Rezolsta

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

REZOLSTA 800 mg/150 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 800 mg of darunavir (as ethanolate) and 150 mg of cobicistat.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).
Pink oval shaped tablet of 23 mm x 11.5 mm, debossed with “800” on one side and “TG” on the other 
side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

REZOLSTA is indicated, in combination with other antiretroviral medicinal products, for the 
treatment of human immunodeficiency virus-1 (HIV-1) infection in adults and adolescents (aged 
12 years and older, weighing at least 40 kg).

Genotypic testing should guide the use of REZOLSTA (see sections 4.2, 4.4 and 5.1).

4.2 Posology and method of administration

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

Posology

The recommended dose regimen in adults and adolescents aged 12 years and older, weighing at least 
40 kg, is one tablet taken once daily with food.

ART-naïve patients
The recommended dose regimen is one film-coated tablet of REZOLSTA once daily taken with food.

ART-experienced patients
One film-coated tablet of REZOLSTA once daily taken with food may be used in patients with prior 
exposure to antiretroviral medicinal products, but without darunavir resistance associated mutations 
(DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/mL and CD4+ cell count 
≥ 100 cells x 106/L (see section 4.1).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V.

In all other ART-experienced patients or if HIV-1 genotype testing is not available, the use of
REZOLSTA is not appropriate and another antiretroviral regimen should be used. Refer to the 
Summary of Product Characteristics of other antiretroviral medicinal products for dosing information.

Advice on missed doses
If REZOLSTA is missed within 12 hours of the time it is usually taken, patients should be instructed 
to take the prescribed dose of REZOLSTA with food as soon as possible. If this is noticed later than 
12 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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If a patient vomits within 4 hours of taking the medicine, another dose of REZOLSTA should be taken 
with food as soon as possible. If a patient vomits more than 4 hours after taking the medicine, the 
patient does not need to take another dose of REZOLSTA until the next regularly scheduled time.

Special populations

Elderly
Limited information is available in this population, and therefore, REZOLSTA should be used with 
caution in patients above 65 years of age (see sections 4.4 and 5.2).

Hepatic impairment
There are no pharmacokinetic data regarding the use of REZOLSTA in patients with hepatic 
impairment.

Darunavir and cobicistat are metabolised by the hepatic system. Separate trials of darunavir/ritonavir 
and cobicistat suggest no dose adjustment is recommended in patients with mild (Child-Pugh Class A) 
or moderate (Child-Pugh Class B) hepatic impairment, however, REZOLSTA should be used with 
caution in these patients.

There are no data regarding the use of darunavir or cobicistat in patients with severe hepatic 
impairment. Severe hepatic impairment could result in an increase of darunavir and/or cobicistat 
exposure and a worsening of its safety profile. Therefore, REZOLSTA must not be used in patients 
with severe hepatic impairment (Child-Pugh Class C) (see sections 4.3, 4.4 and 5.2).

Renal impairment
Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular 
secretion of creatinine. REZOLSTA should not be initiated in patients with creatinine clearance less 
than 70 mL/min, if any co-administered medicinal product (e.g. emtricitabine, lamivudine, tenofovir 
disoproxil (as fumarate, phosphate or succinate), or adefovir dipivoxil) requires dose adjustment based 
on creatinine clearance (see sections 4.4, 4.8 and 5.2).

Based on the very limited renal elimination of cobicistat and darunavir, no special precautions or dose 
adjustments of REZOLSTA are required for patients with renal impairment. Darunavir, cobicistat, or 
the combination of both have not been studied in patients receiving dialysis, and therefore no 
recommendation can be made for these patients (see section 5.2).

For more information consult the cobicistat Summary of Product Characteristics.

Paediatric population
The safety and efficacy of REZOLSTA in paediatric patients aged 3 to 11 years, or weighing < 40 kg,
have not been established (see sections 4.4 and 5.3). No data are available. REZOLSTA should not be 
used in paediatric patients below 3 years of age because of safety concerns (see sections 4.4 and 5.3).

Pregnancy and postpartum
Treatment with REZOLSTA during pregnancy results in low darunavir exposure (see sections 4.4 and 
5.2). Therefore, therapy with REZOLSTA should not be initiated during pregnancy, and women who 
become pregnant during therapy with REZOLSTA should be switched to an alternative regimen (see 
sections 4.4 and 4.6). Darunavir/ritonavir may be considered as an alternative.

Method of administration

Oral use
To ensure administration of the entire dose of both darunavir and cobicistat, the tablet should be 
swallowed whole. For patients unable to swallow the whole tablet, REZOLSTA may be split into two 
pieces using a tablet-cutter, and the entire dose should be consumed immediately after splitting.



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Patients should be instructed to take REZOLSTA within 30 minutes after completion of a meal (see 
sections 4.4, 4.5 and 5.2).

4.3 Contraindications

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

Patients with severe (Child-Pugh Class C) hepatic impairment.

Co-administration with the following medicinal products due to the potential for loss of therapeutic 
effect (see section 4.5):
- carbamazepine, phenobarbital, phenytoin
- rifampicin
- lopinavir/ritonavir
- St John’s wort (Hypericum perforatum).

Co-administration with the following medicinal products due to the potential for serious and/or 
life-threatening adverse reactions (see section 4.5):
- alfuzosin
- amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
- astemizole, terfenadine
- colchicine, when used in patients with renal and/or hepatic impairment (see section 4.5)
- rifampicin
- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
- cisapride
- dapoxetine
- domperidone
- naloxegol
- lurasidone, pimozide, quetiapine, sertindole (see section 4.5)
- elbasvir/grazoprevir
- triazolam, midazolam administered orally (for caution on parenterally administered midazolam, 

see section 4.5)
- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil
- simvastatin, lovastatin and lomitapide (see section 4.5)
- dabigatran, ticagrelor.

4.4 Special warnings and precautions for use

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.

Regular assessment of virological response is advised. In the setting of lack or loss of virological 
response, resistance testing should be performed.

Darunavir binds predominantly to 1-acid glycoprotein. This protein binding is concentration 
dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products 
highly bound to 1-acid glycoprotein cannot be ruled out (see section 4.5).

ART-experienced patients

REZOLSTA should not be used in treatment-experienced patients with one or more DRV-RAMs or 
HIV-1 RNA ≥ 100,000 copies/mL or CD4+ cell count < 100 cells x 106/L (see section 4.2).

