4.1. Therapeutic indications

ISENTRESS is indicated in combination with other anti-retroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection (see sections 4.2, 4.4, 5.1 and 5.2).

4.2. Posology and method of administration

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).

Because the formulations have different pharmacokinetic profiles neither the granules for oral suspension nor the chewable tablets should be substituted for the 400 mg tablet or 600 mg tablet (see section 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 the granules 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 chewable tablet can be used as specified in Table 1 (see section 5.2). Refer to the chewable tablet SmPC 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.

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

(kg)

Volume (Dose) of Suspension to be Administered

Number of Chewable Tablets

3 to less than 4

2.5 mL (25 mg) twice daily

4 to less than 6

3 mL (30 mg) twice daily

6 to less than 8

4 mL (40 mg) twice daily

8 to less than 11

6 mL (60 mg) twice daily

11 to less than 14†

8 mL (80 mg) twice daily

3 x 25 mg twice daily

14 to less than 20†

10 mL (100 mg) twice daily

1 x 100 mg twice daily

20 to less than 25

1.5 x 100 mg‡ twice daily

*The weight-based dosing recommendation for the chewable tablet, and oral suspension in 10 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 to 4 weeks [28 days] of age*

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

Body Weight

(kg)

Volume (Dose) of Suspension to be Administered

Birth to 1 Week - Once daily dosing†

2 to less than 3

0.4 mL (4 mg) once daily

3 to less than 4

0.5 mL (5 mg) once daily

4 to less than 5

0.7 mL (7 mg) once daily

1 to 4 Weeks - Twice daily dosing‡

2 to less than 3

0.8 mL (8 mg) twice daily

3 to less than 4

1 mL (10 mg) twice daily

4 to less than 5

1.5 mL (15 mg) twice daily

*No data are available in pre-term neonates. The use of ISENTRESS is not recommended 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 water giving 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 be adjusted 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 weighing at least 25 kg and able to swallow a tablet. For patients weighing at least 25 kg but are unable to swallow a tablet, consider the chewable tablet. Refer to the 400 mg and chewable tablet SmPCs for additional dosing information.

ISENTRESS is also available for adults and paediatric patients (weighing at least 40 kg), as a 600 mg tablet to be administered as 1,200 mg once daily (two 600 mg tablets) for treatment-naïve patients or patients 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.

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).

Method of administration

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.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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.

Antacids

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

Rifampicin

Caution should be used when co-administering raltegravir with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of raltegravir can be considered in adults. There are no data to guide co-administration of raltegravir with rifampicin in patients below 18 years of age (see section 4.5).

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).

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 or sucrase-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 products for oral use administered concomitantly.

Sodium

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

4.5. Interaction with other medicinal products and other forms of interaction

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

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

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

Effect of raltegravir on the pharmacokinetics of other medicinal products

In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of 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 in darunavir plasma concentrations; the mechanism for this effect is unknown. However, the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically meaningful.

Effect of other medicinal products on the pharmacokinetics of raltegravir

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

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

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

Co-administration of raltegravir with other agents that increase gastric pH (e.g., omeprazole and famotidine) may increase the rate of raltegravir absorption and result in increased plasma levels of raltegravir (see Table 3). Safety profiles in the subgroup of patients in Phase III trials taking proton pump inhibitors or H2 antagonists were comparable with those who were not taking these antacids. Therefore, no dose adjustment is required with use of proton pump inhibitors or H2 antagonists.

All interaction studies were performed in adults.

