Merck_ad.qxp 6/8/08 11:05 am Page IFC1
1. NAME OF THE MEDICINAL PRODUCT: ISENTRESS™
†
400-mg film-coated tablets is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-infected
2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 400 mg mothers should not breastfeed their infants to avoid risking postnatal transmission of HIV.
Table 3: Efficacy Outcome at Week 24
of raltegravir (as potassium). Excipient: Each tablet contains 26.06 mg lactose monohydrate. For 4.7 Effects on ability to drive and use machines No studies have been performed on the effects
BENCHMRK 1 and 2 Pooled ISENTRESS 400 mg Placebo + OBT
a full list of excipients, see section 6.1. of ISENTRESS on the ability to drive and use machines. However, dizziness has been reported in b.i.d. + OBT (N = 237)
3. PHARMACEUTICAL FORM: Film-coated tablet. Pink, oval tablet, marked with “227” on one side. some patients during treatment with regimens containing ISENTRESS, which may influence some
Parameter (N = 462)
4. CLINICAL PARTICULARS
patients’ ability to drive and use machines (see section 4.8).
Percent HIV-RNA < 400 copies/mL (95% CI)
All patients
c
75 (71, 79) 40 (34, 47)
4.1 Therapeutic indications ISENTRESS is indicated in combination with other antiretroviral
4.8 Undesirable effects Treatment-experienced The safety assessment of ISENTRESS in
Baseline Characteristic
d
medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in
treatment-experienced patients is based on the pooled safety data from 3 randomized clinical
HIV-RNA > 100,000 copies/mL 64 (56, 71) 18 (11, 29)
treatment-experienced adult patients with evidence of HIV-1 replication despite ongoing
studies. These studies used the recommended dose of 400 mg twice daily in combination with b 100,000 copies/mL 85 (81, 89) 52 (44, 60)
antiretroviral therapy.
optimized background therapy (OBT) in 507 patients, in comparison to 282 patients taking placebo CD4-count b 50 cells/mm
3
62 (54, 70) 21 (13, 32)
This indication is based on safety and efficacy data from 2 double-blind, placebo-controlled trials
in combination with OBT. During double-blind treatment, the total follow-up was 332.2 patient- > 50 and b 200 cells/mm
3
82 (76, 88) 46 (35, 57)
> 200 cells/mm
3
87 (80, 92) 55 (43, 67)
of 24 weeks’ duration in treatment-experienced patients (see section 5.1).
years in the ISENTRESS 400 mg b.i.d. group and 150.2 patient-years in the placebo group. For
Sensitivity score (GSS)
e
4.2 Posology and method of administration Therapy should be initiated by a physician
patients in the ISENTRESS 400 mg twice daily + OBT arm and the comparator placebo + OBT
0 55 (45, 64) 9 (4, 19)
experienced in the management of HIV infection. ISENTRESS should be used in combination
arm, the most commonly reported adverse reactions (>10 % in either group), of all intensities
1 84 (78, 90) 40 (30, 51)
with other active antiretroviral therapies (ARTs) (see sections 4.4 and 5.1).
and regardless of causality were: diarrhea in 16.6 % and 19.5 %, nausea in 9.9 % and 14.2 %,
2 and above 85 (78, 90) 69 (56, 79)
Posology
headache in 9.7 % and 11.7 %, pyrexia in 4.9 % and 10.3 % of patients, respectively. In this
Adults: The recommended dosage of ISENTRESS is 400 mg administered twice daily
Percent HIV-RNA < 50 copies/mL (95% CI)
All patients
c
63 (58, 67) 34 (28, 40)
with or without food. The effect of food on absorption of raltegravir is uncertain (see section 5.2).
pooled analysis, the rates of discontinuation of therapy due to adverse reactions were 2.0 % in
Baseline Characteristic
d
It is not recommended to chew, crush, or split the tablets.
patients receiving ISENTRESS + OBT and 1.4 % in patients receiving placebo + OBT. Clinical
adverse reactions considered by investigators to be of mild, moderate, or severe intensity, causally
HIV-RNA > 100,000 copies/mL 47 (39, 55) 15 (8, 24)
Elderly: There is limited information regarding the use of ISENTRESS in the elderly (see section
related to any medicinal product in the combination regimen, occurring at a numerically higher
b 100,000 copies/mL 74 (69, 79) 44 (36, 52)
5.2). Therefore ISENTRESS should be used with caution in this population.