Combinations with optimised background regimens (OBRs) other than ≥ 2 NRTIs have not been 
studied in this population. Limited data is available in patients with HIV-1 clades other than B (see 
section 5.1).



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Pregnancy

Treatment with darunavir/cobicistat 800/150 mg during the second and third trimester has been shown
to result in low darunavir exposure, with a reduction of around 90% in Cmin levels (see section 5.2). 
Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in 
darunavir exposure may result in virological failure and an increased risk of mother to child 
transmission of HIV infection. Therefore, therapy with REZOLSTA should not be initiated during 
pregnancy, and women who become pregnant during therapy with REZOLSTA should be switched to 
an alternative regimen (see sections 4.2 and 4.6). Darunavir given with low dose ritonavir may be 
considered as an alternative.

Elderly

As limited information is available on the use of REZOLSTA in patients aged 65 and over, caution 
should be exercised, reflecting the greater frequency of decreased hepatic function and of concomitant 
disease or other therapy (see sections 4.2 and 5.2).

Severe skin reactions

During the darunavir/ritonavir clinical development program (N = 3,063), severe skin reactions, which 
may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of 
patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson 
syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal 
necrolysis and acute generalised exanthematous pustulosis have been reported. REZOLSTA should be 
discontinued immediately if signs or symptoms of severe skin reactions develop. These can include,
but are not limited to, severe rash or rash accompanied with fever, general malaise, fatigue, muscle or
joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.

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

Sulphonamide allergy

Darunavir contains a sulphonamide moiety. REZOLSTA should be used with caution in patients with 
a known sulphonamide allergy.

Hepatotoxicity

Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with 
darunavir/ritonavir. During the clinical development program (N = 3,063), hepatitis was reported in 
0.5% of patients receiving combination antiretroviral therapy with darunavir/ritonavir. Patients with 
pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for 
liver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case of 
concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for 
these medicinal products.

Appropriate laboratory testing should be conducted prior to initiating therapy with REZOLSTA and 
patients should be monitored during treatment. Increased AST/ALT monitoring should be considered 
in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment 
elevations of transaminases, especially during the first several months of REZOLSTA treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of 
liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver 
tenderness, hepatomegaly) in patients using REZOLSTA, interruption or discontinuation of treatment 
should be considered promptly.



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Patients with coexisting conditions

Hepatic impairment
The safety and efficacy of REZOLSTA, darunavir, or cobicistat have not been established in patients 
with severe underlying liver disorders. REZOLSTA is, therefore, contraindicated in patients with 
severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, 
REZOLSTA should be used with caution in patients with mild or moderate hepatic impairment (see 
sections 4.2, 4.3 and 5.2).

Renal impairment
Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular 
secretion of creatinine. This effect on serum creatinine, leading to a decrease in the estimated 
creatinine clearance, should be taken into consideration when REZOLSTA is administered to patients,
in whom the estimated creatinine clearance is used to guide aspects of their clinical management, 
including adjusting doses of co-administered medicinal products. For more information consult the 
cobicistat Summary of Product Characteristics.

REZOLSTA should not be initiated in patients with creatinine clearance less than 70 mL/min when 
co-administered with one or more agent requiring dose adjustment based on creatinine clearance (e.g. 
emtricitabine, lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate) or adefovir
dipivoxil) (see sections 4.2, 4.8 and 5.2).

No special precautions or dose adjustments are required in patients with renal impairment. As 
darunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be 
significantly removed by haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).

There are currently inadequate data to determine whether co-administration of tenofovir disoproxil and 
cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that 
include tenofovir disoproxil without cobicistat.

Haemophiliac patients
There have been reports of increased bleeding, including spontaneous skin haematomas and 
haemarthrosis in patients with haemophilia type A and B treated with HIV PIs. In some patients 
additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was 
continued or reintroduced if treatment had been discontinued. A causal relationship has been 
suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should,
therefore, be made aware of the possibility of increased bleeding.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment. For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Osteonecrosis

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



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Immune reconstitution inflammatory syndrome (IRIS)

In HIV infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, 
such reactions have been observed within the first weeks or months of initiation of CART. Relevant 
examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and 
pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any
inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, 
reactivation of herpes simplex and herpes zoster has been observed in clinical trials with darunavir 
co-administered with low dose ritonavir.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and
these events can occur many months after initiation of treatment (see section 4.8).

Interactions with medicinal products

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and 
strong inhibitors of CYP3A and P-glycoprotein (see section 4.5).

REZOLSTA should not be used in combination with another antiretroviral that requires 
pharmacoenhancement since dosing recommendations for such combination have not been 
established. REZOLSTA should not be used concurrently with products containing ritonavir or 
regimens containing ritonavir or cobicistat.

Unlike ritonavir, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or 
UGT1A1. If switching from ritonavir as a pharmacoenhancer to cobicistat, caution is required during 
the first two weeks of treatment with REZOLSTA, particularly if doses of any concomitantly 
administered medicinal products have been titrated or adjusted during use of ritonavir as a 
pharmacoenhancer.

Paediatric population

REZOLSTA is not recommended for use in paediatric patients (3 to 11 years of age). REZOLSTA 
should not be used in paediatric patients below 3 years of age (see sections 4.2 and 5.3).

4.5 Interaction with other medicinal products and other forms of interaction

As REZOLSTA contains darunavir and cobicistat, interactions that have been identified with 
darunavir (in combination with cobicistat or with low dose ritonavir) or with cobicistat determine the 
interactions that may occur with REZOLSTA. Interaction trials with darunavir/cobicistat, 
darunavir/ritonavir and with cobicistat have only been performed in adults.

Medicinal products that may be affected by darunavir/cobicistat

Darunavir is an inhibitor of CYP3A, a weak inhibitor of CYP2D6 and an inhibitor of P-gp. Cobicistat 
is a mechanism based inhibitor of CYP3A, and a weak CYP2D6 inhibitor. Cobicistat inhibits the 
transporters p-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Co-administration of 
cobicistat with medicinal products that are substrates of these transporters can result in increased 
plasma concentrations of the co-administered medicinal products. Cobicistat is not expected to inhibit 
CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Cobicistat is not expected to induce CYP1A2, 
CYP3A4, CYP2C9, CYP2C19, UGT1A1, or P-gp (MDR1). Co-administration of darunavir/cobicistat
and medicinal products primarily metabolised by CYP3A may result in increased systemic exposure to 
such medicinal products, which could increase or prolong their therapeutic effect and adverse 
reactions.



