Dutrebis

1

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

 

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1. NAME OF THE MEDICINAL PRODUCT

DUTREBIS 150 mg/300 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg of lamivudine and 300 mg of raltegravir (as potassium).

Excipient with known effect: Each tablet contains 39.70 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Green, oval tablet, marked with "144" on one side. 

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

DUTREBIS is indicated in combination with other anti-retroviral medicinal products for the treatment 
of human immunodeficiency virus (HIV-1) infection in adults, adolescents, and children from the age 
of 6 years and weighing at least 30 kg without present or past evidence of viral resistance to antiviral 
agents of the InSTI (Integrase Strand Transfer Inhibitor) and NRTI (Nucleoside Reverse Transcriptase 
Inhibitor) classes (see sections 4.2, 4.4 and 5.1).

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology
DUTREBIS should be used in combination with other active anti-retroviral therapy (ART) (see 
sections 4.4 and 5.1). 

Adults, adolescents, and children (6 through 11 years of age weighing at least 30 kg)
The recommended dosage is one tablet (150 mg lamivudine/300 mg raltegravir) twice daily.

Raltegravir is also available in a chewable tablet formulation for children weighing at least 11 kg and 
in granules for oral suspension formulation for infants and toddlers from 4 weeks of age and weighing 
at least 3 kg to less than 20 kg. Refer to the chewable tablet and granules for oral suspension SmPCs 
for additional dosing information.

Lamivudine is also available as an oral solution for children over three months of age and who weigh 
less than 14 kg or for patients who are unable to swallow tablets.

The maximum dose is one tablet twice daily.

Advice on missed doses
If DUTREBIS is missed within 6 hours of the time it is usually taken, patients should be instructed to 
take the prescribed dose of DUTREBIS as soon as possible. If this is noticed later than 6 hours of the 
time it is usually taken, the missed dose should not be taken and the patient should resume the usual 
dosing schedule.

 

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Elderly
There is limited information regarding the use of lamivudine and raltegravir in the elderly (see 
section 5.2). Therefore DUTREBIS should be used with caution in this population. Because 
lamivudine is substantially excreted by the kidney and older people are more likely to have decreased 
renal function, renal function should be monitored. A reduction in renal function may necessitate 
switching DUTREBIS to a regimen of the individual components (lamivudine and raltegravir). Please 
refer to the SmPC for the individual components of DUTREBIS for dosing instructions.

Renal impairment
DUTREBIS should not be given in patients with a creatinine clearance of <50 ml/min. Renal function 
should be monitored in patients more likely to have decreased renal function. If creatinine clearance 
decreases to <50 ml/min, DUTREBIS should be switched to a regimen of the individual components 
(lamivudine and raltegravir). Please refer to the SmPC for the individual components of DUTREBIS
for dosing instructions. Because the extent to which DUTREBIS may be dialyzable is unknown, 
dosing before a dialysis session should be avoided (see sections 4.2 and 5.2). 

Hepatic impairment
No dosage adjustment for DUTREBIS is required for patients with mild to moderate hepatic 
impairment. The safety and efficacy of lamivudine and raltegravir have not been established in 
patients with severe underlying liver disorders. Therefore, DUTREBIS should be used with caution in 
patients with severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population
DUTREBIS should not be used in children below 6 years of age. Dosing in children less than 6 years 
of age and those weighting less than 30 kg requires weight based dose adjustments for the individual 
components of DUTREBIS. Please refer to the SmPC for the individual components of DUTREBIS
for dosing instructions. Currently available data are described in sections 5.1 and 5.2.

Method of administration
Oral use.
DUTREBIS tablets can be administered with or without food.
The tablets should be swallowed whole, without crushing or chewing.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

DUTREBIS is not recommended for use as monotherapy.

Depression
Depression, including suicidal ideation and behaviours, has been reported with raltegravir, particularly 
in patients with a pre-existing history of depression or psychiatric illness. Caution should be used 
when administering DUTREBIS in patients with a pre-existing history of depression or psychiatric 
illness.

Renal impairment
DUTREBIS should not be given in patients with a creatinine clearance of <50 ml/min. Renal function 
should be monitored in patients more likely to have decreased renal function. If creatinine clearance 
decreases to <50 ml/min, DUTREBIS should be switched to a regimen of the individual components 
(lamivudine and raltegravir) (see section 4.2). Please refer to the SmPC for the individual components 
of DUTREBIS for dosing instructions.

 

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Opportunistic infections
Patients receiving lamivudine or any other ART may continue to develop opportunistic infections and 
other complications of HIV infection, and therefore should remain under close clinical observation by 
physicians experienced in the treatment of patients with associated HIV diseases.

Transmission of HIV
Patients should be advised that current antiretroviral therapy does not cure HIV and has not been 
proven to prevent the risk of transmission of HIV to others through blood contact. While effective 
viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual 
transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken 
in accordance with national guidelines.

Virologic failure and development of resistance
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, 
DUTREBIS should be administered with another active ART to minimise the potential for virological 
failure and the development of resistance (see section 5.1).

Pancreatitis
Cases of pancreatitis have occurred rarely with lamivudine. However, it is not clear whether these 
cases were due to the ART or to the underlying HIV disease. Treatment with DUTREBIS should be 
stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis 
occur.

Lactic acidosis
Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the 
use of nucleoside reverse transcriptase inhibitors (NRTIs), such as lamivudine. Early symptoms 
(symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal 
pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep 
breathing) or neurological symptoms (including motor weakness).

Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal 
failure.

Lactic acidosis generally occurred after a few or several months of treatment.

Treatment with NRTIs should be discontinued in the setting of symptomatic hyperlactatemia and 
metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.

Caution should be exercised when administering NRTIs to any patient (particularly obese women) 
with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis 
(including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated 
with alpha interferon and ribavirin may constitute a special risk.

Patients at increased risk should be followed closely.

Hepatic impairment
No dosage adjustment for DUTREBIS is required for patients with mild to moderate hepatic 
impairment. The safety and efficacy of lamivudine and raltegravir have not been established in 
patients with severe underlying liver disorders. Therefore, DUTREBIS 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 CART and should be monitored according to standard practice. If 

 

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there is evidence of worsening liver disease in such patients, interruption or discontinuation of 
treatment should be considered.

Patients with HIV and hepatitis B or C virus co-infection
Patients with chronic hepatitis B or C treated with ART are at an increased risk for severe and 
potentially fatal hepatic adverse reactions. Physicians should refer to current HIV treatment guidelines 
for the optimal management of HIV infection in patients co-infected with HBV. In case of 
concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information 
for these medicinal products. If DUTREBIS is discontinued in patients co-infected with hepatitis B 
virus, periodic monitoring of liver function tests and markers of HBV replication is recommended, as 
withdrawal of lamivudine may result in an acute exacerbation of hepatitis.

Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported particularly in patients with advanced HIV-disease and/or long-term exposure to CART. 
Patients should be advised to seek medical advice if they experience joint aches and pain, joint 
stiffness or difficulty in movement.

Lipodystrophy
CART has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The 
long-term consequences of these events are currently unknown. Knowledge about the mechanism is 
incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy 
and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual 
factors such as older age, and with drug related factors such as longer duration of ART and associated 
metabolic disturbances. Clinical examination should include evaluation for physical signs of fat 
redistribution. Consideration should be given to the measurement of fasting serum lipids and blood 
glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Immune Reactivation Syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, 
such reactions have been observed within the first few weeks or months of initiation of CART. 
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterium infections, 
and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment 
instituted when necessary. Autoimmune disorders (such as Graves’ disease) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment.

Mitochondrial dysfunction
Nucleoside and nucleotide reverse transcriptase inhibitors have been demonstrated in vitro and in vivo 
to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial 
dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside reverse 
transcriptase inhibitors. The main adverse reactions reported are haematological disorders (anaemia, 
neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. 
Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal 
behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any 
child exposed in utero to nucleoside and nucleotide reverse transcriptase inhibitors, even HIV-negative 
children, should have clinical and laboratory follow-up and should be fully investigated for possible 
mitochondrial dysfunction in case of relevant signs or symptoms.

Myopathy and rhabdomyolysis
Myopathy and rhabdomyolysis have been reported with raltegravir. DUTREBIS should be used 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).

 

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Co-administration of other medicinal products
DUTREBIS should not be taken with any other medicinal products containing lamivudine, raltegravir 
or medicinal products containing emtricitabine.

The combination of lamivudine with cladribine is not-recommended (see section 4.5).

Co-administration of raltegravir with aluminium and magnesium antacids resulted in reduced 
raltegravir plasma levels. Co-administration of DUTREBIS with aluminium and/or magnesium 
antacids is not recommended (see section 4.5).

DUTREBIS should not be co-administered with rifampicin due to reduced plasma concentrations of 
raltegravir (see section 4.5); the impact on the efficacy of raltegravir is unknown. If rifampicin 
administration cannot be avoided, DUTREBIS may be switched to a regimen of the individual 
components (lamivudine and raltegravir). Please refer to the SmPC for the individual components of 
DUTREBIS for dosing instructions.

In addition, caution should also be used when co-administering DUTREBIS with other strong inducers 
of uridine diphosphate glucuronosyltransferase (UGT) 1A1.

Severe skin and hypersensitivity reactions
Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking 
raltegravir, in most cases concomitantly with other medicinal products associated with these reactions. 
These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity 
reactions have also been reported and were characterized by rash, constitutional findings, and 
sometimes, organ dysfunction, including hepatic failure. Discontinue DUTREBIS and other suspect 
agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop 
(including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, 
muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, 
angioedema). Clinical status including liver aminotransferases should be monitored and appropriate 
therapy initiated. Delay in stopping DUTREBIS treatment or other suspect agents after the onset of 
severe rash may result in a life-threatening reaction.

Rash
Rash occurred more commonly in treatment-experienced patients receiving regimens containing 
raltegravir + darunavir compared to patients receiving raltegravir without darunavir or darunavir 
without raltegravir (see section 4.8).

