ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
ISENTRESS 400 mg film-coated tablets
2.
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.
Film-coated tablet.
Pink, oval tablet, marked with "227" on one side.
4.
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).
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).
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
Hypersensitivity to the active substance or to any of the excipients.
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 etiology 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
3
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).
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.
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 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 metabolizing 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,
4
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 C
12hr
↑ 77 %
raltegravir C
max
↑ 24 %
No dose adjustment required
for ISENTRESS.
(UGT1A1 inhibition)
tipranavir /ritonavir
(raltegravir 400 mg Twice Daily)
raltegravir AUC ↓ 24 %
raltegravir C
12hr
↓ 55 %
raltegravir C
max
↓ 18 %
No dose adjustment required
for ISENTRESS.
(UGT1A1 induction)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
efavirenz
(raltegravir 400 mg Single Dose)
raltegravir AUC ↓ 36 %
raltegravir C
12hr
↓ 21 %
raltegravir C
max
↓ 36 %
No dose adjustment required
for ISENTRESS.
(UGT1A1 induction)
etravirine
(raltegravir 400 mg Twice Daily)
raltegravir AUC ↓ 10 %
raltegravir C
12hr
↓ 34 %
raltegravir C
max
↓ 11 %
No dose adjustment required
for ISENTRESS or etravirine.
(UGT1A1 induction)
etravirine AUC ↑ 10 %
etravirine C
12hr
↑ 17 %
etravirine C
max
↑ 4 %
Nucleoside/tide reverse transcriptase inhibitors
tenofovir
(raltegravir 400 mg Twice Daily)
raltegravir AUC ↑ 49 %
raltegravir C
12hr
↑ 3 %
raltegravir C
max
↑ 64 %
No dose adjustment required
for ISENTRESS or tenofovir
disoproxil fumarate.
(mechanism of interaction
unknown)
tenofovir AUC ↓ 10 %
tenofovir C
12hr
↓ 13 %
tenofovir C
max
↓ 23 %
5
Medicinal products by therapeutic
area
Interaction
(mechanism, if known)
Recommendations
concerning
co-administration
CCR5 inhibitors
maraviroc
(raltegravir 400 mg Twice Daily)
raltegravir AUC ↓ 37 %
raltegravir C
12hr
↓ 28 %
raltegravir C
max
↓ 33 %
No dose adjustment required
for ISENTRESS or maraviroc.
(mechanism of interaction
unknown)
maraviroc AUC ↓ 14 %
maraviroc C
12hr
↓ 10 %
maraviroc C
max
↓ 21 %
ANTIMICROBIALS
Antimycobacterial
rifampicin
(raltegravir 400 mg Single Dose)
raltegravir AUC ↓ 40 %
raltegravir C
12hr
↓ 61 %
raltegravir C
max
↓ 38 %
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).
(UGT1A1 induction)
SEDATIVE
midazolam
(
raltegravir
400 mg Twice Daily)
midazolam AUC ↓ 8 %
midazolam C
max
↑ 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.
ANTIULCER
omeprazole
(raltegravir 400 mg Single Dose)
raltegravir AUC ↑ 212 %
raltegravir C
12 hr
↑ 46 %
raltegravir C
max
↑ 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 ↓ 2 %
Ethinyl Estradiol C
max
↑ 1 %
Norelgestromin AUC ↑ 14 %
Norelgestromin C
max
↑ 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 C
max
↔
No dose adjustment required
for ISENTRESS or methadone.
6
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.
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).
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 (≥ 1/100 to < 1/10),
uncommon (≥ 1/1,000 to < 1/100), and not known (cannot be estimated from the available data).