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REZOLSTA must therefore not be combined with medicinal products that are highly dependent on 
CYP3A for clearance and for which increased systemic exposure is associated with serious and/or 
life-threatening events (narrow therapeutic index) (see section 4.3).

Medicinal products that affect darunavir/cobicistat exposure

Darunavir and cobicistat are metabolised by CYP3A. Medicinal products that induce CYP3A activity 
would be expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma 
concentrations of darunavir and cobicistat (e.g. efavirenz, carbamazepine, phenytoin, phenobarbital,
rifampicin, rifapentine, rifabutin, St John’s wort) (see section 4.3 and interaction table below).

Co-administration of REZOLSTA and other medicinal products that inhibit CYP3A may decrease the 
clearance of darunavir and cobicistat and may result in increased plasma concentrations of darunavir 
and cobicistat (e.g. azole antifungals such as clotrimazole). These interactions are described in the 
interaction table below.

REZOLSTA should not be used concurrently with products or regimens containing ritonavir or 
cobicistat. REZOLSTA should not be used in combination with the individual components of 
REZOLSTA (darunavir or cobicistat). REZOLSTA should not be used in combination with another 
antiretroviral that requires pharmacoenhancement since dosing recommendations for such 
combination have not been established.

Interaction table

Expected interactions between REZOLSTA and antiretroviral and non-antiretroviral medicinal 
products are listed in the table below and are based on the identified interactions with 
darunavir/ritonavir, darunavir/cobicistat and with cobicistat.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as 
pharmacokinetic enhancer, therefore there may be different recommendations for the use of darunavir 
with concomitant medicine. In the table below it is specified when recommendations for REZOLSTA 
differ from those for darunavir boosted with low dose ritonavir. Refer to the Summary of Product 
Characteristics for PREZISTA for further information.

The below list of examples of drug drug interactions is not comprehensive and therefore the label of 
each drug that is co-administered with REZOLSTA should be consulted for information related to the 
route of metabolism, interaction pathways, potential risks, and specific actions to be taken with 
regards to co-administration.

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal products by 
therapeutic areas

Interaction Recommendations concerning 
co-administration

HIV ANTIRETROVIRALS
Integrase strand transfer inhibitors

Dolutegravir Based on theoretical 
considerations dolutegravir is not 
expected to affect the 
pharmacokinetics of REZOLSTA.

REZOLSTA and dolutegravir 
can be used without dose 
adjustments.

Raltegravir Some clinical trials suggest 
raltegravir may cause a modest 
decrease in darunavir plasma 
concentrations.

At present the effect of 
raltegravir on darunavir plasma 
concentrations does not appear 
to be clinically relevant;
REZOLSTA and raltegravir can 
be used without dose 
adjustments.



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HIV Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine
400 mg once daily

No mechanistic interaction 
expected based on theoretical 
consideration.

REZOLSTA and didanosine can 
be used without dose 
adjustments.
When didanosine is 
co-administered with 
REZOLSTA, didanosine should 
be administered on an empty 
stomach 1 hour before or 2 hours 
after REZOLSTA (which is 
administered with food).

Tenofovir disoproxil *

*study was done with tenofovir 
disoproxil fumarate

Based on theoretical 
considerations REZOLSTA is 
expected to increase tenofovir 
plasma concentrations.
(P-glycoprotein inhibition)

REZOLSTA and tenofovir 
disoproxil can be used without 
dose adjustments.
Monitoring of renal function 
may be indicated when 
REZOLSTA is given in 
combination with tenofovir 
disoproxil, particularly in 
patients with underlying 
systemic or renal disease, or in 
patients taking nephrotoxic 
agents.

Emtricitabine/tenofovir 
alafenamide

Tenofovir alafenamide ↔
Tenofovir ↑

The recommended dose of 
emtricitabine/tenofovir 
alafenamide is 200/10 mg once 
daily when used with 
REZOLSTA. 

Abacavir
Emtricitabine
Lamivudine
Stavudine
Zidovudine

Based on the different elimination 
pathways of the other NRTIs (i.e. 
emtricitabine, lamivudine, 
stavudine and zidovudine) that are 
primarily renally excreted, and 
abacavir for which metabolism is 
not mediated by CYP, no 
interactions are expected for these 
medicinal compounds and 
REZOLSTA.

REZOLSTA can be used with 
these NRTIs without dose 
adjustment.

HIV Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz Based on theoretical 

considerations efavirenz is 
expected to decrease darunavir 
and/or cobicistat plasma 
concentrations.
(CYP3A induction)

Co-administration of 
REZOLSTA and efavirenz is not 
recommended.

This recommendation is 
different from ritonavir-boosted 
darunavir. Consult the Summary 
of Product Characteristics for 
darunavir for further details.

Etravirine Based on theoretical 
considerations etravirine is
expected to decrease darunavir 
and/or cobicistat plasma 
concentrations.
(CYP3A induction)

Co-administration of 
REZOLSTA and etravirine is 
not recommended.

This recommendation is 
different from ritonavir-boosted 
darunavir. Consult the Summary 
of Product Characteristics for 
darunavir for further details.



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Nevirapine Based on theoretical 
considerations nevirapine is 
expected to decrease darunavir 
and/or cobicistat plasma 
concentrations, (CYP3A 
induction). REZOLSTA is 
expected to increase nevirapine 
plasma concentrations.
(CYP3A inhibition)

Co-administration of
REZOLSTA and nevirapine is 
not recommended.

This recommendation is 
different from ritonavir-boosted 
darunavir. Consult the Summary 
of Product Characteristics for 
darunavir for further details.

Rilpivirine Based on theoretical 
considerations REZOLSTA is 
expected to increase rilpivirine 
plasma concentrations.
(CYP3A inhibition)

Co-administration of
REZOLSTA and rilpivirine can 
be used without dose 
adjustments, as the expected 
increase in rilpivirine 
concentrations is not considered 
clinically relevant.

CCR5 ANTAGONIST
Maraviroc
150 mg twice daily

Based on theoretical 
considerations REZOLSTA is 
expected to increase maraviroc 
plasma concentrations.
(CYP3A inhibition)

The recommended dose of 
maraviroc is 150 mg twice daily 
when co-administered with 
REZOLSTA. For further details, 
consult the maraviroc Summary 
of Product Characteristics.

