Summary of medicine characteristics - ISENTRESS 600 MG FILM-COATED TABLETS
1 NAME OF THE MEDICINAL PRODUCT
ISENTRESS® 600 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 600 mg of raltegravir (as potassium).
Excipient(s) with known effect
Each 600 mg tablet contains 5.72 mg lactose (as monohydrate).
For the full list of excipients, see section 6.1.
Film-coated tablet.
Yellow, oval-shaped, dimensions 19.1 mm x 9.7 mm x 6.1 mm, marked with MSD corporate logo and “242” on one side and plain on the other side.
4.1 Therapeutic indications
ISENTRESS 600 mg film-coated tablets is indicated in combination with other antiretroviral 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
ISENTRESS 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-naive 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. 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, 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).
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.
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. While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
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).
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 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 ^M) and OAT3 (IC50 of 18.8 ^M). 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, coadministration 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 coadministration 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 × 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 disaproxil fumarate) increased raltegravir exposure. Emtricitabine/tenofovir disaproxil 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 disaproxil 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 T 41% raltegravir Ci2hr T 77% raltegravir Cmax T 24% (UGT1A1 inhibition) | No dose adjustment required for raltegravir (400 mg twice daily). |
| atazanavir (raltegravir 1,200 mg single dose) | raltegravir AUC T 67% raltegravir C24hr T 26% raltegravir Cmax T 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 |
| Medicinal products by therapeutic area | Interaction (mechanism, if known) | Recommendations concerning co-administration |
| efavirenz (raltegravir 1,200 mg single dose) | raltegravir AUC ^ 14% raltegravir C24hr ^ 6% raltegravir Cmax ^ 9% (UGT1A1 induction) | for raltegravir (400 mg twice daily and 1,200 mg once daily). |
| etravirine (raltegravir 400 mg Twice Daily) | raltegravir AUC ^ 10% raltegravir C12hr ^ 34% raltegravir Cmax ^ 11% (UGT1A1 induction) etravirine AUC Î 10% etravirine C12hr Î 17% etravirine Cmax Î 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 T 49% raltegravir Ci2hr T 3% raltegravir Cmax f 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 × 600 mg) Once Daily) | Population PK analysis showed that the effect of emtricitabine/tenofovir disaproxil 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. |
| Medicinal products by therapeutic area | Interaction (mechanism, if known) | Recommendations concerning co-administration |
| HCV ANTIVIRALS | ||
| NS3/4A protease inhibitors (PI) | ||
| boceprevir (raltegravir 400 mg Single Dose) | raltegravir AUC Î 4% raltegravir C12hr ¿ 25% raltegravir Cmax Î 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 f 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. |
| Medicinal products by therapeutic area | Interaction (mechanism, if known) | Recommendations concerning co-administration |
| 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. |
| Medicinal products by therapeutic area | Interaction (mechanism, if known) | Recommendations concerning co-administration |
| 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 f 37% raltegravir C12 hr Î 24% raltegravir Cmax f 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 f 44% raltegravir C12 hr Î 6% raltegravir Cmax f 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 f 6% Norelgestromin AUC f 14% Norelgestromin Cmax f 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.
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.
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-naive (N=547) and treatment-experienced (N=462) adults for up to 96 weeks. A further 531 treatment-naive 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 |
| System Organ Class | Frequency | Adverse reactions Raltegravir (alone or in combination with other ART) |
| 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 | 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 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 |
| 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 |
| System Organ Class | Frequency | Adverse reactions Raltegravir (alone or in combination with other ART) |
| 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 |
| 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 |
| System Organ Class | Frequency | Adverse reactions Raltegravir (alone or in combination with other ART) |
| 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-naive 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
ISENTRESS 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 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
4.9 OverdoseNo 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antivirals for systemic use,integrase inhibitors, ATC code: J05AJ01.
Mechanism of action
Raltegravir is an integrase strand transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1). Raltegravir inhibits the catalytic activity of integrase, an HIV-encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of the HIV genome into the host cell genome. HIV genomes that fail to integrate cannot direct the production of new infectious viral particles, so inhibiting integration prevents propagation of the viral infection.