Lactose
DUTREBIS film-coated tablets contain lactose. Patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicine.

4.5 Interaction with other medicinal products and other forms of interaction

As DUTREBIS contains lamivudine and raltegravir, any interactions that have been identified with 
these agents individually, may occur with DUTREBIS. Interaction studies with these agents have only 
been performed in adults.

Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products 
metabolised by this system (e.g. PIs) unlikely.

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, raltegravir is 
not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes 
or P-glycoprotein.

 

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Lamivudine is eliminated mainly by active renal secretion via the organic cationic transport system. 
The possibility of interactions with other medicinal products administered concurrently should be 
considered, particularly when the main route of elimination is active renal secretion via the organic 
cationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are 
eliminated only in part by this mechanism and were shown not to interact with lamivudine. The NRTIs 
(e.g. didanosine, zidovudine) are not eliminated by this mechanism and are unlikely to interact with 
lamivudine.

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. 

In a drug interaction study with DUTREBIS and etravirine, there was no clinically meaningful drug 
interaction between raltegravir and etravirine, with respect to raltegravir. No dosage adjustment is 
necessary when these agents are given together.

Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase in 
lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component did 
not interact. However, unless the patient has renal impairment, no dosage adjustment of DUTREBIS is 
necessary (see section 4.2). Lamivudine has no effect on the pharmacokinetics of trimethoprim or 
sulfamethoxazole. When concomitant administration of DUTREBIS is warranted, patients should be 
monitored clinically. Co-administration of DUTREBIS with high doses of co-trimoxazole for the 
treatment of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis should be avoided.

A modest increase in Cmax (28 %) was observed for zidovudine when administered with lamivudine, 
however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the 
pharmacokinetics of lamivudine (see section 5.2).

In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of 
cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also 
support a possible interaction between lamivudine and cladribine. Therefore, the concomitant use of 
DUTREBIS with cladribine is not recommended (see section 4.4).

In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics 
of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, midazolam, or boceprevir.

In some studies, co-administration of raltegravir with darunavir resulted in a modest decrease in 
darunavir plasma concentrations; the mechanism for this effect is unknown. However, the effect of 
raltegravir on darunavir plasma concentrations does not appear to be clinically meaningful.

DUTREBIS should not be used when co-administered with rifampicin. Rifampicin reduces plasma 
levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if 
co-administration with rifampicin is unavoidable, DUTREBIS may be switched to a regimen of the 
individual components (lamivudine and raltegravir). Please refer to the SmPC for the individual 
components of DUTREBIS for dosing instructions. Given that raltegravir is metabolised primarily via 
UGT1A1, caution should also be used when co-administering DUTREBIS with other strong inducers 
of UGT1A1. 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 DUTREBIS.

 

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Co-administration of DUTREBIS with medicinal products that are known to be potent UGT1A1 
inhibitors (e.g., atazanavir) may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors 
(e.g., indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extent 
compared with atazanavir. In addition, tenofovir may increase plasma levels of raltegravir, however, 
the mechanism for this effect is unknown (see Table 1). From the clinical studies, 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 of DUTREBIS is required.

Co-administration of DUTREBIS with antacids containing divalent metal cations may reduce 
raltegravir absorption by chelation, resulting in a decrease of raltegravir plasma levels. Taking an 
aluminium and magnesium antacid within 6 hours of raltegravir administration significantly decreased 
raltegravir plasma levels. Therefore, co-administration of DUTREBIS with aluminium and/or 
magnesium containing antacids is not recommended. Co-administration of raltegravir with a calcium 
carbonate antacid decreased raltegravir plasma levels; however, this interaction is not considered 
clinically meaningful. Therefore, when DUTREBIS is co-administered with calcium carbonate 
containing antacids no dose adjustment is required.

Co-administration of DUTREBIS with other agents that increase gastric pH (e.g., omeprazole and 
famotidine) may increase the rate of raltegravir absorption and result in increased plasma levels of 
raltegravir (see Table 1). Safety profiles in the subgroup of patients in Phase III studies taking proton 
pump inhibitors or H2 antagonists were comparable with those who were not taking these antacids. 
Therefore no dose adjustment of DUTREBIS is required with use of proton pump inhibitors or H2 
antagonists.

Interactions between the components of DUTREBIS and co-administered medicinal products are listed 
in Table 1 below.

Table 1
Pharmacokinetic Interaction Data between the Individual Components of DUTREBIS and 

Other Medicinal Products

Medicinal products by therapeutic 
area

Interaction
(mechanism, if known)

Recommendations 
concerning 
co-administration with 
DUTREBIS

ANTI-RETROVIRAL
Protease inhibitors (PI)

atazanavir /ritonavir /raltegravir
(raltegravir 400 mg Twice Daily)

raltegravir AUC  41 %
raltegravir C12hr  77 %
raltegravir Cmax  24 %

(UGT1A1 inhibition)

No dose adjustment required 
for DUTREBIS.

atazanavir /ritonavir /lamivudine Interaction not studied
tipranavir /ritonavir /raltegravir
(raltegravir 400 mg Twice Daily)

raltegravir AUC  24 %
raltegravir C12hr  55 %
raltegravir Cmax  18 %

(UGT1A1 induction)

No dose adjustment required 
for DUTREBIS.

tipranavir /ritonavir /lamivudine Interaction not studied

 

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Medicinal products by therapeutic 
area

Interaction
(mechanism, if known)

Recommendations 
concerning 
co-administration with 
DUTREBIS

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
efavirenz /raltegravir
(raltegravir 400 mg Single Dose)

raltegravir AUC  36 %
raltegravir C12hr  21 %
raltegravir Cmax  36 %

(UGT1A1 induction)

No dose adjustment required 
for DUTREBIS.

efavirenz /lamivudine Interaction not studied
etravirine /raltegravir
(raltegravir 400 mg Twice Daily)

raltegravir AUC  10 %
raltegravir C12hr  34 %
raltegravir Cmax  11 %

(UGT1A1 induction)

etravirine AUC  10 %
etravirine C12hr  17 %
etravirine Cmax  4 %

No dose adjustment required 
for DUTREBIS or etravirine.

etravirine /DUTREBIS
(DUTREBIS 150 mg 
lamivudine/300 mg raltegravir)

raltegravir AUC  8 %
raltegravir Cmax  20 %
raltegravir C12hr  14 %

Nucleoside/tide reverse transcriptase inhibitors (NRTIs)
emtricitabine DDI not studied DUTREBIS is not 

recommended for use in 
combination with 
emtricitabine containing 
products, since both 
lamivudine (in DUTREBIS) 
and emtricitabine are cytidine 
analogues (i.e. risk for 
intracellular interactions, (see 
section 4.4).

tenofovir /raltegravir
(raltegravir 400 mg Twice Daily)

raltegravir AUC  49 %
raltegravir C12hr  3 %
raltegravir Cmax ↑ 64 %

(mechanism of interaction 
unknown)

tenofovir AUC  10 %
tenofovir C24hr  13 %
tenofovir Cmax ↓ 23 %

No dose adjustment required 
for DUTREBIS or tenofovir 
disoproxil fumarate.

tenofovir /lamivudine Interaction not studied
zidovudine /lamivudine lamivudine PK ↔

zidovudine Cmax  28 % 
zidovudine AUC ↔

No dose adjustment required 
for DUTREBIS or 
zidovudine.

zidovudine /raltegravir Interaction not studied
cladribine /raltegravir Interaction not studied Concomitant use of 

 

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Medicinal products by therapeutic 
area

Interaction
(mechanism, if known)

Recommendations 
concerning 
co-administration with 
DUTREBIS

cladribine /lamivudine Possible interaction between 
lamivudine and cladribine due 
to inhibition of intracellular 
phosphorylation of cladribine 
by lamivudine.

DUTREBIS with cladribine is 
not recommended.

CCR5 inhibitors
maraviroc /raltegravir
(raltegravir 400 mg Twice Daily)

raltegravir AUC  37 %
raltegravir C12hr  28 %
raltegravir Cmax  33 %

(mechanism of interaction 
unknown)

maraviroc AUC  14 %
maraviroc C12hr  10 %
maraviroc Cmax ↓ 21 %

No dose adjustment required 
for DUTREBIS or maraviroc.

maraviroc /lamivudine Interaction not studied
HCV ANTIVIRALS
NS3/4A protease inhibitors (PI)
boceprevir /raltegravir
(raltegravir 400 mg Single Dose)

raltegravir AUC  4 %
raltegravir C12hr  25 %
raltegravir Cmax  11 %

boceprevir AUC  2 %
boceprevir C8hr  26 %
boceprevir Cmax  4 %

(mechanism of interaction 
unknown)

No dose adjustment required 
for DUTREBIS or boceprevir.

boceprevir /lamivudine Interaction not studied
ANTIMICROBIALS
Antimycobacterial

rifampicin /raltegravir
(raltegravir 400 mg Single Dose)

raltegravir AUC  40 %
raltegravir C12hr  61 %
raltegravir Cmax  38 %

(UGT1A1 induction)

Co-administration of 
rifampicin with DUTREBIS is 
not recommended. If 
co-administration with 
rifampicin is unavoidable, 
DUTREBIS may be switched 
to a regimen of the individual 
components (lamivudine and 
raltegravir). Please refer to the 
SmPC for the individual 
components of DUTREBIS 
for dosing instructions (see 
section 4.4).

rifampicin /lamivudine Interaction not studied

trimethoprim /sulfamethoxazole 
/raltegravir

Interaction not studied No dosage adjustment of 
DUTREBIS or trimethoprim 

 

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Medicinal products by therapeutic 
area

Interaction
(mechanism, if known)

Recommendations 
concerning 
co-administration with 
DUTREBIS

trimethoprim /sulfamethoxazole 
/lamivudine

lamivudine AUC 40 % 

trimethoprim PK ↔
sulfamethoxazole PK ↔

/sulfamethoxazole is 
necessary, unless the patient 
has renal impairment (see 
section 4.2).