α1-ADRENORECEPTOR ANTAGONIST
Alfuzosin Based on theoretical 

considerations REZOLSTA is 
expected to increase alfuzosin 
plasma concentrations.
(CYP3A inhibition)

Co-administration of 
REZOLSTA with alfuzosin is 
contraindicated (see section 4.3).

ANAESTHETIC
Alfentanil Based on theoretical 

considerations REZOLSTA is 
expected to increase alfentanil 
plasma concentrations.

The concomitant use with 
REZOLSTA may require to 
lower the dose of alfentanil and 
requires monitoring for risks of 
prolonged or delayed respiratory 
depression.

ANTACIDS
Aluminium/magnesium
hydroxide
Calcium carbonate

No mechanistic interaction 
expected based on theoretical 
consideration.

REZOLSTA and antacids can be 
used concomitantly without dose 
adjustment.

ANTIANGINA/ANTIARRHYTHMIC
Disopyramide
Flecainide
Lidocaine (systemic)
Mexiletine
Propafenone

Amiodarone
Bepridil
Dronedarone
Ivabradine
Quinidine
Ranolazine

Based on theoretical 
considerations REZOLSTA is 
expected to increase these 
antiarrhythmic plasma 
concentrations.
(CYP3A and/or CYP2D6
inhibition)

Caution is warranted and 
therapeutic concentration 
monitoring, if available, is 
recommended for these
antiarrhythmics when 
co-administered with 
REZOLSTA.

Co-administration of 
amiodarone, bepridil, 
dronedarone, ivabradine, 
quinidine, or ranolazine and 
REZOLSTA is contraindicated 
(see section 4.3).



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Digoxin Based on theoretical 
considerations REZOLSTA is
expected to increase digoxin 
plasma concentrations.
(P-glycoprotein inhibition)

It is recommended that the 
lowest possible dose of digoxin 
should initially be given to 
patients on REZOLSTA. The 
digoxin dose should be carefully 
titrated to obtain the desired
clinical effect while assessing 
the overall clinical state of the 
subject.

ANTIBIOTIC
Clarithromycin Based on theoretical 

considerations clarithromycin is 
expected to increase darunavir 
and/or cobicistat plasma 
concentrations.
(CYP3A inhibition)
Concentrations of clarithromycin 
may be increased upon 
co-administration with 
REZOLSTA.
(CYP3A inhibition)

Caution should be exercised 
when clarithromycin is 
combined with REZOLSTA.

For patients with renal 
impairment the Summary of 
Product Characteristics for 
clarithromycin should be 
consulted for the recommended 
dose.

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban
Edoxaban
Rivaroxaban

Based on theoretical 
considerations co-administration
of REZOLSTA with these 
anticoagulants may increase 
concentrations of the 
anticoagulant, which may lead to 
an increased bleeding risk.
(CYP3A and/or P-glycoprotein 
inhibition)

Co-administration of 
REZOLSTA and these 
anticoagulants is not 
recommended.

Dabigatran
Ticagrelor

Based on theoretical 
considerations co-administration 
of REZOLSTA with dabigatran or
ticagrelor may increase 
concentrations of the 
anticoagulant.
(CYP3A and/or P-glycoprotein 
inhibition).

Concomitant administration of 
REZOLSTA with dabigatran or 
ticagrelor is contraindicated.

Use of other antiplatelets not 
affected by CYP inhibition or 
induction (e.g. prasugrel) is 
recommended (see section 4.3).

Warfarin Based on theoretical 
considerations REZOLSTA may 
alter warfarin plasma 
concentrations.

It is recommended that the 
international normalised ratio 
(INR) be monitored when 
warfarin is co-administered with 
REZOLSTA.

ANTICONVULSANTS
Carbamazepine
Phenobarbital
Phenytoin

Based on theoretical 
considerations these 
anticonvulsants are expected to 
decrease darunavir and/or 
cobicistat plasma concentrations.
(CYP3A induction)

Co-administration of 
REZOLSTA and these 
anticonvulsants is 
contraindicated (see section 4.3).

Clonazepam Based on theoretical 
considerations REZOLSTA is 
expected to increase 
concentrations of clonazepam.
(inhibition of CYP3A)

Clinical monitoring is 
recommended when 
co-administering REZOLSTA 
with clonazepam.



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ANTI-DEPRESSANTS 
Herbal supplements
St John’s wort

Based on theoretical 
considerations St John’s wort is 
expected to decrease darunavir 
and/or cobicistat plasma 
concentrations.
(CYP3A induction)

Co-administration of 
St John’s wort and REZOLSTA 
is contraindicated (see 
section 4.3).

Paroxetine
Sertraline

Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone

Based on theoretical 
considerations REZOLSTA is 
expected to increase these 
anti-depressant plasma 
concentrations.
(CYP2D6 and/or CYP3A 
inhibition)
Prior data with ritonavir-boosted 
darunavir however showed a 
decrease in these anti-depressant 
plasma concentrations (unknown 
mechanism); the latter may be 
specific to ritonavir.

Based on theoretical 
considerations REZOLSTA is 
expected to increase these 
anti-depressant plasma 
concentrations.
(CYP2D6 and/or CYP3A 
inhibition)

If these anti-depressants are to 
be used with REZOLSTA
clinical monitoring is 
recommended and a dose
adjustment of the anti-depressant 
may be needed.

ANTI-DIABETICS 
Metformin Based on theoretical 

considerations REZOLSTA is 
expected to increase metformin 
plasma concentrations.
(MATE1 inhibition)

Careful patient monitoring and 
dose adjustment of metformin is 
recommended in patients who 
are taking REZOLSTA.

ANTIEMETICS
Domperidone Not studied. Co-administration of 

domperidone with REZOLSTA
is contraindicated. 

ANTIFUNGALS
Clotrimazole
Fluconazole
Itraconazole
Isavuconazole
Posaconazole

Voriconazole

Based on theoretical 
considerations REZOLSTA is 
expected to increase these 
antifungal plasma concentrations, 
and darunavir and/or cobicistat 
plasma concentrations may be 
increased by the antifungals.
(CYP3A inhibition and/or P-gp 
inhibition)

Concentrations of voriconazole 
may increase or decrease when 
co-administered with 
REZOLSTA.

