1. Name Of The Medicinal Product
ISENTRESS® 400 mg film-coated tablets
2. Qualitative And Quantitative Composition
Each film-coated tablet contains 400 mg of raltegravir (as potassium).
Excipient: Each tablet contains 26.06 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
Pink, oval tablet, marked with "227" on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
ISENTRESS is indicated in combination with other anti-retroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.
This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients and one double-blind, active-controlled trial in treatment-naïve patients (see sections 4.4 and 5.1).
4.2 Posology And Method Of Administration
Therapy should be initiated by a physician experienced in the management of HIV infection. ISENTRESS should be used in combination with other active anti-retroviral therapies (ARTs) (see sections 4.4 and 5.1). The use of raltegravir in previously ART-naïve patients is based on a study in which it was co-administered with two NRTIs (see sections 4.4 and 5.1).
Posology
Adults
The recommended dosage of ISENTRESS is 400 mg administered twice daily with or without food. The effect of food on absorption of raltegravir is uncertain (see section 5.2). It is not recommended to chew, crush or split the tablets.
Elderly
There is limited information regarding the use of ISENTRESS in the elderly (see section 5.2). Therefore ISENTRESS should be used with caution in this population.
Children and adolescents
Safety and efficacy have not been established in patients below 16 years of age (see sections 5.1 and 5.2).
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 ISENTRESS have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.4 and 5.2).
Method of administration
Oral
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special Warnings And Precautions For Use
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 or sexual contact. Appropriate precautions should continue to be employed.
Overall, considerable inter- and intra-subject variability was observed in the pharmacokinetics of raltegravir (see sections 4.5 and 5.2).
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).
The safety and efficacy of ISENTRESS 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 4.2 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.
There are very limited data on the use of raltegravir in patients co-infected with HIV and hepatitis B virus (HBV) or hepatitis C virus (HCV). 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 events.
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.
Caution should be used when co-administering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.5).
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 ISENTRESS, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS 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 edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.
Rash occurred more commonly in treatment-experienced patients receiving regimens containing ISENTRESS + darunavir compared to patients receiving ISENTRESS without darunavir or darunavir without ISENTRESS (see section 4.8).
ISENTRESS contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
In vitro studies indicated that raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not induce CYP3A4 and does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.
Based on in vitro and in vivo studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.
Although in vitro studies indicated that raltegravir is not an inhibitor of the UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, one clinical study has suggested that some inhibition of UGT1A1 may occur in vivo based on effects observed on bilirubin glucuronidation. However, the magnitude of the effect seems unlikely to result in clinically important drug-drug interactions.
Considerable inter- and intra-individual variability was observed in the pharmacokinetics of raltegravir. The following drug interaction information is based on Geometric Mean values; the effect for an individual patient cannot be predicted precisely.
Effect of raltegravir on the pharmacokinetics of other medicinal products
In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, or midazolam.
Effect of other agents on the pharmacokinetics of raltegravir
Given that raltegravir is metabolised primarily via UGT1A1, caution should be used when co-administering ISENTRESS with strong inducers of UGT1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.4). The impact of other strong inducers of drug metabolising enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with the recommended dose of ISENTRESS.
Co-administration of ISENTRESS with medicinal products that are known to be potent UGT1A1 inhibitors (e.g., atazanavir) may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors (e.g., indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extent compared with atazanavir. In addition, tenofovir may increase plasma levels of raltegravir, however, the mechanism for this effect is unknown (see Table 1). From the clinical trials, a large proportion of patients used atazanavir and / or tenofovir, both agents that result in increases in raltegravir plasma levels, in the optimised background regimens. The safety profile observed in patients who used atazanavir and / or tenofovir was generally similar to the safety profile of patients who did not use these agents. Therefore no dose adjustment is required.