Co-administration of 
DUTREBIS with high doses 
of co-trimoxazole for the 
treatment of Pneumocystis 
carinii pneumonia (PCP) and 
toxoplasmosis should be 
avoided.

SEDATIVE
midazolam /raltegravir
(raltegravir 400 mg Twice Daily)

midazolam AUC  8 %
midazolam Cmax ↑ 3 %

No dosage adjustment 
required for DUTREBIS 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.

midazolam /lamivudine Interaction not studied

METAL CATION ANTACIDS
aluminium and magnesium 
hydroxide antacid /raltegravir
(raltegravir 400 mg Twice Daily)

raltegravir AUC  49 %
raltegravir C12 hr  63 %
raltegravir Cmax  44 %

2 hours before raltegravir
raltegravir AUC  51 %
raltegravir C12 hr  56 %
raltegravir Cmax  51 %

2 hours after raltegravir
raltegravir AUC  30 %
raltegravir C12 hr  57 %
raltegravir Cmax  24 %

6 hours before raltegravir
raltegravir AUC  13 %
raltegravir C12 hr  50 %
raltegravir Cmax  10 %

6 hours after raltegravir
raltegravir AUC  11 %
raltegravir C12 hr  49 %
raltegravir Cmax  10 %

(chelation of metal cations)

Aluminium and magnesium 
containing antacids reduce 
raltegravir plasma levels. 
Co-administration of 
DUTREBIS with aluminium 
and/or magnesium containing 
antacids is not recommended.

 

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Medicinal products by therapeutic 
area

Interaction
(mechanism, if known)

Recommendations 
concerning 
co-administration with 
DUTREBIS

aluminium and magnesium 
hydroxide antacid /lamivudine

Interaction not studied

calcium carbonate antacid 
/raltegravir
(raltegravir 400 mg Twice Daily)

raltegravir AUC  55 %
raltegravir C12 hr  32 %
raltegravir Cmax  52 %

(chelation of metal cations)

No dose adjustment required 
for DUTREBIS.

calcium carbonate antacid 
/lamivudine

Interaction not studied

H2 BLOCKERS AND PROTON PUMP INHIBITORS
omeprazole /raltegravir
(raltegravir 400 mg Twice Daily)

raltegravir AUC ↑ 37 %
raltegravir C12 hr ↑ 24 %
raltegravir Cmax ↑ 51 %

(increased solubility)

No dose adjustment required 
for DUTREBIS.

omeprazole /lamivudine Interaction not studied
famotidine /raltegravir
(raltegravir 400 mg Twice Daily)

raltegravir AUC ↑ 44 %
raltegravir C12 hr ↑ 6 %
raltegravir Cmax ↑ 60 %

(increased solubility)

No dose adjustment required 
for DUTREBIS.

famotidine /lamivudine Interaction not studied
HORMONAL CONTRACEPTIVES

Ethinyl Estradiol
Norelgestromin /raltegravir
(raltegravir 400 mg Twice Daily)

Ethinyl Estradiol AUC  2 %
Ethinyl Estradiol Cmax ↑ 6 %
Norelgestromin AUC ↑ 14 %
Norelgestromin Cmax ↑ 29 %

No dosage adjustment 
required for DUTREBIS or 
hormonal contraceptives 
(oestrogen- and/or 
progesterone-based).Ethinyl Estradiol

Norelgestromin /lamivudine
Interaction not studied

OPIOID ANALGESICS
methadone /raltegravir
(raltegravir 400 mg Twice Daily)

methadone AUC ↔
methadone Cmax ↔

No dose adjustment required 
for DUTREBIS or 
methadone.methadone /lamivudine Interaction not studied

4.6 Fertility, pregnancy and lactation

Pregnancy
DUTREBIS should not be used during pregnancy.

There are no adequate data from the use of raltegravir in pregnant women; however, a large amount of 
data on pregnant women who were administered lamivudine (more than 1,000 exposed outcomes) 
indicate no malformative toxicity. Studies with raltegravir in animals have shown reproductive toxicity 
(see section 5.3). The potential risk for humans is unknown. 

For patients co-infected with hepatitis who are being treated with DUTREBIS and subsequently 
become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on 
discontinuation of DUTREBIS.

 

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Mitochondrial dysfunction
Nucleoside and nucleotide reverse transcriptase inhibitors have been demonstrated in vitro and in vivo 
to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial 
dysfunction in infants exposed in utero and/or post-natally to nucleoside reverse transcriptase 
inhibitors (see section 4.4).

Anti-retroviral Pregnancy Registry
To monitor maternal-foetal outcomes in patients inadvertently administered DUTREBIS while 
pregnant, an Anti-retroviral Pregnancy Registry has been established. Physicians are encouraged to 
register patients in this registry.

As a general rule, when deciding to use anti-retroviral agents for the treatment of HIV infection in 
pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, 
the animal data as well as the clinical experience in pregnant women should be taken into account in 
order to characterise the safety for the foetus.

Breast-feeding
Breastfeeding is not recommended while taking DUTREBIS. As a general rule, it is recommended that 
mothers infected by HIV do not breast-feed their babies in order to avoid transmission of HIV.

Following oral administration, lamivudine was excreted in breast milk at similar concentrations to 
those found in serum. 

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. 

Fertility
No human data on the effect of DUTREBIS on fertility are available. No effect on fertility was seen in 
male and female rats at doses of raltegravir up to 600 mg/kg/day which resulted in 3-fold exposure 
above the exposure at the recommended human dose.

4.7 Effects on ability to drive and use machines

Dizziness has been reported in some patients during treatment with regimens containing raltegravir, 
which may influence some patients' ability to drive and use machines (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile
Clinical studies in patients have not been specifically performed with DUTREBIS. The safety profile 
of DUTREBIS is based on the safety data from the individual components of DUTREBIS (lamivudine 
and raltegravir).

The most common adverse reactions reported during treatment with lamivudine are headache, nausea, 
malaise, fatigue, nasal signs and symptoms, diarrhoea and cough. The most frequently reported 
adverse reactions during treatment with raltegravir were headache and nausea.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic 
steatosis, have been reported with the use of nucleoside analogues (see section 4.4).

Cancers were reported in treatment-experienced and treatment-naïve patients who initiated raltegravir
in conjunction with other antiretroviral agents. The types and rates of specific cancers were those 
expected in a highly immunodeficient population. The risk of developing cancer in these studies was 
similar in the groups receiving raltegravir and in the groups receiving comparators.

 

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Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with raltegravir. 
Myopathy and rhabdomyolysis have been reported. Use DUTREBIS 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).

CART has been associated with redistribution of body fat (lipodystrophy) in HIV patients including 
the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast 
hypertrophy and dorsocervical fat accumulation (buffalo hump).

CART has been associated with metabolic abnormalities such as hypertriglyceridaemia, 
hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (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 CART. The frequency of this is unknown (see 
section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune 
disorders (such as Graves’ disease) have also been reported to occur in the setting of immune 
reactivation; however, the reported time to onset is more variable and these events can occur many 
months after initiation of treatment (see section 4.4).

Tabulated list of adverse reactions
The following adverse reactions have been reported during therapy for HIV disease with lamivudine
and/or raltegravir (alone or in combination with other ART).

The adverse reactions seen in clinical studies and in post-marketing experience are listed below by 
body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), 
common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare 
(<1/10,000). 

System Organ 
Class

Frequency Lamivudine and/or Raltegravir (alone or in combination with 
other ART)*

Infections and 
infestations

uncommon genital herpes, folliculitis, gastroenteritis, herpes simplex, herpes 
virus infection, herpes zoster, influenza, lymph node abscess, 
molluscum contagiosum, nasopharyngitis, upper respiratory tract 
infection

Neoplasms 
benign, 
malignant and 
unspecified 
(including cysts 
and polyps)

uncommon skin papilloma

Blood and 
lymphatic 
system 
disorders

uncommon iron deficiency anaemia, lymph node pain, lymphadenopathy, 
neutropenia and anaemia (both occasionally severe), 
thrombocytopenia

very rare pure red cell aplasia

Immune system 
disorders

uncommon immune reconstitution syndrome, drug hypersensitivity, 
hypersensitivity

Metabolism and 
nutrition 
disorders

common decreased appetite

uncommon cachexia, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, 
hyperglycaemia, hyperlipidaemia, hyperphagia, increased appetite, 
polydipsia, body fat disorder

 

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System Organ 
Class

Frequency Lamivudine and/or Raltegravir (alone or in combination with 
other ART)*

Psychiatric 
disorders

common abnormal dreams, insomnia, nightmare, abnormal behaviour, 
depression

uncommon mental disorder, suicide attempt, anxiety, confusional state, depressed 
mood, major depression, middle insomnia, mood altered, panic 
attack, sleep disorder, suicidal ideation, suicidal behaviour 
(particularly in patients with a pre-existing history of psychiatric 
illness)

Nervous system 
disorders

common dizziness, headache, psychomotor hyperactivity

uncommon amnesia, carpal tunnel syndrome, cognitive disorder, disturbance in 
attention, dizziness postural, dysgeusia, hypersomnia, hypoaesthesia, 
lethargy, memory impairment, migraine, neuropathy peripheral, 
paraesthesia, somnolence, tension headache, tremor, poor quality 
sleep

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

common cough, nasal congestion
uncommon dysphonia, epistaxis

Gastrointestinal 
disorders

common abdominal distention, diarrhoea, flatulence, nausea, vomiting, 
dyspepsia, abdominal pain or cramps

uncommon gastritis, abdominal discomfort, abdominal pain upper, abdominal 
tenderness, anorectal discomfort, constipation, dry mouth, epigastric 
discomfort, erosive duodenitis, eructation, gastrooesophageal reflux 
disease, gingivitis, glossitis, odynophagia, pancreatitis, peptic ulcer, 
rectal haemorrahage

Hepato-biliary 
disorders

uncommon hepatitis, hepatic steatosis, hepatitis alcoholic, hepatic failure

Skin and 
subcutaneous 

common rash, alopecia

 