Antiviral activity in vitro
Raltegravir at concentrations of 31 ± 20 nM resulted in 95 % inhibition (IC95) of HIV-1 replication (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir inhibited viral replication in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates from 5 non-B subtypes, and isolates resistant to reverse transcriptase inhibitors and protease inhibitors. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV isolates representing 5 non-B subtypes and 5 circulating recombinant forms with IC50 values ranging from 5 to 12 nM.
Resistance
Most viruses isolated from patients failing raltegravir had high-level raltegravir resistance resulting from the appearance of two or more mutations in integrase. Most had a signature mutation at amino acid 155 (N155 changed to H), amino acid 148 (Q148 changed to H, K, or R), or amino acid 143 (Y143 changed to H, C, or R), along with one or more additional integrase mutations (e.g., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, S230R). The signature mutations decrease viral susceptibility to raltegravir and addition of other mutations results in a further decrease in raltegravir susceptibility. Factors that reduced the likelihood of developing resistance included lower baseline viral load and use of other active anti-retroviral agents. Mutations conferring resistance to raltegravir generally also confer resistance to the integrase strand transfer inhibitor elvitegravir. Mutations at amino acid 143 confer greater resistance to raltegravir than to elvitegravir, and the E92Q mutation confers greater resistance to elvitegravir than to raltegravir. Viruses harbouring a mutation at amino acid 148, along with one or more other raltegravir resistance mutations, may also have clinically significant resistance to dolutegravir.
Clinical experience
The evidence of efficacy of raltegravir was based on the analyses of 96-week data from two randomised, double-blind, placebo-controlled trials (BENCHMRK 1 and BENCHMRK 2, Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult patients, the analysis of 240-week data from randomised, double-blind, active-control trial (STARTMRK, Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult patients and the analysis of 96-week data from randomised, double-blind, active-control trial (ONCEMRK, Protocol 292) in antiretroviral treatment-naïve HIV-1 infected adult patients.
Efficacy
Treatment-experienced adult patients (400 mg twice daily)
BENCHMRK 1 and BENCHMRK 2 (multi-centre, randomised, double-blind, placebo-controlled trials) evaluated the safety and anti-retroviral activity of raltegravir 400 mg twice daily vs. placebo in a combination with optimised background therapy (OBT), in HIV-infected patients, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NRTIs, NNRTIs, PIs) of anti-retroviral therapies. Prior to randomisation, OBT were selected by the investigator based on the patient's prior treatment history, as well as baseline genotypic and phenotypic viral resistance testing.
Patient demographics (gender, age and race) and baseline characteristics were comparable between the groups receiving raltegravir 400 mg twice daily and placebo. Patients had prior exposure to a median of 12 anti-retrovirals for a median of 10 years. A median of 4 ARTs was used in OBT.
Results 48-week and 96-week analyses
Durable outcomes (Week 48 and Week 96) for patients on the recommended dose raltegravir 400 mg twice daily from the pooled studies BENCHMRK 1 and
BENCHMRK 2 are shown in Table 2.
Table 2
Efficacy Outcome at Weeks 48 and 96
| BENCHMRK 1 and 2 Pooled | 48 Weeks | 96 Weeks | ||
| Raltegravir | Placebo + | Raltegravir | Placebo + | |
