegravir C m ax \| 60 % (increased solubility)	No dose adjustment required for ISENTRESS.
HORMONAL CONTRACEPTIVES
Ethinyl Estradiol Norelgestromin (raltegravir 400 mg Twice Daily)	Ethinyl Estradiol AUC \| 2 % Ethinyl Estradiol C m ax \| 6 % Norelgestromin AUC \| 14 % Norelgestromin C m ax \| 29 %	No dosage adjustment required for ISENTRESS or hormonal contraceptives (estrogen- and/or progesterone-based).
OPIOID ANALGESICS
methadone (raltegravir 400 mg Twice Daily)	methadone AUC - methadone C m ax -	No dose adjustment required for ISENTRESS or methadone.

BENCHMRK 1 and 2 Pooled	48 Weeks ISENTRESS Placebo +		96 Weeks ISENTRESS Placebo + OBT
Parameter	400 mg twice daily + OBT (N = 462)	O B T (N = 237)	400 mg twice daily + OBT (N = 462)	(N = 237)
Percent HIV-RNA < 400 copies/ml (95 % CI)
All patients +	72 (68, 76)	37 (31, 44)	62 (57, 66)	28 (23, 34)
Baseline Characteristic ++
HIV-RNA > 100,000 copies/ml	62 (53, 69)	17 (9, 27)	53 (45, 61)	15 (8, 25)
<= 100,000 copies/ml	82 (77, 86)	49 (41, 58)	74 (69, 79)	39 (31, 47)
CD4-count <= 50 cells/mm 3	61 (53, 69)	21 (13, 32)	51 (42, 60)	14 (7, 24)
> 50 and <= 200 cells/mm 3	80 (73, 85)	44 (33, 55)	70 (62, 77)	36 (25, 48)
> 200 cells/mm 3	83 (76, 89)	51 (39, 63)	78 (70, 85)	42 (30, 55)
Sensitivity score (GSS) SS
0	52 (42, 61)	8 (3, 17)	46 (36, 56)	5 (1, 13)
1	81 (75, 87)	40 (30, 51)	76 (69, 83)	31 (22, 42)
2 and above	84 (77, 89)	65 (52, 76)	71 (63, 78)	56 (43, 69)
Percent HIV-RNA < 50 copies/ml (95 % CI)
All patients +	62 (57, 67)	33 (27, 39)	57 (52, 62)	26 (21, 32)
Baseline Characteristic ++
HIV-RNA > 100,000 copies/ml	48 (40, 56)	16 (8, 26)	47 (39, 55)	13 (7, 23)
<= 100,000 copies/ml	73 (68, 78)	43 (35, 52)	70 (64, 75)	36 (28, 45)
CD4-count <= 50 cells/mm 3	50 (41, 58)	20 (12, 31)	50 (41, 58)	13 (6, 22)
> 50 and <= 200 cells/mm 3	67 (59, 74)	39 (28, 50)	65 (57, 72)	32 (22, 44)
> 200 cells/mm 3	76 (68, 83)	44 (32, 56)	71 (62, 78)	41 (29, 53)
Sensitivity score (GSS) SS
0	45 (35, 54)	3 (0, 11)	41 (32, 51)	5 (1, 13)
1	67 (59, 74)	37 (27, 48)	72 (64, 79)	28 (19, 39)
2 and above	75 (68, 82)	59 (46, 71)	65 (56, 72)	53 (40, 66)
Mean CD4 Cell Change (95 % CI), cells/mm 3
All patients ++	109 ( 98, 121)	45 ( 32, 57)	123 (110, 137)	49 (35, 63)
Baseline Characteristic ++
HIV-RNA > 100,000 copies/ml	126 ( 107, 144)	36 ( 17, 55)	140 (115, 165)	40 (16, 65)
<= 100,000 copies/ml	100 ( 86, 115)	49 ( 33, 65)	114 (98, 131)	53 (36, 70)
CD4-count <= 50 cells/mm 3	121 ( 100, 142)	33 ( 18, 48)	130 (104, 156)	42 (17, 67)
> 50 and <= 200 cells/mm 3	104 ( 88, 119)	47 ( 28, 66)	123 (103, 144)	56 (34, 79)
> 200 cells/mm 3	104 ( 80, 129)	54 ( 24, 84)	117 (90, 143)	48 (23, 73)
Sensitivity score (GSS) SS
0	81 ( 55, 106)	11 ( 4, 26)	97 (70, 124)	15 (-0, 31)
1	113 ( 96, 130)	44 ( 24, 63)	132 (111, 154)	45 (24, 66)

