4.1. Therapeutic indications

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

4.2. Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Raltegravir should be used in combination with other active anti-retroviral therapies (ARTs) (see sections 4.4 and 5.1).

Adults and paediatric population

In adults and paediatric patients (weighing at least 40 kg), the recommended dosage is 1,200 mg (two 600 mg tablets) once daily for treatment-naïve patients or patients who are virologically suppressed on an initial regimen of RALTEGRAVIR 400 mg twice daily.

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

The maximum dose of the chewable tablet is 300 mg twice daily. Because the formulations have different pharmacokinetic profiles neither the chewable tablets nor the granules for oral suspension should be substituted for the 400 mg tablet or the 600 mg tablet (see section 5.2). The chewable tablets and the granules for oral suspension have not been studied in HIV-infected adolescents (12 to 18 years) or adults.

Elderly

There is limited information regarding the use of raltegravir in the elderly (see section 5.2). Therefore, Raltegravir 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, RALTEGRAVIR should be used with caution in patients with severe hepatic impairment (see sections 4.4 and 5.2).

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

Method of administration

Oral use.

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

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

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.

Atazanavir

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

Tipranavir/ritonavir

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

Antacids

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

Strong inducers of drug metabolizing enzymes

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

Myopathy and rhabdomyolysis

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

Severe skin and hypersensitivity reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking raltegravir, in most cases concomitantly with other medicinal products associated with these reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterised by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue raltegravir and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping raltegravir treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Rash

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

Sodium

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

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

In vitro, raltegravir is a weak inhibitor of organic anion transporter (OAT) 1 (IC50 of 109 µM) and OAT3 (IC50 of 18.8 µM). Caution is recommended when co-administering raltegravir 1,200 mg once daily with sensitive OAT1 and/or OAT3 substrates.

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

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

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

Effect of raltegravir on the pharmacokinetics of other medicinal products

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

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

Effect of other medicinal products on the pharmacokinetics of raltegravir

Inducers of drug metabolizing enzymes

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

Inhibitors of UGT1A1

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

Antacids

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

Agents that increase gastric pH

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

Additional considerations

No studies have been conducted to evaluate the drug interactions of ritonavir, tipranavir/ritonavir, boceprevir or etravirine with raltegravir 1,200 mg (2 x 600 mg) once daily. While the magnitudes of change on raltegravir exposure from raltegravir 400 mg twice daily by ritonavir, boceprevir or etravirine were small, the impact from tipranavir/ritonavir was greater (GMR Ctrough=0.45, GMR AUC=0.76). Co-administration of raltegravir 1,200 mg once daily and tipranavir/ritonavir is not recommended.

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

All interaction studies were performed in adults.

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

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

Table 1

Pharmacokinetic Interaction Data

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 (400 mg twice daily).

atazanavir

(raltegravir 1,200 mg single dose)

raltegravir AUC ↑ 67%

raltegravir C24hr ↑ 26%

raltegravir Cmax ↑ 16%

(UGT1A1 inhibition)

Co-administration of raltegravir (1,200 mg once daily) is not recommended.

tipranavir /ritonavir

(raltegravir 400 mg Twice Daily)

raltegravir AUC ↓ 24%

raltegravir C12hr ↓ 55%

raltegravir Cmax ↓ 18%

(UGT1A1 induction)

No dose adjustment required for raltegravir (400 mg twice daily).

Extrapolated from 400 mg twice daily study

Co-administration of raltegravir (1,200 mg once daily) is not recommended.

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 (400 mg twice daily and 1,200 mg once daily).

efavirenz

(raltegravir 1,200 mg single dose)

raltegravir AUC ↓ 14%

raltegravir C24hr ↓ 6%

raltegravir Cmax ↓ 9%

(UGT1A1 induction)

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 (400 mg twice daily and 1,200 mg once daily) 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 (400 mg twice daily and 1,200 mg once daily) or tenofovir disoproxil fumarate.

emtricitabine and tenofovir disoproxil fumarate

(raltegravir 1,200 mg (2 x 600 mg) Once Daily)

Population PK analysis showed that the effect of emtricitabine/tenofovir disoproxil fumarate on raltegravir pharmacokinetics was minimal (12% increase in relative bioavailability), and was not statistically or clinically significant.

(Mechanism of interaction unknown)

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 (400 mg twice daily and 1,200 mg once daily) 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 (400 mg twice daily and 1,200 mg once daily) 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 (400 mg twice daily) can be considered.

Extrapolated from 400 mg twice daily study

Co-administration of raltegravir (1,200 mg once daily) is not recommended.

SEDATIVE

midazolam

(raltegravir 400 mg Twice Daily)

midazolam AUC ↓ 8%

midazolam Cmax ↑ 3%

No dosage adjustment required for raltegravir (400 mg twice daily and 1,200 mg once daily) 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 (400 mg twice daily and 1,200 mg once daily) with aluminium and/or magnesium containing antacids is not recommended.

aluminium/magnesium hydroxide antacid

(raltegravir 1,200 mg single dose)

12 hours after raltegravir

raltegravir AUC ↓ 14%

raltegravir C24 hr ↓ 58%

raltegravir Cmax ↓ 14%

(chelation of metal ions)

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 (400 mg twice daily).

calcium carbonate antacid

(raltegravir 1,200 mg single dose)

raltegravir AUC ↓ 72%

raltegravir C24 hr ↓ 48%

raltegravir Cmax ↓ 74%

12 hours after raltegravir

raltegravir AUC ↓ 10%

raltegravir C24 hr ↓ 57%

raltegravir Cmax ↓ 2%

(chelation of metal ions)

Co-administration of raltegravir (1,200 mg once daily) is not recommended.

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 (400 mg twice daily and 1,200 mg once daily).

famotidine

(raltegravir 400 mg Twice Daily)

raltegravir AUC ↑ 44%

raltegravir C12 hr ↑ 6%

raltegravir Cmax ↑ 60%

(increased solubility)

gastric pH altering agents:

proton pump inhibitors (e.g. omeprazole), H2 blockers (e.g. famotidine, ranitidine, cimitedine)

(raltegravir 1,200 mg)

Population PK analysis showed that the effect of gastric pH altering agents on raltegravir pharmacokinetics was minimal (8.8% decrease in relative bioavailability), and was not statistically or clinically significant.

(Increased drug solubility)

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 (400 mg twice daily and 1,200 mg once daily) 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 (400 mg twice daily and 1,200 mg once daily) or methadone.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

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

Raltegravir 1,200 mg is not recommended during pregnancy.

Anti-retroviral Pregnancy Registry

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

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

Breast-feeding

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

A risk to the newborns/infants cannot be excluded.

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

Fertility

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

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 reactions were 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

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

Grade 2-4 creatine kinase laboratory abnormalities were observed in 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

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

Children and adolescents 2 to 18 years of age

Raltegravir twice daily has been studied in 126 antiretroviral treatment-experienced HIV-1 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 twice daily.

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 twice daily 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 RALTEGRAVIR 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.