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System Organ 
Class

Frequency Lamivudine and/or Raltegravir (alone or in combination with 
other ART)*

tissue disorders uncommon acne, dermatitis acneiforme, dry skin, erythema, facial wasting, 
hyperhidrosis, lipoatrophy, lipodystrophy acquired, lipohypertrophy, 
night sweats, prurigo, pruritus, pruritus generalised, rash macular, 
rash maculo-papular, rash pruritic, skin lesion, urticaria, xeroderma, 
Stevens Johnson syndrome, drug rash with eosinophilia and systemic 
symptoms (DRESS)

rare angioedema
Musculoskeletal 
and connective 
tissue disorders

common arthralgia, muscle disorders
uncommon arthritis, back pain, flank pain, musculoskeletal pain, myalgia, neck 

pain, osteopenia, pain in extremity, tendonitis, rhabdomyolysis

Renal and 
urinary 
disorders

uncommon renal failure, nephritis, nephrolithiasis, nocturia, renal cyst, renal 
impairment, tubulointerstitial nephritis

Reproductive 
system and 
breast disorders

uncommon erectile dysfunction, gynaecomastia, menopausal symptoms

General 
disorders and 
administration 
site conditions

common asthenia, fatigue, malaise, fever

uncommon chest discomfort, chills, face oedema, fat tissue increased, feeling 
jittery, submandibular mass, oedema peripheral, pain

Investigations common atypical lymphocytes, elevations in liver enzymes (AST, ALT), blood 
triglycerides increased, lipase increased, blood pancreatic amylase 
increased

uncommon absolute neutrophil count decreased, alkaline phosphatase increased, 
blood albumin decreased, blood amylase increased, blood bilirubin 
increased, blood cholesterol increased, blood creatinine increased, 
blood glucose increased, blood urea nitrogen increased, creatine 
phosphokinase increased, fasting blood glucose increased, glucose 
urine present, high density lipoprotein increased, international 
normalised ratio increased, low density lipoprotein increased, platelet 
count decreased, red blood cells urine positive, waist circumference 
increased, weight increased, white blood cell count decreased

Injury, 
poisoning and 
procedural 
complications

uncommon accidental overdose

*The adverse reaction data was collected based on each individual component of DUTREBIS.

Description of selected adverse reactions
For each of the following clinical adverse reactions reported for raltegravir there was at least one 
serious occurrence: genital herpes, anaemia, immune reconstitution syndrome, depression, mental 
disorder, suicide attempt, gastritis, hepatitis, renal failure, accidental overdose.

In clinical studies of treatment-experienced patients receiving raltegravir, rash, irrespective of 
causality, was more commonly observed with regimens containing raltegravir and darunavir compared 
to those containing raltegravir without darunavir or darunavir without raltegravir. Rash considered by 
the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all 
causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash
were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to 
moderate in severity and did not result in discontinuation of therapy (see section 4.4).

 

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Patients co-infected with hepatitis B and/or hepatitis C virus 
In Phase III studies with raltegravir, treatment-experienced patients (N = 114/699 or 16 %; HBV=6 %, 
HCV=9 %, HBV+HCV=1 %) and treatment-naïve patients (N = 34/563 or 6 %; HBV=4 %, 
HCV=2 %, HBV+HCV=0.2 %) with chronic (but not acute) active hepatitis B and/or hepatitis C 
co-infection were permitted to enrol provided that baseline liver function tests did not exceed 5 times 
the upper limit of normal. In general the safety profile of raltegravir in patients with hepatitis B and/or 
hepatitis C virus co-infection was similar to that in patients without hepatitis B and/or hepatitis C virus 
co-infection, although the rates of AST and ALT abnormalities were somewhat higher in the subgroup 
with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. At 96-weeks, in 
treatment-experienced patients, Grade 2 or higher laboratory abnormalities that represent a worsening 
Grade from baseline of AST, ALT or total bilirubin occurred in 29 %, 34 % and 13 %, respectively, of 
co-infected subjects treated with raltegravir as compared to 11 %, 10 % and 9 % of all other subjects 
treated with raltegravir. At 240-weeks, in treatment-naïve patients, Grade 2 or higher laboratory 
abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred 
in 22 %, 44 % and 17 %, respectively, of co-infected subjects treated with raltegravir as compared to 
13 %, 13 % and 5 % of all other subjects treated with raltegravir.

The following adverse reactions were identified through post-marketing surveillance of raltegravir: 
thrombocytopenia, suicidal ideation, suicidal behaviour (particularly in patients with a pre-existing 
history of psychiatric illness), hepatic failure, Stevens Johnson syndrome, drug rash with eosinophilia 
and systemic symptoms (DRESS), rhabdomyolysis.

Paediatric population
DUTREBIS should not be used in children below 6 years of age or in patients weighing less than 
30 kg due to weight based dosing requirements in this patient population (see section 5.2).

Raltegravir has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and 
adolescents 2 through 18 years of age, in combination with other antiretroviral agents in IMPAACT 
P1066 (see sections 5.1 and 5.2). Of the 126 patients, 96 received the recommended dose of 
raltegravir.

In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions 
through Week 48 were comparable to those observed in adults.

One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, 
abnormal behaviour and insomnia; one patient experienced a Grade 2 serious drug related allergic 
rash.

One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which 
were considered serious.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

Administration of lamivudine at very high dose levels in acute animal studies did not result in any 
organ toxicity. Limited data are available on the consequences of ingestion of acute overdoses in 
humans. No fatalities occurred, and the patients recovered. No specific signs or symptoms have been 
identified following such overdose.

 

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18

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.

Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, 
although this has not been studied.

No specific information is available on the treatment of overdose with raltegravir. 

It should be taken into account that raltegravir is presented for clinical use as the potassium salt. The 
extent to which raltegravir may be dialysable is unknown.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use; antivirals for treatment of HIV infections, 
combinations, ATC code: J05AR16

Mechanism of action
Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) which has activity against human 
immunodeficiency virus (HIV) and hepatitis B virus (HBV). 

Raltegravir is an integrase strand transfer inhibitor active against the Human Immunodeficiency Virus 
(HIV-1). 

Antiviral activity in vitro
In vitro data tend to suggest that the continuation of lamivudine in anti-retroviral regimen despite the 
development of M184V might provide residual anti-retroviral activity (likely through impaired viral 
fitness). The clinical relevance of these findings is not established. 
Raltegravir at concentrations of 31  20 nM resulted in 95 % inhibition (IC95) of HIV-1 replication 
(relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the 
cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir inhibited viral replication in cultures of
mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical 
isolates of HIV-1, including isolates from 5 non-B subtypes, and isolates resistant to reverse 
transcriptase inhibitors and protease inhibitors. In a single-cycle infection assay, raltegravir inhibited 
infection of 23 HIV isolates representing 5 non-B subtypes and 5 circulating recombinant forms with 
IC50 values ranging from 5 to 12 nM. 

Resistance
HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the 
active site of the viral reverse transcriptase (RT). This variant arises both in vitro and in HIV-1 
infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display 
greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. In 
vitro studies indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when 
they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains, 
however, not well defined.

Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of 
antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against 
lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine 
resistant HIV-1 harbouring only the M184V mutation. The M184V RT mutant shows a <4-fold 
decrease in susceptibility to didanosine; the clinical significance of these findings is unknown. In vitro 
susceptibility testing has not been standardised and results may vary according to methodological 
factors.

 

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Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established 
lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells in 
vitro.

Most viruses isolated from patients failing raltegravir had high-level raltegravir resistance resulting 
from the appearance of two or more mutations. Most had a signature mutation at amino acid 155 
(N155 changed to H), amino acid 148 (Q148 changed to H, K, or R), or amino acid 143 (Y143 
changed to H, C, or R), along with one or more additional integrase mutations (e.g., L74M, E92Q, 
T97A, E138A/K, G140A/S, V151I, G163R, S230R). The signature mutations decrease viral 
susceptibility to raltegravir and addition of other mutations results in a further decrease in raltegravir 
susceptibility. Factors that reduced the likelihood of developing resistance included lower baseline 
viral load and use of other active anti-retroviral agents. Mutations conferring resistance to raltegravir 
generally also confer resistance to the integrase strand transfer inhibitor elvitegravir. Mutations at 
amino acid 143 confer greater resistance to raltegravir than to elvitegravir, and the E92Q mutation 
confers greater resistance to elvitegravir than to raltegravir. Viruses harbouring a mutation at amino 
acid 148, along with one or more other raltegravir resistance mutations, may also have clinically 
significant resistance to dolutegravir.

Clinical efficacy with lamivudine
In clinical studies, lamivudine in combination with zidovudine has been shown to reduce HIV-1 viral 
load and increase CD4 cell count. Clinical end-point data indicate that lamivudine in combination with 
zidovudine, results in a significant reduction in the risk of disease progression and mortality. 

Evidence from clinical studies shows that lamivudine plus zidovudine delays the emergence of 
zidovudine resistant isolates in individuals with no prior antiretroviral therapy.

Lamivudine has been widely used as a component of antiretroviral combination therapy with other 
antiretroviral agents of the same class (NRTIs) or different classes (PIs, non-nucleoside reverse 
transcriptase inhibitors, integrase inhibitors).

Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective in 
antiretrovirally-naive patients as well as in patients presenting with viruses containing the M184V 
mutations.

The relationship between in vitro susceptibility of HIV to lamivudine and clinical response to 
lamivudine-containing therapy remains under investigation.

Lamivudine has not been specifically investigated in HIV patients co-infected with HBV.

Clinical efficacy with raltegravir
The evidence of efficacy of raltegravir was based on the analyses of 96-week data from two  
randomised, double-blind, placebo-controlled studies, (BENCHMRK 1 and BENCHMRK 2, 
Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult patients and the 
analysis of 240-week data from randomised, double-blind, active-control trial, (STARTMRK, 
Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult patients.

Treatment-experienced adult patients
BENCHMRK 1 and BENCHMRK 2 (multi-centre, randomised, double-blind, placebo-controlled 
studies) evaluated the safety and anti-retroviral activity of raltegravir 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 medicinal product 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. 

