ISENTRESS

Therapy should be initiated by a physician experienced in the management of HIV infection. 1). Adults and paediatric population In adults and paediatric patients (weighing at least 40 kg), the recommended dosage is 1,200 mg (two 600 mg tablets) once daily for treatment-naïve patients or patients who are virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily.

Additional formulations and strengths available:

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

ISENTRESS is also available in a chewable tablet formulation and in granules for oral suspension formulation. Refer to the chewable tablet and granules for oral suspension SmPCs for additional dosing information. The safety and efficacy of raltegravir in preterm (<37 weeks of gestation) and low birth weight (<2,000 g) newborns have not been established.

No data are available in this population and no dosing recommendations can be made. The maximum dose of the chewable tablet is 300 mg twice daily. 2). The chewable tablets and the granules for oral suspension have not been studied in HIV-infected adolescents (12 to 18 years) or adults.

2). Therefore, ISENTRESS should be used with caution in this population. 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.

2). ISENTRESS 600 mg film-coated tablet formulation should not be used in children weighing less than 40 kg. Method of administration Oral use. ISENTRESS 600 mg tablets can be administered with or without food as a 1,200 mg once daily dose.

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

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. 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 Uncommon decreased appetite cachexia, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperphagia, increased appetite, polydipsia, body fat disorder Psychiatric disorders Common Uncommon abnormal dreams, insomnia, nightmare, abnormal behaviour, depression 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 Uncommon dizziness, headache, psychomotor hyperactivity 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 Uncommon vertigo 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 System Organ Class Frequency Adverse reactions Raltegravir (alone or in combination with other ART) Gastrointestinal disorders Common Uncommon abdominal distention, abdominal pain, diarrhoea, flatulence, nausea, vomiting, dyspepsia 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 Uncommon rash 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 Uncommon asthenia, fatigue, pyrexia chest discomfort, chills, face oedema, fat tissue increased, feeling jittery, malaise, submandibular mass, oedema peripheral, pain System Organ Class Frequency Adverse reactions Raltegravir (alone or in combination with other ART) Investigations Common Uncommon alanine aminotransferase increased, atypical lymphocytes, aspartate aminotransferase increased, blood triglycerides increased, lipase increased, blood pancreatic amylase increased 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 […]

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.

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.

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.

5). 5). 5). , 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. 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.

8). Lactose This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Sodium This medicinal product […]

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