| Parameter | 400 mg twice | OBT | 400 mg twice | OBT |
| daily + OBT | (N = 237) | daily + OBT | (N = 237) | |
| (N = 462) | (N = 462) | |||
| Percent HIV-RNA < 400 copies/mL (95 % CI) | ||||
| All patients' | 72 (68, 76) | 37 (31, 44) | 62 (57, 66) | 28 (23, 34) |
| Baseline Characteristic1 | ||||
| HIV-RNA > 100,000 copies/mL | 62 (53, 69) | 17 (9, 27) | 53 (45, 61) | 15 (8, 25) |
| < 100,000 copies/mL | 82 (77, 86) | 49 (41, 58) | 74 (69, 79) | 39 (31, 47) |
| CD4-count < 50 cells/mm3 | 61 (53, 69) | 21 (13, 32) | 51 (42, 60) | 14 (7, 24) |
| > 50 and | 80 (73, 85) | 44 (33, 55) | 70 (62, 77) | 36 (25, 48) |
| < 200 cells/mm3 | ||||
| > 200 cells/mm3 | 83 (76, 89) | 51 (39, 63) | 78 (70, 85) | 42 (30, 55) |
| Sensitivity score (GSS) § | ||||
| 0 | 52 (42, 61) | 8 (3, 17) | 46 (36, 56) | 5 (1, 13) |
| 1 | 81 (75, 87) | 40 (30, 51) | 76 (69, 83) | 31 (22, 42) |
| 2 and above | 84 (77, 89) | 65 (52, 76) | 71 (63, 78) | 56 (43, 69) |
| Percent HIV-RNA < 50 copies/mL (95 % CI) | ||||
| All patients' | 62 (57, 67) | 33 (27, 39) | 57 (52, 62) | 26 (21, 32) |
| Baseline Characteristic1 | ||||
| HIV-RNA > 100,000 copies/mL | 48 (40, 56) | 16 (8, 26) | 47 (39, 55) | 13 (7, 23) |
| < 100,000 copies/mL | 73 (68, 78) | 43 (35, 52) | 70 (64, 75) | 36 (28, 45) |
| CD4-count < 50 cells/mm3 | 50 (41, 58) | 20 (12, 31) | 50 (41, 58) | 13 (6, 22) |
| > 50 and | 67 (59, 74) | 39 (28, 50) | 65 (57, 72) | 32 (22, 44) |
| < 200 cells/mm3 | ||||
| > 200 cells/mm3 | 76 (68, 83) | 44 (32, 56) | 71 (62, 78) | 41 (29, 53) |
| Sensitivity score (GSS) § | ||||
| 0 | 45 (35, 54) | 3 (0, 11) | 41 (32, 51) | 5 (1, 13) |
| 1 | 67 (59, 74) | 37 (27, 48) | 72 (64, 79) | 28 (19, 39) |
| 2 and above | 75 (68, 82) | 59 (46, 71) | 65 (56, 72) | 53 (40, 66) |
| Mean CD4 Cell Change (95 % CI), cells/mm3 | ||||
| All patients' | 109 (98, 121) | 45 (32, 57) | 123 (110, 137) | 49 (35, 63) |
| Baseline Characteristic' | ||||
| HIV-RNA > 100,000 copies/mL | 126 (107, | 36 (17, 55) | 140 (115, 165) | 40 (16, 65) |
| 144) | ||||
| < 100,000 copies/mL | 100 (86, 115) | 49 (33, 65) | 114 (98, 131) | 53 (36, 70) |
| CD4-count < 50 cells/mm3 | 121 (100, | 33 (18, 48) | 130 (104, 156) | 42 (17, 67) |
| 142) | ||||
| > 50 and | 104 (88, 119) | 47 (28, 66) | 123 (103, 144) | 56 (34, 79) |
| < 200 cells/mm3 | ||||
| > 200 cells/mm3 | 104 (80, 129) | 54 (24, 84) | 117 (90, 143) | 48 (23, 73) |
| Sensitivity score (GSS) § | ||||
| 0 | 81 (55, 106) | 11 (4, 26) | 97 (70, 124) | 15 (-0, 31) |
| 1 | 113 (96, 130) | 44 (24, 63) | 132 (111, 154) | 45 (24, 66) |
| 2 and above | 125 (105, 144) | 76 (48, | 134 (108, 159) | 90 (57, 123) |
| 103) |
BENCHMRK 1 and 2 Pooled
48 Weeks
96 Weeks
| Raltegravir | Placebo + | Raltegravir | Placebo + | |
| Parameter | 400 mg twice | OBT | 400 mg twice | OBT |
| daily + OBT | (N = 237) | daily + OBT | (N = 237) | |
| (N = 462) | (N = 462) |
T Non-completer is failure imputation: patients who discontinued prematurely are imputed as failure thereafter. Percent of patients with response and associated 95 % confidence interval (CI) are reported.
$ For analysis by prognostic factors, virologic failures were carried forward for percent < 400 and 50 copies/mL. For mean CD4 changes, baseline-carry-forward was used for virologic failures.
§ The Genotypic Sensitivity Score (GSS) was defined as the total oral ARTs in the optimised background therapy (OBT) to which a patient's viral isolate showed genotypic sensitivity based upon genotypic resistance test. Enfuvirtide use in OBT in enfuvirtide-naíve patients was counted as one active drug in OBT. Similarly, darunavir use in OBT in darunavir-naive patients was counted as one active drug in OBT.