Table 3

Pharmacokinetic Interaction Data

Medicinal products by therapeutic area

Interaction

(mechanism, if known)

Recommendations concerning co-administration

ANTI-RETROVIRAL

Protease inhibitors (PI)

atazanavir /ritonavir

(raltegravir 400 mg Twice Daily)

raltegravir AUC ↑ 41 %

raltegravir C12hr ↑ 77 %

raltegravir Cmax ↑ 24 %

(UGT1A1 inhibition)

No dose adjustment required for raltegravir.

tipranavir /ritonavir

(raltegravir 400 mg Twice Daily)

raltegravir AUC ↓ 24 %

raltegravir C12hr ↓ 55 %

raltegravir Cmax ↓ 18 %

(UGT1A1 induction)

No dose adjustment required for raltegravir.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

efavirenz

(raltegravir 400 mg Single Dose)

raltegravir AUC ↓ 36 %

raltegravir C12hr ↓ 21 %

raltegravir Cmax ↓ 36 %

(UGT1A1 induction)

No dose adjustment required for raltegravir.

etravirine

(raltegravir 400 mg Twice Daily)

raltegravir AUC ↓ 10 %

raltegravir C12hr ↓ 34 %

raltegravir Cmax ↓ 11 %

(UGT1A1 induction)

etravirine AUC ↑ 10 %

etravirine C12hr ↑ 17 %

etravirine Cmax ↑ 4 %

No dose adjustment required for raltegravir or etravirine.

Nucleoside/tide reverse transcriptase inhibitors

tenofovir disoproxil fumarate

(raltegravir 400 mg Twice Daily)

raltegravir AUC ↑ 49 %

raltegravir C12hr ↑ 3 %

raltegravir Cmax ↑ 64 %

(mechanism of interaction unknown)

tenofovir AUC ↓ 10 %

tenofovir C24hr ↓ 13 %

tenofovir Cmax ↓ 23 %

No dose adjustment required for raltegravir or tenofovir disoproxil fumarate.

CCR5 inhibitors

maraviroc

(raltegravir 400 mg Twice Daily)

raltegravir AUC ↓ 37 %

raltegravir C12hr ↓ 28 %

raltegravir Cmax ↓ 33 %

(mechanism of interaction unknown)

maraviroc AUC ↓ 14 %

maraviroc C12hr ↓ 10 %

maraviroc Cmax ↓ 21 %

No dose adjustment required for raltegravir or maraviroc.

HCV ANTIVIRALS

NS3/4A protease inhibitors (PI)

boceprevir

(raltegravir 400 mg Single Dose)

raltegravir AUC ↑ 4 %

raltegravir C12hr ↓ 25 %

raltegravir Cmax ↑ 11 %

(mechanism of interaction unknown)

No dose adjustment required for raltegravir or boceprevir.

ANTIMICROBIALS

Antimycobacterial

rifampicin

(raltegravir 400 mg Single Dose)

raltegravir AUC ↓ 40 %

raltegravir C12hr ↓ 61 %

raltegravir Cmax ↓ 38 %

(UGT1A1 induction)

Rifampicin reduces plasma levels of raltegravir. If co-administration with rifampicin is unavoidable, a doubling of the dose of raltegravir can be considered (see section 4.4).

SEDATIVE

midazolam

(raltegravir 400 mg Twice Daily)

midazolam AUC ↓ 8 %

midazolam Cmax ↑ 3 %

No dosage adjustment required for raltegravir or midazolam.

These results indicate that raltegravir is not an inducer or inhibitor of CYP3A4, and raltegravir is thus not anticipated to affect the pharmacokinetics of medicinal products which are CYP3A4 substrates.

METAL CATION ANTACIDS

aluminium and magnesium hydroxide antacid

(raltegravir 400 mg Twice Daily)

raltegravir AUC ↓ 49 %

raltegravir C12 hr ↓ 63 %

raltegravir Cmax ↓ 44 %

2 hours before raltegravir

raltegravir AUC ↓ 51 %

raltegravir C12 hr ↓ 56 %

raltegravir Cmax ↓ 51 %

2 hours after raltegravir

raltegravir AUC ↓ 30 %

raltegravir C12 hr ↓ 57 %

raltegravir Cmax ↓ 24 %

6 hours before raltegravir

raltegravir AUC ↓ 13 %

raltegravir C12 hr ↓ 50 %

raltegravir Cmax ↓ 10 %

6 hours after raltegravir

raltegravir AUC ↓ 11 %

raltegravir C12 hr ↓ 49 %

raltegravir Cmax ↓ 10 %

(chelation of metal cations)

Aluminium and magnesium containing antacids reduce raltegravir plasma levels. Co-administration of raltegravir with aluminium and/or magnesium containing antacids is not recommended.

calcium carbonate antacid

(raltegravir 400 mg Twice Daily)

raltegravir AUC ↓ 55 %

raltegravir C12 hr ↓ 32 %

raltegravir Cmax ↓ 52 %

(chelation of metal cations)

No dose adjustment required for raltegravir.