Caution is warranted and clinical 
monitoring is recommended.

When co-administration is 
required, the daily dose of 
itraconazole should not exceed 
200 mg.

Voriconazole should not be 
combined with REZOLSTA 
unless an assessment of the 
benefit/risk ratio justifies the use 
of voriconazole.



13

ANTIGOUT MEDICINES
Colchicine Based on theoretical 

considerations REZOLSTA is 
expected to increase colchicine 
plasma concentrations.
(CYP3A and/or P-glycoprotein 
inhibition)

A reduction in colchicine dosage 
or an interruption of colchicine 
treatment is recommended in 
patients with normal renal or 
hepatic function if treatment 
with REZOLSTA is required.
The combination of colchicine 
and REZOLSTA is 
contraindicated in patients with 
renal or hepatic impairment (see 
section 4.3).

ANTIMALARIALS
Artemether/Lumefantrine Based on theoretical 

considerations REZOLSTA is 
expected to increase lumefantrine 
plasma concentrations.
(CYP3A inhibition)

REZOLSTA and 
artemether/lumefantrine can be 
used without dose adjustments; 
however, due to the increase in 
lumefantrine exposure, the 
combination should be used with 
caution.

ANTIMYCOBACTERIALS
Rifampicin Based on theoretical 

considerations rifampin is 
expected to decrease darunavir 
and/or cobicistat plasma 
concentrations.
(CYP3A induction)

The combination of rifampicin 
and REZOLSTA is 
contraindicated (see section 4.3).

Rifabutin
Rifapentine

Based on theoretical 
considerations these 
antimycobacterials are expected to 
decrease darunavir and/or 
cobicistat plasma concentrations.
(CYP3A induction)

Co-administration of 
REZOLSTA with rifabutin and 
rifapentine is not recommended. 
If the combination is needed, the 
recommended dose of rifabutin 
is 150 mg 3 times per week on 
set days (for example 
Monday-Wednesday-Friday). 
Increased monitoring for 
rifabutin associated adverse 
reactions including neutropenia 
and uveitis is warranted due to 
an expected increase in exposure 
to rifabutin. Further dosage 
reduction of rifabutin has not 
been studied. It should be kept in 
mind that the twice weekly 
dosage of 150 mg may not 
provide an optimal exposure to 
rifabutin thus leading to a risk of 
rifamycin resistance and a 
treatment failure. Consideration 
should be given to official 
guidance on the appropriate
treatment of tuberculosis in HIV 
infected patients.

This recommendation is 
different from ritonavir-boosted 
darunavir. Consult the Summary 
of Product Characteristics for 
darunavir for further details.



14

ANTI-NEOPLASTICS
Dasatinib
Nilotinib
Vinblastine
Vincristine

Everolimus
Irinotecan

Based on theoretical 
considerations REZOLSTA is 
expected to increase these 
anti-neoplastic plasma 
concentrations.
(CYP3A inhibition)

Concentrations of these 
medicinal products may be 
increased when co-administered 
with REZOLSTA resulting in 
the potential for increased 
adverse events usually 
associated with these medicinal 
products.
Caution should be exercised 
when combining one of these 
anti-neoplastic agents with 
REZOLSTA.

Concomitant use of everolimus 
or irinotecan and REZOLSTA is 
not recommended.

ANTIPSYCHOTICS/NEUROLEPTICS
Perphenazine
Risperidone
Thioridazine

Lurasidone
Pimozide
Sertindole
Quetiapine

Based on theoretical 
considerations REZOLSTA is 
expected to increase these 
neuroleptic plasma concentrations.
(CYP3A, CYP2D6 and/or P-gp
inhibition)

Clinical monitoring is 
recommended when 
co-administering REZOLSTA 
perphenazine, risperidone or 
thioridazine. For these 
neuroleptics, consider reducing 
the dose of the neuroleptic upon 
co-administration with 
REZOLSTA.

The combination of lurasidone, 
pimozide, quetiapine or 
sertindole and REZOLSTA is 
contraindicated (see section 4.3).

β-BLOCKERS
Carvedilol
Metoprolol
Timolol

Based on theoretical 
considerations REZOLSTA is 
expected to increase these beta 
blocker plasma concentrations.
(CYP3A inhibition)

Clinical monitoring is 
recommended when 
co-administering REZOLSTA 
with beta-blockers and a lower 
dose of the beta-blocker should 
be considered.

CALCIUM CHANNEL BLOCKERS
Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil

Based on theoretical 
considerations REZOLSTA is 
expected to increase these calcium 
channel blocker plasma 
concentrations.
(CYP3A and/or CYP2D6 
inhibition)

Clinical monitoring of 
therapeutic and adverse effects is 
recommended when these 
medicines are co-administered 
with REZOLSTA.



15

CORTICOSTEROIDS
Corticosteroids primarily 
metabolised by CYP3A 
(including betamethasone, 
budesonide, fluticasone, 
mometasone, prednisone, 
triamcinolone).

Interaction not studied with any of 
the components of REZOLSTA.

Plasma concentrations of these 
medicinal products may be 
increased when co-administered 
with REZOLSTA, resulting in 
reduced serum cortisol 
concentrations. 

Concomitant use of REZOLSTA 
and corticosteroids that are 
metabolised by CYP3A (e.g. 
fluticasone propionate or other
inhaled or nasal corticosteroids) 
may increase the risk of 
development of systemic 
corticosteroid effects, including 
Cushing’s syndrome and adrenal 
suppression.

Co-administration with CYP3A-
metabolised corticosteroids is 
not recommended unless the 
potential benefit to the patient 
outweighs the risk, in which case 
patients should be monitored for 
systemic corticosteroid effects.
Alternative corticosteroids 
which are less dependent on 
CYP3A metabolism e.g.
beclomethasone for intranasal or 
inhalational use should be 
considered, particularly for long 
term use.

Dexamethasone (systemic) Based on theoretical
considerations (systemic) 
dexamethasone is expected to 
decrease darunavir and/or 
cobicistat plasma concentrations.
(CYP3A induction)

Systemic dexamethasone should 
be used with caution when 
combined with REZOLSTA.

ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan Based on theoretical 

considerations bosentan is 
expected to decrease darunavir 
and/or cobicistat plasma 
concentrations.
(CYP3A induction)
REZOLSTA is expected to 
increase bosentan plasma 
concentrations.
(CYP3A inhibition)

Co-administration of 
REZOLSTA and bosentan is not 
recommended.