 

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Patient demographics (gender, age and race) and baseline characteristics were comparable between the 
groups receiving raltegravir 400 mg twice daily and placebo. Patients had prior exposure to a median 
of 12 anti-retrovirals for a median of 10 years. A median of 4 ARTs was used in OBT. 

Results 48 week and 96 week analyses
Durable outcomes (Week 48 and Week 96) for patients on the recommended dose raltegravir 400 mg 
twice daily from the pooled studies BENCHMRK 1 and BENCHMRK 2 are shown in Table 2. 

Table 2
Efficacy Outcome at Weeks 48 and 96

BENCHMRK 1 and 2 Pooled

Parameter

48 Weeks 96 Weeks

Raltegravir400 mg 
twice daily + OBT

(N = 462)

Placebo + 
OBT

(N = 237)

Raltegravir400 mg 
twice daily + OBT

(N = 462)

Placebo + 
OBT

(N = 237)

Percent HIV-RNA 
< 400 copies/ml (95 % CI) 
       All patients† 72 (68, 76) 37 (31, 44) 62 (57, 66) 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/mm3 61 (53, 69) 21 (13, 32) 51 (42, 60) 14 (7, 24)
                                  > 50 and 
≤ 200 cells/mm3

80 (73, 85) 44 (33, 55) 70 (62, 77) 36 (25, 48)

                                  
> 200 cells/mm3

83 (76, 89) 51 (39, 63) 78 (70, 85) 42 (30, 55)

                Sensitivity score (GSS) §

                                  0 52 (42, 61) 8 (3, 17)  46 (36, 56) 5 (1, 13)
                                  1 81 (75, 87) 40 (30, 51) 76 (69, 83) 31 (22, 42)
                                  2 and above 84 (77, 89) 65 (52, 76) 71 (63, 78) 56 (43, 69)

Percent HIV-RNA < 50 copies/ml 
(95 % CI)
       All patients† 62 (57, 67) 33 (27, 39) 57 (52, 62) 26 (21, 32)
           Baseline 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)

               CD4-count ≤ 50 cells/mm3 50 (41, 58) 20 (12, 31) 50 (41, 58) 13 (6, 22)
                                 > 50 and 
≤ 200 cells/mm3

67 (59, 74) 39 (28, 50) 65 (57, 72) 32 (22, 44)

                                  
> 200 cells/mm3

76 (68, 83) 44 (32, 56) 71 (62, 78) 41 (29, 53)

                Sensitivity score (GSS) §

                                  0 45 (35, 54) 3 (0, 11) 41 (32, 51) 5 (1, 13)
                                  1 67 (59, 74) 37 (27, 48) 72 (64, 79) 28 (19, 39)
                                  2 and above 75 (68, 82) 59 (46, 71) 65 (56, 72) 53 (40, 66)
Mean CD4 Cell Change (95 % 
CI), cells/mm3

       All patients‡ 109 (98, 121) 45 (32, 57) 123 (110, 137) 49 (35, 63)
           Baseline Characteristic‡

               HIV-RNA 
> 100,000 copies/ml

126 (107, 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/mm3 121 (100, 142) 33 (18, 48) 130 (104, 156) 42 (17, 67)
                                  > 50 and 
≤ 200 cells/mm3

104 (88, 119) 47 (28, 66) 123 (103, 144) 56 (34, 79)

 

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BENCHMRK 1 and 2 Pooled

Parameter

48 Weeks 96 Weeks

Raltegravir400 mg 
twice daily + OBT

(N = 462)

Placebo + 
OBT

(N = 237)

Raltegravir400 mg 
twice daily + OBT

(N = 462)

Placebo + 
OBT

(N = 237)
                                  
> 200 cells/mm3

104 (80, 129) 54 (24, 84) 117 (90, 143) 48 (23, 73)

                Sensitivity score (GSS) §

                                  0 81 (55, 106) 11 (4, 26) 97 (70, 124) 15 (-0, 31)
                                  1 113 (96, 130) 44 (24, 63) 132 (111, 154) 45 (24, 66)
                                  2 and above 125 (105, 144) 76 (48, 

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 
versus 90.6 % of the lopinavir (+) ritonavir group, (Non-completers = Failure). See section 4.4 
regarding the need to administer raltegravir with another active agent.

Treatment-naive adult patients
STARTMRK (multi-centre, randomised, double-blind, active-control study) evaluated the safety and 
anti-retroviral activity of raltegravir 400 mg twice daily vs. efavirenz 600 mg at bedtime, in a 
combination with emtricitabine (+) tenofovir, 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 raltegravir 400 mg twice daily and the group receiving efavirenz 600 mg at bedtime. 

Results 48-week and 240-week analyses
With respect to the primary efficacy endpoint, the proportion (%) of patients achieving HIV RNA 
< 50 copies/ml at Week 48 was 241/280 (86.1 %) in the group receiving raltegravir and 230/281 
(81.9 %) in the group receiving efavirenz. The treatment difference (raltegravir– efavirenz) was 4.2 % 
with an associated 95 % CI of (-1.9, 10.3) establishing that raltegravir is non-inferior to efavirenz 
(p-value for non-inferiority < 0.001). At Week 240, the treatment difference (raltegravir – efavirenz) 
was 9.5 % with an associated 95 % CI of (1.7, 17.3). Week 48 and Week 240 outcomes for patients on 
the recommended dose of raltegravir 400 mg twice daily from STARTMRK are shown in Table 3.

 

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Table 3
Efficacy Outcome at Weeks 48 and 240

STARTMRK Study

Parameter

48 Weeks 240 Weeks

Raltegravir
400 mg twice 

daily
(N = 281)

Efavirenz
600 mg

at bedtime
(N = 282)

Raltegravir
400 mg twice 

daily 
(N = 281)

Efavirenz
600 mg

at bedtime
(N = 282)

Percent HIV-RNA < 50 copies/ml 
(95 % CI) 
       All patients† 86 (81, 90) 82 (77, 86) 71 (65, 76) 61 (55, 67)

           Baseline Characteristic‡

               HIV-RNA  > 100,000 copies/ml 91 (85, 95) 89 (83, 94) 70 (62, 77) 65 (56, 72)

                                  ≤ 100,000 copies/ml 93 (86, 97) 89 (82, 94) 72 (64, 80) 58 (49, 66)

               CD4-count ≤ 50 cells/mm3 84 (64, 95) 86 (67, 96) 58 (37, 77) 77 (58, 90)

                                  > 50 and 
≤ 200 cells/mm3

89 (81, 95) 86 (77, 92) 67 (57, 76) 60 (50, 69)

                                  > 200 cells/mm3 94 (89, 98) 92 (87, 96) 76 (68, 82) 60 (51, 68)

              Viral Subtype Clade B 90 (85, 94) 89 (83, 93) 71 (65, 77) 59 (52, 65)

                                     Non-Clade B 96 (87, 100) 91 (78, 97) 68 (54, 79) 70 (54, 82)

Mean CD4 Cell Change (95 % CI), 
cells/mm3

       All patients‡ 189 (174, 
204)

163 (148, 
178)

374 (345, 403) 312 (284, 339) 

           Baseline Characteristic‡

               HIV-RNA  > 100,000 copies/ml 196 (174, 
219)

192 (169, 
214)

392 (350, 435) 329 (293, 364)

                                  ≤ 100,000 copies/ml 180 (160, 
200)

134 (115, 
153)

350 (312, 388) 294 (251, 337)

               CD4-count ≤ 50 cells/mm3 170 (122, 
218)

152 (123, 
180)

304 (209, 399) 314 (242, 386)

                                  > 50 and 
≤ 200 cells/mm3

193 (169, 
217)

175 (151, 
198)

413 (360, 465) 306 (264, 348)

                                  > 200 cells/mm3 190 (168, 
212)

157 (134, 
181)

358 (321, 395) 316 (272, 359)

              Viral Subtype Clade B 187 (170, 
204)

164 (147, 
181)

380 (346, 414) 303 (272, 333)

                                     Non-Clade B 189 (153, 
225)

156 (121, 
190)

332 (275, 388) 329 (260, 398) 

† 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.
Raltegravir and efavirenz were administered with emtricitabine (+) tenofovir.

Paediatric population
DUTREBIS should not be used in children below 6 years of age or in patients weighing less than 30 
kg due to weight based dosing requirements in this patient population (see section 5.2).

IMPAACT P1066 is a Phase I/II open label multicentre study to evaluate the pharmacokinetic profile, 
safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled 

 

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126 treatment experienced children and adolescents 2 to 18 years of age. Patients were stratified by 
age, enrolling adolescents first and then successively younger children. Patients received either the 
400 mg tablet formulation (6 to 18 years of age) or the chewable tablet formulation (2 to less than
12 years of age). Raltegravir was administered with an optimized background regimen.

The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based 
upon achieving similar raltegravir plasma exposure and trough concentration as seen in adults, and 
acceptable short term safety. After dose selection, additional patients were enrolled for evaluation of 
long term safety, tolerability and efficacy. Of the 126 patients, 96 received the recommended dose of 
raltegravir (see section 4.2).

Table 4
Baseline Characteristics and Efficacy Outcomes at Weeks 24 and 48 from IMPAACT P1066

(2 to 18 years of age)

Parameter
Final dose population

N=96

Demographics
Age (years), median [range] 13 [2 – 18]
Male Gender 49 %
Race

Caucasian 34 %
Black 59 %

Baseline Characteristics
Plasma HIV-1 RNA (log10 copies/ml), mean [range] 4.3 [2.7 – 6]
CD4 cell count (cells/mm3 ), median [range] 481 [0 – 2361]
CD4 percent, median [range] 23.3 % [0 – 44]
HIV-1 RNA >100,000 copies/ml 8 %
CDC HIV category B or C 59 %

Prior ART Use by Class
NNRTI 78 %
PI 83 %

Response Week 24 Week 48
Achieved ≥1 log10 HIV RNA drop from baseline or 
<400 copies/ml 72 % 79 %
Achieved HIV RNA <50 copies/ml 54 % 57 %
Mean CD4 cell count (%) increase from baseline 119 cells/mm3

(3.8 %)
156 cells/mm3 

(4.6 %)

5.2 Pharmacokinetic properties

The comparative bioavailability of DUTREBIS (150 mg lamivudine/300 mg raltegravir) fixed-dose 
combination tablet was assessed relative to individual components administered concomitantly 
(150 mg of lamivudine and 400 mg of raltegravir) in 108 healthy subjects. Lamivudine in the fixed-
dose combination tablet was bioequivalent with the lamivudine (single agent) after administration of 
the individual component. Raltegravir in the fixed-dose combination tablet was not bioequivalent with 
respect to C12, however, based on PK/PD modelling, no clinically meaningful differences in 
raltegravir exposure are expected following administration of the fixed-dose combination tablet 
compared to administration of raltegravir as a single agent.