Other METAL CATION

Iron salts

Expected:

Raltegravir AUC ↓

(chelation of metal cations)

Given simultaneously iron salts are expected to reduce raltegravir plasma levels; taking iron salts at least two hours from the administration of raltegravir may allow to limit this effect.

H2 BLOCKERS AND PROTON PUMP INHIBITORS

omeprazole

(raltegravir 400 mg Twice Daily)

raltegravir AUC ↑ 37 %

raltegravir C12 hr ↑ 24 %

raltegravir Cmax ↑ 51 %

(increased solubility)

No dose adjustment required for raltegravir.

famotidine

(raltegravir 400 mg Twice Daily)

raltegravir AUC ↑ 44 %

raltegravir C12 hr ↑ 6 %

raltegravir Cmax ↑ 60 %

(increased solubility)

No dose adjustment required for raltegravir.

HORMONAL CONTRACEPTIVES

Ethinyl Estradiol

Norelgestromin

(raltegravir 400 mg Twice Daily)

Ethinyl Estradiol AUC ↓ 2 %

Ethinyl Estradiol Cmax ↑ 6 %

Norelgestromin AUC ↑ 14 %

Norelgestromin Cmax ↑ 29 %

No dosage adjustment required for raltegravir or hormonal contraceptives (estrogen- and/or progesterone-based).

OPIOID ANALGESICS

methadone

(raltegravir 400 mg Twice Daily)

methadone AUC ↔

methadone Cmax ↔

No dose adjustment required for raltegravir or methadone.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data for the use of raltegravir granules for oral suspension 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 granules for oral suspension should be used during pregnancy only if the expected benefit justifies 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 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.

4.7. Effects on ability to drive and use machines

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).

4.8. Undesirable effects

Summary of the safety profile

In randomised clinical trials raltegravir 400 mg twice daily was administered in combination with fixed 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 received raltegravir 1,200 mg once daily with emtricitabine and tenofovir disoproxil fumarate for up to 96 weeks. See section 5.1.

The most frequently reported adverse reactions during treatment were headache, nausea and abdominal pain. The most frequently reported serious adverse reaction was immune reconstitution syndrome and rash. The rates of discontinuation of raltegravir due to adverse reactions were 5% or less in clinical trials.

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

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).

System Organ Class

Frequency

Adverse reactions

Raltegravir (alone or in combination with other ART)

Infections and infestations

Uncommon

genital herpes, folliculitis, gastroenteritis, herpes simplex, herpes virus infection, herpes zoster, influenza, lymph node abscess, molluscum contagiosum, nasopharyngitis, upper respiratory tract infection

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon

skin papilloma

Blood and lymphatic system disorders

Uncommon

anaemia, iron deficiency anaemia, lymph node pain, lymphadenopathy, neutropenia, thrombocytopenia

Immune system disorders

Uncommon

immune reconstitution syndrome, drug hypersensitivity, hypersensitivity

Metabolism and nutrition disorders

Common

decreased appetite

Uncommon

cachexia, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperphagia, increased appetite, polydipsia, body fat disorder

Psychiatric disorders

Common

abnormal dreams, insomnia, nightmare, abnormal behaviour, depression

Uncommon

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

Nervous system disorders

Common

dizziness, headache, psychomotor hyperactivity

Uncommon

amnesia, carpal tunnel syndrome, cognitive disorder, disturbance in attention, dizziness postural, dysgeusia, hypersomnia, hypoaesthesia, lethargy, memory impairment, migraine, neuropathy peripheral, paraesthesia, somnolence, tension headache, tremor, poor quality sleep