Raltegravir achieved virologic responses (using Not Completer=Failure approach) of HIV RNA < 50 copies/mL in 61.7 % of patients at Week 16, in 62.1 % at Week 48 and in 57.0 % at Week 96. Some patients experienced viral rebound between Week 16 and Week 96. Factors associated with failure include high baseline viral load and OBT that did not include at least one potent active agent.
Switch to raltegravir (400 mg twice daily)
The SWITCHMRK 1 & 2 (Protocols 032 & 033) studies evaluated HIV-infected patients receiving suppressive (screening HIV RNA < 50 copies/mL; stable regimen > 3 months) therapy with lopinavir 200 mg (+) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors and randomised them 1:1 to continue lopinavir (+) ritonavir 2 tablets twice daily (n=174 and n=178, respectively) or replace lopinavir (+) ritonavir with raltegravir 400 mg twice daily (n=174 and n=176, respectively). Patients with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited.
These studies were terminated after the primary efficacy analysis at Week 24 because they failed to demonstrate non-inferiority of raltegravir versus lopinavir (+) ritonavir. In both studies at Week 24, suppression of HIV RNA to less than 50 copies/mL was maintained in 84.4 % of the raltegravir group versus 90.6 % of the lopinavir (+) ritonavir group, (Non-completers = Failure). See section 4.4 regarding the need to administer raltegravir with two other active agents.
Treatment-naïve adult patients (400 mg twice daily)
STARTMRK (multi-centre, randomised, double-blind, active-control trial) evaluated the safety and anti-retroviral activity of raltegravir 400 mg twice daily vs. efavirenz 600 mg at bedtime, in a combination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naïve HIV-infected patients with HIV
RNA > 5,000 copies/mL. Randomisation was stratified by screening HIV RNA level (< 50,000 copies/mL; and > 50,000 copies/mL) and by hepatitis B or C status (positive or negative).
Patient demographics (gender, age and race) and baseline characteristics were comparable between the group receiving raltegravir 400 mg twice daily and the group receiving efavirenz 600 mg at bedtime.
Results 48-week and 240-week analyses
With respect to the primary efficacy endpoint, the proportion of patients achieving HIV RNA < 50 copies/mL at Week 48 was 241/280 (86.1 %) in the group receiving raltegravir and 230/281 (81.9 %) in the group receiving efavirenz. The treatment difference (raltegravir – efavirenz) was 4.2 % with an associated 95 % CI of (-1.9, 10.3) establishing that raltegravir is non-inferior to efavirenz (p-value for noninferiority < 0.001). At Week 240, the treatment difference (raltegravir – efavirenz) was 9.5 % with an associated 95 % CI of (1.7, 17.3). Week 48 and Week 240 outcomes for patients on the recommended dose of raltegravir 400 mg twice daily from STARTMRK are shown in Table 3.
Table 3
Efficacy Outcome at Weeks 48 and 240
| STARTMRK Study Parameter | 48 Weeks | 240 Weeks | ||
| Raltegravir 400 mg twice daily (N = 281) | Efavirenz 600 mg at bedtime (N = 282) | Raltegravir 400 mg twice daily (N = 281) | Efavirenz 600 mg at bedtime (N = 282) | |
| Percent HIV-RNA < 50 copies/mL (95 % CI) | ||||
| All patientsT | 86 (81, 90) | 82 (77, 86) | 71 (65, 76) | 61 (55, 67) |
| Baseline Characteristic | ||||
| HIV-RNA > 100,000 copies/mL | 91 (85, 95) | 89 (83, 94) | 70 (62, 77) | 65 (56, 72) |
| < 100,000 copies/mL | 93 (86, 97) | 89 (82, 94) | 72 (64, 80) | 58 (49, 66) |
| CD4-count < 50 cells/mm3 | 84 (64, 95) | 86 (67, 96) | 58 (37, 77) | 77 (58, 90) |
