Chemical formula: C₂₀H₂₁FN₆O₅ Molecular mass: 444.416 g/mol PubChem compound: 54671008
Raltegravir interacts in the following cases:
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.
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.
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.
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.
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.
Interaction (mechanism, if known):
Aluminium and magnesium hydroxide antacid (raltegravir 400 mg Twice Daily):
| AUC | C12hr | Cmax | |
| raltegravir | ↓49% | ↓63% | ↓44% |
| 2 hours before raltegravir | ↓51% | ↓56% | ↓51% |
| 2 hours after raltegravir | ↓30% | ↓57% | ↓24% |
| 6 hours before raltegravir | ↓13% | ↓50% | ↓10% |
| 6 hours after raltegravir | ↓11% | ↓49% | ↓10% |
(chelation of metal cations)
Recommendations concerning co-administration: 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.
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.
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.
Interaction (mechanism, if known):
Rifampicin (raltegravir 400 mg Single Dose):
(UGT1A1 induction)
Recommendations concerning co-administration: Rifampicin reduces plasma levels of raltegravir. If co-administration with rifampicin is unavoidable, a doubling of the dose of raltegravir can be considered.
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.
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.
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.
In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral 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.
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.
There are no data for the use of raltegravir 1,200 mg once daily in pregnant women. A moderate amount of data on pregnant women (between 300-1,000 pregnancy outcomes from first trimester exposure) indicate no malformative or feto/neonatal toxicity of raltegravir 400 mg twice daily. Animal studies have shown reproductive toxicity. Raltegravir 1,200 mg is not recommended during pregnancy.
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.
It is unknown whether raltegravir/metabolites are excreted in human milk. Available pharmacodynamics/toxicological data in animals have shown excretion of raltegravir/metabolites in milk.
A risk to the newborns/infants cannot be excluded.
Raltegravir should not be used during breast-feeding. As a general rule, it is recommended that mothers infected by HIV do not breast-feed their babies in order to avoid transmission of HIV.
No effect on fertility was seen in male and female rats at doses up to 600 mg/kg/day which resulted in 3-fold exposure above the exposure at the recommended human dose.
Dizziness has been reported in some patients during treatment with regimens containing raltegravir. Dizziness may influence some patients' ability to drive and use machines.
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 treatmentexperienced (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.
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.
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).
Adverse reactions Raltegravir (alone or in combination with other ART):
Uncommon: genital herpes, folliculitis, gastroenteritis, herpes simplex, herpes virus infection, herpes zoster, influenza, lymph node abscess, molluscum contagiosum, nasopharyngitis, upper respiratory tract infection
Uncommon: skin papilloma
Uncommon: anaemia, iron deficiency anaemia, lymph node pain, lymphadenopathy, neutropenia, thrombocytopenia
Uncommon: immune reconstitution syndrome, drug hypersensitivity, hypersensitivity
Common: decreased appetite
Uncommon: cachexia, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperphagia, increased appetite, polydipsia, body fat disorder
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)
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
Uncommon: visual impairment
Common: Uncommon vertigo tinnitus
Uncommon: palpitations, sinus bradycardia, ventricular extrasystoles
Uncommon: hot flush, hypertension Respiratory, thoracic and mediastinal disorders
Uncommon: dysphonia, epistaxis, nasal congestion
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
Uncommon: hepatitis, hepatic steatosis, hepatitis alcoholic, hepatic failure
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 maculopapular, rash pruritic, skin lesion, urticaria, xeroderma, Stevens Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS)
Uncommon: arthralgia, arthritis, back pain, flank pain, musculoskeletal pain, myalgia, neck pain, osteopenia, pain in extremity, tendonitis, rhabdomyolysis
__Uncommon :__renal failure, nephritis, nephrolithiasis, nocturia, renal cyst, renal impairment, tubulointerstitial nephritis
Uncommon: erectile dysfunction, gynaecomastia, menopausal symptoms
Common: asthenia, fatigue, pyrexia Uncommon chest discomfort, chills, face oedema, fat tissue increased, feeling jittery, malaise, submandibular mass, oedema peripheral, pain
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
Uncommon: accidental overdose
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.
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 .
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.
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.
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.
Raltegravir 600 mg tablet formulation has not been studied in paediatric patients.
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. 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.
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.
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.
In IMPAACT P1110 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).
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