CD4-count b 50 cells/mm
3
44 (35, 52) 17 (10, 28)
rate among treatment-experienced patients (507) receiving ISENTRESS + OBT than patients
Children and adolescents: Safety and efficacy have not been established in patients below 16
> 50 and b 200 cells/mm
3
69 (61, 76) 43 (33, 55)
receiving Placebo + OBT (282), with an incidence r1%, are listed below by System Organ Class. > 200 cells/mm3 80 (73, 87) 42 (31, 54)
years of age (see sections 5.1 and 5.2). Renal impairment: No dosage adjustment is required
Frequencies are defined as common ( r1/100 to <1/10) and uncommon ( r1/1,000 to <1/100). Sensitivity score (GSS)
e
for patients with renal impairment (see section 5.2). Hepatic impairment: No dosage adjustment 0 44 (35, 54) 6 (2, 15)
is required for patients with mild to moderate hepatic impairment. The safety and efficacy of
System Organ Class Adverse reaction Frequency
1 71 (63, 77) 37 (28, 48)
ISENTRESS have not been established in patients with severe underlying liver disorders. Therefore Nervous system disorders dizziness common 2 and above 71 (63, 78) 56 (43, 68)
ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections Ear and labyrinth disorders vertigo common
Mean CD4 Cell Change (95% CI), cells/mm
3
4.4 and 5.2). Method of administration Oral Gastrointestinal disorders abdominal pain, flatulence, constipation common
All patients
c
84 (75, 93) 37 (27, 46)
Baseline Characteristic
d
4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients. Skin and subcutaneous tissue disorders pruritus, lipodystrophy acquired, hyperhidrosis common
HIV-RNA > 1100,000 copies/mL 105 (90, 120) 32 (16, 47)
4.4Specialwarningsandprecautionsforuse Patients should be advised that current antiretroviral
Musculoskeletal and connective tissue arthralgia common
b 100,000 copies/mL 72 (61, 83) 39 (27, 51)
therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others
disorders
CD4-count b 50 cells/mm
3
89 (76, 102) 36 (22, 50)
General disorders and administration fatigue, asthenia common
through blood or sexual contact. Appropriate precautions should continue to be employed.
site conditions
> 50 and b 200 cells/mm
3
95 (81, 109) 40 (27, 52)
Overall, considerable inter- and intra-subject variability was observed in the pharmacokinetics
> 200 cells/mm
3
64 (46, 82) 34 (11, 56)
of raltegravir (see sections 4.5 and 5.2). Higher response rates were observed in patients with
Sensitivity score (GSS)
e
Clinically important (serious and/or severe) adverse reactions occurring in adult patients receiving 0 77 (56, 97) 15 (2, 27)
Genotypic Sensitivity Score (GSS)>0. Patients with GSS or Phenotypic Sensitivity Score (PSS)=0
ISENTRESS + OBT in the 3 randomized clinical studies are presented below. 1 86 (74, 99) 35 (19, 51)
had a higher risk of developing resistance to raltegravir (see section 5.1). Raltegravir should 2 and above 83 (69, 98) 58 (39, 77)
be used in combination with at least one other active agent to enhance benefit and to reduce
c
System Organ Class Adverse reaction Frequency
Non-completeris failure imputation: patients who discontinued prematurely are imputed as failure thereafter. Percent
the risk of virologic failure and development of resistance to raltegravir. The safety and efficacy
of patients with response and associated 95% confidence interval (CI) are reported.
Cardiac disorders myocardial infarction uncommon d
of ISENTRESS have not been established in patients with severe underlying liver disorders.