| > 50 and | 89 (81, 95) | 86 (77, 92) | 67 (57, 76) | 60 (50, 69) |
| < 200 cells/mm3 | ||||
| > 200 cells/mm3 | 94 (89, 98) | 92 (87, 96) | 76 (68, 82) | 60 (51, 68) |
| Viral Subtype Clade B | 90 (85, 94) | 89 (83, 93) | 71 (65, 77) | 59 (52, 65) |
| Non-Clade B | 96 (87, 100) | 91 (78, 97) | 68 (54, 79) | 70 (54, 82) |
| Mean CD4 Cell Change (95 % CI), cells/mm3 | ||||
| All patients' | 189 (174, 204) | 163 (148, 178) | 374 (345, 403) | 312 (284, 339) |
| Baseline Characteristic' | ||||
| HIV-RNA > 100,000 copies/mL | 196 (174, 219) | 192 (169, 214) | 392 (350, 435) | 329 (293, 364) |
| < 100,000 copies/mL | 180 (160, 200) | 134 (115, 153) | 350 (312, 388) | 294 (251, 337) |
| CD4-count < 50 cells/mm3 | 170 (122, 218) | 152 (123, 180) | 304 (209, 399) | 314 (242, 386) |
| > 50 and < 200 cells/mm3 | 193 (169, 217) | 175 (151, 198) | 413 (360, 465) | 306 (264, 348) |
| > 200 cells/mm3 | 190 (168, 212) | 157 (134, 181) | 358 (321, 395) | 316 (272, 359) |
| Viral Subtype Clade B | 187 (170, 204) | 164 (147, 181) | 380 (346, 414) | 303 (272, 333) |
| Non-Clade B | 189 (153, 225) | 156 (121, 190) | 332 (275, 388) | 329 (260, 398) |
| T Non-completer is failure imputation: patients who discontinued prematurely response and associated 95 % confidence interval (CI) are reported. | are imputed as failure thereafter. Percent of patients with | |||
| ' For analysis by prognostic factors, virologic failures were carried forward for percent < 50 and 400 copies/mL. For mean | CD4 changes, | |||
| baseline-carry-forward was used for virologic failures. Notes: The analysis is based on all available data. | ||||
| Raltegravir and efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate. | ||||
Treatment-naive adult patients (1,200 mg [2 × 600 mg] once daily)
ONCEMRK (multi-centre, randomised, double-blind, active-control trial;
Protocol 292) evaluated the safety and anti-retroviral activity of raltegravir 1,200 mg once daily + emtricitabine (+) tenofovir disoproxil fumarate vs. raltegravir 400 mg twice daily, in combination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naive HIV-infected patients with HIV RNA > 1,000 copies/mL.
Randomisation was stratified by screening HIV RNA level (< 100,000 copies/mL; and > 100,000 copies/mL) and by hepatitis B or C status (positive or negative).
Patient demographics (gender, age and race) and baseline characteristics were comparable between the group receiving raltegravir 1,200 mg once daily and the group receiving raltegravir 400 mg twice daily.
Results of Week 48 and 96 analyses
With respect to the primary efficacy endpoint, the proportion of patients achieving HIV RNA < 40 copies/mL at Week 48 was 472/531(88.9 %) in the group receiving raltegravir 1,200 mg once daily and 235/266 (88.3 %) in the group receiving raltegravir 400 mg twice daily. The treatment difference (raltegravir 1,200 mg once daily-raltegravir 400 mg twice daily) was 0.5 % with an associated 95 % CI of (-4.2, 5.2) establishing that raltegravir 1,200 mg once daily is non-inferior to raltegravir 400 mg twice daily.
At Week 96, the proportion of patients achieving HIV RNA < 40 copies/mL was 433/531(81.5 %) in the group receiving raltegravir 1,200 mg once daily and 213/266 (80.1 %) in the group receiving raltegravir 400 mg twice daily. The treatment difference (raltegravir 1,200 mg once daily-raltegravir 400 mg twice daily) was 1.5 % with an associated 95 % CI of (-4.4, 7.3). Week 48 and Week 96 outcomes from ONCEMRK are shown in Table 4.