In healthy subjects, co-administration of ISENTRESS with omeprazole increases raltegravir plasma levels. As the effects of increasing gastric pH on the absorption of raltegravir in HIV-infected patients are uncertain, use ISENTRESS with medicinal products that increase gastric pH (e.g., proton pump inhibitors and H2 antagonists) only if unavoidable.
Table 1
Pharmacokinetic Interaction Data
Medicinal products by therapeutic area
|
Interaction
(mechanism, if known)
|
Recommendations concerning co-administration
|
ANTI-RETROVIRAL
|
|
|
Protease inhibitors (PI)
|
|
|
atazanavir /ritonavir
(raltegravir 400 mg Twice Daily)
|
raltegravir AUC ↑41%
raltegravir C12hr ↑77%
raltegravir Cmax ↑24%
(UGT1A1 inhibition)
|
No dose adjustment required for ISENTRESS.
|
tipranavir /ritonavir
(raltegravir 400 mg Twice Daily)
|
raltegravir AUC
raltegravir C12hr
raltegravir Cmax
(UGT1A1 induction)
|
No dose adjustment required for ISENTRESS.
|
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
|
|
|
efavirenz
(raltegravir 400 mg Single Dose)
|
raltegravir AUC
raltegravir C12hr
raltegravir Cmax
(UGT1A1 induction)
|
No dose adjustment required for ISENTRESS.
|
etravirine
(raltegravir 400 mg Twice Daily)
|
raltegravir AUC
raltegravir C12hr
raltegravir Cmax
(UGT1A1 induction)
etravirine AUC ↑ 10%
etravirine C12hr ↑ 17%
etravirine Cmax ↑ 4%
|
No dose adjustment required for ISENTRESS or etravirine.
|
Nucleoside/tide reverse transcriptase inhibitors
|
|
|
tenofovir
(raltegravir 400 mg Twice Daily)
|
raltegravir AUC ↑49%
raltegravir C12hr ↑3%
raltegravir Cmax ↑64%
(mechanism of interaction unknown)
tenofovir AUC
tenofovir C12hr
tenofovir Cmax
|
No dose adjustment required for ISENTRESS or tenofovir disoproxil fumarate.
|
CCR5 inhibitors
|
|
|
maraviroc
(raltegravir 400 mg Twice Daily)
|
raltegravir AUC
raltegravir C12hr
raltegravir Cmax
(mechanism of interaction unknown)
maraviroc AUC
maraviroc C12hr
maraviroc Cmax
|
No dose adjustment required for ISENTRESS or maraviroc.
|
ANTIMICROBIALS
|
|
|
Antimycobacterial
|
|
|
rifampicin
(raltegravir 400 mg Single Dose)
|
raltegravir AUC
raltegravir C12hr
raltegravir Cmax
(UGT1A1 induction)
|
Rifampicin reduces plasma levels of ISENTRESS. If co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.4).
|
SEDATIVE
|
|
|
midazolam
(raltegravir 400 mg Twice Daily)
|
midazolam AUC
midazolam Cmax↑3%
|
No dosage adjustment required for ISENTRESS 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.
|
ANTI-ULCER
|
|
|
omeprazole
(raltegravir 400 mg Single Dose)
|
raltegravir AUC ↑ 212%
raltegravir C12 hr↑ 46%
raltegravir Cmax↑ 315%
|
Co-administration of proton pump inhibitors or other antiulcer medicinal products may increase plasma levels of raltegravir.
Do not use ISENTRESS with medicinal products that increase gastric pH unless this is unavoidable.
|
HORMONAL CONTRACEPTIVES
|
|
|
Ethinyl Estradiol
Norelgestromin
(raltegravir 400 mg Twice Daily)
|
Ethinyl Estradiol AUC
Ethinyl Estradiol Cmax↑ 1%
Norelgestromin AUC ↑ 14%
Norelgestromin Cmax↑ 29%
|
No dosage adjustment required for ISENTRESS 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 ISENTRESS or methadone.
|
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data from the use of raltegravir in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. ISENTRESS should not be used during pregnancy.