Foranalysis by prognostic factors, virologic failures were carried forward for percent < 400 and 50 copies/mL. For
Blood and lymphatic system disorders anemia, neutropenia uncommon mean CD4 changes, baseline-carry-forward was used for virologic failures.
Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment eThe Genotypic Sensitivity Score (GSS) was defined as the total oral ARTs in the optimized background therapy (OBT)
(see sections 4.2 and 5.2). Patients with preexisting liver dysfunction including chronic hepatitis
Nervous system disorders allodynia, headache uncommon
to which a patient’s viral isolate showed genotypic sensitivity based upon genotypic resistance test. Enfuvirtide use in
have an increased frequency of liver function abnormalities during combination antiretroviral
Gastrointestinal disorders abdominal pain, flatulence, gastritis, vomiting uncommon
OBT in enfuvirtide-naïve patients was counted as one active drug in OBT. Similarly, darunavir use in OBT in darunavir-
therapy and should be monitored according to standard practice. If there is evidence of worsening
Renal and urinary disorders nephropathy toxic, nephritic syndrome, renal failure, uncommon naïve patients was counted as one active drug in OBT.
renal failure chronic, renal tubular necrosis
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
Musculoskeletal and connective tissue muscle spasms, pain in extremity uncommon
disorders
Long-term results Long-term efficacy data of ISENTRESS 400 mg b.i.d. in treatment-experienced
B virus (HBV) or hepatitis C virus (HCV). Patients with chronic hepatitis B or C and treated with
Metabolism and nutrition disorders hypertriglyceridemia uncommon
patients up to 48 weeks is available from the phase 2 dose-finding study (Protocol 005). At week
combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic
Infections and infestations herpes simplex uncommon
24, 71% of patients receiving ISENTRESS 400 mg b.i.d. maintained HIV RNA <400 copies/
adverse events. Osteonecrosis Although the etiology is considered to be multifactorial (including mL and 56% also maintained HIV RNA <50 copies/mL. Through 48 weeks of treatment, 64%
corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index),
Injury, poisoning, and procedural accidental overdose uncommon
complications receiving ISENTRESS 400 mg b.i.d. maintained HIV RNA <400 copies/mL and 46 % also
cases of osteonecrosis have been reported particularly in patients with advanced HIV disease
Immune system disorders drug hypersensitivity, hypersensitivity
a
uncommon
maintained HIV RNA <50 copies/mL.
and/or long-term exposure to combination antiretroviral therapy. Patients should be advised
Hepatobiliary disorders hepatitis uncommon This medicinal product has been authorized under a so-called “conditional approval” scheme.
to seek medical advice if they experience joint aches and pain, joint stiffness, or difficulty in
a This means that further evidence on this medicinal product is awaited. The European Medicines
movement. Immune reactivation syndrome In HIV-infected patients with severe immune deficiency
Hypersensitivity was seen in 2 patients with ISENTRESS. Therapy was interrupted and upon rechallenge the patients
were able to resume medicinal product. Agency (EMEA) will review new information on the product every year and this SPC will be
at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to
updated as necessary.
asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions,
Cancers were reported in treatment-experienced patients who initiated ISENTRESS with OBT; 5.2 Pharmacokinetic properties
or aggravation of symptoms. Typically, such reactions have been observed within the first weeks
several were recurrent. The types and rates of specific cancers were those expected in a highly
or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalized
Absorption As demonstrated in healthy volunteers administered single oral doses of raltegravir
immunodeficient population (many had CD4 cell counts below 50 cells/mm
3
and most had prior
and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly
in the fasted state, raltegravir is rapidly absorbed with a t
max
of approximately 3 hours postdose.
