ISENTRESS 600mg tablets medication leaflet

ISENTRESS 600 mg film-coated tablets

Each film-coated tablet contains 600 mg of raltegravir (as potassium).

Each 600 mg tablet contains 5.72 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Yellow, oval-shaped, dimensions 19.1 mm x 9.7 mm x 6.1 mm, marked with MSD corporate logo and“242” on one side and plain on the other side.

ISENTRESS 600 mg film-coated tablets is indicated in combination with other anti-retroviralmedicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adults,and paediatric patients weighing at least 40 kg (see sections 4.2, pct. 4.4, 5.1 and 5.2).

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) (seesections 4.4 and 5.1).

Adults and paediatric population

In adults and paediatric patients (weighing at least 40 kg), the recommended dosage is 1,200 mg (two600 mg tablets) once daily for treatment-naïve patients or patients who are virologically suppressed onan initial regimen of ISENTRESS 400 mg twice daily.

Additional formulations and strengths available:

ISENTRESS is also available as a 400 mg tablet for twice daily use in HIV infected adults or childrenand adolescents at least 25 kg. The 400 mg tablet should not be used to administer 1,200 mg oncedaily regimen (please refer to the 400 mg Summary of Product Characteristics).

ISENTRESS is also available in a chewable tablet formulation and in granules for oral suspensionformulation. Refer to the chewable tablet and granules for oral suspension SmPCs for additionaldosing information.

The safety and efficacy of raltegravir in preterm (<37 weeks of gestation) and low birth weight(<2,000 g) newborns have not been established. No data are available in this population and no dosingrecommendations can be made.

The maximum dose of the chewable tablet is 300 mg twice daily. Because the formulations havedifferent pharmacokinetic profiles neither the chewable tablets nor the granules for oral suspensionshould be substituted for the 400 mg tablet or the 600 mg tablet (see section 5.2). The chewable tabletsand the granules for oral suspension have not been studied in HIV-infected adolescents (12 to18 years) or adults.

There is limited information regarding the use of raltegravir in the elderly (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 safetyand 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 (seesections 4.4 and 5.2).

ISENTRESS 600 mg film-coated tablet formulation should not be used in children weighing less than40 kg.

Oral use.

ISENTRESS 600 mg tablets can be administered with or without food as a 1,200 mg once daily dose.

The tablets should not be chewed, crushed or split due to anticipated changes in the pharmacokineticprofile.

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

Patients should be advised that current anti-retroviral therapy does not cure HIV and has not beenproven to prevent the transmission of HIV to others through blood contact.

Raltegravir has a relatively low genetic barrier to resistance. Therefore, whenever possible, raltegravirshould be administered with two other active ARTs to minimise the potential for virological failureand the development of resistance (see section 5.1).

In treatment-naïve patients, the clinical study data on use of raltegravir are limited to use incombination with two nucleotide reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovirdisoproxil fumarate).

Depression

Depression, including suicidal ideation and behaviours, has been reported, particularly in patients witha pre-existing history of depression or psychiatric illness. Caution should be used in patients with apre-existing history of depression or psychiatric illness.

The safety and efficacy of raltegravir have not been established in patients with severe underlying liverdisorders. Therefore, raltegravir should be used with caution in patients with severe hepaticimpairment (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency ofliver function abnormalities during combination anti-retroviral therapy and should be monitoredaccording 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 anincreased risk for severe and potentially fatal hepatic adverse reactions.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly in patients with advanced HIV disease and/or long-term exposure to combinationanti-retroviral therapy. Patients should be advised to seek medical advice if they experience joint achesand 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 opportunisticpathogens 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. Relevantexamples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections andpneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Anyinflammatory symptoms should be evaluated and treatment instituted when necessary.

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

Co-administration of raltegravir 1,200 mg once daily with atazanavir resulted in increased raltegravirplasma levels; therefore, co-administration is not recommended (see section 4.5).

Tipranavir/ritonavir

Co-administration of raltegravir 1,200 mg once daily with tipranavir/ritonavir could result in decreasedraltegravir trough plasma levels; therefore, co-administration is not recommended (see section 4.5).

Antacids

Co-administration of raltegravir 1,200 mg once daily with calcium carbonate andaluminium/magnesium containing antacids resulted in reduced raltegravir plasma levels; therefore,co-administration is not recommended (see section 4.5).

Strong inducers of drug metabolizing enzymes

Strong inducers of drug metabolizing enzymes (e.g., rifampicin) have not been studied with raltegravir1,200 mg once daily, but could result in decreased raltegravir trough plasma levels; therefore,co-administration with raltegravir 1,200 mg once daily is not recommended.

Myopathy and rhabdomyolysis

Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have hadmyopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinalproducts associated with these conditions (see section 4.8).

Severe skin and hypersensitivity reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients takingraltegravir, in most cases concomitantly with other medicinal products associated with these reactions.

These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivityreactions have also been reported and were characterised by rash, constitutional findings, andsometimes, organ dysfunction, including hepatic failure. Discontinue raltegravir and other suspectagents 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 appropriatetherapy initiated. Delay in stopping raltegravir treatment or other suspect agents after the onset ofsevere rash may result in a life-threatening reaction.

Rash occurred more commonly in treatment-experienced patients receiving regimens containingraltegravir and darunavir compared to patients receiving raltegravir without darunavir or darunavirwithout raltegravir (see section 4.8).

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

In vitro, raltegravir is a weak inhibitor of organic anion transporter (OAT) 1 (IC50 of 109 µM) and

OAT3 (IC50 of 18.8 µM). Caution is recommended when co-administering raltegravir 1,200 mg oncedaily with sensitive OAT1 and/or OAT3 substrates.

In vitro studies indicate that raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, doesnot inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not inhibit

UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, does not induce CYP3A4 and is not an inhibitorof P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transportingpolypeptides (OATP) 1B1, OATP1B3, organic cation transporters (OCT)1 and OCT2, or multidrugand toxin extrusion proteins (MATE)1 and MATE2-K. Based on these data, raltegravir is not expectedto affect the pharmacokinetics of medicinal products that are substrates of these enzymes ortransporters.

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 ofraltegravir.

Effect of raltegravir on the pharmacokinetics of other medicinal products

In drug interaction studies performed using raltegravir 400 mg twice daily, raltegravir did not have aclinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir disoproxilfumarate, hormonal contraceptives, methadone, midazolam or boceprevir. These findings can beextended to raltegravir 1,200 mg once daily and no dosage adjustment is required for these agents.

In some studies, co-administration of raltegravir 400 mg tablets twice daily with darunavir resulted ina modest but clinically insignificant decrease in darunavir plasma concentrations. Based on themagnitude of effect seen with raltegravir 400 mg tablets twice daily, it is expected that the effect ofraltegravir 1,200 mg once daily on darunavir plasma concentrations is likely to be not clinicallymeaningful.

Effect of other medicinal products on the pharmacokinetics of raltegravir

Inducers of drug metabolizing enzymes

The impact of medicinal products that are strong inducers of UGT1A1 such as rifampicin onraltegravir 1,200 mg once daily is unknown, but co-administration is likely to decrease raltegravirtrough levels based on the reduction in trough concentrations observed with raltegravir 400 mg twicedaily; therefore, co-administration with raltegravir 1,200 mg once daily is not recommended. Theimpact of other strong inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital,on UGT1A1 is unknown; therefore, co-administration with raltegravir 1,200 mg once daily is notrecommended. In drug interaction studies, efavirenz did not have a clinically meaningful effect on thepharmacokinetics of raltegravir 1,200 mg once daily; therefore, other less potent inducers (e.g.,efavirenz, nevirapine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with therecommended dose of raltegravir.

Inhibitors of UGT1A1

Co-administration of atazanavir with raltegravir 1,200 mg once daily significantly increased plasmalevels of raltegravir; therefore, co-administration of raltegravir 1,200 mg once daily and atazanavir isnot recommended.

Antacids

Co-administration of raltegravir 1,200 mg once daily with aluminium/magnesium and calciumcarbonate containing antacids are likely to result in clinically meaningful reductions in the plasmatrough levels of raltegravir. Based on these findings, co-administration of aluminium/magnesium andcalcium carbonate containing antacids with raltegravir 1,200 mg once daily is not recommended.

Agents that increase gastric pH

Population pharmacokinetic analysis from ONCEMRK (Protocol 292) showed that co-administrationof raltegravir 1,200 mg once daily with PPIs or H2 blockers did not result in statistically significantchanges in the pharmacokinetics of raltegravir. Comparable efficacy and safety results were obtainedin the absence or presence of these gastric pH-altering agents. Based on these data, proton pumpinhibitors and H2 blockers may be co-administered with raltegravir 1,200 mg once daily.

Additional considerations

No studies have been conducted to evaluate the drug interactions of ritonavir, tipranavir/ritonavir,boceprevir or etravirine with raltegravir 1,200 mg (2 x 600 mg) once daily. While the magnitudes ofchange on raltegravir exposure from raltegravir 400 mg twice daily by ritonavir, boceprevir oretravirine were small, the impact from tipranavir/ritonavir was greater (GMR Ctrough=0.45, GMR

AUC=0.76). Co-administration of raltegravir 1,200 mg once daily and tipranavir/ritonavir is notrecommended.

Previous studies of raltegravir 400 mg twice daily showed that co-administration of tenofovirdisoproxil fumarate (a component of emtricitabine/tenofovir disoproxil fumarate) increased raltegravirexposure. Emtricitabine/tenofovir disoproxil fumarate was identified to increase raltegravir 1,200 mgonce daily bioavailability by 12%, however its impact is not clinically meaningful. Therefore, co-administration of emtricitabine/tenofovir disoproxil fumarate and raltegravir 1,200 mg once daily ispermitted.

All interaction studies were performed in adults.

Comprehensive drug interaction studies were performed with raltegravir 400 mg twice daily and alimited number of drug interaction studies were performed for raltegravir 1,200 mg once daily.

Table 1 displays all available interaction study data along with recommendations forco-administration.

Table 1

Pharmacokinetic Interaction Data

Medicinal products by therapeutic Interaction Recommendationsarea (mechanism, if known) concerningco-administration

ANTI-RETROVIRAL

Protease inhibitors (PI)atazanavir /ritonavir raltegravir AUC  41% No dose adjustment required(raltegravir 400 mg Twice Daily) raltegravir C12hr  77% for raltegravir (400 mg twiceraltegravir Cmax  24% daily).

(UGT1A1 inhibition)atazanavir raltegravir AUC  67% Co-administration of raltegravir(raltegravir 1,200 mg single dose) raltegravir C24hr  26% (1,200 mg once daily) is notraltegravir Cmax  16% recommended.

(UGT1A1 inhibition)tipranavir /ritonavir raltegravir AUC  24% No dose adjustment required(raltegravir 400 mg Twice Daily) raltegravir C12hr  55% for raltegravir (400 mg twiceraltegravir Cmax  18% daily).

(UGT1A1 induction)

Extrapolated from 400 mg Co-administration of raltegravirtwice daily study (1,200 mg once daily) is notrecommended.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)efavirenz raltegravir AUC  36%(raltegravir 400 mg Single Dose) raltegravir C12hr  21%raltegravir Cmax  36%(UGT1A1 induction) No dose adjustment requiredefavirenz raltegravir AUC  14% for raltegravir (400 mg twice(raltegravir 1,200 mg single dose) raltegravir C24hr  6% daily and 1,200 mg once daily).

raltegravir Cmax  9%(UGT1A1 induction)etravirine raltegravir AUC  10%(raltegravir 400 mg Twice Daily) raltegravir C12hr  34%raltegravir Cmax  11%

No dose adjustment required(UGT1A1 induction) for raltegravir (400 mg twicedaily and 1,200 mg once daily)etravirine AUC  10% or etravirine.

etravirine C12hr  17%etravirine Cmax  4%

Medicinal products by therapeutic Interaction Recommendationsarea (mechanism, if known) concerningco-administration

Nucleoside/tide reverse transcriptase inhibitorstenofovir disoproxil fumarate raltegravir AUC  49%(raltegravir 400 mg Twice Daily) raltegravir C12hr  3%raltegravir Cmax ↑ 64%(mechanism of interactionunknown)tenofovir AUC  10%tenofovir C24hr  13% No dose adjustment requiredtenofovir C ↓ 23% for raltegravir (400 mg twicemaxemtricitabine and tenofovir Population PK analysis showed daily and 1,200 mg once daily)disoproxil fumarate that the effect of or tenofovir disoproxil(raltegravir 1,200 mg (2 x 600 mg) emtricitabine/tenofovir fumarate.

Once Daily) disoproxil fumarate onraltegravir pharmacokineticswas minimal (12% increase inrelative bioavailability), andwas not statistically or clinicallysignificant.

(Mechanism of interactionunknown)

CCR5 inhibitorsmaraviroc raltegravir AUC  37% No dose adjustment required(raltegravir 400 mg Twice Daily) raltegravir C12hr  28% for raltegravir (400 mg twiceraltegravir Cmax  33% daily and 1,200 mg once daily)or maraviroc.

(mechanism of interactionunknown)maraviroc AUC  14%maraviroc C12hr  10%maraviroc Cmax ↓ 21%

HCV ANTIVIRALS

NS3/4A protease inhibitors (PI)boceprevir raltegravir AUC  4% No dose adjustment required(raltegravir 400 mg Single Dose) raltegravir C12hr  25% for raltegravir (400 mg twiceraltegravir Cmax  11% daily and 1,200 mg once daily)or boceprevir.

(mechanism of interactionunknown)

ANTIMICROBIALS

Antimycobacterialrifampicin raltegravir AUC  40% Rifampicin reduces plasma(raltegravir 400 mg Single Dose) raltegravir C12hr  61% levels of raltegravir. Ifraltegravir Cmax  38% co-administration withrifampicin is unavoidable, a(UGT1A1 induction) doubling of the dose ofraltegravir (400 mg twice daily)can be considered.

Extrapolated from 400 mg Co-administration of raltegravirtwice daily study (1,200 mg once daily) is notrecommended.

Medicinal products by therapeutic Interaction Recommendationsarea (mechanism, if known) concerningco-administration

SEDATIVEmidazolam midazolam AUC  8% No dosage adjustment required(raltegravir 400 mg Twice Daily) midazolam Cmax ↑ 3% for raltegravir (400 mg twicedaily and 1,200 mg once daily)or midazolam.

These results indicate thatraltegravir is not an inducer orinhibitor of CYP3A4, andraltegravir is thus notanticipated to affect thepharmacokinetics of medicinalproducts which are CYP3A4substrates.

METAL CATION ANTACIDSaluminium and magnesium raltegravir AUC  49%hydroxide antacid raltegravir C12 hr  63%(raltegravir 400 mg Twice Daily) raltegravir Cmax  44%2 hours before raltegravirraltegravir AUC  51%raltegravir C12 hr  56%raltegravir Cmax  51%2 hours after raltegravirraltegravir AUC  30%raltegravir C12 hr  57%raltegravir Cmax  24% Aluminium and magnesiumcontaining antacids reduce6 hours before raltegravir raltegravir plasma levels.raltegravir AUC  13% Co-administration of raltegravirraltegravir C12 hr  50% (400 mg twice daily andraltegravir Cmax  10% 1,200 mg once daily) withaluminium and/or magnesium6 hours after raltegravir containing antacids is notraltegravir AUC  11% recommended.raltegravir C12 hr  49%raltegravir Cmax  10%(chelation of metal cations)aluminium/magnesium hydroxide 12 hours after raltegravirantacid raltegravir AUC  14%(raltegravir 1,200 mg single dose) raltegravir C24 hr  58%raltegravir Cmax  14%(chelation of metal ions)calcium carbonate antacid raltegravir AUC  55% No dose adjustment required(raltegravir 400 mg Twice Daily) raltegravir C12 hr  32% for raltegravir (400 mg twiceraltegravir Cmax  52% daily).

(chelation of metal cations)

Medicinal products by therapeutic Interaction Recommendationsarea (mechanism, if known) concerningco-administrationcalcium carbonate antacid raltegravir AUC  72% Co-administration of raltegravir(raltegravir 1,200 mg single dose) raltegravir C24 hr  48% (1,200 mg once daily) is notraltegravir Cmax  74% recommended.

12 hours after raltegravirraltegravir AUC  10%raltegravir C24 hr  57%raltegravir Cmax  2%(chelation of metal ions)

Other METAL CATION

Iron salts Expected: Given simultaneously iron salts

Raltegravir AUC  are expected to reduceraltegravir plasma levels;taking iron salts at least two(chelation of metal cations) hours from the administrationof raltegravir may allow tolimit this effect.

H2 BLOCKERS AND PROTON PUMP INHIBITORSomeprazole raltegravir AUC ↑ 37%(raltegravir 400 mg Twice Daily) raltegravir C12 hr ↑ 24%raltegravir Cmax ↑ 51%(increased solubility)famotidine raltegravir AUC ↑ 44%(raltegravir 400 mg Twice Daily) raltegravir C12 hr ↑ 6%raltegravir Cmax ↑ 60% No dose adjustment requiredfor raltegravir (400 mg twice(increased solubility) daily and 1,200 mg once daily).gastric pH altering agents: Population PK analysis showedproton pump inhibitors (e.g. that the effect of gastric pHomeprazole), H2 blockers (e.g. altering agents on raltegravirfamotidine, ranitidine, cimitedine) pharmacokinetics was minimal(8.8% decrease in relative(raltegravir 1,200 mg) bioavailability), and was notstatistically or clinicallysignificant.

(Increased drug solubility)

HORMONAL CONTRACEPTIVES

Ethinyl Estradiol Ethinyl Estradiol AUC  2% No dosage adjustment required

Norelgestromin Ethinyl Estradiol Cmax ↑ 6% for raltegravir (400 mg twice(raltegravir 400 mg Twice Daily) Norelgestromin AUC ↑ 14% daily and 1,200 mg once daily)

Norelgestromin Cmax ↑ 29% or hormonal contraceptives(estrogen- and/orprogesterone-based).

OPIOID ANALGESICSmethadone methadone AUC ↔ No dose adjustment required(raltegravir 400 mg Twice Daily) methadone Cmax ↔ for raltegravir (400 mg twicedaily and 1,200 mg once daily)or methadone.

There are no data for the use of raltegravir 1,200 mg once daily in pregnant women. A large amount ofdata on pregnant women with exposure to raltegravir 400 mg twice daily during the first trimester(more than 1,000 prospective pregnancy outcomes) indicates no malformative toxicity. Animal studieshave shown reproductive toxicity (see section 5.3).

A moderate amount of data on pregnant women with exposure to raltegravir 400 mg twice dailyduring the second and/or third trimester (between 300-1,000 prospective pregnancy outcomes)indicates no increased risk of feto/neonatal toxicity.

Raltegravir 1,200 mg is not recommended during pregnancy.

Anti-retroviral Pregnancy Registry

To monitor maternal-foetal outcomes in patients inadvertently administered raltegravir while pregnant,an Anti-retroviral Pregnancy Registry has been established. Physicians are encouraged to registerpatients in this registry.

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection inpregnant 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 inorder to characterise the safety for the foetus.

Raltegravir/metabolites are excreted in human milk to such an extent that effects on the breastfednewborns/infants are likely. Available pharmacodynamics/toxicological data in animals have shownexcretion of raltegravir/metabolites in milk (for details see section 5.3).

A risk to the newborns/infants cannot be excluded.

It is recommended that women living with HIV do not breast-feed their infants in order to avoidtransmission of HIV.

No effect on fertility was seen in male and female rats at doses up to 600 mg/kg/day which resulted in3-fold exposure above the exposure at the recommended human dose.

Dizziness has been reported in some patients during treatment with regimens containing raltegravir.

Dizziness may influence some patients' ability to drive and use machines (see section 4.8).

In randomised clinical trials raltegravir 400 mg twice daily was administered in combination withfixed or optimised background treatment regimens to treatment-naïve (N=547) and treatment-experienced (N=462) adults for up to 96 weeks. A further 531 treatment-naïve adults have receivedraltegravir 1,200 mg once daily with emtricitabine and tenofovir disoproxil fumarate for up to96 weeks. See section 5.1.

The most frequently reported adverse reactions during treatment were headache, nausea andabdominal pain. The most frequently reported serious adverse reactions were immune reconstitutionsyndrome and rash. The rates of discontinuation of raltegravir due to adverse reactions were 5% or lessin clinical trials.

Rhabdomyolysis was an uncommonly reported serious adverse reaction in post-marketing use ofraltegravir 400 mg twice daily.

Adverse reactions considered by investigators to be causally related to raltegravir (alone or incombination with other ART), as well as adverse reactions established in post-marketing experience,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

Raltegravir (alone or in combination withother ART)

Infections and infestations Uncommon genital herpes, folliculitis, gastroenteritis, herpessimplex, herpes virus infection, herpes zoster,influenza, lymph node abscess, molluscumcontagiosum, nasopharyngitis, upper respiratorytract infection

Neoplasms benign, Uncommon skin papillomamalignant and unspecified(including cysts and polyps)

Blood and lymphatic system Uncommon anaemia, iron deficiency anaemia, lymph nodedisorders pain, lymphadenopathy, neutropenia,thrombocytopenia

Immune system disorders Uncommon immune reconstitution syndrome, drughypersensitivity, hypersensitivity

Metabolism and nutrition Common decreased appetitedisorders

Uncommon cachexia, diabetes mellitus, dyslipidaemia,hypercholesterolaemia, hyperglycaemia,hyperlipidaemia, hyperphagia, increasedappetite, polydipsia, body fat disorder

Psychiatric disorders Common abnormal dreams, insomnia, nightmare,abnormal behaviour, depression

Uncommon mental disorder, suicide attempt, anxiety,confusional state, depressed mood, majordepression, middle insomnia, mood altered,panic attack, sleep disorder, suicidal ideation,suicidal behaviour (particularly in patients witha pre-existing history of psychiatric illness)

Nervous system disorders Common dizziness, headache, psychomotor hyperactivity

Uncommon amnesia, carpal tunnel syndrome, cognitivedisorder, disturbance in attention, dizzinesspostural, dysgeusia, hypersomnia,hypoaesthesia, lethargy, memory impairment,migraine, neuropathy peripheral, paraesthesia,somnolence, tension headache, tremor, poorquality sleep

System Organ Class Frequency Adverse reactions

Raltegravir (alone or in combination withother ART)

Eye disorders Uncommon visual impairment

Ear and labyrinth disorders Common vertigo

Uncommon tinnitus

Cardiac disorders Uncommon palpitations, sinus bradycardia, ventricularextrasystoles

Vascular disorders Uncommon hot flush, hypertension

Respiratory, thoracic and Uncommon dysphonia, epistaxis, nasal congestionmediastinal disorders

Gastrointestinal disorders Common abdominal distention, abdominal pain,diarrhoea, flatulence, nausea, vomiting,dyspepsia

Uncommon gastritis, abdominal discomfort, abdominal painupper, abdominal tenderness, anorectaldiscomfort, constipation, dry mouth, epigastricdiscomfort, erosive duodenitis, eructation,gastroesophageal reflux disease, gingivitis,glossitis, odynophagia, pancreatitis acute, pepticulcer, rectal haemorrhage

Hepato-biliary disorders Uncommon hepatitis, hepatic steatosis, hepatitis alcoholic,hepatic failure

Skin and subcutaneous tissue Common rashdisorders

Uncommon 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, drugrash with eosinophilia and systemic symptoms(DRESS)

Musculoskeletal and Uncommon arthralgia, arthritis, back pain, flank pain,connective tissue disorders 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, tubulointerstitialnephritis

Reproductive system and Uncommon erectile dysfunction, gynaecomastia,breast disorders menopausal symptoms

General disorders and Common asthenia, fatigue, pyrexiaadministration siteconditions Uncommon chest discomfort, chills, face oedema, fat tissueincreased, feeling jittery, malaise,submandibular mass, oedema peripheral, pain

System Organ Class Frequency Adverse reactions

Raltegravir (alone or in combination withother ART)

Investigations Common alanine aminotransferase increased, atypicallymphocytes, aspartate aminotransferaseincreased, blood triglycerides increased, lipaseincreased, blood pancreatic amylase increased

Uncommon absolute neutrophil count decreased, alkalinephosphatase increased, blood albumindecreased, blood amylase increased, bloodbilirubin increased, blood cholesterol increased,blood creatinine increased, blood glucoseincreased, blood urea nitrogen increased,creatine phosphokinase increased, fasting bloodglucose increased, glucose urine present, highdensity lipoprotein increased, internationalnormalised ratio increased, low densitylipoprotein increased, platelet count decreased,red blood cells urine positive, waistcircumference increased, weight increased,white blood cell count decreased

Injury, poisoning and Uncommon accidental overdoseprocedural complications

In studies of raltegravir 400 mg twice daily, cancers were reported in treatment-experienced andtreatment-naïve patients who initiated raltegravir in conjunction with other antiretroviral agents. Thetypes and rates of specific cancers were those expected in a highly immunodeficient population. Therisk of developing cancer in these studies was similar in the groups receiving raltegravir and in thegroups receiving comparators.

Grade 2-4 creatine kinase laboratory abnormalities were observed in patients treated with raltegravir.

Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have hadmyopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinalproducts associated with these conditions (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, 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 combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported; however, the reported time to onset is more variable and these events can occurmany months after initiation of treatment (see section 4.4).

For each of the following clinical adverse reactions there was at least one serious occurrence: genitalherpes, 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 morecommonly observed with regimens containing raltegravir and darunavir compared to those containingraltegravir without darunavir or darunavir without raltegravir. Rash considered by the investigator tobe 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 2.3per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severityand did not result in discontinuation of therapy (see section 4.4).

Patients co-infected with hepatitis B and/or hepatitis C virus

In clinical trials, there were 79 patients co-infected with hepatitis B, 84 co-infected with hepatitis C,and 8 patients co-infected with hepatitis B and C who were treated with raltegravir in combinationwith other agents for HIV-1. In general, the safety profile of raltegravir in patients with hepatitis Band/or hepatitis C virus co-infection was similar to that in patients without hepatitis B and/orhepatitis C virus co-infection, although the rates of AST and ALT abnormalities were somewhathigher in the subgroup co-infected with hepatitis B and/or hepatitis C virus.

At 96-weeks, in treatment-experienced patients, Grade 2 or higher laboratory abnormalities thatrepresent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29 %, 34 % and13 %, respectively, of co-infected patients treated with raltegravir as compared to 11 %, 10 % and 9 %of all other patients treated with raltegravir. At 240-weeks, in treatment-naïve patients, Grade 2 orhigher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or totalbilirubin occurred in 22 %, 44 % and 17 %, respectively, of co-infected patients treated withraltegravir as compared to 13 %, 13 % and 5 % of all other patients treated with raltegravir.

ISENTRESS 600 mg tablet formulation has not been studied in paediatric patients (see section 4.2).

Children and adolescents 2 to 18 years of age

Raltegravir twice daily has been studied in 126 antiretroviral treatment-experienced HIV-1 infectedchildren and adolescents 2 to 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 doseof raltegravir twice daily.

In these 96 children and adolescents, frequency, type and severity of drug related adverse reactionsthrough 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 allergicrash.

One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, whichwere considered serious.

Infants and toddlers 4 weeks to less than 2 years of age

Raltegravir twice daily has also been studied in 26 HIV-1 infected infants and toddlers 4 weeks to lessthan 2 years of age, in combination with other antiretroviral agents in IMPAACT P1066 (seesections 5.1 and 5.2).

In these 26 infants and toddlers, the frequency, type and severity of drug related adverse reactionsthrough Week 48 were comparable to those observed in adults.

One patient experienced a Grade 3 serious drug related allergic rash that resulted in treatmentdiscontinuation.

HIV-1 Exposed Neonates

In IMPAACT P1110 (see section 5.2) eligible infants were at least 37 weeks gestation and at least 2 kgin weight. Sixteen (16) neonates received 2 doses of ISENTRESS in first 2 weeks of life, and26 neonates received 6 weeks of daily dosing; all were followed for 24 weeks. There were no drugrelated clinical adverse experiences and three drug-related laboratory adverse experiences (one atransient Grade 4 neutropenia in a subject receiving zidovudine containing prevention of mother tochild transmission (PMTCT), and two bilirubin elevations (one each, Grade 1 and Grade 2) considerednon-serious and not requiring specific therapy).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No specific information is available on the treatment of overdose with raltegravir.

In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., removeunabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining anelectrocardiogram), and institute supportive therapy if required. It should be taken into account thatraltegravir is presented for clinical use as the potassium salt. The extent to which raltegravir may bedialysable is unknown.

Pharmacotherapeutic group: antivirals for systemic use, integrase inhibitors, ATC code: J05AJ01.

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 isrequired for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, ofthe HIV genome into the host cell genome. HIV genomes that fail to integrate cannot direct theproduction of new infectious viral particles, so inhibiting integration prevents propagation of the viralinfection.

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 thecell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir inhibited viral replication in cultures ofmitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinicalisolates of HIV-1, including isolates from 5 non-B subtypes, and isolates resistant to reversetranscriptase inhibitors and protease inhibitors. In a single-cycle infection assay, raltegravir inhibitedinfection 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 resultingfrom the appearance of two or more mutations in integrase. Most had a signature mutation at aminoacid 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 viralsusceptibility to raltegravir and addition of other mutations results in a further decrease in raltegravirsusceptibility. Factors that reduced the likelihood of developing resistance included lower baselineviral load and use of other active anti-retroviral agents. Mutations conferring resistance to raltegravirgenerally also confer resistance to the integrase strand transfer inhibitor elvitegravir. Mutations atamino acid 143 confer greater resistance to raltegravir than to elvitegravir, and the E92Q mutationconfers greater resistance to elvitegravir than to raltegravir. Viruses harbouring a mutation at aminoacid 148, along with one or more other raltegravir resistance mutations, may also have clinicallysignificant resistance to dolutegravir.

The evidence of efficacy of raltegravir was based on the analyses of 96-week data from tworandomised, double-blind, placebo-controlled trials (BENCHMRK 1 and BENCHMRK 2,

Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult patients, theanalysis of 240-week data from randomised, double-blind, active-control trial (STARTMRK,

Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult patients and the analysis of96-week data from randomised, double-blind, active-control trial (ONCEMRK, Protocol 292) inantiretroviral treatment-naïve HIV-1 infected adult patients.

Treatment-experienced adult patients (400 mg twice daily)

BENCHMRK 1 and BENCHMRK 2 (multi-centre, randomised, double-blind, placebo-controlledtrials) evaluated the safety and anti-retroviral activity of raltegravir 400 mg twice daily vs. placebo in acombination with optimised 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) ofanti-retroviral therapies. Prior to randomisation, OBT were selected by the investigator based on thepatient'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 thegroups receiving raltegravir 400 mg twice daily and placebo. Patients had prior exposure to a medianof 12 anti-retrovirals for a median of 10 years. A median of 4 ARTs was used in OBT.

Results 48-week and 96-week analyses

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

Table 2

Efficacy Outcome at Weeks 48 and 96

BENCHMRK 1 and 2 Pooled 48 Weeks 96 Weeks

Raltegravir Placebo + Raltegravir Placebo +

Parameter 400 mg twice OBT 400 mg twice OBTdaily + OBT (N = 237) daily + OBT (N = 237)(N = 462) (N = 462)

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/mm3 61 (53, 69) 21 (13, 32) 51 (42, 60) 14 (7, 24)> 50 and ≤ 200 cells/mm3 80 (73, 85) 44 (33, 55) 70 (62, 77) 36 (25, 48)> 200 cells/mm3 83 (76, 89) 51 (39, 63) 78 (70, 85) 42 (30, 55)

Sensitivity score (GSS) §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)

BENCHMRK 1 and 2 Pooled 48 Weeks 96 Weeks

Raltegravir Placebo + Raltegravir Placebo +

Parameter 400 mg twice OBT 400 mg twice OBTdaily + OBT (N = 237) daily + OBT (N = 237)(N = 462) (N = 462)

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/mm3 50 (41, 58) 20 (12, 31) 50 (41, 58) 13 (6, 22)> 50 and ≤ 200 cells/mm3 67 (59, 74) 39 (28, 50) 65 (57, 72) 32 (22, 44)> 200 cells/mm3 76 (68, 83) 44 (32, 56) 71 (62, 78) 41 (29, 53)

Sensitivity score (GSS) §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/mm3

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/mm3 121 (100, 142) 33 (18, 48) 130 (104, 156) 42 (17, 67)> 50 and ≤ 200 cells/mm3 104 (88, 119) 47 (28, 66) 123 (103, 144) 56 (34, 79)> 200 cells/mm3 104 (80, 129) 54 (24, 84) 117 (90, 143) 48 (23, 73)

Sensitivity score (GSS) §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)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 andassociated 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.

§ The Genotypic Sensitivity Score (GSS) was defined as the total oral ARTs in the optimised background therapy (OBT) to which a patient's viral isolateshowed genotypic sensitivity based upon genotypic resistance test. Enfuvirtide use in OBT in enfuvirtide-naïve patients was counted as one active drug in

OBT. Similarly, darunavir use in OBT in darunavir-naïve patients was counted as one active drug in OBT.

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 withfailure include high baseline viral load and OBT that did not include at least one potent active agent.

Switch to raltegravir (400 mg twice daily)

The SWITCHMRK 1 & 2 (Protocols 032 & 033) studies evaluated HIV-infected patients receivingsuppressive (screening HIV RNA < 50 copies/mL; stable regimen > 3 months) therapy with lopinavir200 mg (+) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptaseinhibitors and randomised them 1:1 to continue lopinavir (+) ritonavir 2 tablets twice daily (n=174 andn=178, respectively) or replace lopinavir (+) ritonavir with raltegravir 400 mg twice daily (n=174 andn=176, respectively). Patients with a prior history of virological failure were not excluded and thenumber of previous antiretroviral therapies was not limited.

These studies were terminated after the primary efficacy analysis at Week 24 because they failed todemonstrate 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 groupversus 90.6 % of the lopinavir (+) ritonavir group, (Non-completers = Failure). See section 4.4regarding the need to administer raltegravir with two other active agents.

Treatment-naïve adult patients (400 mg twice daily)

STARTMRK (multi-centre, randomised, double-blind, active-control trial) evaluated the safety andanti-retroviral activity of raltegravir 400 mg twice daily vs. efavirenz 600 mg at bedtime, in acombination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naïve HIV-infectedpatients with HIV RNA > 5,000 copies/mL. Randomisation was stratified by screening HIV RNAlevel (≤ 50,000 copies/mL; and > 50,000 copies/mL) and by hepatitis B or C status (positive ornegative).

Patient demographics (gender, age and race) and baseline characteristics were comparable between thegroup receiving raltegravir 400 mg twice daily and the group receiving efavirenz 600 mg at bedtime.

Results 48-week and 240-week analyses

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 raltegravir and 230/281(81.9 %) in the group receiving efavirenz. The treatment difference (raltegravir - efavirenz) was 4.2 %with an associated 95 % CI of (-1.9, 10.3) establishing that raltegravir is non-inferior to efavirenz(p-value for non-inferiority < 0.001). At Week 240, the treatment difference (raltegravir - efavirenz)was 9.5 % with an associated 95 % CI of (1.7, 17.3). Week 48 and Week 240 outcomes for patients onthe recommended dose of raltegravir 400 mg twice daily from STARTMRK are shown in Table 3.

Table 3

Efficacy Outcome at Weeks 48 and 240

STARTMRK Study 48 Weeks 240 Weeks

Raltegravir Efavirenz Raltegravir Efavirenz

Parameter 400 mg twice 600 mg 400 mg twice 600 mgdaily at bedtime daily at bedtime(N = 281) (N = 282) (N = 281) (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/mm3 84 (64, 95) 86 (67, 96) 58 (37, 77) 77 (58, 90)> 50 and ≤ 200 cells/mm3 89 (81, 95) 86 (77, 92) 67 (57, 76) 60 (50, 69)> 200 cells/mm3 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/mm3

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/mm3 170 (122, 218) 152 (123, 180) 304 (209, 399) 314 (242, 386)> 50 and ≤ 200 cells/mm3 193 (169, 217) 175 (151, 198) 413 (360, 465) 306 (264, 348)> 200 cells/mm3 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 andassociated 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.

Raltegravir and efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate.

Treatment-naïve adult patients (1,200 mg [2 x 600 mg] once daily)

ONCEMRK (multi-centre, randomised, double-blind, active-control trial; Protocol 292) evaluated thesafety and anti-retroviral activity of raltegravir 1,200 mg once daily + emtricitabine (+) tenofovirdisoproxil fumarate vs. raltegravir 400 mg twice daily, in combination with emtricitabine (+) tenofovirdisoproxil fumarate, in treatment-naïve HIV-infected patients with HIV RNA > 1,000 copies/mL.

Randomisation was stratified by screening HIV RNA level (≤ 100,000 copies/mL; and> 100,000 copies/mL) and by hepatitis B or C status (positive or negative).

Patient demographics (gender, age and race) and baseline characteristics were comparable between thegroup receiving raltegravir 1,200 mg once daily and the group receiving raltegravir 400 mg twicedaily.

Results of Week 48 and 96 analyses

With respect to the primary efficacy endpoint, the proportion of patients achieving HIV RNA< 40 copies/mL at Week 48 was 472/531(88.9 %) in the group receiving raltegravir 1,200 mg oncedaily and 235/266 (88.3 %) in the group receiving raltegravir 400 mg twice daily. The treatmentdifference (raltegravir 1,200 mg once daily-raltegravir 400 mg twice daily) was 0.5 % with anassociated 95 % CI of (-4.2, pct. 5.2) establishing that raltegravir 1,200 mg once daily is non-inferior toraltegravir 400 mg twice daily.

At Week 96, the proportion of patients achieving HIV RNA < 40 copies/mL was 433/531(81.5 %) inthe group receiving raltegravir 1,200 mg once daily and 213/266 (80.1 %) in the group receivingraltegravir 400 mg twice daily. The treatment difference (raltegravir 1,200 mg once daily-raltegravir400 mg twice daily) was 1.5 % with an associated 95 % CI of (-4.4, 7.3). Week 48 and Week 96outcomes from ONCEMRK are shown in Table 4.

Table 4

Efficacy Outcome at Weeks 48 and 96

ONCEMRK Study 48 Weeks 96 Weeks

Raltegravir Raltegravir Raltegravir Raltegravir

Parameter 600 mg 400 mg 600 mg 400 mg(1,200 mg twice daily (1,200 mg twice dailyonce daily) (N = 266) once daily) (N = 266)(N = 531) (N = 531)

Percent HIV-RNA < 40 copies/mL(95 % CI)

All patients† 88.9 (85.9, 91.4) 88.3 (83.9, 91.9) 81.5 (78.0, 84.8) 80.1 (74.8, 84.7)

Baseline Characteristic‡

HIV-RNA 86.7 (80.0, 91.8) 83.8 (73.4, 91.3) 84.7 (77.5, 90.3) 82.9 (72.0, 90.8)> 100,000 copies/mL97.2 (94.9, 98.7) 97.7 (94.3, 99.4) 91.9 (88.5, 94.5) 93.0 (89.1, 97.1)≤ 100,000 copies/mL

CD4-count ≤ 200 cells/mm385.1 (74.3, 92.6) 87.9 (71.8, 96.6) 79.0 (66.8, 88.3) 80 (61.4, 92.3)> 200 cells/mm395.6 (93.2, 97.3) 94.5 (90.6, 97.1) 91.4 (88.3, 93.9) 92.2 (87.6, 95.5)

Viral Subtype Clade B 94.6 (91.4, 96.8) 93.7 (89.0, 96.8) 90.0 (86.0, 93.2) 88.9 (83.0, 93.3)

Non-Clade B 93.6 (89.1, 96.6) 93.2 (84.9, 97.8) 89.5 (84.1, 93.6) 94.4 (86.2, 98.4)

ONCEMRK Study 48 Weeks 96 Weeks

Raltegravir Raltegravir Raltegravir Raltegravir

Parameter 600 mg 400 mg 600 mg 400 mg(1,200 mg twice daily (1,200 mg twice dailyonce daily) (N = 266) once daily) (N = 266)(N = 531) (N = 531)

Mean CD4 Cell Change (95 % CI),cells/mm3

All patients‡232 (215, 249) 234 (213, 255) 262 (243, 280) 262 (236, 288)

Baseline Characteristic‡

HIV-RNA 276 (245, 308) 256 (218, 294) 297 (263, 332) 281 (232, 329)> 100,000 copies/mL214 (194, 235) 225 (199, 251) 248 (225, 270) 254 (224, 285)≤ 100,000 copies/mL

CD4 count ≤ 200 cells/mm3209 (176, 243) 209 (172, 245) 239 (196, 281) 242 (188, 296)> 200 cells/mm3235 (216, 255) 238 (214, 262) 265 (245, 286) 265 (237, 294)

Viral Subtype Clade B 232 (209, 254) 240 (213, 266) 270 (245, 296) 267 (236, 297)

Non-Clade B 233 (205, 261) 226 (191, 261) 246 (219, 274) 259 (211, 307)† Non-completer is failure imputation: patients who discontinued prematurely are imputed as failure thereafter. Percent of patients withresponse and associated 95 % confidence interval (CI) are reported.

‡ For analysis by prognostic factors, virologic failures were carried forward for percent < 40 copies/mL. For mean CD4 changes, baseline-carry-forward was used for virologic failures.

Raltegravir 1,200 mg QD and raltegravir 400 mg BID were administered with emtricitabine (+) tenofovir disoproxil fumarate.

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 increasesdose proportionally over the dose range of 100 to 800 mg and increases slightly less than doseproportionally over the dose range 100 mg to 1,600 mg.

With twice-daily dosing, pharmacokinetic steady state is achieved rapidly, within approximately thefirst 2 days of dosing. There is little to no accumulation in AUC and Cmax and evidence of slightaccumulation in C12 hr. The absolute bioavailability of raltegravir has not been established.

Raltegravir 1,200 mg once daily is also rapidly absorbed with median Tmax ~1.5 to 2 hours in the fastedstate and generates a sharper absorption peak with a tendency to higher Cmax in comparison toraltegravir twice daily (1 x 400 mg tablet twice daily). In addition, relative to the raltegravir 400 mgformulation the raltegravir 600 mg formulation used in the 1,200 mg (2 x 600 mg) once daily dosingregimen has higher relative bioavailability (by 21 to 66%). Once absorbed, both formulations ofraltegravir exhibit similar systemic pharmacokinetics. In patients, after 1,200 mg once daily raltegravirdosing, steady state AUC0-24 was 53.7 h·μM, C24 was 75.6 nM, and median Tmax was 1.50 h.

Raltegravir 400 mg twice daily may be administered with or without food. Raltegravir wasadministered 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 hrwas 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 approximately2-fold and increased C12 hr by 4.1-fold. Administration of raltegravir following a low-fat mealdecreased AUC and Cmax by 46 % and 52 %, respectively; C12 hr was essentially unchanged. Foodappears to increase pharmacokinetic variability relative to fasting.

Raltegravir 600 mg tablets (2 x 600 mg once daily) may be administered with or without food. Asingle dose food effect study demonstrated that the 1,200 mg once daily had similar or smaller foodeffects when studied under high-fat and low-fat meal conditions when compared to the 400 mg twicedaily. Administration of a low-fat meal with raltegravir 1,200 mg once daily resulted in a 42%decrease in AUC0-last, 52% decrease in Cmax, and 16% decrease in C24 hr. Administration of a high fatmeal resulted in a 1.9% increase in AUC0-last, 28% decrease in Cmax, and 12% decrease in C24 hr.

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 inco-administration with food and concomitant medicines.

Raltegravir is approximately 83 % bound to human plasma protein over the concentration range of 2 to10 µM.

Raltegravir readily crossed the placenta in rats, but did not penetrate the brain to any appreciableextent.

In two studies of HIV-1 infected patients who received raltegravir 400 mg twice daily, raltegravir wasreadily detected in the cerebrospinal fluid. In the first study (n=18), the median cerebrospinal fluidconcentration was 5.8 % (range 1 to 53.5 %) of the corresponding plasma concentration. In the secondstudy (n=16), the median cerebrospinal fluid concentration was 3 % (range 1 to 61 %) of thecorresponding plasma concentration. These median proportions are approximately 3- to 6-fold lowerthan the free fraction of raltegravir in plasma.

Biotransformation and excretion

The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life(~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeledraltegravir, approximately 51 and 32 % of the dose was excreted in faeces and urine, respectively. Infaeces, only raltegravir was present, most of which is likely to be derived from hydrolysis ofraltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namelyraltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and23 % of the dose, respectively. The major circulating entity was raltegravir and representedapproximately 70 % of the total radioactivity; the remaining radioactivity in plasma was accounted forby raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed

UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for theformation of raltegravir-glucuronide. Thus, the data indicate that the major mechanism of clearance ofraltegravir in humans is UGT1A1-mediated glucuronidation.

UGT1A1 Polymorphism

In a comparison of 30 subjects with *28/*28 genotype to 27 subjects with wild-type genotype, thegeometric mean ratio (90 % CI) of AUC was 1.41 (0.96, 2.09) and the geometric mean ratio of C12 hrwas 1.91 (1.43, 2.55). Dose adjustment is not considered necessary in subjects with reduced UGT1A1activity due to genetic polymorphism.

Based on a formulation comparison study in healthy adult volunteers, the chewable tablet and granulesfor oral suspension have 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 C12 hr compared to administration in the fasted state.

Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokineticsto a clinically meaningful degree and the chewable tablet can be administered without regard to food.

The effect of food on the granules for oral suspension formulation was not studied.

Table 5 displays pharmacokinetic parameters in the 400 mg tablet, the chewable tablet, and thegranules for oral suspension, by body weight.

Table 5

Raltegravir Pharmacokinetic Parameters IMPAACT P1066 Following Administration of Dosesin Section 4.2 (excluding neonates)

Geometric mean Geometric mean(%CV†) (%CV†)

Body weight Formulation Dose N* AUC0-12hr (μM●hr) C12hr (nM)

Film-coated≥ 25 kg tablet 400 mg twice daily 18 14.1 (121 %) 233 (157 %)

Weight based dosing, seedosing tables for the≥ 25 kg Chewable tablet chewable tablet 9 22.1 (36 %) 113 (80 %)

Weight based dosing, see11 to less than dosing tables for the25 kg Chewable tablet chewable tablet 13 18.6 (68 %) 82 (123 %)

Weight based dosing, see3 to less than dosing table for granules20 kg Oral suspension for oral suspension 19 24.5 (43 %) 113 (69 %)

*Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose.†Geometric coefficient of variation.

There was no clinically meaningful effect of age on raltegravir pharmacokinetics over the age rangestudied with raltegravir 400 mg twice daily. There was no clinically meaningful effect of age onraltegravir pharmacokinetics over the age range studied in ONCEMRK with raltegravir 1,200 mg(2 x 600 mg) once daily.

Gender, race, ethnicity and body weight

There were no clinically important pharmacokinetic differences due to gender, race, ethnicity or bodyweight in adults for raltegravir 400 mg twice daily, and no clinically meaningful effect on raltegravirpharmacokinetics was concluded. For raltegravir 1,200 mg (2 x 600 mg) once daily, population

PK analysis also demonstrated that the impacts of gender, race, ethnicity and body weight are notclinically meaningful.

Renal clearance of unchanged medicinal product is a minor pathway of elimination. In adults, therewere no clinically important pharmacokinetic differences between patients with severe renalinsufficiency and healthy subjects (see section 4.2 of the 400 mg twice daily SmPC). Because theextent to which raltegravir may be dialysable is unknown, dosing before a dialysis session should beavoided. No renal impairment study was conducted with raltegravir 1,200 mg once daily however,based on results with the 400 mg twice daily tablet, no clinically meaningful effect is anticipated.

Raltegravir is eliminated primarily by glucuronidation in the liver. In adults, there were no clinicallyimportant pharmacokinetic differences between patients with moderate hepatic insufficiency andhealthy subjects. The effect of severe hepatic insufficiency on the pharmacokinetics of raltegravir hasnot been studied (see sections 4.2 and 4.4 of the 400 mg twice daily SmPC). No hepatic impairmentstudy has been conducted with raltegravir 1,200 mg once daily, however, based on results with the400 mg twice daily tablet, no clinically meaningful effect is expected for mild and moderate hepaticimpairment.

Non-clinical toxicology studies, including conventional studies of safety pharmacology, repeated-dosetoxicity, genotoxicity, developmental toxicity and juvenile toxicity, have been conducted withraltegravir in mice, rats, dogs and rabbits. Effects at exposure levels sufficiently in excess of clinicalexposure 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 chromosomalaberration studies.

A carcinogenicity study of raltegravir in mice did not show any carcinogenic potential. At the highestdose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was similar tothat at the clinical dose of 1,200 mg once daily. In rats, tumours (squamous cell carcinoma) of thenose/nasopharynx were identified at 300 and 600 mg/kg/day in females and at 300 mg/kg/day inmales. This neoplasia could result from local deposition and/or aspiration of drug on the mucosa of thenose/nasopharynx during oral gavage dosing and subsequent chronic irritation and inflammation; it islikely that it is of limited relevance for the intended clinical use. At the NOAEL, systemic exposurewas similar to that at the clinical dose of 1,200 mg once daily. Standard genotoxicity studies toevaluate mutagenicity and clastogenicity were negative.

Developmental toxicity

Raltegravir was not teratogenic in developmental toxicity studies in rats and rabbits. A slight increasein incidence of supernumerary ribs, a variant in the normal developmental process, was observed in ratfoetuses of dams exposed to raltegravir at approximately 4.4-fold human exposure at therecommended human dose (RHD) based on AUC0-24 hr. No development effects were seen at 3.4-foldhuman exposure at the RHD. Similar findings were not observed in rabbits.

- Microcrystalline cellulose

- Hypromellose 2910

- Magnesium stearate

- Croscarmellose sodium

- Lactose monohydrate

- Hypromellose 2910

- Titanium dioxide

- Triacetin

- Iron oxide yellow

- Black iron oxide

The tablet may also contain trace amount of carnauba wax.

Not applicable.

2 years

Keep the bottle tightly closed, with the desiccant in order to protect from moisture.

High density polyethylene (HDPE) bottle with a child-resistant polypropylene closure, induction seal andsilica gel desiccant.

Two pack sizes are available: 1 bottle with 60 tablets, and a multipack containing 180 (3 bottles of 60)tablets.

Not all pack sizes may be marketed.

No special requirements for disposal.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/07/436/006

EU/1/07/436/007

Date of first authorisation: 20 December 2007

Date of latest renewal: 14 May 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.