Absorption
When DUTREBIS is administered, raltegravir is absorbed with a Tmax of approximately 1 hour in the 
fasted state. This is slightly faster than the raltegravir poloxamer formulation, which has a Tmax of 
approximately 3 hours. The bioavailablity of the raltegravir component of DUTREBIS in the fasted 
state is approximately 60 %, which is higher than the bioavailability of raltegravir in the raltegravir 
poloxamer formulation, and accounts for the difference in raltegravir dose. Once absorbed the 
lamivudine and raltegravir distribution, metabolism, and excretion are similar to those of the reference 
components administered individually as described in the following paragraphs.

 

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Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral lamivudine 
in adults is normally between 80 and 85 %. Following oral administration, the mean time (tmax) to 
maximal serum concentrations (Cmax) is about an hour. Based on data derived from a study in healthy 
volunteers, at a therapeutic dose of 150 mg twice daily, mean (CV) steady-state Cmax and Cmin of 
lamivudine in plasma are 1.2 μg/ml (24 %) and 0.09 μg/ml (27 %), respectively. The mean (CV) AUC 
over a dosing interval of 12 hours is 4.7 μg•h/ml (18 %). At a therapeutic dose of 300 mg once daily, 
the mean (CV) steady-state Cmax, Cmin and 24h AUC are 2.0 μg/ml (26 %), 0.04 μg/ml (34 %) and 
8.9 μg•h/ml (21 %), respectively.

Co-administration of zidovudine with lamivudine results in a 13 % increase in zidovudine exposure 
and a 28 % increase in peak plasma levels. This is not considered to be of significance to patient safety 
and therefore no dosage adjustments are necessary.

As demonstrated in healthy volunteers administered single oral doses of raltegravir in the fasted state,
raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1,600 mg. 
Raltegravir C12 hr increases dose proportionally over the dose range of 100 to 800 mg and increases 
slightly less than dose proportionally over the dose range 100 mg to 1,600 mg. Dose proportionality 
has not been established in patients.

With twice-daily dosing of raltegravir, pharmacokinetic steady state is achieved rapidly, within 
approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax and 
evidence of slight accumulation in C12 hr. 

Overall, considerable variability was observed in the pharmacokinetics of raltegravir. For observed 
C12 hr in BENCHMRK 1 and 2 the coefficient of variation (CV) for inter-subject variability = 212 % 
and the CV for intra-subject variability = 122 %. Sources of variability within the BENCHMRK study 
may include differences in co-administration with food and concomitant medicines. Overall, the 
results of the clinical pharmacology studies with DUTREBIS demonstrate similar drug exposures 
compared to the individual components of lamivudine and raltegravir, including similar variability in 
raltegravir C12hr and Cmax. The pharmacokinetic properties, use in special populations and drug-drug 
interactions for each of the individual components (lamivudine and raltegravir) are applicable to 
DUTREBIS.

An open-label, single-dose, randomized, two-period crossover study assessed the effect of a high fat 
meal on DUTREBIS administered to 20 healthy male and female subjects. Similar AUC values for fed 
vs. fasted and somewhat lower Cmax values (23 % for raltegravir and 21 % for lamivudine) were 
observed with DUTREBIS. In addition, higher C12h levels (20 % for raltegravir and 53 % for 
lamivudine) were observed. These changes are not considered clinically meaningful; therefore,
DUTREBIS may be administered with or without food.

Distribution
In intravenous studies with lamivudine, the mean volume of distribution is 1.3 l/kg. The observed 
half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 
0.32 l/h/kg, with predominantly renal clearance (> 70 %) via the organic cationic transport system.

Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited 
binding to the major plasma protein albumin (< 16 % - 36 % to serum albumin in in vitro studies).

Limited data show that lamivudine penetrates the central nervous system and reaches the cerebrospinal 
fluid (CSF). The mean ratio CSF/serum lamivudine concentration 2-4 hours after oral administration 
was approximately 0.12. The true extent of penetration or relationship with any clinical efficacy is 
unknown.

Raltegravir is approximately 83 % bound to human plasma protein over the concentration range of 2 to 
10 µM. 

 

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Raltegravir readily crossed the placenta in rats, but did not penetrate the brain to any appreciable 
extent.

In two studies of HIV-1 infected patients who received raltegravir 400 mg twice daily, raltegravir was 
readily detected in the cerebrospinal fluid. In the first study (n=18), the median cerebrospinal fluid 
concentration was 5.8 % (range 1 to 53.5 %) of the corresponding plasma concentration. In the second 
study (n=16), the median cerebrospinal fluid concentration was 3 % (range 1 to 61 %) of the 
corresponding plasma concentration. These median proportions are approximately 3- to 6-fold lower 
than the free fraction of raltegravir in plasma.

Biotransformation and excretion 
The active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-life in the cell 
(16 to 19 hours) compared to the plasma lamivudine half-life (5 to 7 hours). 

Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic 
interactions of lamivudine with other medicinal products is low due to the small extent of hepatic 
metabolism (5-10 %) and low plasma protein binding.

Studies in patients with renal impairment show lamivudine elimination is affected by renal 
dysfunction. DUTREBIS should not be given in patients with a creatinine clearance of <50 ml/min 
(see section 4.2).

An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40 % increase in 
lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient also 
has renal impairment (see sections 4.5 and 4.2). Administration of co-trimoxazole with lamivudine in 
patients with renal impairment should be carefully assessed.

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 
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 receiving raltegravir with *28/*28 genotype to 27 subjects with 
wild-type genotype, the geometric mean ratio (90 % CI) of AUC was 1.41 (0.96, 2.09) and the 
geometric mean ratio of C12 hr was 1.91 (1.43, 2.55). Dose adjustment is not considered necessary in 
subjects with reduced UGT1A1 activity due to genetic polymorphism.

Special populations

Paediatric population
The pharmacokinetics of DUTREBIS in the paediatric patient population has not been studied in 
clinical studies. DUTREBIS should not be used in children below 6 years of age or in patients 
weighing less than 30 kg due to weight based dosing requirements in this patient population.

The dosing regimen of the lamivudine component of DUTREBIS in the paediatric population is the 
same as the dosing regimen of the individual component (EPIVIR).

 

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The raltegravir component in DUTREBIS (300 mg raltegravir) fixed-dose combination tablet was not 
bioequivalent with respect to C12, however, based on PK/PD modelling, no clinically meaningful 
differences in raltegravir exposure are expected. Based on modelling and simulation using raltegravir 
pharmacokinetic data in adults, the pharmacokinetics of raltegravir in DUTREBIS in children was 
projected to result in exposures that have been previously shown to be safe and efficacious in adults. 

The pharmacokinetics of DUTREBIS in children under 6 years of age has not been established.

Elderly
No dosage adjustment is necessary for DUTREBIS based on age. The pharmacokinetics of lamivudine 
after administration to patients over 65 years of age have not been studied; however, 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
No dosage adjustment is necessary for DUTREBIS based on gender, race, or BMI. There were no 
clinically important pharmacokinetic differences due to gender, race or body mass index (BMI) for 
raltegravir in adults.

Renal impairment
No study has been performed with DUTREBIS in subjects with renal insufficiency. Recommendations 
are based on available data from the individual components. DUTREBIS should not be given in 
patients with a creatinine clearance of <50 ml/min. Renal function should be monitored in patients 
more likely to have decreased renal function. If the creatinine clearance decreases to <50 ml/min, 
DUTREBIS should be switched to a regimen of the individual components (lamivudine and 
raltegravir). Please refer to the SmPC for the individual components of DUTREBIS for dosing 
instructions. Because the extent to which DUTREBIS may be dialyzable is unknown, dosing before a 
dialysis session should be avoided (see section 4.2). 

The pharmacokinetic properties of lamivudine have been determined in a small group of 
HIV-1-infected adults with impaired renal function.

Exposure (AUC∞), Cmax, and half-life increased with diminishing renal function (as expressed by 
creatinine clearance). Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine 
clearance decreased. Tmax was not significantly affected by renal function.  

For raltegravir, renal clearance of unchanged drug is a minor pathway of elimination. A study of the 
pharmacokinetics of raltegravir was performed in adult patients with severe renal insufficiency. 
Additionally, renal insufficiency was evaluated in the composite pharmacokinetic analysis. There were 
no clinically important pharmacokinetic differences between patients with severe renal insufficiency 
and healthy subjects. 

Hepatic impairment
No study has been performed with DUTREBIS in subjects with hepatic insufficiency. 
Recommendations are based on available data from the individual components. No dosage adjustment 
for DUTREBIS is required for patients with mild to moderate hepatic insufficiency.

The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic 
function. Pharmacokinetic parameters were not altered by diminishing hepatic function; therefore, no 
dose adjustment for lamivudine is required for patients with impaired hepatic function. Safety and 
efficacy of lamivudine have not been established in the presence of decompensated liver disease.

Raltegravir is eliminated primarily by glucuronidation in the liver. In adults, there were no clinically 
important pharmacokinetic differences between patients with moderate hepatic insufficiency and 
healthy subjects. The effect of severe hepatic insufficiency on the pharmacokinetics of raltegravir has 
not been studied (see sections 4.2 and 4.4).