AIDS diagnoses). The cancers included Kaposi’s sarcoma, lymphoma, squamous cell carcinoma,
known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment
Raltegravir AUC and C
max
increase dose proportionally over the dose range 100 mg to 1600
hepatocellular carcinoma, and anal cancer. Most patients had other risk factors for cancer including
instituted when necessary. Caution should be used when coadministering ISENTRESS with strong
mg. Raltegravir C
12 hr
increases dose proportionally over the dose range of 100 to 800 mg and
tobacco use, papillomavirus, and active hepatitis B virus infection. It is unknown if these cancer
inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (eg, rifampicin). Rifampicin
increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg. Dose
diagnoses were related to ISENTRESS use (see section 4.4). Grade 2-4 creatine kinase laboratory
reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However,
proportionality has not been established in patients. With twice-daily dosing, pharmacokinetic
abnormalities were observed in subjects treated with ISENTRESS (see Table 2). Myopathy and
if coadministration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be
steady state is achieved rapidly, within approximately the first 2 days of dosing. There is little
rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events
considered (see section 4.5). Myopathy and rhabdomyolysis have been reported; however, the
to no accumulation in AUC and C
is not known. Use with caution in patients who have had myopathy or rhabdomyolysis in the
max
and evidence of slight accumulation in C
12 hr
. The absolute
relationship of ISENTRESS to these events is not known. Use with caution in patients who have
bioavailability of raltegravir has not been established. ISENTRESS may be administered with
past or have any predisposing issues including other medicinal products associated with these
had myopathy or rhabdomyolysis in the past or have any predisposing issues including other
or without food. Raltegravir was administered without regard to food in the pivotal safety and
conditions (see section 4.4). Cases of osteonecrosis have been reported, particularly in patients
medicinal products associated with these conditions (see section 4.8). During the clinical studies
efficacy studies in HIV-infected patients. Administration of multiple doses of raltegravir following a
with generally acknowledged risk factors, advanced HIV disease, or long-term exposure to
in treatment-experienced HIV-infected patients there was a slightly higher rate of cancer in the
moderate-fat meal did not affect raltegravir AUC to a clinically meaningful degree with an increase
combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).
raltegravir group compared to the group that received only optimized background therapy. At
of 13% relative to fasting. Raltegravir C
12 hr
was 66% higher and C
max
was 5% higher following
present there are insufficient data to be able to exclude the possibility that raltegravir might be
Patients co-infected with hepatitis B and/or hepatitis C virus In phase 3 studies, patients with a moderate-fat meal compared to fasting. Administration of raltegravir following a high-fat meal
associated with a risk of cancer (see section 4.8). ISENTRESS contains lactose. Patients with rare
chronic active hepatitis B and/or hepatitis C co-infection (N = 113/699 or 16.2%; HBV=6 %, increased AUC and C
max
by approximately 2-fold and increased C
12 hr
by 4.1-fold. Administration
hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose
HCV=9 %, HBV+HCV=1%) were permitted to enroll provided that AST, ALT, and alkaline of raltegravir following a low-fat meal decreased AUC and C
max
by 46% and 52%, respectively;
malabsorption should not take this medicine.
phosphatase tests did not exceed 5 times the upper limit of normal. In general the safety profile C
of ISENTRESS in patients with hepatitis B and/or hepatitis C virus co-infection was similar to that
12 hr
was essentially unchanged. Food appears to increase pharmacokinetic variability relative
4.5 Interaction with other medicinal products and other forms of interaction Raltegravir is not
to fasting. Overall, considerable variability was observed in the pharmacokinetics of raltegravir.
in patients without hepatitis B and/or hepatitis C virus co-infection. Grade 2 or higher laboratory
a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8,
For observed C
abnormalities that represent a worsening from baseline of AST, ALT, or total bilirubin occurred
12hr
in BENCHMRK 1 and 2 the coefficient of variation (CV) for inter-subject
CYP2C9, CYP2C19, CYP2D6, or CYP3A, and does not induce CYP3A4. Raltegravir is not an
variability = 212% and the CV for intra-subject variability = 122%. Sources of variability may
in 26%, 27%, and 12%, respectively, of raltegravir-treated co-infected subjects as compared
inhibitor of the UDP-glucuronosyltransferases (UGTs) 1A1 and 2B7, and raltegravir does not
include differences in coadministration with food and concomitant medications. Distribution
to 9%, 8%, and 7% of all other raltegravir-treated subjects. Laboratory Abnormalities Selected
inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected
Raltegravir is approximately 83% bound to human plasma protein over the concentration range
laboratory abnormalities (Grades 2-4) that represent a worsening from baseline observed in
to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or
of 2 to 10 µM. Raltegravir readily crossed the placenta in rats, but did not penetrate the brain to
treatment-experienced patients are presented in Table 2.