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A inhibitors

Elbasvir/grazoprevir Based on theoretical 
considerations REZOLSTA may 
increase the exposure to 
grazoprevir.
(OATP1B and CYP3A inhibition)

Concomitant use of REZOLSTA 
with elbasvir/grazoprevir is 
contraindicated (see section 4.3).

Glecaprevir/pibrentasvir Based on theoretical 
considerations REZOLSTA may 
increase the exposure to 
glecaprevir and pibrentasvir.
(P-gp, BCRP and/or OATP1B1/3
inhibition)

It is not recommended to 
co-administer REZOLSTA with 
glecaprevir/pibrentasvir.



16

HMG CO-A REDUCTASE INHIBITORS
Atorvastatin
Fluvastatin
Pitavastatin
Pravastatin
Rosuvastatin

Lovastatin
Simvastatin

Atorvastatin (10 mg once daily):
atorvastatin AUC ↑ 290%
atorvastatin Cmax ↑ 319%
atorvastatin Cmin ND

Rosuvastatin (10 mg once daily):
rosuvastatin AUC ↑ 93%
rosuvastatin Cmax ↑ 277%
rosuvastatin Cmin ND

Based on theoretical 
considerations REZOLSTA is 
expected to increase the plasma 
concentrations of fluvastatin, 
pitavastatin, pravastatin, lovastatin 
and simvastatin.
(CYP3A inhibition and/or 
transport)

Concomitant use of a HMG CoA 
reductase inhibitor and 
REZOLSTA may increase 
plasma concentrations of the 
lipid lowering agent, which may 
lead to adverse events such as 
myopathy.

When administration of 
HMG CoA reductase inhibitors 
and REZOLSTA is desired, it is 
recommended to start with the 
lowest dose and titrate up to the 
desired clinical effect while 
monitoring for safety.

Concomitant use of REZOLSTA 
with lovastatin and simvastatin 
is contraindicated (see 
section 4.3).

OTHER LIPID MODIFYING AGENTS
Lomitapide Based on theoretical 

considerations, REZOLSTA is
expected to increase the exposure 
of lomitapide when 
co-administered.
(CYP3A inhibition)

Co-administration is 
contraindicated (see section 4.3)

H2-RECEPTOR ANTAGONISTS
Cimetidine
Famotidine
Nizatidine
Ranitidine

Based on theoretical 
considerations, no mechanistic 
interaction is expected.

REZOLSTA can be 
co-administered with 
H2-receptor antagonists without 
dose adjustments.

IMMUNOSUPPRESSANTS
Ciclosporin
Sirolimus
Tacrolimus

Everolimus

Based on theoretical 
considerations REZOLSTA is 
expected to increase these 
immunosuppressant plasma 
concentrations.
(CYP3A inhibition)

Therapeutic drug monitoring of 
the immunosuppressive agent 
must be done when 
co-administration occurs.

Concomitant use of everolimus 
and REZOLSTA is not 
recommended.

INHALED BETA AGONISTS
Salmeterol Based on theoretical 

considerations REZOLSTA is 
expected to increase salmeterol 
plasma concentrations.
(CYP3A inhibition)

Concomitant use of salmeterol 
and REZOLSTA is not 
recommended. The combination 
may result in increased risk of 
cardiovascular adverse event 
with salmeterol, including QT 
prolongation, palpitations and 
sinus tachycardia.

NARCOTIC ANALGESICS/TREATMENT OF OPIOID DEPENDENCE
Buprenorphine/naloxone Based on theoretical 

considerations REZOLSTA may 
increase buprenorphine and/or 
norbuprenorphine plasma 
concentrations.

Dose adjustment for 
buprenorphine may not be 
necessary when co-administered 
with REZOLSTA but a careful 
clinical monitoring for signs of 
opiate toxicity is recommended.



17

Methadone Based on theoretical 
considerations REZOLSTA may 
increase methadone plasma 
concentrations.

With ritonavir-boosted darunavir, 
a small decrease in methadone 
plasma concentrations was 
observed. Consult the Summary of 
Product Characteristics for 
darunavir for further details.

No adjustment of methadone 
dosage is expected when 
initiating co-administration with 
REZOLSTA. Clinical 
monitoring is recommended, as 
maintenance therapy may need 
to be adjusted in some patients.

Fentanyl
Oxycodone
Tramadol

Based on theoretical 
considerations REZOLSTA may 
increase plasma concentrations of 
these analgesics.
(CYP2D6 and/or CYP3A 
inhibition)

Clinical monitoring is 
recommended when 
co-administering REZOLSTA 
with these analgesics.

OESTROGEN-BASED CONTRACEPTIVES
Drospirenone (3 mg once daily)

Ethinylestradiol (0.02 mg once 
daily)

Norethindrone

drospirenone AUC ↑ 58%
drospirenone Cmax ↑ 15%
drospirenone Cmin ND

ethinylestradiol AUC  30%
ethinylestradiol Cmax  14%
ethinylestradiol Cmin ND

Based on theoretical 
considerations REZOLSTA may 
alter norethindrone plasma 
concentrations.
(CYP3A inhibition, UGT/SULT
induction)

Alternative or additional 
contraceptive measures are 
recommended when oestrogen 
based contraceptives are co 
administered with REZOLSTA. 
Patients using oestrogens as
hormone replacement therapy
should be clinically monitored 
for signs of oestrogen 
deficiency.
When REZOLSTA is 
co-administered with a 
drospirenone-containing 
product, clinical monitoring is 
recommended due to the 
potential for hyperkalaemia.

OPIOID ANTAGONIST
Naloxegol Not studied. Co-administration of 

REZOLSTA and naloxegol is 
contraindicated.

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of erectile 
dysfunction

Sildenafil
Tadalafil
Vardenafil

Avanafil

Based on theoretical 
considerations REZOLSTA is 
expected to increase these PDE-5 
inhibitor plasma concentrations.
(CYP3A inhibition)

Concomitant use of PDE-5 
inhibitors for the treatment of 
erectile dysfunction with 
REZOLSTA should be done 
with caution. If concomitant use 
of REZOLSTA with sildenafil, 
vardenafil or tadalafil is 
indicated, sildenafil at a single 
dose not exceeding 25 mg in 
48 hours, vardenafil at a single 
dose not exceeding 2.5 mg in 
72 hours or tadalafil at a single 
dose not exceeding 10 mg in 
72 hours is recommended.

