4.1     Therapeutic indications

Isentress 600 mg film-coated tablets is indicated in combination with other anti-retroviral medicinal 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, 4.4, 5.1 and 5.2).

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).

Adults and paediatric population

In adults and paediatric patients (weighing at least 40 kg), the recommended dosage is 1,200 mg (two 600 mg tablets) once daily for treatment-naïve patients or patients who are virologically suppressed on an 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 children and adolescents at least 25 kg. The 400 mg tablet should not be used to administer 1,200 mg once daily 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 suspension formulation. Refer to the chewable tablet and granules for oral suspension SmPCs for additional dosing 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 dosing recommendations can be made.

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

18 years) or adults.

Elderly

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.

Renal impairment

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

Hepatic impairment

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).

ISENTRESS 600 mg film-coated tablet formulation should not be used in children weighing less than 40 kg.

Method of administration

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 pharmacokinetic profile.

General

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 contact.

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-naïve patients, the clinical study data on use of raltegravir are limited to use in combination with two nucleotide reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovir disoproxil fumarate).

Depression

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.

Hepatic impairment

The safety and efficacy of raltegravir have not been established in patients with severe underlying liver disorders. Therefore, raltegravir 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 reactions.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long‑term exposure to combination anti-retroviral therapy. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination anti-retroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) 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.

Atazanavir

Co-administration of raltegravir 1,200 mg once daily with atazanavir resulted in increased raltegravir plasma 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 decreased raltegravir 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 and aluminium/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 raltegravir 1,200 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 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 skin and hypersensitivity reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking raltegravir, 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 characterised by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue raltegravir 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 raltegravir treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Rash

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

Lactose

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

Sodium

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 once daily with sensitive OAT1 and/or OAT3 substrates.

In vitro studies indicate that raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not inhibit UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, does not induce CYP3A4 and is not an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polypeptides (OATP) 1B1, OATP1B3, organic cation transporters (OCT)1 and OCT2, or multidrug and toxin extrusion proteins (MATE)1 and MATE2-K. Based on these data, raltegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or transporters.

Based on in vitro and in vivo studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Considerable inter- and intra-individual variability was observed in the pharmacokinetics of raltegravir.

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 a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir disoproxil fumarate, hormonal contraceptives, methadone, midazolam or boceprevir. These findings can be extended 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 in a modest but clinically insignificant decrease in darunavir plasma concentrations. Based on the magnitude of effect seen with raltegravir 400 mg tablets twice daily, it is expected that the effect of raltegravir 1,200 mg once daily on darunavir plasma concentrations is likely to be not clinically meaningful.

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 on raltegravir 1,200 mg once daily is unknown, but co-administration is likely to decrease raltegravir trough levels based on the reduction in trough concentrations observed with raltegravir 400 mg twice daily; therefore, co-administration with raltegravir 1,200 mg once daily is not recommended. The impact 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 not recommended. In drug interaction studies, efavirenz did not have a clinically meaningful effect on the pharmacokinetics 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 the recommended dose of raltegravir.

Inhibitors of UGT1A1

Co-administration of atazanavir with raltegravir 1,200 mg once daily significantly increased plasma levels of raltegravir; therefore, co-administration of raltegravir 1,200 mg once daily and atazanavir is not recommended.

Antacids

Co-administration of raltegravir 1,200 mg once daily with aluminium/magnesium and calcium carbonate containing antacids are likely to result in clinically meaningful reductions in the plasma trough levels of raltegravir. Based on these findings, co-administration of aluminium/magnesium and calcium 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-administration of raltegravir 1,200 mg once daily with PPIs or H2 blockers did not result in statistically significant changes in the pharmacokinetics of raltegravir. Comparable efficacy and safety results were obtained in the absence or presence of these gastric pH-altering agents. Based on these data, proton pump inhibitors 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 of change on raltegravir exposure from raltegravir 400 mg twice daily by ritonavir, boceprevir or etravirine 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 not recommended.