7
System Organ Class
Frequency
Adverse reactions
ISENTRESS (alone or in combination with
other ART)
Infections and infestations
uncommon
genital herpes
†
, folliculitis, gastroenteritis,
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
abnormal dreams, insomnia
uncommon
mental disorder
†
, suicide attempt
†
, anxiety,
confusional state, depressed mood, depression,
major depression, middle insomnia, mood
altered, nightmare, panic attack, sleep disorder
uncommon
suicidal ideation
‡‡
, suicidal behaviour
(particularly in patients with a pre-existing
history of psychiatric illness)
‡‡
Nervous system disorders
common
dizziness, headache
uncommon
amnesia, carpal tunnel syndrome, cognitive
disorder, disturbance in attention, dizziness
postural, dysgeusia, hypersomnia,
hypoaesthesia, lethargy, memory impairment,
migraine, neuropathy peripheral, paraesthesia,
somnolence, tension headache, tremor
Eye disorders
uncommon
visual impairment
Ear and labyrinth disorders
common
vertigo
uncommon
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
8
System Organ Class
Frequency
Adverse reactions
ISENTRESS (alone or in combination with
other ART)
Gastrointestinal disorders
common
abdominal distention, abdominal pain,
diarrhoea, flatulence, nausea, vomiting
uncommon
gastritis
†
, abdominal discomfort, abdominal
pain upper, abdominal tenderness, anorectal
discomfort, constipation, dry mouth, dyspepsia,
epigastric discomfort, erosive duodenitis,
eructation, gastrooesophageal reflux disease,
gingivitis, glossitis, odynophagia, pancreatitis
acute, peptic ulcer, rectal haemorrahage
Hepato-biliary disorders
uncommon
hepatitis
†
, hepatic steatosis
Skin and subcutaneous tissue
disorders
common
rash
‡
uncommon
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
uncommon
Stevens Johnson syndrome
‡‡
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
asthenia, fatigue, pyrexia
uncommon
chest discomfort, chills, face oedema, fat tissue
increased, feeling jittery, malaise, oedema
peripheral, pain
9
System Organ Class
Frequency
Adverse reactions
ISENTRESS (alone or in combination with
other ART)
Investigations
common
alanine aminotransferase increased, atypical
lymphocytes, aspartate aminotransferase
increased, blood triglycerides increased, lipase
increased
uncommon
absolute neutrophil count decreased, alkaline
phosphatase increased, blood albumin
decreased, blood amylase increased, blood
bilirubin increased, blood cholesterol increased,
blood creatinine increased, blood glucose
increased, blood urea nitrogen increased,
creatine phosphokinase increased, fasting blood
glucose increased, glucose urine present, high
density lipoprotein increased, 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
10
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.
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 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 ISENTRESS may be
dialysable is unknown.
5.
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 (IC
95
) 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
11
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 optimized 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 randomization, 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
48 Weeks
96 Weeks
ISENTRESS
400 mg twice
daily + OBT
(N = 462)
Placebo +
ISENTRESS
400 mg
twice daily +
OBT
(N = 462)
Placebo + OBT
(N = 237)
Parameter
O
B
T
(N = 237)
Percent HIV-RNA < 400 copies/ml
(95 % CI)
All patients
†
72 (68, 76)
37 (31, 44)
62 (57, 66)
28 (23, 34)
Baseline Characteristic
‡
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/mm
3
61 (53, 69)
21 (13, 32)