 

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Pharmacokinetics in pregnancy
Following oral administration, lamivudine pharmacokinetics in late pregnancy were similar to 
non-pregnant women.

5.3 Preclinical safety data

No animal studies have been conducted with DUTREBIS. The following data are based on findings in 
separate studies with the individual components of DUTREBIS (lamivudine and raltegravir).

Administration of lamivudine in animal toxicity studies at high doses was not associated with any 
major organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidney 
function were seen together with occasional reductions in liver weight. The clinically relevant effects 
noted were a reduction in red blood cell count and neutropenia.

Non-clinical toxicology studies, including conventional studies of safety pharmacology, repeated-dose 
toxicity, genotoxicity, developmental toxicity and juvenile toxicity, have been conducted with 
raltegravir, in mice, rats, dogs and rabbits. Effects at exposure levels sufficiently in excess of clinical 
exposure levels indicate no special hazard for humans.

Mutagenicity
Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, showed activity 
in an in vitro cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic in vivo 
at doses that gave plasma concentrations around 40-50 times higher than the anticipated clinical 
plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed in in vivo tests, 
it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing 
treatment.

A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with the 
combination of zidovudine and lamivudine at human-equivalent exposures. The study demonstrated 
that foetuses exposed in utero to the combination sustained a higher level of nucleoside 
analogue-DNA incorporation into multiple foetal organs, and showed evidence of more telomere 
shortening than in those exposed to zidovudine alone. The clinical significance of these findings is 
unknown.

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 conducted with raltegravir.

Carcinogenicity
The results of long-term carcinogenicity studies with lamivudine in rats and mice did not show any 
carcinogenic potential relevant for humans.

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 
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 AUC0-24 hr. No development 

 

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effects were seen at 3.4-fold human exposure at 400 mg twice daily based on AUC0-24 hr (see 
section 4.6). Similar findings were not observed in rabbits.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core
Hypromellose, 2910
Croscarmellose sodium 
Lactose monohydrate 
Silicon dioxide, colloidal 
Magnesium stearate 
Microcrystalline cellulose 

Film-coating
Hypromellose
Lactose monohydrate
Triacetin
Yellow iron oxide
Indigo Carmine (E132) Aluminium Lake
Titanium dioxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

After first opening of the medicinal product, the in-use shelf life is 30 days, below 30°C.

6.4 Special precautions for storage

Store in the original package in order to protect from moisture.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with a child-resistant closure (HDPE) with foil induction seal 
liner.
Pack size: 1 bottle containing 60 tablets. 

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom

 

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8. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/995/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 

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ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT

 

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

Merck Sharp & Dohme B.V.
Waarderweg 39
NL-2031 BN Haarlem
The Netherlands

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic safety update reports

The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation. Subsequently, the marketing authorisation holder shall 
submit periodic safety update reports for this product in accordance with the requirements set out in 
the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.

If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same 
time.

 

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ANNEX III

LABELLING AND PACKAGE LEAFLET

 

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A. LABELLING

 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Carton 

1. NAME OF THE MEDICINAL PRODUCT

DUTREBIS 150 mg/300 mg film-coated tablets
lamivudine/raltegravir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 150 mg of lamivudine and 300 mg of raltegravir (as potassium)

3. LIST OF EXCIPIENTS

Contains lactose. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

60 film-coated tablets

5. METHOD AND ROUTES OF ADMINISTRATION

Read the package leaflet before use. 
Oral use. 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/995/001

13. BATCH NUMBER

Batch 

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

DUTREBIS

 

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

Bottle label 

1. NAME OF THE MEDICINAL PRODUCT

DUTREBIS 150 mg/300 mg film-coated tablets
lamivudine/raltegravir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 150 mg of lamivudine and 300 mg of raltegravir (as potassium)

3. LIST OF EXCIPIENTS

Contains lactose. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

60 film-coated tablets

5. METHOD AND ROUTES OF ADMINISTRATION

Read the package leaflet before use. 
Oral use. 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

MSD + logo

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/995/001

13. BATCH NUMBER

Batch 

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

 

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B. PACKAGE LEAFLET

 

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Package leaflet: Information for the user

DUTREBIS 150 mg/300 mg film-coated tablets
lamivudine/raltegravir

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
If you are the parent of a child taking DUTREBIS, please read this information carefully with 
your child.
 Keep this leaflet. You may need to read it again.
 If you have any further questions, ask your doctor, pharmacist or nurse.
 This medicine has been prescribed for you or your child only. Do not pass it on to others. It may 

harm them, even if their signs of illness are the same as yours.
 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What DUTREBIS is and what it is used for
2. What you need to know before you take DUTREBIS
3. How to take DUTREBIS
4. Possible side effects
5. How to store DUTREBIS
6. Contents of the pack and other information

1. What DUTREBIS is and what it is used for

What DUTREBIS is
DUTREBIS is an antiretroviral medicine used to treat infection with human immunodeficiency virus 
(HIV). It contains the active substances lamivudine and raltegravir:
 Lamivudine belongs to a group of medicines called nucleoside analogue reverse transcriptase 

inhibitors (NRTIs)
 Raltegravir belongs to a group of medicines called HIV integrase strand transfer inhibitors

What DUTREBIS is used for
DUTREBIS is used to treat HIV (Human Immunodeficiency Virus). HIV is the virus that causes 
Acquired Immune Deficiency Syndrome (AIDS).

DUTREBIS is used in combination with other medicines to treat adults, adolescents, and children 
6 years of age and older and weighing at least 30 kg who are infected by HIV. Your doctor has 
prescribed DUTREBIS to help control your HIV infection.

How DUTREBIS works
When used with other medicines, DUTREBIS may:
 reduce the amount of HIV in your blood (this is called your "viral load")
 increase your CD4-cell count (a type of white blood cell 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. 
DUTREBIS also helps stop the production of an enzyme called “HIV integrase”. This enzyme is 
needed for HIV to make more virus.
DUTREBIS is not a cure for HIV infection.

 

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2. What you need to know before you take DUTREBIS

Do not take DUTREBIS:
 If you are allergic to lamivudine, raltegravir or any of the other ingredients in this medicine 

listed in section 6.
If you are not sure, talk to your doctor, pharmacist or nurse before taking DUTREBIS.

Warnings and precautions
Remember that DUTREBIS is not a cure for HIV infection. This means that you may keep getting 
infections or other illnesses associated with HIV, if you don’t take DUTREBIS as your doctor has 
instructed you.

Talk to your doctor, pharmacist or nurse before taking DUTREBIS if:
 you have a history of depression or psychiatric illness. Depression, including suicidal thoughts 

and behaviours, has been reported in some patients taking raltegravir (one of the medicines in
DUTREBIS), particularly in patients with a prior history of depression or psychiatric illness.

 you have kidney problems - Your doctor may decide to change your dose by using the 
medicines in DUTREBIS separately.

 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 this medicine. Do not 
stop taking DUTREBIS without your doctor’s advice.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking DUTREBIS.

Passing HIV to others
HIV infection is spread by contact with blood or sexual contact with a person with HIV. You can still 
pass on HIV when taking this medicine, although the risk is lowered by effective therapy. Discuss 
with your doctor the precautions needed to avoid infecting other people.

Look out for side effects
DUTREBIS can cause some side effects that you need to talk to your doctor, pharmacist or nurse 
about. See section 4 for more information about side effects.

Skin problems
Talk to your doctor immediately if you develop a rash. Severe and life-threatening skin reactions 
and allergic reactions have been reported in some patients taking raltegravir (one of the medicines 
in DUTREBIS).

Muscle problems
Talk to your doctor, pharmacist or nurse immediately if you experience unexplained muscle pain, 
tenderness or weakness while taking this medicine.

Infections
Tell your doctor, pharmacist or nurse immediately if you notice any symptoms of infection, such 
as:
 fever, and/or feeling unwell. 
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 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. 

In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the 
immune system attacks healthy body tissue) may also occur after you start taking medicines for 
the treatment of your HIV infection. Autoimmune disorders may occur many months after the start 
of treatment. 

 

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Tell your doctor, pharmacist or nurse immediately if you notice any symptoms of infection or 
other symptoms such as:
 muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 
the body, palpitations, tremor or hyperactivity.

Lactic acidosis
Some people taking DUTREBIS, or similar medicines, may get a side effect called “lactic 
acidosis” and a swollen liver. Lactic acidosis is caused by a build-up of lactic acid in the body. It 
is rare (may affect up to 1 in 1,000 people) and if it does happen, it usually happens after a few 
months of treatment. It can be life-threatening, and cause internal organs to fail.
 Lactic acidosis is more likely to happen in people who have liver problems, or in people who 
are very overweight, especially women.
During your treatment, your doctor will check you for signs of lactic acidosis. 
Tell your doctor immediately if you have any of the following signs of lactic acidosis, or any other 
symptoms that worry you:
 deep, fast, difficult breathing, feeling drowsy, numb or weak arms or legs, feeling or being sick 
(nausea or vomiting), stomach pain. 

Bone problems
Some patients taking combination treatment for HIV may develop a bone disease called 
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). This may be more 
likely with long-term HIV treatment, more severe damage to the immune system, overweight, or 
the use of alcohol or other medicines called corticosteroids.
Tell your doctor if you notice any of the following signs of osteonecrosis:
 joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty moving. 

Changes in body shape
Talk to your doctor if you notice changes in your body shape. People taking anti-retroviral 
medicines may find that their body shape changes. This is because of changes in fat distribution:
 fat may be lost from the legs, arms or face; extra fat may build up around the tummy, breasts or 
internal organs; fatty lumps (sometimes called buffalo hump) may appear on the back of the neck. 
It is not yet known what causes these changes, or whether they have any long-term effects. 

Some people taking DUTREBIS or other antiretroviral medicines may have other effects show up 
in their blood tests: 
 increased levels of lactic acid in the blood, which on rare occasions can lead to lactic acidosis; 
increased levels of sugar and fats (triglycerides and cholesterol) in the blood; resistance to insulin 
(so if you are diabetic, you may have to change your insulin dose to control your blood sugar).