P-glycoprotein. Based on in vitro and in vivo studies, raltegravir is eliminated mainly by metabolism
any appreciable extent. Metabolism and excretion The apparent terminal half-life of raltegravir
via a UGT1A1-mediated glucuronidation pathway. Considerable inter- and intra-individual
is approximately 9 hours, with a shorter . -phase half-life (~1 hour) accounting for much of the
Table 2: Selected Grades 2–4 Laboratory Abnormalities
variability was observed in the pharmacokinetics of raltegravir. The following drug interaction Reported in Treatment-Experienced Patients
AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 %
information is based on Geometric Mean values; the effect for an individual patient cannot be Laboratory Parameter Limit ISENTRESS
b
Placebo
b and 32 % of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was
predicted precisely. Effect of raltegravir on the pharmacokinetics of other medicinal products In (N = 507) (N = 282)
present, most of which is likely to be derived from hydrolysis of raltegravir-glucuronide secreted
interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics
Blood chemistry in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-
of tenofovir or midazolam.
Total serum bilirubin glucuronide, were detected in urine and accounted for approximately 9 % and 23 % of the
Effect of other agents on the pharmacokinetics of raltegravir Given that raltegravir is metabolized
Grade 2 1.6 – 2.5 x ULN 5.3% 6.7% dose, respectively. The major circulating entity was raltegravir and represented approximately
primarily via UGT1A1, caution should be used when coadministering ISENTRESS with strong
Grade 3 2.6 - 5.0 x ULN 3.2% 2.5%
70 % of the total radioactivity; the remaining radioactivity in plasma was accounted for by
Grade 4 >5.0 x ULN 0.8% 0.0%
inducers of UGT1A1 (eg, rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on
raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed
Serum aspartate aminotransferase
the efficacy of raltegravir is unknown. However, if coadministration with rifampicin is unavoidable,
Grade 2 2.6 – 5.0 x ULN 9.1% 5.7%
UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for
a doubling of the dose of ISENTRESS can be considered (see section 4.4). The impact of other Grade 3 5.1 - 10.0 x ULN 2.2% 2.1%
the formation of raltegravir-glucuronide. Thus the data indicate that the major mechanism of
strong inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 Grade 4 >10.0 x ULN 0.4% 0.7%
clearance of raltegravir in humans is UGT1A1-mediated glucuronidation. UGT1A1 Polymorphism
is unknown. Less potent inducers (eg, efavirenz, nevirapine, rifabutin, glucocorticoids, St John’s Serum alanine aminotransferase
In a comparison of 30 subjects with *28/*28 genotype to 27 subjects with wild-type genotype,
wort, pioglitazone) may be used with the recommended dose of ISENTRESS. Coadministration Grade 2 2.6 – 5.0 x ULN 6.9% 7.8%
the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09) and the geometric mean ratio
of ISENTRESS with medicinal products that are known to be potent UGT1A1 inhibitors (eg,
Grade 3 5.1 - 10.0 x ULN 3.0% 1.4% of C
12 hr
was 1.91 (1.43, 2.55). Dose adjustment is not considered necessary in subjects with
atazanavir) may increase plasma levels of raltegravir. In addition, tenofovir may increase plasma
Grade 4 >10.0 x ULN 0.6% 1.1% reduced UGT1A1 activity due to genetic polymorphism. Special populations Children: The
levels of raltegravir, however, the mechanism for this effect is unknown (see Table 1). From the
Serum creatine kinase pharmacokinetics of raltegravir in pediatric patients has not been established. Elderly: There
clinical trials, a large proportion of patients used atazanavir and/or tenofovir, both agents that
Grade 2 6.0 – 9.9 x ULN 2.2% 1.4%
was no clinically meaningful effect of age on raltegravir pharmacokinetics over the age range
result in increases in raltegravir plasma levels, in the optimized background regimens. The safety
Grade 3 10.0 - 19.9 x ULN 2.4% 1.8%
studied (19 to 71 years, with few (8) subjects over the age of 65). Gender, Race, and BMI: There
Grade 4 r20.0 x ULN 2.2% 0.7%
profile observed in patients who used atazanavir and/or tenofovir was generally similar to the b
ISENTRESS 400 mg and placebo were administered with Optimized Background Therapy (OBT).
were no clinically important pharmacokinetic differences due to gender, race, or body mass index
safety profile of patients who did not use these agents. Therefore no dose adjustment is required.
ULN = Upper limit of normal range.
(BMI). Renal impairment: Renal clearance of unchanged medicinal product is a minor pathway
In healthy subjects, coadministration of ISENTRESS with omeprazole increases raltegravir plasma of elimination. There were no clinically important pharmacokinetic differences between patients
levels. As the effects of increasing gastric pH on the absorption of raltegravir in HIV-infected
In patients receiving atazanavir and/or tenofovir, Grade 2 laboratory abnormalities that represent
with severe renal insufficiency and healthy subjects (see section 4.2). Because the extent to
patients are uncertain, use ISENTRESS with medicinal products that increase gastric pH (eg,
a worsening from baseline of AST or ALT occurred in 8.9% and 7.4%, respectively, of patients
which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be
proton pump inhibitors and H
2
antagonists) only if unavoidable.
treated with ISENTRESS as compared to 3.2% and 6.8%, respectively, of placebo-treated patients.
avoided. Hepatic impairment: Raltegravir is eliminated primarily by glucuronidation in the liver.
Similarly, in patients receiving atazanavir and/or tenofovir, Grade 3 / 4 laboratory abnormalities
There were no clinically important pharmacokinetic differences between patients with moderate
Table 1 Pharmacokinetic Interaction Data
Medicinal products by Interaction (mechanism, if known) Recommendations concerning
of AST or ALT occurred in 2.8% and 3.1%, respectively, of patients treated with ISENTRESS
hepatic insufficiency and healthy subjects. The effect of severe hepatic insufficiency on the
therapeutic area coadministration
as compared to 3.2% and 2.3%, respectively, of placebo-treated patients. In patients receiving
pharmacokinetics of raltegravir has not been studied (see sections 4.2 and 4.4).
ANTIRETROVIRAL tipranavir, Grade 2 laboratory abnormalities that represent a worsening from baseline of AST or
5.3 Preclinical safety data Nonclinical toxicology studies, including conventional studies of
Protease inhibitors (PI) ALT occurred in 14.3% and 9.2%, respectively, of patients treated with ISENTRESS as compared
safety pharmacology, repeated-dose toxicity, genotoxicity, and developmental toxicity, have been
atazanavir/ritonavir raltegravir AUC 9 41% No dose adjustment required for ISENTRESS
to 8.9% and 6.7%, respectively, of placebo-treated patients. In patients receiving tipranavir,
conducted with raltegravir in mice, rats, dogs, and rabbits. Effects at exposure levels sufficiently
raltegravir C12hr 9 77%
(raltegravir 400 mg BID) raltegravir C
Grade 3 / 4 laboratory abnormalities of AST or ALT occurred in 3.1% and 9.2%, respectively, of
in excess of clinical exposure levels indicate no special hazard for humans. Mutagenicity No
max 9 24%
(UGT1A1 inhibition)
patients treated with ISENTRESS compared to 6.7% and 11.1%, respectively, of placebo-treated
evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames)
ritonavir raltegravir AUC ; 16% No dose adjustment required for ISENTRESS patients.
tests, in vitro alkaline elution assays for DNA breakage, and in vitro and in vivo chromosomal
(raltegravir 400 mg SD) raltegravir C12hr ; 1%
4.9 Overdose No specific information is available on the treatment of overdosage with
aberration studies. Carcinogenicity Long-term (2-year) carcinogenicity studies of raltegravir in
raltegravir Cmax ; 24%
tipranavir /ritonavir raltegravir AUC ; 24% No dose adjustment required for ISENTRESS
ISENTRESS. In the event of an overdose, it is reasonable to employ the standard supportive
rodents are ongoing but have not been completed. Developmental Toxicity Raltegravir was not
(raltegravir 400 mg BID) raltegravir C
measures, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical
teratogenic in developmental toxicity studies in rats and rabbits. A slight increase in incidence of
12hr ; 55%
raltegravir Cmax ; 18% monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
supernumerary ribs was observed in rat pups of dams exposed to raltegravir at approximately
(UGT1A1 induction) It should be taken into account that raltegravir is presented for clinical use as the potassium salt. 4.4-fold human exposure at 400 mg twice daily based on AUC
0-24 hr
. No development effects were
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
The extent to which ISENTRESS may be dialyzable is unknown.
seen at 3.4-fold human exposure at 400 mg twice daily based on AUC
efavirenz raltegravir AUC ; 36% No dose adjustment required for ISENTRESS
0-24 hr
(see section 4.6).
(raltegravir 400 mg SD) raltegravir C
5. PHARMACOLOGICAL PROPERTIES
Similar findings were not observed in rabbits.
12hr ; 21%
raltegravir Cmax ; 36% 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiviral for systemic use,
6. PHARMACEUTICAL PARTICULARS
(UGT1A1 induction) Other Antivirals, ATC code: J05AX08. Mechanism of action Raltegravir is an integrase strand 6.1 List of excipients
Nucleoside/tide reverse transcriptase inhibitors
transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1). Raltegravir inhibits
Tablet core
tenofovir raltegravir AUC 9 49% No dose adjustment required for ISENTRESS
(raltegravir 400 mg BID) raltegravir C
the catalytic activity of integrase, an HIV-encoded enzyme that is required for viral replication.
- microcrystalline cellulose
12hr 9 3% or tenofovir disoproxil fumarate
raltegravir Cmax 9 64% Inhibition of integrase prevents the covalent insertion, or integration, of the HIV genome into the
- lactose monohydrate
(mechanism of interaction unknown) host cell genome. HIV genomes that fail to integrate cannot direct the production of new infectious - calcium phosphate dibasic anhydrous
tenofovir AUC ; 10%
viral particles, so inhibiting integration prevents propagation of the viral infection. Antiviral activity - hypromellose 2208
tenofovir C12hr ; 13%
tenofovir C
in vitro Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (IC - poloxamer 407
max ; 33% 95
)ofHIV-1
ANTIMICROBIALS
replication (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures - sodium stearyl fumarate
Antimycobacterial infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir inhibited viral
- magnesium stearate
rifampicin raltegravir AUC ; 40% Rifampicin reduces plasma levels of replication in cultures of mitogen-activated human peripheral blood mononuclear cells infected Film-coating
(raltegravir 400 mg SD) raltegravir C12hr ; 61% ISENTRESS. If coadministration with
with diverse, primary clinical isolates of HIV-1, including isolates resistant to reverse transcriptase - polyvinyl alcohol
raltegravir Cmax ; 38% rifampicin is unavoidable, a doubling of the
(UGT1A1 induction) dose of ISENTRESS can be considered (see
inhibitors and protease inhibitors. - titanium dioxide (E 171)
section 4.4). Resistance Most viruses isolated from patients failing raltegravir had high-level raltegravir - polyethylene glycol 3350
SEDATIVE resistance resulting from the appearance of 2 or more mutations. Most had a signature -talc
midazolam midazolam AUC ; 8% No dose adjustment required for ISENTRESS
mutation at amino acid 155 (N155 changed to H), amino acid 148 (Q148 changed to H, K, or -redironoxide(E172)
(raltegravir 400 mg BID) midazolam Cmax 9 3% or midazolam. These results indicate that
raltegravir is not an inducer or inhibitor of
R), or amino acid 143 (Y143 changed to H, C, or R), along with one or more additional integrase - black iron oxide (E 172)
CYP3A4, and raltegravir is thus not anticipated
mutations. These signature mutations decrease viral susceptibility to raltegravir and addition of 6.2 Incompatibilities Not applicable.
to affect the pharmacokinetics of medicinal other mutations results in a further decrease in raltegravir susceptibility. Factors that reduced 6.3 Shelf life 30 months
products which are CYP3A4 substrates.
the likelihood of developing resistance included lower baseline viral load and use of other active
ANTIULCER
6.4 Special precautions for storage This medicinal product does not require any special storage
omeprazole raltegravir AUC 9 321% Coadministration of proton pump
antiretroviral agents. Preliminary data indicate that there is potential for at least some degree of
conditions.
(raltegravr 400 mg SD) raltegravir C
cross-resistance to occur between raltegravir and other integrase inhibitors.
12hr 9 146% inhibitors or other antiulcer medicinal 6.5 Nature and contents of container High density polyethylene (HDPE) bottle with a child-
raltegravir Cmax 9 415% products may increase plasma levels of Clinical experience Efficacy of ISENTRESS in treatment-experienced patients BENCHMRK 1
resistant polypropylene closure. Two pack sizes are available: 1 bottle with 60 tablets, and a
raltegravir. Do not use ISENTRESS with and BENCHMRK 2 (ongoing multicentre, randomized, double-blind, placebo-controlled trials)
medicinal products that increase gastric pH
multi-pack containing 3 bottles of 60 tablets. Not all pack sizes may be marketed.
unless this is unavoidable.
evaluate the safety and antiretroviral activity of ISENTRESS 400 mg b.i.d. vs placebo in a
combination with optimized background therapy (OBT), in HIV-infected patients, 16 years or
6.6 Special precautions for disposal No special requirements.
4.6 Pregnancy and lactation Pregnancy There are no adequate data from the use of raltegravir
older, with documented resistance to at least 1 drug in each of 3 classes (NRTIs, NNRTIs, PIs)
7. MARKETING AUTHORIZATION HOLDER
in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The
of antiretroviral therapies. Prior to randomization, OBT were selected by the investigator based
Merck Sharp & Dohme Limited
potential risk for humans is unknown. ISENTRESS should not be used during pregnancy.
on the patient’s prior treatment history, as well as baseline genotypic and phenotypic viral
Hertford Road, Hoddesdon
Antiretroviral Pregnancy Registry To monitor maternal-fetal outcomes in patients inadvertently
resistance testing. Patient demographics (gender, age, and race) and baseline characteristics Hertfordshire EN11 9BU, United Kingdom
were comparable between ISENTRESS 400 mg b.i.d. and placebo groups. Patients had prior 8. MARKETING AUTHORIZATION NUMBER(S) EU/1/07/436/001 EU/1/07/436/002
administered ISENTRESS while pregnant, an Antiretroviral Pregnancy Registry has been
exposure to a median of 12 antiretrovirals for a median of 10 years. A median of 4 ARTs was
established. Physicians are encouraged to register patients in this registry. Lactation It is not
9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION
used in OBT. Results 24-week analyses Week 24 outcomes for patients on the recommended
known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the
Date of first authorization: 20 December 2007
dose ISENTRESS 400 mg b.i.d. from the pooled studies BENCHMRK 1 and BENCHMRK 2 are
milk of lactating rats. In rats, at a maternal dose of 600 mg/kg/day, mean active substance
10.DATEOFREVISIONOFTHETEXT
shown in Table 3.
concentrations in milk were approximately 3-fold greater than in maternal plasma. Breastfeeding
Detailed information on this medicinal product is available on the Web site of the European
†
Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA
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