Table 4
| Efficacy Outcome at Weeks 48 and 96 | ||||
| ONCEMRK Study Parameter | 48 Weeks | 96 Weeks | ||
| Raltegravir 600 mg (1,200 mg once daily) (N = 531) | Raltegravir 400 mg twice daily (N = 266) | Raltegravir 600 mg (1,200 mg once daily) (N = 531) | Raltegravir 400 mg twice daily (N = 266) | |
| Percent HIV-RNA < 40 copies/mL (95 % CI) All patients* | 88.9 (85.9, 91.4) | 88.3 (83.9, 91.9) | 81.5 (78.0, 84.8) | 80.1 (74.8, 84.7) |
| Baseline Characteristic* HIV-RNA | 86.7 (80.0, 91.8) | 83.8 (73.4, 91.3) | 84.7 (77.5, 90.3) | 82.9 (72.0, 90.8) |
| > 100,000 copies/mL | 97.2 (94.9, 98.7) | 97.7 (94.3, 99.4) | 91.9 (88.5, 94.5) | 93.0 (89.1, 97.1) |
| < 100,000 copies/mL CD4– | 85.1 (74.3, 92.6) | 87.9 (71.8, 96.6) | 79.0 (66.8, 88.3) | 80 (61.4, 92.3) |
| count < 200 cells/mm3 | 95.6 (93.2, 97.3) | 94.5 (90.6, 97.1) | 91.4 (88.3, 93.9) | 92.2 (87.6, 95.5) |
| > 200 cells/mm3 Viral Subtype Clade B | 94.6 (91.4, 96.8) | 93.7 (89.0, 96.8) | 90.0 (86.0, 93.2) | 88.9 (83.0, 93.3) |
| Non-Clade B | 93.6 (89.1, 96.6) | 93.2 (84.9, 97.8) | 89.5 (84.1, 93.6) | 94.4 (86.2, 98.4) |
Mean CD4 Cell Change (95 %
CI), cells/mm3
| All patients* | 232 (215, 249) | 234 (213, 255) | 262 (243, 280) | 262 (236, 288) |
| Baseline Characteristic* | ||||
| HIV-RNA | 276 (245, 308) | 256 (218, 294) | 297 (263, 332) | 281 (232, 329) |
| > 100,000 copies/mL | 248 (225, 270) | 254 (224, 285) | ||
| 214 (194, 235) | 225 (199, 251) | |||
| < 100,000 copies/mL | ||||
| CD4 count | 209 (176, 243) | 209 (172, 245) | 239 (196, 281) | 242 (188, 296) |
| < 200 cells/mm3 | ||||
| 235 (216, 255) | 238 (214, 262) | 265 (245, 286) | 265 (237, 294) | |
| > 200 cells/mm3 | ||||
| Viral Subtype Clade B | 232 (209, 254) | 240 (213, 266) | 270 (245, 296) | 267 (236, 297) |
| Non-Clade | 233 (205, 261) | 226 (191, 261) | 246 (219, 274) | 259 (211, 307) |
B
T Non-completer is failure imputation: patients who discontinued prematurely are imputed as failure thereafter. Percent of patients with response and associated 95 % confidence interval (CI) are reported.
* For analysis by prognostic factors, virologic failures were carried forward for percent < 40 copies/mL. For mean CD4 changes, baseline-carry-forward was used for virologic failures.
Raltegravir 1,200 mg QD and raltegravir 400 mg BID were administered with emtricitabine (+) tenofovir disoproxil fumarate.
5.2 Pharmacokinetic properties
Absorption
As demonstrated in healthy volunteers administered single oral doses of raltegravir in the fasted state, raltegravir is rapidly absorbed with a tmax of approximately 3 hours postdose. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1,600 mg. Raltegravir C12 hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1,600 mg.
With twice-daily dosing, pharmacokinetic steady state is achieved rapidly, within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax and evidence of slight accumulation in C12 hr. The absolute bioavailability of raltegravir has not been established.
Raltegravir 1,200 mg once daily is also rapidly absorbed with median Tmax ~1.5 to 2 hours in the fasted state and generates a sharper absorption peak with a tendency to higher Cmax in comparison to raltegravir twice daily (1 × 400 mg tablet twice daily). In addition, relative to the raltegravir 400 mg formulation the raltegravir 600 mg formulation used in the 1,200 mg (2 × 600 mg) once daily dosing regimen has higher relative bioavailability (by 21 to 66%). Once absorbed, both formulations of raltegravir exhibit similar systemic pharmacokinetics. In patients, after 1,200 mg once daily raltegravir dosing, steady state AUC0.24 was 53.7 hytM, C24 was 75.6 nM, and median Tmax was 1.50 h.