51 (42, 60)
14 (7, 24)
> 50 and
≤ 200 cells/mm
3
80 (73, 85)
44 (33, 55)
70 (62, 77)
36 (25, 48)
> 200 cells/mm
3
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 Characteristic
‡
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)
12
BENCHMRK 1 and 2 Pooled
48 Weeks
96 Weeks
Parameter
ISENTRESS
400 mg twice
daily + OBT
(N = 462)
Placebo +
ISENTRESS
400 mg
twice daily +
OBT
(N = 462)
Placebo + OBT
(N = 237)
O
B
T
(N = 237)
CD4-count ≤ 50 cells/mm
3
50 (41, 58)
20 (12, 31)
50 (41, 58)
13 (6, 22)
> 50 and
≤ 200 cells/mm
3
67 (59, 74)
39 (28, 50)
65 (57, 72)
32 (22, 44)
> 200 cells/mm
3
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/mm
3
All patients
‡
109 ( 98, 121)
45 ( 32, 57)
123 (110,
137)
49 (35, 63)
Baseline Characteristic
‡
HIV-RNA > 100,000 copies/ml
126 ( 107,
144)
36 ( 17, 55)
140 (115,
165)
40 (16, 65)
≤ 100,000 copies/ml 100 ( 86, 115)
49 ( 33, 65) 114 (98, 131)
53 (36, 70)
CD4-count ≤ 50 cells/mm
3
121 ( 100,
142)
33 ( 18, 48)
130 (104,
156)
42 (17, 67)
> 50 and
≤ 200 cells/mm
3
104 ( 88, 119)
47 ( 28, 66)
123 (103,
144)
56 (34, 79)
> 200 cells/mm
3
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, 103)
134 (108,
159)
90 (57, 123)
†
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-naïve patients was
counted as one active drug in OBT. Similarly, darunavir use in OBT in darunavir-naïve 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
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 randomized 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
13
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-naive patients
STARTMRK (ongoing multi-centre, randomised, double-blind, active-control trial) evaluates the
safety and anti-retroviral activity of ISENTRESS 400 mg twice daily vs. efavirenz 600 mg at bedtime,
in a combination with emtricitabine (+) tenofovir, in treatment-naïve HIV-infected patients with HIV
RNA > 5,000 copies/ml. Randomization 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 ISENTRESS 400 mg twice daily and the group receiving efavirenz 600 mg at
bedtime.
Results 48-week and 96-week analyses
With respect to the primary efficacy endpoint, the proportion (%) of patients achieving
HIV RNA < 50 copies/ml at Week 96 was 228/281 (81.1 %) in the group receiving ISENTRESS and
222/282 (78.7 %) in the group receiving efavirenz. The treatment difference (ISENTRESS –
efavirenz) was 2.4 % with an associated 95 % CI of (-4.3, 9.0) establishing that ISENTRESS is non-
inferior to efavirenz (p-value for non-inferiority < 0.001). Durable outcomes (Week 48 and Week 96)
for patients on the recommended dose of ISENTRESS 400 mg twice daily from STARTMRK are
shown in Table 3.
Table 3
Efficacy Outcome at Weeks 48 and 96
STARTMRK Study
48 Weeks
96 Weeks
Parameter
ISENTRESS
400 mg twice
daily
(N = 281)
Efavirenz
600 mg
at bedtime
(N = 282)
ISENTRESS
400 mg twice
daily
(N = 281)
Efavirenz
600 mg
at bedtime
(N = 282)
Percent HIV-RNA < 50 copies/ml
(95 % CI)
All patients
†
86 (81, 90)
82 (77, 86)
81 (76, 86)
79 (73, 83)
Baseline Characteristic
‡
HIV-RNA > 100,000 copies/ml 91 (85, 95)
89 (83, 94)
89 (83, 94)
90 (84, 95)
≤ 100,000 copies/ml 93 (86, 97)
89 (82, 94)
91 (84, 96)
89 (82, 94)
CD4-count ≤ 50 cells/mm
3
84 (64, 95)
86 (67, 96)
80 (59, 93)
86 (68, 96)
> 50 and
≤ 200 cells/mm
3
89 (81, 95)
86 (77, 92)
89 (81, 95)
86 (77, 92)
> 200 cells/mm
3
94 (89, 98)
92 (87, 96)
93 (87, 96)
93 (87, 97)
Viral Subtype Clade B
90 (85, 94)
89 (83, 93)
89 (83, 93)
90 (84, 93)
Non-Clade B
96 (87, 100)
91 (78, 97)
95 (85, 99)
88 (75, 96)
Mean CD4 Cell Change (95 % CI),
cells/mm
3
All patients
‡
189 (174,
204)
163 (148,
178)