ISENTRESS P arameter 400 mg twice daily + OBT (N = 462)		Placebo + O B T (N = 237)	ISENTRESS 400 mg twice daily + OBT (N = 462)	Placebo + OBT (N = 237)
2 and above	125 ( 105, 144)	76 ( 48, 103)	134 (108, 159)	90 (57, 123)
+ Non-completer is failure imputation: patients who discontinued prematurely are imputed as failure thereafter. Percent of patients with response and associated 95 % confidence interval (CI) are reported. ++ For analysis by prognostic factors, virologic failures were carried forward for percent < 400 and 50 copies/ml. For mean CD4 changes, baseline-carry-forward was used for virologic failures. SS The Genotypic Sensitivity Score (GSS) was defined as the total oral ARTs in the optimised background therapy (OBT) to which a patient's viral isolate showed genotypic sensitivity based upon genotypic resistance test. Enfuvirtide use in OBT in enfuvirtide-naive patients was counted as one active drug in OBT. Similarly, darunavir use in OBT in darunavir-naive patients was counted as one active drug in OBT.

STARTMRK Study	48 Weeks ISENTRESS Efavirenz		240 Weeks ISENTRESS Efavirenz
P arameter 400 mg twice daily (N = 281)		600 mg at bedtime (N = 282)	400 mg twice daily (N = 281)	600 mg at bedtime (N = 282)
Percent HIV-RNA < 50 copies/ml (95 % CI)
All patients +	86 (81, 90)	82 (77, 86)	71 (65, 76)	61 (55, 67)
Baseline Characteristic ++
HIV-RNA > 100,000 copies/ml	91 (85, 95)	89 (83, 94)	70 (62, 77)	65 (56, 72)
<= 100,000 copies/ml	93 (86, 97)	89 (82, 94)	72 (64, 80)	58 (49, 66)
CD4-count <= 50 cells/mm 3	84 (64, 95)	86 (67, 96)	58 (37, 77)	77 (58, 90)
> 50 and <= 200 cells/mm 3	89 (81, 95)	86 (77, 92)	67 (57, 76)	60 (50, 69)
> 200 cells/mm 3	94 (89, 98)	92 (87, 96)	76 (68, 82)	60 (51, 68)
Viral Subtype Clade B	90 (85, 94)	89 (83, 93)	71 (65, 77)	59 (52, 65)
Non-Clade B	96 (87, 100)	91 (78, 97)	68 (54, 79)	70 (54, 82)
Mean CD4 Cell Change (95 % CI), cells/mm 3
All patients ++	189 (174, 204)	163 (148, 178)	374 (345, 403)	312 (284, 339)
Baseline Characteristic ++
HIV-RNA > 100,000 copies/ml	196 (174, 219)	192 (169, 214)	392 (350, 435)	329 (293, 364)
<= 100,000 copies/ml	180 (160, 200)	134 (115, 153)	350 (312, 388)	294 (251, 337)
CD4-count <= 50 cells/mm 3	170 (122, 218)	152 (123, 180)	304 (209, 399)	314 (242, 386)
> 50 and <= 200 cells/mm 3	193 (169, 217)	175 (151, 198)	413 (360, 465)	306 (264, 348)
> 200 cells/mm 3	190 (168, 212)	157 (134, 181)	358 (321, 395)	316 (272, 359)
Viral Subtype Clade B	187 (170, 204)	164 (147, 181)	380 (346, 414)	303 (272, 333)
Non-Clade B	189 (153, 225)	156 (121, 190)	332 (275, 388)	329 (260, 398)
+ Non-completer is failure imputation: patients who discontinued prematurely are imputed as failure thereafter. Percent of patients with response and associated 95 % confidence interval (CI) are reported. ++ For analysis by prognostic factors, virologic failures were carried forward for percent < 50 and 400 copies/ml. For mean CD4 changes, baseline-carry-forward was used for virologic failures. Notes: The analysis is based on all available data. ISENTRESS and efavirenz were administered with emtricitabine (+) tenofovir.

Parameter	Final Dose Population
N=96
Demographics
Age (years), median [range]			13 [2 - 18]
Male Gender				49 %
Race
Caucasian				34 %
Black				59 %
Baseline Characteristics
Plasma HIV-1 RNA (log 10 copies/ml), mean [range]			4.3 [2.7 - 6)]
CD4 cell count (cells/mm 3 ), median [range]		481 [0 - 2361]
CD4 percent, median [range]		23.3 % [0 - 44]
HIV-1 RNA >100,000 copies/ml				8 %
CDC HIV category B or C				59 %
Prior ART Use by Class
NNRTI				78 %
PI				83 %
Response	Week 24			Week 48
Achieved >=1 log 10 HIV RNA drop from baseline or <400 copies/mL	72 %			79 %
Achieved HIV RNA <50 copies/mL	54 %			57 %
Mean CD4 cell count (%) increase from baseline	119 cells/mm 3 (3.8 %)			156 cells/mm 3 (4.6 %)

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

PHARMACEUTICAL FORM

CLINICAL PARTICULARS

Therapeutic indications

Posology and method of administration