Raltegravir 400 mg twice daily may be administered with or without food. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-infected patients. Administration of multiple doses of raltegravir following a moderate-fat meal did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13 % relative to fasting. Raltegravir C12 hr was 66 % higher and Cmax was 5 % higher following a moderate-fat meal compared to fasting. Administration of raltegravir following a high-fat meal increased AUC and Cmax by approximately 2-fold and increased C12 hr by 4.1-fold. Administration of raltegravir following a low-fat meal decreased AUC and Cmax by 46 % and 52 %, respectively; C12 hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.
Raltegravir 600 mg tablets (2 × 600 mg once daily) may be administered with or without food. A single dose food effect study demonstrated that the 1,200 mg once daily had similar or smaller food effects when studied under high-fat and low-fat meal conditions when compared to the 400 mg twice daily. Administration of a low-fat meal with raltegravir 1,200 mg once daily resulted in a 42% decrease in AUC0-last, 52% decrease in Cmax, and 16% decrease in C24 hr. Administration of a high fat meal resulted in a 1.9% increase in AUC0-last, 28% decrease in Cmax, and 12% decrease in C24 hr.
Overall, considerable variability was observed in the pharmacokinetics of raltegravir. For observed C12 hr in BENCHMRK 1 and 2 the coefficient of variation (CV) for inter-subject variability = 212 % and the CV for intra-subject variability = 122 %. Sources of variability may include differences in co-administration with food and concomitant medicines.
Distribution
Raltegravir is approximately 83 % bound to human plasma protein over the concentration range of 2 to 10 ^M.
Raltegravir readily crossed the placenta in rats, but did not penetrate the brain to any appreciable extent.
In two studies of HIV-1 infected patients who received raltegravir 400 mg twice daily, raltegravir was readily detected in the cerebrospinal fluid. In the first study(n=18), the median cerebrospinal fluid concentration was 5.8 % (range 1 to 53.5 %) of the corresponding plasma concentration. In the second study (n=16), the median cerebrospinal fluid concentration was 3 % (range 1 to 61 %) of the corresponding plasma concentration. These median proportions are approximately 3– to 6-fold lower than the free fraction of raltegravir in plasma.
Biotransformation and excretion
The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter a-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32 % of the dose was excreted in faeces and urine, respectively. In faeces, only raltegravir was present, most of which is likely to be derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23 % of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70 % of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.
UGT1A1 Polymorphism
In a comparison of 30 subjects with 28/28 genotype to 27 subjects with wild-type genotype, the geometric mean ratio (90 % CI) of AUC was 1.41 (0.96, 2.09) and the geometric mean ratio of C12 hr was 1.91 (1.43, 2.55). Dose adjustment is not considered necessary in subjects with reduced UGT1A1 activity due to genetic polymorphism.
Special populations
Paediatric population
Based on a formulation comparison study in healthy adult volunteers, the chewable tablet and granules for oral suspension have higher oral bioavailability compared to the 400 mg tablet.
In this study, administration of the chewable tablet with a high fat meal led to an average 6 % decrease in AUC, 62 % decrease in Cmax, and 188 % increase in C12 hr compared to administration in the fasted state. Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food. The effect of food on the granules for oral suspension formulation was not studied.
Table 5 displays pharmacokinetic parameters in the 400 mg tablet, the chewable tablet, and the granules for oral suspension, by body weight.
Table 5
Raltegravir Pharmacokinetic Parameters IMPAACT P1066 Following Administration of Doses in Section 4.2 (excluding neonates)
| Body weight | Formulation | Dose | N* | Geometric mean (%cV ) AUCo—i2hr(nM«hr) | Geometric mean (%cV) C12hr(nM) |
| > 25 kg | Film-coated tablet | 400 mg twice daily | 18 | 14.1 (121 %) | 233 (157 %) |
| > 25 kg | Chewable tablet | Weight based dosing, see dosing tables for the chewable tablet | 9 | 22.1 (36 %) | 113 (80 %) |
| 11 to less than 25 kg | Chewable tablet | Weight based dosing, see dosing tables for the chewable tablet | 13 | 18.6 (68 %) | 82 (123 %) |
| 3 to less than 20 kg | Oral suspension | Weight based dosing, see dosing table for granules for oral suspension | 19 | 24.5 (43 %) | 113 ( 69 % ) |
| *Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose. ^Geometric coefficient of variation. | |||||
Elderly
There was no clinically meaningful effect of age on raltegravir pharmacokinetics over the age range studied with raltegravir 400 mg twice daily. There was no clinically meaningful effect of age on raltegravir pharmacokinetics over the age range studied in ONCEMRK with raltegravir 1,200 mg (2 × 600 mg) once daily.
Gender, race, ethnicity and body weight
There were no clinically important pharmacokinetic differences due to gender, race, ethnicity or body weight in adults for raltegravir 400 mg twice daily, and no clinically meaningful effect on raltegravir pharmacokinetics was concluded. For raltegravir 1,200 mg (2 × 600 mg) once daily, population PK analysis also demonstrated that the impacts of gender, race, ethnicity and body weight are not clinically meaningful.
Renal impairment
Renal clearance of unchanged medicinal product is a minor pathway of elimination. In adults, there were no clinically important pharmacokinetic differences between patients with severe renal insufficiency and healthy subjects (see section 4.2 of the 400 mg twice daily SmPC). Because the extent to which raltegravir may be dialysable is unknown, dosing before a dialysis session should be avoided. No renal impairment study was conducted with raltegravir 1,200 mg once daily however, based on results with the 400 mg twice daily tablet, no clinically meaningful effect is anticipated.
Hepatic impairment
Raltegravir is eliminated primarily by glucuronidation in the liver. In adults, there were no clinically important pharmacokinetic differences between patients with moderate hepatic insufficiency and healthy subjects. The effect of severe hepatic insufficiency on the pharmacokinetics of raltegravir has not been studied (see sections 4.2 and 4.4 of the 400 mg twice daily SmPC). No hepatic impairment study has been conducted with raltegravir 1,200 mg once daily, however, based on results with the 400 mg twice daily tablet, no clinically meaningful effect is expected for mild and moderate hepatic impairment.
5.3 Preclinical safety data
5.3 Preclinical safety dataNon-clinical toxicology studies, including conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, developmental toxicity and juvenile toxicity, have been conducted with raltegravir in mice, rats, dogs and rabbits. Effects at exposure levels sufficiently in excess of clinical exposure levels indicate no special hazard for humans.
Mutagenicity
No evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage and in vitro and in vivo chromosomal aberration studies.
Carcinogenicity
A carcinogenicity study of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was similar to that at the clinical dose of 1,200 mg once daily. In rats, tumours (squamous cell carcinoma) of the nose/nasopharynx were identified at 300 and 600 mg/kg/day in females and at 300 mg/kg/day in males. This neoplasia could result from local deposition and/or aspiration of drug on the mucosa of the nose/nasopharynx during oral gavage dosing and subsequent chronic irritation and inflammation; it is likely that it is of limited relevance for the intended clinical use. At the NOAEL, systemic exposure was similar to that at the clinical dose of 1,200 mg once daily. Standard genotoxicity studies to evaluate mutagenicity and clastogenicity were negative.
Developmental toxicity
Raltegravir was not teratogenic in developmental toxicity studies in rats and rabbits. A slight increase in incidence of supernumerary ribs, a variant in the normal developmental process, was observed in rat foetuses of dams exposed to raltegravir at approximately 4.4-fold human exposure at the recommended human dose (RHD) based on AUC0–24 hr. No development effects were seen at 3.4-fold human exposure at the RHD. Similar findings were not observed in rabbits.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core
– Microcrystalline cellulose
– Hypromellose 2910
– Magnesium stearate
– Croscarmellose sodium
Film-coating
– Lactose monohydrate
– Hypromellose 2910
– Titanium dioxide
– Triacetin
– Iron oxide yellow
– Black iron oxide
The tablet may also contain trace amount of carnauba wax.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months
6.4 Special precautions for storage
Keep the bottle tightly closed, with the desiccant in order to protect from moisture.
6.5 Nature and contents of container
High density polyethylene (HDPE) bottle with a child-resistant polypropylene closure, induction seal and silica gel desiccant.
Two pack sizes are available: 1 bottle with 60 tablets, and a multipack containing 180 (3 bottles of 60) tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalNo special requirements for disposal.
7 MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme (UK) Limited
120 Moorgate
London
EC2M 6UR
United Kingdom