The combination of avanafil and 
REZOLSTA is contraindicated 
(see section 4.3).



18

For the treatment of pulmonary 
arterial hypertension

Sildenafil
Tadalafil

Based on theoretical 
considerations REZOLSTA is 
expected to increase these PDE-5 
inhibitor plasma concentrations.
(CYP3A inhibition)

A safe and effective dose of 
sildenafil for the treatment of 
pulmonary arterial hypertension 
co-administered with 
REZOLSTA has not been 
established. There is an 
increased potential for 
sildenafil-associated adverse 
events (including visual 
disturbances, hypotension, 
prolonged erection and
syncope). Therefore, 
co-administration of 
REZOLSTA and sildenafil when 
used for the treatment of 
pulmonary arterial hypertension 
is contraindicated (see 
section 4.3).

Co-administration of tadalafil for 
the treatment of pulmonary 
arterial hypertension with 
REZOLSTA is not 
recommended.

PROTON PUMP INHIBITORS
Dexlansoprazole
Esomeprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole

Based on theoretical 
considerations, no mechanistic 
interaction is expected.

REZOLSTA can be 
co-administered with proton 
pump inhibitors without dose 
adjustments.



19

SEDATIVES/HYPNOTICS
Buspirone
Clorazepate
Diazepam
Estazolam
Flurazepam
Midazolam (parenteral)
Zolpidem

Midazolam (oral)
Triazolam

Based on theoretical 
considerations REZOLSTA is 
expected to increase these 
sedative/hypnotic plasma 
concentrations.
(CYP3A inhibition)

Clinical monitoring is 
recommended when 
co-administering REZOLSTA 
with these sedatives/hypnotics 
and a lower dose of the 
sedatives/hypnotics should be 
considered.

Caution should be used with 
co-administration of 
REZOLSTA and parenteral 
midazolam.

If REZOLSTA is 
co-administered with parenteral 
midazolam, it should be done in 
an intensive care unit or similar 
setting, which ensures close 
clinical monitoring and 
appropriate medical 
management in case of 
respiratory depression and/or 
prolonged sedation. Dose 
adjustment for midazolam 
should be considered, especially 
if more than a single dose of 
midazolam is administered.

Co-administration of oral 
midazolam or triazolam and 
REZOLSTA is contraindicated 
(see section 4.3).

TREATMENT FOR PREMATURE EJACULATION
Dapoxetine Not studied. Co-administration of 

REZOLSTA with dapoxetine is 
contraindicated.

UROLOGICAL DRUGS
Fesoterodine
Solifenacin

Not studied. Use with caution. Monitor for 
fesoterodine or solifenacin 
adverse reactions, dose reduction 
of fesoterodine or solifenacin
may be necessary.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well controlled trials with darunavir, or cobicistat, in pregnant women.
Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 
development, parturition or postnatal development (see section 5.3).

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure 
(see section 5.2), which may be associated with an increased risk of treatment failure and an increased 
risk of HIV transmission to the child. Therapy with REZOLSTA should not be initiated during 
pregnancy, and women who become pregnant during therapy with REZOLSTA should be switched to 
an alternative regimen (see sections 4.2 and 4.4).



20

Breast-feeding

It is not known whether darunavir or cobicistat are excreted in human milk. Studies in rats have 
demonstrated that darunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted in 
toxicity. Studies in animals have demonstrated that cobicistat is excreted in milk. Because of both the 
potential for HIV transmission and the potential for adverse reactions in breast-fed infants, mothers 
should be instructed not to breast-feed under any circumstances if they are receiving REZOLSTA.

Fertility

No human data on the effect of darunavir or cobicistat on fertility are available. There was no effect on 
mating or fertility in animals (see section 5.3). Based on animal studies, no effect on mating or fertility 
is expected with REZOLSTA.

4.7 Effects on ability to drive and use machines

REZOLSTA may have a minor influence on the ability to drive and use machines. Dizziness has been 
reported in some patients during treatment with regimens containing darunavir administered with 
cobicistat and should be borne in mind when considering a patient’s ability to drive or operate 
machinery.

4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of REZOLSTA is based on available clinical trial data from darunavir 
boosted with either cobicistat or ritonavir, from cobicistat and from post-marketing data from 
darunavir/ritonavir.

As REZOLSTA contains darunavir and cobicistat, the adverse reactions associated with each of the 
individual compounds may be expected.

The most frequent adverse reactions reported in the pooled data of the Phase III study GS-US-216-130 
and the REZOLSTA arm of Phase III study TMC114FD2HTX3001 were diarrhoea (23%), nausea
(17%), rash (13%), and headache (10%). Serious adverse reactions were diabetes mellitus, (drug) 
hypersensitivity, immune reconstitution inflammatory syndrome, rash, Stevens-Johnson syndrome,
and vomiting. All of these serious ADRs occurred in one (0.1%) subject except for rash in 4 (0.6%) 
subjects.

The most frequent adverse reactions reported during the darunavir/ritonavir clinical development 
program and as spontaneous reports are diarrhoea, nausea, rash, headache, and vomiting. The most 
frequent serious reactions are acute renal failure, myocardial infarction, immune reconstitution 
inflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis, and pyrexia.

In the 96 week analysis, the safety profile of darunavir/ritonavir 800/100 mg once daily in 
treatment-naïve subjects was similar to that seen with darunavir/ritonavir 600/100 mg twice daily in 
treatment-experienced subjects except for nausea which was observed more frequently in 
treatment-naïve subjects. This was driven by mild intensity nausea. 

Tabulated list of adverse reactions

Adverse reactions are listed by system organ class (SOC) and frequency category. Within each 
frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency 
categories are defined as follows: 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) and not known (frequency cannot be estimated 
from the available data).