240 (220, 259)
225 (206, 244)
Baseline Characteristic
‡
HIV-RNA > 100,000 copies/ml 196 (174,
219)
192 (169,
214)
253 (224, 282)
257 (229, 286)
≤ 100,000 copies/ml 180 (160,
200)
134 (115,
153)
223 (197, 249)
191 (168, 215)
CD4-count ≤ 50 cells/mm
3
170 (122,
218)
152 (123,
180)
222 (164, 280)
223 (178, 269)
> 50 and
≤ 200 cells/mm
3
193 (169,
217)
175 (151,
198)
260 (229, 291)
233 (200, 266)
> 200 cells/mm
3
190 (168,
212)
157 (134,
181)
229 (200, 258)
219 (192, 247)
14
STARTMRK Study
48 Weeks
96 Weeks
Parameter
ISENTRESS
400 mg twice
daily
(N = 281)
Efavirenz
600 mg
at bedtime
(N = 282)
ISENTRESS
400 mg twice
daily
(N = 281)
Efavirenz
600 mg
at bedtime
(N = 282)
Viral Subtype Clade B
187 (170,
204)
164 (147,
181)
243 (220, 266)
227 (206, 248)
Non-Clade B
189 (153,
225)
156 (121,
190)
221 (182, 261)
220 (169, 271)
†
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 < 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.
ISENTRESS and efavirenz were administered with emtricitabine (+) tenofovir.
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 t
max
of approximately 3 hours postdose. Raltegravir AUC and
C
max
increase dose proportionally over the dose range 100 mg to 1600 mg. Raltegravir C
12 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 1600 mg. Dose proportionality has not been established
in patients.
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 C
max
and evidence of slight
accumulation in C
12 hr
. The absolute bioavailability of raltegravir has not been established.
ISENTRESS 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 C
12 hr
was 66 % higher and
C
max
was 5 % higher following a moderate-fat meal compared to fasting. Administration of raltegravir
following a high-fat meal increased AUC and C
max
by approximately 2-fold and increased C
12 hr
by
4.1-fold. Administration of raltegravir following a low-fat meal decreased AUC and C
max
by 46 % and
52 %, respectively; C
12 hr
was essentially unchanged. Food appears to increase pharmacokinetic
variability relative to fasting.
Overall, considerable variability was observed in the pharmacokinetics of raltegravir. For observed
C
12 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 medications.
Distribution
Raltegravir is approximately 83 % bound to human plasma protein over the concentration range of 2 to
10 µM.
Raltegravir readily crossed the placenta in rats, but did not penetrate the brain to any appreciable
extent.
Metabolism and excretion
The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-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
15
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 C
12 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
Children
The pharmacokinetics of raltegravir in paediatric patients has not been established.
Elderly
There was no clinically meaningful effect of age on raltegravir pharmacokinetics over the age range
studied (19 to 71 years, with few (8) subjects over the age of 65).
Gender, Race and BMI
There were no clinically important pharmacokinetic differences due to gender, race or body mass
index (BMI).
Renal impairment
Renal clearance of unchanged medicinal product is a minor pathway of elimination. There were no
clinically important pharmacokinetic differences between patients with severe renal insufficiency and
healthy subjects (see section 4.2). Because the extent to which ISENTRESS may be dialysable is
unknown, dosing before a dialysis session should be avoided.
Hepatic impairment
Raltegravir is eliminated primarily by glucuronidation in the liver. 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).
5.3 Preclinical safety data
Non-clinical toxicology studies, including conventional studies of safety pharmacology, repeated-dose
toxicity, genotoxicity, and developmental 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 400 mg twice 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. These neoplasia could result from local deposition and/or aspiration of drug on the mucosa of
16
the nose/nasopharynx during oral gavage dosing and subsequent chronic irritation and inflammation; it
is likely that they are of limited relevance for the intended clinical use. At the NOAEL, systemic
exposure was similar to that at the clinical dose of 400 mg twice 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 was observed in rat pups of dams exposed to raltegravir at
approximately 4.4-fold human exposure at 400 mg twice daily based on AUC
0-24 hr
. No development
effects were seen at 3.4-fold human exposure at 400 mg twice daily based on AUC
0-24 hr
(see
section 4.6). Similar findings were not observed in rabbits.
6.
6.1 List of excipients
Tablet core
- microcrystalline cellulose
- lactose monohydrate
- calcium phosphate dibasic anhydrous
- hypromellose 2208
- poloxamer 407
- sodium stearyl fumarate
- magnesium stearate
Film-coating
- polyvinyl alcohol
- titanium dioxide (E 171)
- polyethylene glycol 3350
- talc
- red iron oxide (E 172)
- black iron oxide (E 172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
High density polyethylene (HDPE) bottle with a child-resistant polypropylene closure.
Two pack sizes are available: 1 bottle with 60 tablets, and a multi-pack containing 3 bottles of
60 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
17
7.
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8.
EU/1/07/436/001
EU/1/07/436/002
9.
Date of first authorisation: 20 December 2007
Date of last renewal: 20 December 2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu
18
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
19
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Merck Sharp & Dohme B.V.
Waarderweg 39
P.O.Box 581
2003 PC Haarlem
The Netherlands
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 6.0 (of 22 June
2009) presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 4 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
20
ANNEX III
LABELLING AND PACKAGE LEAFLET
21
A. LABELLING
22
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton for individual packs
1.
ISENTRESS 400 mg film-coated tablets
raltegravir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 400 mg of raltegravir (as potassium).
3.
LIST OF EXCIPIENTS
Contains lactose.
See leaflet for further information.
4.
60 film-coated tablets
5.
METHOD AND ROUTES OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
23
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/07/436/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
ISENTRESS
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton for multi-packs
1.
ISENTRESS 400 mg film-coated tablets
raltegravir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 400 mg of raltegravir (as potassium).
3.
LIST OF EXCIPIENTS
Contains lactose.
See leaflet for further information.
4.
Multi-pack containing 180 (3 bottles of 60) film-coated tablets
5.
METHOD AND ROUTES OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
25
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/07/436/002
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
ISENTRESS
26
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
ISENTRESS 400 mg – bottle labelling for individual packs
1.
ISENTRESS 400 mg film-coated tablets
raltegravir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 400 mg of raltegravir (as potassium).
3.
LIST OF EXCIPIENTS
Contains lactose.
See leaflet for further information.
4.
60 film-coated tablets
5.
METHOD AND ROUTES OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
27
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/07/436/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
28
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
ISENTRESS 400 mg – bottle labelling for multi-packs
1.
ISENTRESS 400 mg film-coated tablets
raltegravir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 400 mg of raltegravir (as potassium).
3.
LIST OF EXCIPIENTS
Contains lactose.
See leaflet for further information.
4.
Component of a multi-pack comprising 3 bottles, each containing 60 film-coated tablets.
5.
METHOD AND ROUTES OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
29
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/07/436/002
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
30
B. PACKAGE LEAFLET
31
PACKAGE LEAFLET: INFORMATION FOR THE USER
ISENTRESS 400 mg tablets
raltegravir
Read all of this leaflet carefully before you start taking this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist.
•
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
•
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What ISENTRESS is and what it is used for
2.
Before you take ISENTRESS
4.
Possible side effects
5.
How to store ISENTRESS
6.
Further information
1.
WHAT ISENTRESS IS AND WHAT IT IS USED FOR
What ISENTRESS is
ISENTRESS works against the Human Immunodeficiency Virus (HIV). This is the virus that causes
Acquired Immune Deficiency Syndrome (AIDS).
How ISENTRESS works
The virus produces an enzyme called HIV integrase. This helps the virus to multiply in the cells in
your body. ISENTRESS stops this enzyme working. When used with other medicines, ISENTRESS
may reduce the amount of HIV in your blood (this is called your "viral load") and increase your CD4-
cell count (a type of white blood cells that plays an important role in maintaining a healthy immune
system to help fight infection). Reducing the amount of HIV in the blood may improve the functioning
of your immune system. This means your body may fight infection better.
ISENTRESS may not have these effects in all patients.
ISENTRESS is not a cure for HIV infection.
When ISENTRESS should be used
ISENTRESS is used to treat adults who are infected by HIV. Your doctor has prescribed ISENTRESS
to help control your HIV infection.
2.
BEFORE YOU TAKE ISENTRESS
Do not take ISENTRESS
•
If you are allergic (hypersensitive) to raltegravir or to any of the other ingredients in the tablets
(listed in 6. Further information).
Take special care with ISENTRESS
Remember that ISENTRESS is not a cure for HIV infection. This means that you may keep getting
infections or other illnesses associated with HIV. You should keep seeing your doctor regularly while
taking ISENTRESS.
ISENTRESS is not for use in children and adolescents.
32
3.
How to take ISENTRESS
Some patients taking combination anti-retroviral therapy may develop a bone disease called
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of
combination anti-retroviral therapy, corticosteroid use, alcohol consumption, severe
immunosuppression, higher body mass index, among others, may be some of the many risk factors for
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please
inform your doctor.
Tell your doctor if you have had problems with your liver before, including hepatitis B or C. Your
doctor may evaluate how severe your liver disease is before deciding if you can take ISENTRESS.
HIV infection is spread by contact with blood or sexual contact with a person with HIV. Taking
ISENTRESS has not been shown to reduce the risk of giving HIV to others through sexual contact or
contact with blood.
Tell your doctor immediately if you notice any symptoms of infection. In some patients with advanced
HIV infection and a history of opportunistic infection, signs and symptoms of inflammation from
previous infections may occur soon after anti-HIV treatment is started. It is believed that these
symptoms are due to an improvement in the body’s immune response, enabling the body to fight
infections that may have been present with no obvious symptoms.
Contact your doctor promptly if you experience unexplained muscle pain, tenderness, or weakness
while taking ISENTRESS.
In patients taking ISENTRESS and darunavir, rashes (generally mild or moderate) may occur more
frequently than in patients taking either drug separately.
Taking other medicines
ISENTRESS might interact with other medicines. Raltegravir is not known to have an important effect
on blood levels of other agents used to treat HIV. Also, blood levels of raltegravir are not known to be
affected to an important extent by other agents used to treat HIV. However, further information is
expected to become available as experience with the use of raltegravir increases.
Please tell your doctor or pharmacist if you are now or have recently taken:
•
rifampicin (a medicine used to treat some infections such as tuberculosis)
•
medicines used to treat stomach ulcer or heartburn (e.g., omeprazole, cimetidine, ranitidine)
•
any other medicines with or without a prescription.
Taking ISENTRESS with food and drink
You can take ISENTRESS with or without food or drink.
Pregnancy and breast-feeding
Talk to your doctor before taking ISENTRESS if you are pregnant, might become pregnant or are
breastfeeding. If you become pregnant, tell your doctor straight away.
•
ISENTRESS is not recommended in pregnancy because it has not been studied in pregnant
women.
•
Women with HIV should not breast-feed their infants because babies can be infected with HIV
through their breast milk. Talk with your doctor about the best way to feed your baby.
Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breast-
feeding.
Driving and using machines
Do not operate machines or drive if you feel dizzy after taking ISENTRESS.
33
Important information about some of the ingredients of ISENTRESS
ISENTRESS contains lactose. If you have been told by your doctor that you have an intolerance to
some sugars, talk to your doctor before taking this medicine.