Previous studies of raltegravir 400 mg twice daily showed that co-administration of tenofovir disoproxil fumarate (a component of emtricitabine/tenofovir disaproxil fumarate) increased raltegravir exposure. Emtricitabine/tenofovir disaproxil fumarate was identified to increase raltegravir 1,200 mg

once daily bioavailability by 12%, however its impact is not clinically meaningful. Therefore, co- administration of emtricitabine/tenofovir disaproxil fumarate and raltegravir 1,200 mg once daily is permitted.

All interaction studies were performed in adults.

Comprehensive drug interaction studies were performed with raltegravir 400 mg twice daily and a limited 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 for co-administration.

Table 1

Pharmacokinetic Interaction Data

Pregnancy

There are no data for the use of raltegravir 1,200 mg once daily in pregnant women. A large amount of data 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 studies have shown reproductive toxicity (see section 5.3).

A moderate amount of data on pregnant women with exposure to raltegravir 400 mg twice daily during 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 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.

Breast-feeding

Raltegravir/metabolites are excreted in human milk to such an extent that effects on the breastfed newborns/infants are likely. Available pharmacodynamics/toxicological data in animals have shown excretion 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 avoid transmission of HIV.

Fertility

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.

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).

Summary of the safety profile

The safety profile of raltegravir was established in two Phase III randomised clinical studies in treatment-experienced adult patients and two Phase III randomised clinical studies in treatment-naïve adult patients. Data from post-authorisation safety studies and spontaneous reporting have also contributed to the safety profile of raltegravir.

In treatment-experienced patients, the two 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 raltegravir 400 mg twice daily, and

244 patient-years in the group receiving placebo.

In treatment-naïve patients, one study used the recommended dose of 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir disoproxil fumarate 245 mg in

281 patients, in comparison to 282 patients taking efavirenz (EFV) 600 mg (at bedtime) in

combination with emtricitabine (+) tenofovir disoproxil fumarate. During double-blind treatment, the total follow-up was 1,104 patient-years in the group receiving raltegravir 400 mg twice daily, and

1,036 patient-years in the group receiving efavirenz 600 mg at bedtime. The second study evaluated raltegravir in 797 treatment-naïve HIV-1 infected patients, comparing 531 patients receiving raltegravir 1,200 mg once daily with 266 patients receiving raltegravir 400 mg twice daily, each in

combination with emtricitabine (+) tenofovir disoproxil fumarate. The total follow-up for patients on raltegravir 1,200 mg once daily was 515.6 patient-years and for raltegravir 400 mg twice daily was

257.7 patient-years.

The most frequently reported adverse reactions during treatment were headache and nausea and abdominal pain, occurring at 5% or greater. The most frequently reported serious adverse reactions were immune reconstitution syndrome and serious rash. Rhabdomyolysis was an uncommonly reported serious adverse reaction in post-marketing use of raltegravir 400 mg twice daily.

In the pooled analysis of treatment-experienced patients, the rates of discontinuation of therapy due to adverse reactions were 3.9 % in patients receiving raltegravir + OBT and 4.6 % in patients receiving placebo + OBT. The rates of discontinuation of therapy in naïve patients due to adverse reactions were

5.0 % in patients receiving raltegravir + emtricitabine (+) tenofovir disoproxil fumarate and 10.0 % in patients receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate.

Tabulated summary of adverse reactions

Adverse reactions considered by investigators to be causally related to raltegravir (alone or in combination 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).

Description of selected adverse reactions

In studies of raltegravir 400 mg twice daily, cancers were reported in treatment-experienced and treatment-naïve patients who initiated raltegravir 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 raltegravir and in the groups receiving comparators.

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with raltegravir. 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 raltegravir and darunavir compared to those containing raltegravir without darunavir or darunavir without raltegravir. 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 of raltegravir, patients with chronic (but not acute) active hepatitis B and/or hepatitis C co-infection were permitted to enroll provided that baseline liver function tests did not

exceed 5 times the upper limit of normal. In the treatment experienced studies, BENCHMRK 1 and

BENCHMRK 2 (Protocol 018 and Protocol 019), 16% of all patients (114/699) were co-infected; in the treatment-naïve studies, STARTMRK (Protocol 021) and ONCEMRK (Protocol 292), 6%

(34/563) and 2.9% (23/797), respectively, were co-infected. In general the safety profile of raltegravir

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 raltegravir as compared to 11 %, 10 % and 9 % of all other subjects treated with raltegravir. At 240-weeks, in treatment-naïve patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total

bilirubin occurred in 22 %, 44 % and 17 %, respectively, of co-infected subjects treated with raltegravir as compared to 13 %, 13 % and 5 % of all other subjects treated with raltegravir.

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 :

  To report any side effect(s):

·         Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC). SFDA

o Fax: +966-11-205-7662

o Call NPC at +966-11-20382222, Exts: 2317-2356-2353-2354-2334-2340.

o Toll free phone: 8002490000

o E-mail: npc.drug@sfda.gov.sa

o Website: www.sfda.gov.sa/npc

·         Other GCC States:

Please contact the relevant competent authority.

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., 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.

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.

Antiviral activity in vitro

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.

Resistance

Resistance analyses were performed in twice daily and once daily studies of raltegravir. In twice daily studies, 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. Raltegravir mutations identified in a once daily study were similar to those previously identified in twice daily studies (N155H, N155H/I203M and L74M/E92Q). Factors that reduced the likelihood of developing resistance included lower baseline viral load and use of other active

anti-retroviral agents. Mutations conferring resistance to raltegravir generally also confer resistance to the integrase strand transfer inhibitor elvitegravir. Mutations at amino acid 143 confer greater

resistance to raltegravir than to elvitegravir, and the E92Q mutation confers greater resistance to

elvitegravir than to raltegravir. Viruses harbouring a mutation at amino acid 148, along with one or more other raltegravir resistance mutations, may also have clinically significant resistance to dolutegravir.

Clinical experience

The evidence of efficacy of raltegravir was based on the analyses of 96-week data from two randomised, double-blind, placebo-controlled trials (BENCHMRK 1 and BENCHMRK 2, Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult patients, the analysis 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 of

48-week data from randomised, double-blind, active-control trial (ONCEMRK Protocol 292) in antiretroviral treatment-naïve HIV-1 infected adult patients.

Efficacy

Treatment-experienced adult patients (400 mg twice daily)

BENCHMRK 1 and BENCHMRK 2 (multi-centre, randomised, double-blind, placebo-controlled

trials) evaluated the safety and anti-retroviral activity of raltegravir 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 raltegravir 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.

Results 48-week and 96-week analyses

Durable outcomes (Week 48 and Week 96) for patients on the recommended dose raltegravir 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

BENCHMRK 1 and 2 Pooled

48 Weeks                                             96 Weeks

Parameter

Percent HIV-RNA < 400 copies/ml (95 % CI)

Raltegravir

400 mg twice daily + OBT (N = 462)

Placebo + OBT

(N = 237)

Raltegravir

400 mg twice daily + OBT (N = 462)

Placebo + OBT

(N = 237)

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)

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 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.

§ The Genotypic Sensitivity Score (GSS) was defined as the total oral ARTs in the optimised background therapy (OBT) to which a patient'sviral isolate

showed 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 with

failure 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 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.

Treatment-naïve adult patients (400 mg twice daily)

STARTMRK (multi-centre, randomised, double-blind, active-control trial) evaluated the safety and anti-retroviral activity of raltegravir 400 mg twice daily vs. efavirenz 600 mg at bedtime, in a

combination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naïve 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 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 on the

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

Baseline Characteristic‡

STARTMRK Study

48 Weeks                                            240 Weeks

Parameter

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

Raltegravir

400 mg twice daily

(N = 281)

Efavirenz

600 mg

at bedtime

(N = 282)

Raltegravir

400 mg twice daily

(N = 281)

Efavirenz

600 mg

at bedtime

(N = 282)

All patients‡                                                                                           189 (174, 204)      163 (148, 178)                                                                   374 (345, 403)      312 (284, 339)

Baseline Characteristic‡

† 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.

 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) evaluated the safety and anti-retroviral activity of raltegravir 1,200 mg once daily + emtricitabine (+) tenofovir disoproxil

fumarate vs. raltegravir 400 mg twice daily, in combination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naïve HIV-infected patients with HIV RNA > 1,000 copies/ml. Randomization

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 the group receiving raltegravir 1,200 mg once daily and the group receiving raltegravir 400 mg twice

daily.