Children and adolescents
DUTREBIS is not for use in children below 6 years of age.

Other medicines and DUTREBIS
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. This is because DUTREBIS might interact with other medicines.

DUTREBIS must not be used with the following medicines. Tell your doctor, pharmacist or nurse if 
you are taking, have recently taken or might take:
 medicines containing lamivudine – used to treat HIV or hepatitis B.
 medicines containing raltegravair or emtricitabine – used to treat HIV.
 high doses of co-trimoxazole – used to treat infections.
 trimethoprim – used to treat infections.
 interferons taken with or without ribavirin – used to treat hepatitis.
 cladribine – used to treat hairy cell leukaemia.
 antacids containing aluminium and/or magnesium – used for heartburn. Talk to your doctor 

about other medicines you can take.

 

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 rifampicin – used to treat some infections such as tuberculosis. Rifampicin may decrease your 
levels of raltegravir (one of the medicines in DUTREBIS). Your doctor may decide to change 
your dose by using the medicines in DUTREBIS separately, if you are taking rifampicin.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.
 DUTREBIS is not recommended in pregnancy. 
 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, pharmacist or nurse for advice before taking any medicine if you are pregnant or 
breast-feeding.

Driving and using machines
Do not operate machines, drive or cycle if you feel dizzy after taking this medicine.

DUTREBIS film-coated tablets contain 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 DUTREBIS

Always take this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your 
doctor, pharmacist or nurse if you are not sure. DUTREBIS must be used in combination with other
medicines for HIV. 

How much to take
Adults, children, and adolescents
The recommended dose is 1 tablet twice a day.

Taking this medicine
 Swallow the tablet whole (do not crush or chew). 
 This medicine can be taken with or without food or drink.

If you take more DUTREBIS 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 DUTREBIS
If you forget to take a dose, take it as soon as you remember it. If you notice within 6 hours, you must 
take the tablet immediately. If you notice after 6 hours, then skip the intake and take the next doses as 
usual.

If you stop taking DUTREBIS
It is important that you take DUTREBIS 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 DUTREBIS 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 DUTREBIS and become harder to treat.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

 

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4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

DUTREBIS contains two medicines: lamivudine and raltegravir. The side effects for the two 
individual medicines contained in DUTREBIS are presented below.

Serious side effects 
See a doctor immediately, if you notice any of the following: 
These are uncommon (may affect up to 1 in 100 people)
 herpes infections including shingles
 anaemia including due to low iron
 signs and symptoms of infection or inflammation
 mental disorder
 suicide intention or attempt
 stomach inflammation
 inflammation of liver (hepatitis); When hepatitis causes symptoms, they can include: 

belly pain; nausea and vomiting; not feeling hungry; jaundice, which is when the skin or 
white part of the eye turns yellow

 liver failure (the liver stops working , which may cause heavy bleeding, swelling, and 
breathing problems)

 allergic rash (including red spots or blotches sometimes with blistering and swelling of 
the skin)

 certain kinds of kidney problems, including conditions in which the kidneys lose the 
ability to remove waste and excess water from the bloodstream. As waste and fluids 
accumulate, other body systems are affected, potentially leading to complications

 taking drug in quantities greater than recommended
These are rare (may affect up to 1 in 1,000 people)
 lactic acidosis – signs include deep, fast, difficult breathing, feeling drowsy, numb or 

weak arms or legs, feeling or being sick (nausea or vomiting), stomach pain

See a doctor immediately, if you notice any of the side effects above.

Other side effects
Common (may affect up to 1 in 10 people)
 headache; feeling dizzy
 feeling or being sick (nausea or vomiting), diarrhoea, stomach pain
 feeling tired, lack of energy, difficulty in sleeping (insomnia)
 fever, general feeling of being unwell
 muscle pain and discomfort, joint pain
 cough, irritated or runny nose
 rash, hair loss (alopecia)
 decreased appetite
 abnormal dreams; nightmare; abnormal behaviour; feelings of deep sadness and 

unworthiness
 spinning sensation
 bloating; excessive gas in the stomach or bowel; indigestion; belching
 rash (more often when used in combination with darunavir)
 increased liver blood tests; abnormal white blood cells; increased fat levels in blood (such 

as cholesterol and triglycerides); increased level of enzyme from salivary glands or 
pancreas

 

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Uncommon (may affect up to 1 in 100 people)
 infection of the hair roots; influenza; skin infection due to virus; upper respiratory tract 

infection(such as inflammation of the nasal cavity or sinuses located around the nose; 
common cold); infection in the lymph node (gland in the neck, armpit, or groin)

 wart
 low count of white blood cells that fight infection; pain or swollen glands (lymph nodes)

in the neck, armpit and groin
 allergic reaction
 increased appetite; diabetes; high sugar levels in the blood; excessive thirst; severe weight 

loss; body fat disorder
 feeling anxious; feeling of confusion; depressed mood; mood changes; 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; reduced sense of touch, numbness or weakness 
of the arms and/or legs; tingling; sleepiness; tension headache; tremors; poor quality sleep

 visual disturbance
 buzzing, hissing, whistling, ringing or other persistent noise in the ears
 palpitations; slow heart rate; fast or irregular heart beats
 hot flush; high blood pressure
 harsh, raspy, or strained voice; nosebleed; nasal congestion
 pain in the upper part of the belly; rectal discomfort; constipation; dry mouth; heartburn; 

pain when swallowing; inflammation of the pancreas (pancreatitis); ulcer or sore in 
stomach or upper intestine; bleeding from anus; stomach discomfort; inflammation of the 
gums; swollen, red sore tongue

 accumulation of fat in the liver
 acne; unusual hair loss or thinning; redness of skin; unusual distribution of fat on the 

body, this 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

 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

 kidney stones; urination at night; kidney cyst
 erectile dysfunction; breast enlargement in men; menopausal symptoms
 chest discomfort; chills; swelling of face; feeling jittery; lump in the neck; swelling of 

hands, ankles or feet; pain
 blood test showing decreased count of platelets in blood (a kind of cell that helps blood 

clot); blood test showing reduced kidney function; 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); increase in time for blood to clot; blood test showing 
low red blood cell count (anaemia)

Rare (may affect up to 1 in 1,000 people)
 serious allergic reaction causing swelling of the face, tongue or throat which may cause 

difficulty in swallowing or breathing
 breakdown of muscle tissue
 liver problems, such as yellowing of the skin or whites of the eyes, swollen or fatty liver 
 blood test showing an increase in an enzyme called amylase

Very rare (may affect up to 1 in 10,000 people)
 blood test showing failure of the bone marrow to produce new red blood cells (pure red 

cell aplasia) 

Additional side effects in children and adolescents
 hyperactivity

 

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Muscle pain, tenderness, or weakness have been reported during treatment with raltegravir.

Patients with HIV are at higher risk of developing cancer than patients without the disease. In clinical 
studies, the number of HIV patients taking raltegravir who developed cancer was similar to that of 
patients taking other HIV medicines.

Tell your doctor, pharmacist or nurse if you notice any of the side effects above.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store DUTREBIS

 Keep this medicine out of the sight and reach of children.
 Do not take this medicine after the expiry date which is stated on the bottle after EXP. The 

expiry date refers to the last day of that month.
 Store in the original package in order to protect from moisture.

 Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 
how to throw away medicines you no longer use. These measures will help protect the 
environment.

6. Contents of the pack and other information

What DUTREBIS contains
 The active substances are lamivudine and raltegravir. Each film-coated tablet contains 150 mg 

of lamivudine and 300 mg of raltegravir (as potassium).
 The other ingredients are: hypromellose (2910), croscarmellose sodium, lactose monohydrate, 

silicon dioxide (colloidal), magnesium stearate, and microcrystalline cellulose. In addition, the 
film coating contains the following inactive ingredients: hypromellose, lactose monohydrate, 
triacetin, yellow iron oxide, Indigo Carmine (E132) Aluminium Lake, and titanium dioxide. 

What DUTREBIS looks like and contents of the pack
The film-coated tablet is oval-shaped, green, marked with "144" on one side. One pack size is
available: 1 bottle with 60 tablets.

Marketing Authorisation Holder

Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom

Manufacturer

Merck Sharp & Dohme B. V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder.

BE/LU
MSD Belgium BVBA/SPRL
Tél/Tel: 0800 38 693 (+32(0)27766211)
dpoc_belux@merck.com

LT
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


46

BG
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

HU
MSD Pharma Hungary Kft.
Tel.: +361 888 53 00
hungary_msd@merck.com

CZ
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

MT
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

DK
MSD Danmark ApS
Tlf: +45 4482 4000
dkmail@merck.com

NL
Merck Sharp & Dohme B.V.
Tel: 0800 99 99 000 (+31 23 5153153)
medicalinfo.nl@merck.com

DE
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

NO
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

EE
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

AT
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

EL
MSD Α.Φ.Β.Ε.Ε.
Τηλ: + 30 210 98 97 300
dpoc_greece@merck.com

PL
MSD Polska Sp.z o.o. 
Tel.: +48 22 549 51 00
msdpolska@merck.com

ES
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

PT
Merck Sharp & Dohme, Lda
Tel: +351 21 446 5700
clic@merck.com

FR
MSD France
Tél: + 33 (0) 1 80 46 40 40

RO
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com

HR
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 66 11 333
croatia_info@merck.com

SI
Merck Sharp & Dohme, inovativna zdravila d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com

IE
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

SK
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

IS
Vistor hf.
Sími: +354 535 7000

FI
MSD Finland Oy
Puh/Tel: +358 (0) 9 804 650
info@msd.fi

 

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47

IT
MSD Italia S.r.l.
Tel: +39 06 361911
medicalinformation.it@merck.com

SE
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

CY
Merck Sharp & Dohme Cyprus Limited
Τηλ: 800 00 673 (+357 22866700)
cyprus_info@merck.com

UK
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

LV
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364 224
msd_lv@merck.com

This leaflet was last revised in {MM/YYYY}

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.

 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET