ISENTRESS 100mg oral suspension pellets medication leaflet

ISENTRESS 100 mg granules for oral suspension

Each sachet contains 100 mg of raltegravir (as potassium). Following reconstitution, the oralsuspension has a concentration of 10 mg per mL.

Each sachet contains up to: 0.5 mg fructose, 1.5 mg sorbitol and 4.7 mg sucrose.

For the full list of excipients, see section 6.1.

Granules for oral suspension.

White to off-white, granular powder that may contain yellow or beige to tan particles, in a single-usesachet.

ISENTRESS is indicated in combination with other anti-retroviral medicinal products for thetreatment of human immunodeficiency virus (HIV-1) infection (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).

Because the formulations have different pharmacokinetic profiles neither the granules for oralsuspension nor the chewable tablets should be substituted for the 400 mg tablet or 600 mg tablet (seesection 5.2). The granules for oral suspension and the chewable tablets have not been studied in

HIV-infected adolescents (12 to 18 years) or adults.

Neonates, Infants and Toddlers

Dosing is weight based from birth as specified in Table 1 and Table 2. Patients can remain on thegranules for oral suspension as long as their weight is below 20 kg.

For patients weighing between 11 and 20 kg, either the granules for oral suspension or the chewabletablet can be used as specified in Table 1 (see section 5.2). Refer to the chewable tablet SmPC foradditional 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 dosingrecommendations can be made.

Table 1

Recommended Dose* for ISENTRESS Granules For Oral Suspension and Chewable Tablets in

Paediatric Patients at least 4 weeks of age and weighing 3 to 25 kg

Body Weight Volume (Dose) of Number of Chewable(kg) Suspension Tabletsto be Administered3 to less than 4 2.5 mL (25 mg) twice daily4 to less than 6 3 mL (30 mg) twice daily6 to less than 8 4 mL (40 mg) twice daily8 to less than 11 6 mL (60 mg) twice daily11 to less than 14† 8 mL (80 mg) twice daily 3 x 25 mg twice daily14 to less than 20† 10 mL (100 mg) twice daily 1 x 100 mg twice daily20 to less than 25 1.5 x 100 mg‡ twice daily

*The weight-based dosing recommendation for the chewable tablet, and oral suspension in10 mL of water is based on approximately 6 mg/kg/dose twice daily (see section 5.2)†For weight between 11 and 20 kg either formulation can be used.

Note: The chewable tablets are available as 25 mg and 100 mg tablets.‡The 100 mg chewable tablet can be divided into equal 50 mg doses.

However, breaking the tablets should be avoided whenever possible.

Table 2

Recommended Dose for ISENTRESS For Oral Suspension in Full-Term Neonates (Birth to4 weeks [28 days] of age*

Note: If the mother has taken ISENTRESS 2-24 hours before delivery, the infant’s first dose should begiven between 24-48 hours after birth.

Body Weight Volume (Dose) of Suspension(kg) to be Administered

Birth to 1 Week - Once daily dosing†2 to less than 3 0.4 mL (4 mg) once daily3 to less than 4 0.5 mL (5 mg) once daily4 to less than 5 0.7 mL (7 mg) once daily1 to 4 Weeks - Twice daily dosing‡2 to less than 3 0.8 mL (8 mg) twice daily3 to less than 4 1 mL (10 mg) twice daily4 to less than 5 1.5 mL (15 mg) twice daily

*No data are available in pre-term neonates. The use of ISENTRESS is notrecommended in pre-term neonates.†The dosing recommendations are based on approximately:1.5 mg/kg/dose.‡The dosing recommendations are based on approximately:3 mg/kg/dose.

Maximum dose of oral suspension is 100 mg twice daily.

Each single-use sachet contains 100 mg of raltegravir which is to be suspended in 10 mL of watergiving a final concentration of 10 mg per mL (see section 6.6).