Results 48-week 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 once daily and 235/266 (88.3%) in the group receiving raltegravir 400 mg twice daily. The treatment difference

(raltegravir 1,200 mg once daily-raltegravir 400 mg twice daily) was 0.5% with an associated 95% CI

of (-4.2, 5.2) establishing that raltegravir 1,200 mg once daily is non-inferior to raltegravir 400 mg twice daily. Week 48 outcomes from ONCEMRK are shown in Table 4.

Table 4

Efficacy Outcome at Weeks 48

ONCEMRK Study

Raltegravir

48 Weeks

Raltegravir

Parameter

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

600 mg (1,200 mg once daily)

(N = 531)

400 mg twice daily (N = 266)

All patients†                                                                                                                                           88.9 (85.9, 91.4)                                                                                               88.3 (83.9, 91.9)

Baseline Characteristic‡

ONCEMRK Study

Raltegravir

48 Weeks

Raltegravir

Parameter

600 mg (1,200 mg once daily)

(N = 531)

400 mg twice daily (N = 266)

Non-Clade B                                                    93.6 (89.1, 96.6)                                                                 93.2 (84.9, 97.8)

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

All patients‡                                                                                                                                             232 (215, 249)                                                                                                  234 (213, 255)

Baseline Characteristic‡

† 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 < 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.

Absorption

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.

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.

Raltegravir 1,200 mg once daily is also rapidly absorbed with median Tmax ~1.5 to 2 hours in the fasted state and generates a sharper absorption peak with a tendency to higher Cmax in comparison to raltegravir twice daily (1 x 400 mg tablet twice daily). In addition, relative to the raltegravir 400 mg formulation the raltegravir 600 mg formulation used in the 1,200 mg (2 x 600 mg) once daily dosing regimen has higher relative bioavailability (by 21 to 66%). Once absorbed, both formulations of raltegravir exhibit similar systemic pharmacokinetics. In patients, after 1,200 mg once daily raltegravir dosing, 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 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.

Raltegravir 600 mg tablets (2 x 600 mg once daily) may be administered with or without food. A single dose food effect study demonstrated that the 1,200 mg once daily had similar or smaller food effects when studied under high-fat and low-fat meal conditions when compared to the 400 mg twice

daily. 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 C24hr. Administration of a high fat meal 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 in

co-administration with food and concomitant medicines.

Distribution

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

10 µM.

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.

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 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.

UGT1A1 Polymorphism

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.

Special populations

Elderly

There was no clinically meaningful effect of age on raltegravir pharmacokinetics over the age range studied with raltegravir 400 mg twice daily. There was no clinically meaningful effect of age on

raltegravir pharmacokinetics over the age range studied in Protocol 292 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 body weight in adults for raltegravir 400 mg twice daily, and no clinically meaningful effect on raltegravir pharmacokinetics 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 not clinically meaningful.

Renal impairment

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 of the 400 mg twice daily SmPC). Because the extent to which raltegravir may be dialysable is unknown, dosing before a dialysis session should be avoided. 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.

Hepatic impairment

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 of the 400 mg twice daily SmPC). No hepatic impairment study has been conducted with raltegravir 1,200 mg once daily, however, based on results with the

400 mg twice daily tablet, no clinically meaningful effect is expected for mild and moderate hepatic impairment.

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.

Mutagenicity

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.

Carcinogenicity

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 1,200 mg once 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. This 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 it is of limited relevance for the intended clinical use. At the NOAEL, systemic exposure was similar to that at the clinical dose of 1,200 mg once daily. Standard genotoxicity studies to

evaluate mutagenicity and clastogenicity were negative.

Developmental toxicity

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 1,200 mg once daily based on AUC0-24 hr. No development effects were seen at 3.4-fold human exposure at 1,200 mg once daily based on AUC0-24 hr (see

section 4.6). Similar findings were not observed in rabbits.

6.1     List of excipients

Tablet core

- Microcrystalline cellulose

- Hypromellose 2910

- Magnesium stearate

- Croscarmellose sodium

Film-coating

- 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.

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

Store below 30°C

High density polyethylene (HDPE) bottle with a child-resistant polypropylene closure, induction seal and silica gel dessicant.

One pack size is available: 1 bottle with 60 tablets.

No special requirements for disposal.