3.
HOW TO TAKE ISENTRESS
Always take ISENTRESS exactly as your doctor has told you. You should check with your doctor if
you are not sure. ISENTRESS must be used in combination with other medicines for HIV.
How much to take
•
The usual dose of ISENTRESS is 1 tablet (400 mg) by mouth twice a day.
•
It is recommended not to chew, crush or split the tablets.
•
You can take ISENTRESS with or without food or drink.
•
Do not change your dose or stop taking ISENTRESS without first talking with your doctor.
If you take more ISENTRESS than you should
Do not take more tablets than the doctor recommends. If you do take too many tablets, contact your
doctor.
If you forget to take ISENTRESS
•
If you forget to take a dose, take it as soon as you remember it.
•
However, if it is time for your next dose, skip the missed dose and go back to your regular
schedule.
•
Do not take a double dose of ISENTRESS to make up for a forgotten dose.
If you stop taking ISENTRESS
It is important that you take ISENTRESS exactly as your doctor has instructed. Do not stop taking it
because:
•
It is very important to take all your HIV medicines as prescribed and at the right times of day.
This can help your medicines work better. It also lowers the chance that your medicines will
stop being able to fight HIV (also called "drug resistance").
•
When your supply of ISENTRESS starts to run low, get more from your doctor or pharmacy.
This is because it is very important not to be without the medicine, even for a short time.
During a short break in taking the medicine the amount of virus in your blood may increase.
This may mean that the HIV virus will develop resistance to ISENTRESS and become harder to
treat.
If you have any further questions on the use of ISENTRESS, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, ISENTRESS can cause side effects, although not everybody gets them.
Common side effects (affects 1 to 10 users in 100):
•
trouble sleeping; abnormal dreams
•
feeling dizzy; headache
•
spinning sensation
•
bloating; abdominal pain; diarrhoea; excessive gas in the stomach or bowel; feeling sick;
vomiting
•
certain kinds of rash (more often when used in combination with darunavir)
•
tiredness, unusual tiredness or weakness; fever
•
increased liver blood tests; abnormal white blood cells; increased fat levels in blood; increased
level of enzyme from salivary glands or pancreas
34
Uncommon side effects (affects 1 to 10 users in 1,000):
•
herpes infections including shingles; infection of the hair roots; influenza; skin infection due to
virus; vomiting or diarrhoea due to an infectious agent; upper respiratory tract infection
•
wart
•
anaemia including due to low iron; lymph node pain; low count of white blood cells that fight
infection; swollen glands in the neck, armpit and groin
•
allergic reaction; signs and symptoms of inflammation from previous infections
•
decreased or increased appetite; diabetes; increased blood cholesterol and lipids; high sugar
levels in the blood; excessive thirst; severe weight loss; high levels of fat (such as cholesterol
and triglycerides) in the blood
•
mental disorder; feeling anxious; feeling of confusion; depressed mood; feelings of deep
sadness and unworthiness; mood changes; nightmare; suicide attempt; panic attack
•
loss of memory; pain in the hand due to nerve compression; disturbance in attention; dizziness
with rapid changes in posture; abnormal taste; increased sleepiness; lack of energy;
forgetfulness; migraine headache; loss of feeling, numbness or weakness of the arms and/or
legs; tingling; sleepiness; tension headache; tremors
•
visual disturbance
•
buzzing, hissing, whistling, ringing or other persistent noise in the ears
•
palpitations; slow heart rates; fast or irregular heart beats
•
hot flush; high blood pressure
•
harsh, raspy, or strained voice; nosebleed; nasal congestion
•
stomach inflammation; abdominal pain upper; rectal discomfort; constipation; dry mouth;
indigestion; belching; heartburn; pain when swallowing; inflammation of the pancreas; ulcer or
sore in stomach or upper intestine; bleeding at anus; stomach discomfort; inflammation of the
gums; swollen, red sore tongue
•
inflammation of liver; accumulation of fat in the liver
•
acne; unusual hair loss or thinning; redness of skin; unusual distribution of fat on the body,
these may include loss of fat from legs, arms, and face, and increase in abdomen fat; excessive
sweating; night sweats; thickening and itching of the skin due to repeated scratching; skin
lesion; dry skin
•
joint pain; painful joint disease; back pain; pain in bone/muscle; muscle tenderness or
weakness; neck pain; pain in arms or legs; inflammation of the tendons; decrease in the amount
of minerals in the bone
•
certain kinds of kidney problems; kidney stones; urination at night; kidney cyst
•
erectile dysfunction; breast enlargement in men; menopausal symptoms
•
chest discomfort; chills; swelling of face; feeling jittery; generally feeling unwell; swelling of
hands, ankles or feet; pain
•
decreased white blood cell count; decreased count of platelets in blood (a kind of cell that helps
blood clot); blood test showing reduced kidney function; high blood sugar level; increased
muscle enzyme in blood; sugar present in urine; red blood cells present in urine; weight gain;
increase in waist size; decreased blood protein (albumin)
•
drug ingestion in quantities greater than recommended
During post-marketing experience the following side effects have been reported (frequency =
uncommon):
•
Severe skin reactions
•
Suicidal thoughts and actions
•
Localised loss of bone material
There have been reports of muscle pain, tenderness, or weakness during treatment with ISENTRESS.
In clinical studies, cancers were observed in patients receiving ISENTRESS at a rate similar to that
observed in the patients receiving other HIV medicines.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
35
5.
HOW TO STORE ISENTRESS
•
Keep out of the reach and sight of children.
•
Do not take ISENTRESS after the expiry date which is stated on the bottle after EXP. The
expiry date refers to the last day of that month.
•
This product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What ISENTRESS contains
The active substance is raltegravir. Each film-coated tablet contains 400 mg of raltegravir (as
potassium).
The other ingredients are: lactose monohydrate, microcrystalline cellulose, calcium phosphate dibasic
anhydrous, hypromellose 2208, poloxamer 407, sodium stearyl fumarate, and magnesium stearate. In
addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium
dioxide (E 171), polyethylene glycol 3350, talc, red iron oxide (E 172) and black iron oxide (E 172).
What ISENTRESS looks like and contents of the pack
The film-coated tablet is oval-shaped, pink, marked with "227" on one side. Two pack sizes are
available: 1 bottle with 60 tablets, and a multi-pack containing 3 bottles of 60 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
The
Marketing Authorisation
Holder
is:
The
Product Manufacturer
is:
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
Merck Sharp & Dohme B. V.
Waarderweg 39, Postbus 581
NL-2003 PC Haarlem
The Netherlands
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 38693
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge
Tél: +32 (0) 800 38693
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Magyarország
MSD Magyarország Kft.
Tel.: +361 888 53 00
hungary_msd@merck.com
36
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme (Middle East) Limited
Tel: +357 22866700
info_cyprus@merck.com
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme B.V.
Tel: +31 (0) 23 5153153
msdbvnl@merck.com
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp.z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
ISENTRESS@msd.es
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0) 1 47 54 87 00
contact@msd-france.com
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
Ireland
Merck Sharp and Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com
Slovenija
Merck Sharp & Dohme, inovativna zdravila
d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Merck Sharp & Dohme (Italia) S.p.A.
Tel: +39 06 361911
doccen@merck.com
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme (Middle East) Limited
Τηλ: +357 22866700
info_cyprus@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 1400
medicinskinfo@merck.com
37
Latvija
SIA “Merck Sharp & Dohme Latvija”
Tel: +371 67364 224
msd_lv@merck.com.
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medinfo_uk@merck.com
Lietuva
UAB “Merck Sharp & Dohme”
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
38
Source: European Medicines Agency
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