Eye disorders

Uncommon

visual impairment

Ear and labyrinth disorders

Common

vertigo

Uncommon

tinnitus

Cardiac disorders

Uncommon

palpitations, sinus bradycardia, ventricular extrasystoles

Vascular disorders

Uncommon

hot flush, hypertension

Respiratory, thoracic and mediastinal disorders

Uncommon

dysphonia, epistaxis, nasal congestion

Gastrointestinal disorders

Common

abdominal distention, abdominal pain, diarrhoea, flatulence, nausea, vomiting, dyspepsia

Uncommon

gastritis, abdominal discomfort, abdominal pain upper, abdominal tenderness, anorectal discomfort, constipation, dry mouth, epigastric discomfort, erosive duodenitis, eructation, gastroesophageal reflux disease, gingivitis, glossitis, odynophagia, pancreatitis acute, peptic ulcer, rectal haemorrhage

Hepato-biliary disorders

Uncommon

hepatitis, hepatic steatosis, hepatitis alcoholic, hepatic failure

Skin and subcutaneous tissue disorders

Common

rash

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, drug rash with eosinophilia and systemic symptoms (DRESS)

Musculoskeletal and connective tissue disorders

Uncommon

arthralgia, arthritis, back pain, flank pain, musculoskeletal pain, myalgia, neck pain, osteopenia, pain in extremity, tendonitis, rhabdomyolysis

Renal and urinary disorders

Uncommon

renal failure, nephritis, nephrolithiasis, nocturia, renal cyst, renal impairment, tubulointerstitial nephritis

Reproductive system and breast disorders

Uncommon

erectile dysfunction, gynaecomastia, menopausal symptoms

General disorders and administration site conditions

Common

asthenia, fatigue, pyrexia

Uncommon

chest discomfort, chills, face oedema, fat tissue increased, feeling jittery, malaise, submandibular mass, oedema peripheral, pain

Investigations

Common

alanine aminotransferase increased, atypical lymphocytes, aspartate aminotransferase increased, blood triglycerides increased, lipase increased, blood pancreatic amylase increased

Uncommon

absolute neutrophil count decreased, alkaline phosphatase increased, blood albumin decreased, blood amylase increased, blood bilirubin increased, blood cholesterol increased, blood creatinine increased, blood glucose increased, blood urea nitrogen increased, creatine phosphokinase increased, fasting blood glucose increased, glucose urine present, high density lipoprotein increased, international normalised ratio increased, low density lipoprotein increased, platelet count decreased, red blood cells urine positive, waist circumference increased, weight increased, white blood cell count decreased

Injury, poisoning and procedural complications

Uncommon

accidental overdose

Description of selected adverse reactions

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 patients 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 and autoimmune hepatitis) 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 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 combination with other agents for HIV-1. 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 co-infected with hepatitis B and/or hepatitis C virus

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 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 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 patients treated with raltegravir as compared to 13 %, 13 % and 5 % of all other patients treated with raltegravir.

Paediatric population

Children and adolescents 2 to 18 years of age

Raltegravir has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 to 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066 (see sections 5.1 and 5.2). Of the 126 patients, 96 received the recommended dose of raltegravir.

In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through Week 48 were comparable to those observed in adults.

One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behaviour and insomnia; one patient experienced a Grade 2 serious drug related allergic rash.

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

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 than 2 years of age, in combination with other antiretroviral agents in IMPAACT P1066 (see sections 5.1 and 5.2).

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

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

HIV-1 Exposed Neonates

In IMPAACT P1110 (see section 5.2) eligible infants were at least 37 weeks gestation and at least 2 kg in weight. Sixteen (16) neonates received 2 doses of ISENTRESS in first 2 weeks of life, and 26 neonates received 6 weeks of daily dosing; all were followed for 24 weeks. There were no drug related clinical adverse experiences and three drug-related laboratory adverse experiences (one a transient Grade 4 neutropenia in a subject receiving zidovudine containing prevention of mother to child transmission (PMTCT), and two bilirubin elevations (one each, Grade 1 and Grade 2) considered non-serious and not requiring specific therapy).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.