Scheduled appointments for the patient should be kept because the ISENTRESS dosage should beadjusted as the child grows.

Additional formulations and strengths available:

ISENTRESS is also available in a 400 mg tablet for use in adults, adolescents and children weighingat least 25 kg and able to swallow a tablet. For patients weighing at least 25 kg but are unable toswallow a tablet, consider the chewable tablet. Refer to the 400 mg and chewable tablet SmPCs foradditional dosing information.

ISENTRESS is also available for adults and paediatric patients (weighing at least 40 kg), as a 600 mgtablet to be administered as 1,200 mg once daily (two 600 mg tablets) for treatment-naïve patients orpatients who are virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily.

Refer to the 600 mg tablet SmPC for additional dosing information.

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).

Oral use.

ISENTRESS granules for oral suspension can be administered with or without food (see section 5.2).

For details on preparation and administration of the suspension, see section 6.6.

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.

Antacids

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

Caution should be used when co-administering raltegravir with strong inducers of uridine diphosphateglucuronosyltransferase (UGT) 1A1 (e.g., rifampicin). Rifampicin reduces plasma levels ofraltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration withrifampicin is unavoidable, a doubling of the dose of raltegravir can be considered in adults. There areno data to guide co-administration of raltegravir with rifampicin in patients below 18 years of age (seesection 4.5).

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).

Fructose

This medicinal product contains up to 0.5 mg fructose per sachet.

Fructose may damage teeth.

Sucrose

This medicinal product contains up to 4.7 mg sucrose per sachet.

Sucrose may be harmful to the teeth.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption orsucrase-isomaltase insufficiency should not take this medicine.

Sorbitol

This medicine contains sorbitol (E 420) up to 1.5 mg per sachet.

In medicinal products for oral use, sorbitol may affect the bioavailability of other medicinal productsfor oral use administered concomitantly.

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

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 does not inhibit

P-glycoprotein-mediated transport. Based on these data, raltegravir is not expected to affect thepharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.

Based on in vitro and in vivo studies, raltegravir is eliminated mainly by metabolism via a

UGT1A1-mediated glucuronidation pathway.

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

Effect of raltegravir on the pharmacokinetics of other medicinal products

In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokineticsof etravirine, maraviroc, tenofovir disoproxil fumarate, hormonal contraceptives, methadone,midazolam or boceprevir.

In some studies, co-administration of raltegravir with darunavir resulted in a modest decrease indarunavir plasma concentrations; the mechanism for this effect is unknown. However, the effect ofraltegravir on darunavir plasma concentrations does not appear to be clinically meaningful.

Effect of other medicinal products on the pharmacokinetics of raltegravir

Given that raltegravir is metabolised primarily via UGT1A1, caution should be used whenco-administering raltegravir with strong inducers of UGT1A1 (e.g., rifampicin). Rifampicin reducesplasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, ifco-administration with rifampicin is unavoidable, a doubling of the dose of raltegravir can beconsidered in adults. There are no data to guide co-administration of raltegravir with rifampicin inpatients below 18 years of age (see section 4.4). The impact of other strong inducers of drugmetabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potentinducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, glucocorticoids, St. John's wort,pioglitazone) may be used with the recommended dose of raltegravir.

Co-administration of raltegravir with medicinal products that are known to be potent UGT1A1inhibitors (e.g., atazanavir) may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors(e.g., indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extentcompared with atazanavir. In addition, tenofovir disoproxil fumarate may increase plasma levels ofraltegravir, however, the mechanism for this effect is unknown (see Table 3). From the clinical trials, alarge proportion of patients used atazanavir and/or tenofovir disoproxil fumarate, both agents thatresult in increases in raltegravir plasma levels, in the optimised background regimens. The safetyprofile observed in patients who used atazanavir and/or tenofovir disoproxil fumarate was generallysimilar to the safety profile of patients who did not use these agents. Therefore, no dose adjustment isrequired.

Co-administration of raltegravir with antacids containing divalent metal cations may reduce raltegravirabsorption by chelation, resulting in a decrease of raltegravir plasma levels. Taking an aluminium andmagnesium antacid within 6 hours of raltegravir administration significantly decreased raltegravirplasma levels. Therefore, co-administration of raltegravir with aluminium and/or magnesiumcontaining antacids is not recommended. Co-administration of raltegravir with a calcium carbonateantacid decreased raltegravir plasma levels; however, this interaction is not considered clinicallymeaningful. Therefore, when raltegravir is co-administered with calcium carbonate containingantacids no dose adjustment is required.

Co-administration of raltegravir with other agents that increase gastric pH (e.g., omeprazole andfamotidine) may increase the rate of raltegravir absorption and result in increased plasma levels ofraltegravir (see Table 3). Safety profiles in the subgroup of patients in Phase III trials taking protonpump inhibitors or H2 antagonists were comparable with those who were not taking these antacids.

Therefore, no dose adjustment is required with use of proton pump inhibitors or H2 antagonists.

All interaction studies were performed in adults.

Table 3

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.

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

raltegravir Cmax  18 %(UGT1A1 induction)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)efavirenz raltegravir AUC  36 % No dose adjustment required(raltegravir 400 mg Single Dose) raltegravir C12hr  21 % for raltegravir.

raltegravir Cmax  36 %(UGT1A1 induction)etravirine raltegravir AUC  10 % No dose adjustment required(raltegravir 400 mg Twice Daily) raltegravir C12hr  34 % for raltegravir or etravirine.

raltegravir Cmax  11 %(UGT1A1 induction)etravirine AUC  10 %etravirine C12hr  17 %etravirine Cmax  4 %

Nucleoside/tide reverse transcriptase inhibitorstenofovir disoproxil fumarate raltegravir AUC  49 % No dose adjustment required(raltegravir 400 mg Twice Daily) raltegravir C12hr  3 % for raltegravir or tenofovirraltegravir Cmax ↑ 64 % disoproxil fumarate.

(mechanism of interactionunknown)tenofovir AUC  10 %tenofovir C24hr  13 %tenofovir Cmax ↓ 23 %

CCR5 inhibitorsmaraviroc raltegravir AUC  37 % No dose adjustment required(raltegravir 400 mg Twice Daily) raltegravir C12hr  28 % for raltegravir or maraviroc.

raltegravir Cmax  33 %(mechanism of interactionunknown)maraviroc AUC  14 %maraviroc C12hr  10 %maraviroc Cmax ↓ 21 %

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

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 or boceprevir.

raltegravir Cmax  11 %(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 can be considered(see section 4.4).

SEDATIVEmidazolam midazolam AUC  8 % No dosage adjustment required(raltegravir 400 mg Twice Daily) midazolam Cmax ↑ 3 % for raltegravir 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 % Aluminium and magnesiumhydroxide antacid raltegravir C12 hr  63 % containing antacids reduce(raltegravir 400 mg Twice Daily) raltegravir Cmax  44 % raltegravir plasma levels.

Co-administration of2 hours before raltegravir raltegravir with aluminiumraltegravir AUC  51 % and/or magnesium containingraltegravir C  56 % antacids is not recommended.12 hrraltegravir Cmax  51 %2 hours after raltegravirraltegravir AUC  30 %raltegravir C12 hr  57 %raltegravir Cmax  24 %6 hours before raltegravirraltegravir AUC  13 %raltegravir C12 hr  50 %raltegravir Cmax  10 %6 hours after raltegravirraltegravir AUC  11 %raltegravir C12 hr  49 %raltegravir Cmax  10 %(chelation of metal cations)

Medicinal products by therapeutic Interaction Recommendationsarea (mechanism, if known) concerningco-administrationcalcium carbonate antacid raltegravir AUC  55 % No dose adjustment required(raltegravir 400 mg Twice Daily) raltegravir C12 hr  32 % for raltegravir.

raltegravir Cmax  52 %(chelation of metal cations)

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 % No dose adjustment required(raltegravir 400 mg Twice Daily) raltegravir C12 hr ↑ 24 % for raltegravir.

raltegravir Cmax ↑ 51 %(increased solubility)famotidine raltegravir AUC ↑ 44 % No dose adjustment required(raltegravir 400 mg Twice Daily) raltegravir C12 hr ↑ 6 % for raltegravir.

raltegravir Cmax ↑ 60 %(increased solubility)

HORMONAL CONTRACEPTIVES

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

Norelgestromin Ethinyl Estradiol Cmax ↑ 6 % for raltegravir or hormonal(raltegravir 400 mg Twice Daily) Norelgestromin AUC ↑ 14 % contraceptives (estrogen-

Norelgestromin Cmax ↑ 29 % and/or progesterone-based).

OPIOID ANALGESICSmethadone methadone AUC ↔ No dose adjustment required(raltegravir 400 mg Twice Daily) methadone Cmax ↔ for raltegravir or methadone.

There are no data for the use of raltegravir granules for oral suspension in pregnant women. A largeamount of data on pregnant women with exposure to raltegravir 400 mg twice daily during the firsttrimester (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 dailyduring the second and/or third trimester (between 300-1,000 prospective pregnancy outcomes)indicates no increased risk of feto/neonatal toxicity.

Raltegravir granules for oral suspension should be used during pregnancy only if the expected benefitjustifies the potential risk to the fetus. See section 4.2 for dosing recommendations.

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 reaction was 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

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

System Organ Class Frequency Adverse reactions

Raltegravir (alone or in combination withother ART)

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

Cancers were reported in treatment-experienced and treatment-naïve patients who initiated raltegravirin conjunction with other antiretroviral agents. The types and rates of specific cancers were thoseexpected in a highly immunodeficient population. The risk of developing cancer in these studies wassimilar in the groups receiving raltegravir and in the groups 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.

Children and adolescents 2 to 18 years of age

Raltegravir has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children andadolescents 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 dose of raltegravir.

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 has also been studied in 26 HIV-1 infected infants and toddlers 4 weeks to less than2 years of age, in combination with other antiretroviral agents in IMPAACT P1066 (see sections 5.1and 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 and theanalysis of 240-week data from a randomised, double-blind, active-control trial (STARTMRK,

Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult patients.

Treatment-experienced adult patients

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 3.

Table 4

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)

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/mm3104 (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

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

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) was9.5 % with an associated 95 % CI of (1.7, 17.3). Week 48 and Week 240 outcomes for patients on therecommended dose of raltegravir 400 mg twice daily from STARTMRK are shown in Table 5.

Table 5

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.

Children and adolescents 2 to 18 years of age

IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile,safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled126 treatment experienced children and adolescents 2 to 18 years of age. Patients were stratified byage, enrolling adolescents first and then successively younger children. Patients received either the400 mg tablet formulation (6 to 18 years of age) or the chewable tablet formulation (2 to less than12 years of age). Raltegravir was administered with an optimised background regimen.

The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was basedupon achieving similar raltegravir plasma exposure and trough concentration as seen in adults, andacceptable short-term safety. After dose selection, additional patients were enrolled for evaluation oflong-term safety, tolerability and efficacy. Of the 126 patients, 96 received the recommended dose ofraltegravir (see section 4.2).

Table 6

Baseline Characteristics and Efficacy Outcomes at Weeks 24 and 48 from IMPAACT P1066(2 to 18 years of age)

Final dose population

Parameter N=96

Demographics

Age (years), median [range] 13 [2 - 18]

Male Gender 49 %

Caucasian 34 %

Black 59 %

Baseline Characteristics

Plasma HIV-1 RNA (log10 copies/mL), mean [range] 4.3 [2.7 - 6]

CD4 cell count (cells/mm3 ), median [range] 481 [0 - 2361]

CD4 percent, median [range] 23.3 % [0 - 44]

HIV-1 RNA >100,000 copies/mL 8 %

CDC HIV category B or C 59 %

Prior ART Use by Class

NNRTI 78 %

PI 83 %

Response Week 24 Week 48

Achieved ≥1 log10 HIV RNA drop from baseline or<400 copies/mL 72 % 79 %

Achieved HIV RNA <50 copies/mL 54 % 57 %

Mean CD4 cell count (%) increase from baseline 119 cells/mm3 156 cells/mm3(3.8 %) (4.6 %)

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

IMPAACT P1066 also enrolled HIV-infected, infants and toddlers 4 weeks to less than 2 years of agewho had received prior antiretroviral therapy either as prophylaxis for prevention of mother to childtransmission (PMTCT) and/or as combination antiretroviral therapy for treatment of HIV infection.

Raltegravir was administered as granules for oral suspension formulation without regard to food incombination with an optimised background regimen that included lopinavir plus ritonavir in two-thirdsof patients.

Table 7

Baseline Characteristics and Efficacy Outcomes at Weeks 24 and 48 from IMPAACT P1066(4 weeks to less than 2 years of age)

Parameter N=26

Demographics

Age (weeks), median [range] 28 [4 -100]

Male Gender 65 %

Caucasian 8 %

Black 85 %

Baseline Characteristics

Plasma HIV-1 RNA (log10 copies/mL), mean [range] 5.7 [3.1 - 7]

CD4 cell count (cells/mm3 ), median [range] 1,400 [131 -3,648]

CD4 percent, median [range] 18.6 % [3.3 - 39.3]

HIV-1 RNA >100,000 copies/mL 69 %

CDC HIV category B or C 23 %

Prior ART Use by Class

NNRTI 73 %

NRTI 46%

PI 19 %

Response Week 24 Week 48

Achieved ≥1 log10 HIV RNA drop from baseline or<400 copies/mL 91 % 85 %

Achieved HIV RNA <50 copies/mL 43 % 53 %

Mean CD4 cell count (%) increase from baseline 500 cells/mm3 492 cells/mm3(7.5 %) (7.8 %)

Virologic failure Week 24 Week 48

Non-responder 0 0

Rebounder 0 4

Number with genotype available* 0 2

*One patient had a mutation at the 155 position.

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. Dose proportionality has not been establishedin patients.

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 may be administered with or without food. Raltegravir was administered without regard tofood in the pivotal safety and efficacy studies in HIV-infected patients. Administration of multipledoses of raltegravir following a moderate-fat meal did not affect raltegravir AUC to a clinicallymeaningful 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 raltegravirfollowing a high-fat meal increased AUC and Cmax by approximately 2-fold and increased C12 hr by4.1-fold. Administration of raltegravir following a low-fat meal decreased AUC and Cmax by 46 % and52 %, respectively; C12 hr was essentially unchanged. Food appears to increase pharmacokineticvariability relative to fasting.

Overall, considerable variability was observed in the pharmacokinetics of raltegravir. For observed

C12 hr in BENCHMRK 1 and 2 the coefficient of variation (CV) for inter-subject variability = 212 %and the CV for intra-subject variability = 122 %. Sources of variability may include differences 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 8 displays pharmacokinetic parameters in the 400 mg tablet, the chewable tablet, and thegranules for oral suspension, by body weight.

Table 8

Raltegravir Pharmacokinetic Parameters IMPAACT P1066 Following Administration of Dosesin Section 4.2

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 %)3 to less than Weight based dosing, see20 kg Oral suspension dosing Table 1 19 24.5 (43 %) 113 (69 %)

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

HIV-1 Exposed Neonates

IMPAACT P1110 is a Phase I trial to evaluate the safety and pharmacokinetics of raltegravir granulesfor suspension (GFS) with standard care PMTCT in full term HIV-1-exposed neonates. Cohort 1(N=16, 10 exposed and 6 unexposed to raltegravir in utero) received 2 single doses of raltegravir GFS(within 48 hours and 7 - 10 days after birth); Cohort 2 (N=26, all raltegravir unexposed in utero)received raltegravir GFS for 6 weeks: 1.5 mg/kg once daily starting within 48 hours of birth through

Week 1; 3 mg/kg twice daily Weeks 2 to 4; and 6 mg/kg twice daily Weeks 5 and 6.

Table 9 displays pharmacokinetic parameters for neonates in Cohort 2 at birth and at 2 weeks of age.

Elimination of raltegravir in vivo in human is primarily through the UGT1A1-mediatedglucuronidation pathway. UGT1A1 catalytic activity is negligible at birth and matures after birth. Thedose recommended for neonates less than 4 weeks of age takes into consideration the rapidlyincreasing UGT1A1 activity and drug clearance from birth to 4 weeks of age.

Table 9: Raltegravir Pharmacokinetic Parameters IMPAACT P1110 Following Age and Weight

Based Dosing of the Granules for Suspension

Geometric Mean Geometric Mean

Age (hours/days) at PK (%CV†) (% CV†)

Sampling Dose (See Table 2) N* AUC (mg*hr/L) Ctrough (ng/mL)

Birth - 48 hours 1.5 mg/kg once daily 25 38.2 (38.4%)‡ 947.9 (64.2%) ‡15 to 18 days 3.0 mg/kg twice daily 23 14.3 (43.3%) § 558 (83.7%) §

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

†Geometric coefficient of variation.

‡ AUC0-24hr (N = 24); C24hr§AUC0-12hr; C12hr

There was no clinically meaningful effect of age on raltegravir pharmacokinetics in healthy subjectsand patients with HIV-1 infection, over the age range studied (19 to 84 years, with few individualsover the age of 65).

Gender, race and BMI

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

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). Because the extent to which raltegravir may bedialysable is unknown, dosing before a dialysis session should be avoided.

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).

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 400 mg twice 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 400 mg twice daily. Standard genotoxicity studies to evaluatemutagenicity 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 400 mg twicedaily based on AUC0-24 hr. No development effects were seen at 3.4-fold human exposure at 400 mgtwice daily based on AUC0-24 hr. Similar findings were not observed in rabbits.

- Hydroxypropyl cellulose

- Sucralose

- Mannitol (E 421)

- Monoammonium glycyrrhizinate

- Sorbitol (E 420)

- Fructose

- Banana flavour

- Sucrose

- Crospovidone, TypeA

- Magnesium stearate

- Hypromellose 2910/6cP

- Macrogol/PEG 400

- Ethylcellulose 20 cP

- Ammonium hydroxide

- Medium chain triglycerides

- Oleic acid

- Microcrystalline cellulose

- Carmellose sodium

Not applicable.

3 years for unopened sachet.

After reconstitution: 30 minutes when stored at or below 30 °C.

This medicinal product does not require any special temperature storage conditions. Store in theoriginal package in order to protect from moisture.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

PET/aluminium/LLDPE sachets.

One carton contains 60 sachets, two 1 mL, two 3 mL and two 10 mL oral dosing syringes and2 mixing cups.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Each single-use sachet contains 100 mg of raltegravir which is to be suspended in 10 mL of watergiving a final concentration of 10 mg per mL.

After administration of the required volume, the remaining suspension in the mixing cup cannot be re-used and must be discarded.

Parents and/or caregivers should be instructed to read the instructions for use booklet before preparingand administering ISENTRESS granules for oral suspension to paediatric patients.

The dose should be administered orally within 30 minutes of mixing.

Complete details on preparation and administration of the suspension can be found in the instructionsfor use booklet that is included in the carton.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/07/436/005

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.