Anti-retroviral Pregnancy Registry
To monitor maternal-foetal outcomes in patients inadvertently administered ISENTRESS while pregnant, an Anti-retroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry.
Lactation
It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. In rats, at a maternal dose of 600 mg/kg/day, mean active substance concentrations in milk were approximately 3-fold greater than in maternal plasma. Breastfeeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-infected mothers should not breastfeed their infants to avoid risking postnatal transmission of HIV.
4.7 Effects On Ability To Drive And Use Machines
No studies have been performed on the effects of ISENTRESS on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing ISENTRESS, which may influence some patients' ability to drive and use machines (see section 4.8).
4.8 Undesirable Effects
The safety profile of ISENTRESS was based on the pooled safety data from two Phase III clinical studies in treatment-experienced patients and one Phase III clinical study in treatment-naïve patients; described below.
In treatment-experienced patients, the two randomised clinical studies used the recommended dose of 400 mg twice daily in combination with optimised background therapy (OBT) in 462 patients, in comparison to 237 patients taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 708 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 244 patient-years in the group receiving placebo.
In treatment-naïve patients, the multi-centre, randomised, double-blind, active-controlled clinical study used the recommended dose of 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 245 mg in 281 patients, in comparison to 282 patients taking efavirenz (EFV) 600 mg (at bedtime) in combination with emtricitabine (+) tenofovir. During double-blind treatment, the total follow-up was 480 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 463 patient-years in the group receiving efavirenz 600 mg at bedtime.
In the pooled analysis of treatment-experienced patients, the rates of discontinuation of therapy due to adverse reactions were 3.9 % in patients receiving ISENTRESS + OBT and 4.6 % in patients receiving placebo + OBT. The rates of discontinuation of therapy in naïve patients due to adverse reactions were 3.6 % in patients receiving ISENTRESS + emtricitabine (+) tenofovir and 6.7 % in patients receiving efavirenz + emtricitabine (+) tenofovir.
Adverse reactions considered by investigators to be causally related to ISENTRESS (alone or in combination with other ART) are listed below by System Organ Class. Any term that includes at least one serious adverse reaction is identified with a dagger (†). Adverse reactions identified from post-marketing experience are included in italics.
Frequencies are defined as common (
System Organ Class
|
Frequency
|
Adverse reactions
ISENTRESS (alone or in combination with other ART)
|
Infections and infestations
|
uncommon
|
genital herpes†, folliculitis, gastro-enteritis, herpes simplex, herpes virus infection, herpes zoster, influenza, 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
|
uncommon
|
thrombocytopenia‡‡
|
|
Immune system disorders
|
uncommon
|
immune reconstitution syndrome†, drug hypersensitivity, hypersensitivity
|
Metabolism and nutrition disorders
|
uncommon
|
anorexia, cachexia, decreased appetite, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperphagia, increased appetite, polydipsia
|
Psychiatric disorders
|
common
uncommon
uncommon
|
abnormal dreams, insomnia
mental disorder†, suicide attempt†, anxiety, confusional state, depressed mood, depression, major depression, middle insomnia, mood altered, nightmare, 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
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
|
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
|
Gastro-intestinal disorders
|
common
uncommon
|
abdominal distention, abdominal pain, diarrhoea, flatulence, nausea, vomiting
gastritis†, abdominal discomfort, abdominal pain upper, abdominal tenderness, anorectal discomfort, dry mouth, constipation, dyspepsia, epigastric discomfort, erosive duodenitis, eructation, gastro-oesophageal reflux disease, gingivitis, glossitis, odynophagia, pancreatitis acute, peptic ulcer, rectal haemorrhage
|
Hepato-biliary disorders
|
uncommon
|
hepatitis†, hepatic steatosis
|
Skin and subcutaneous tissue disorders
|
common
uncommon
uncommon
|
rash‡
acne, alopecia, dermatitis acneiforme, dry skin, erythema, facial wasting, hyperhidrosis, 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
|
Uncommon
|
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, oedema peripheral, pain
|
Investigations
|
common
uncommon
|
alanine aminotransferase increased, atypical lymphocytes, aspartate aminotransferase increased, blood triglycerides increased, lipase 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, low density lipoprotein decreased, low density lipoprotein increased, platelet count decreased, red blood cells urine positive, waist circumference increased, weight increased, white blood cell count decreased
|
Injury, poisoning and procedural complications
|
uncommon
|
accidental overdose†
|
† Includes at least one serious adverse reaction
‡ In clinical studies of treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing ISENTRESS + darunavir compared to those containing ISENTRESS without darunavir or darunavir without ISENTRESS. 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).
‡‡ This adverse reaction was identified through post-marketing surveillance but not reported as drug-related in randomised controlled Phase III clinical trials (Protocols 018, 019, and 021). The frequency category of "uncommon" was defined per the Summary of Product Characteristics (SmPC) guidance (rev. 2, Sept 2009) on the basis of an estimated upper bound of the 95% confidence interval for 0 events given the number of subjects treated with ISENTRESS in the Phase III clinical program (n=743).
|
|
|
Cancers were reported in treatment-experienced and treatment-naïve patients who initiated ISENTRESS 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 ISENTRESS and in the groups receiving comparators.
Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS. 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).
Patients co-infected with hepatitis B and/or hepatitis C virus
In Phase III studies, treatment-experienced patients (N = 114/699 or 16%; HBV=6 %, HCV=9 %, HBV+HCV=1%) and treatment-naïve patients (N = 34/563 or 6 %; HBV=4 %, HCV=2 %, HBV+HCV=0.2 %) with chronic (but not acute) active hepatitis B and/or hepatitis C co-infection were permitted to enrol provided that baseline liver function tests did not exceed 5 times the upper limit of normal. In general the safety profile of ISENTRESS 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 with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. 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 subjects treated with ISENTRESS as compared to 11 %, 10 % and 9 % of all other subjects treated with ISENTRESS. 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 17 %, 28 % and 17 %, respectively, of co-infected subjects treated with ISENTRESS as compared to 6 %, 6 % and 3 % of all other subjects treated with ISENTRESS.
4.9 Overdose
No specific information is available on the treatment of overdosage with ISENTRESS.
In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastro-intestinal 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 ISENTRESS may be dialysable is unknown.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antiviral for systemic use, Other Antivirals, ATC code: J05AX08.
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. 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. Preliminary data indicate that there is potential for at least some degree of cross-resistance to occur between raltegravir and other integrase inhibitors.
Clinical experience
The evidence of efficacy of ISENTRESS is based on the analyses of 96-week data from two ongoing, randomised, double-blind, placebo-controlled trials, (BENCHMRK 1 and BENCHMRK 2, Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult patients and the analysis of 96-week data from an ongoing, randomised, double-blind, active-control trial, (STARTMRK, Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult patients.
Efficacy
Treatment-experienced patients
BENCHMRK 1 and BENCHMRK 2 (ongoing multi-centre, randomised, double-blind, placebo-controlled trials) evaluate the safety and anti-retroviral activity of ISENTRESS 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 ISENTRESS 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 ISENTRESS 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
Parameter
|
48 Weeks
|
96 Weeks
|
|
|
ISENTRESS 400 mg twice daily + OBT
(N = 462)
|
Placebo + OBT
(N = 237)
|
ISENTRESS 400 mg twice daily + OBT
(N = 462)
|
Placebo + OBT
(N = 237)
|
|
Percent HIV-RNA < 400 copies/ml (95% CI)
|
|
|
|
|
All patients†
|
72 (68, 76)
|
37 (31, 44)
|
62 (57, 66)
|
|