21

Adverse reactions with darunavir/cobicistat in adult patients

MedDRA system organ class
Frequency category

Adverse reaction

Immune system disorders
Common (drug) hypersensitivity

Uncommon immune reconstitution inflammatory syndrome
Metabolism and nutrition disorders
Common anorexia, hypercholesterolaemia, 

hypertriglyceridaemia

Uncommon diabetes mellitus, dyslipidaemia, 
hyperglycaemia, hyperlipidaemia

Psychiatric disorders
Common abnormal dreams
Nervous system disorders
Very common headache
Gastrointestinal disorders
Very common diarrhoea, nausea

Common vomiting, abdominal pain, abdominal distension, 
dyspepsia, flatulence

Uncommon pancreatitis acute, pancreatic enzymes increased
Hepatobiliary disorders
Common hepatic enzyme increased

Uncommon hepatitis*, cytolytic hepatitis*
Skin and subcutaneous tissue disorders
Very common rash (including macular, maculopapular, 

papular, erythematous, pruritic rash, generalised 
rash, and allergic dermatitis)

Common pruritus

Uncommon Stevens-Johnson syndrome#, angioedema,
urticaria

Rare drug reaction with eosinophilia and systemic 
symptoms*

Not known toxic epidermal necrolysis*, acute generalised 
exanthematous pustulosis*

Musculoskeletal and connective tissue disorders
Common myalgia

Uncommon osteonecrosis*
Reproductive system and breast disorders
Uncommon gynaecomastia*
General disorders and administration site conditions
Common fatigue, asthenia
Investigations
Common increased blood creatinine



22

* These adverse drug reactions have not been reported in clinical trial experience with darunavir/cobicistat but have
been noted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.

#
When also taking into account the clinical trial data of DRV/COBI/emtricitabine/tenofovir alafenamide, Stevens-
Johnson syndrome occurred rarely (in 1 out of 2,551 subjects) consistent with the DRV/rtv clinical trial program (see 
Severe skin reactions in section 4.4).

Description of selected adverse reactions

Rash
In clinical trials with darunavir/ritonavir and darunavir/cobicistat, rash was mostly mild to moderate, 
often occurring within the first four weeks of treatment and resolving with continued dosing (see 
section 4.4). The pooled data of a single-arm trial investigating darunavir 800 mg once daily in 
combination with cobicistat 150 mg once daily and other antiretrovirals and one arm of a trial in which
REZOLSTA 800/150 mg once daily and other antiretrovirals were administered, showed that 1.9% of 
patients discontinued treatment due to rash.

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see 
section 4.4).

Musculoskeletal abnormalities
Increased CPK, myalgia, myositis and, rarely, rhabdomyolysis have been reported with the use of HIV 
protease inhibitors, particularly in combination with NRTIs.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). 
The frequency of this is unknown (see section 4.4).

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

Bleeding in haemophiliac patients
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving 
antiretroviral protease inhibitors (see section 4.4).

Decrease estimated creatinine clearance
Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of renal tubular
secretion of creatinine. An increase in serum creatinine due to the inhibitory effect of cobicistat 
generally does not exceed 0.4 mg/dL.

The effect of cobicistat on serum creatinine was investigated in a Phase I trial in subjects with normal 
renal function (eGFR ≥ 80 mL/min, n = 12) and mild to moderate renal impairment 
(eGFR:50-79 mL/min, n = 18). Change of estimated glomerular filtration rate calculated by 
Cockcroft-Gault method (eGFRCG) from baseline was observed within 7 days after start of treatment 
with cobicistat 150 mg among subjects with normal renal function (-9.9 ± 13.1 mL/min) and mild to 
moderate renal impairment (-11.9 ± 7.0 mL/min). These decreases in eGFRCG were reversible after
cobicistat was discontinued and did not affect the actual glomerular filtration rate, as determined by 
the clearance of probe drug iohexol.

In the Phase III single-arm trial (GS-US-216-130), a decrease in eGFRCG was noted at week 2, which 
remained stable through week 48. The mean eGFRCG change from baseline was –9.6 mL/min at 
week 2, and –9.6 mL/min at week 48. In the REZOLSTA arm of Phase III trial
TMC114FD2HTX3001, mean eGFRCG change from baseline was -11.1 mL/min at week 48 and mean 
eGFRcystatin C change from baseline was +2.9 mL/min/1.73 m² at week 48.



23

For more information consult the cobicistat Summary of Product Characteristics.

Paediatric population

The safety of components of REZOLSTA was evaluated in adolescents aged 12 to less than 18 years,
weighing at least 40 kg through the clinical trial GS-US-216-0128 (treatment-experienced, 
virologically suppressed, N = 7). Safety analyses of this study in adolescent subjects did not identify
new safety concerns compared to the known safety profile of darunavir and cobicistat in adult 
subjects.

Other special populations

Patients co-infected with hepatitis B and/or hepatitis C virus
Limited information is available on the use of REZOLSTA in patients co-infected with hepatitis B 
and/or C virus. Among 1,968 treatment-experienced patients receiving darunavir co-administered with 
ritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected 
patients were more likely to have baseline and treatment emergent hepatic transaminase elevations 
than those without chronic viral hepatitis (see section 4.4).

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

Human experience of acute overdose with REZOLSTA or darunavir in combination with cobicistat is 
limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the 
tablet formulation of darunavir in combination with ritonavir have been administered to healthy 
volunteers without untoward symptomatic effects.

There is no specific antidote for overdose with REZOLSTA. Treatment of overdose with REZOLSTA
consists of general supportive measures including monitoring of vital signs and observation of the 
clinical status of the patient. Since darunavir and cobicistat are highly protein bound, dialysis is 
unlikely to be beneficial in significant removal of the active substances.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infection,
combinations ATC code: J05AR14

Mechanism of action

Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease 
(KD of 4.5 x 10

-12M). It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus 
infected cells, thereby preventing the formation of mature infectious virus particles.

Cobicistat is a mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition 
of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, 
such as darunavir, where bioavailability is limited and half-life is shortened due to CYP3A-dependent 
metabolism.

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


24

Antiviral activity in vitro

Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory 
strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and 
human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to
5.0 ng/mL). Darunavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M 
(A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from < 0.1 to 4.3 nM.
These EC50 values are well below the 50% cellular toxicity concentration range of 87 µM to
> 100 µM.

Cobicistat has no detectable antiviral activity against HIV-1 and does not antagonise the antiviral 
effect of darunavir.

Resistance

In vitro selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years). The 
selected viruses were unable to grow in the presence of darunavir concentrations above 400 nM. 
Viruses selected in these conditions and showing decreased susceptibility to darunavir (range: 
23-50-fold) harboured 2 to 4 amino acid substitutions in the protease gene. The decreased 
susceptibility to darunavir of the emerging viruses in the selection experiment could not be explained 
by the emergence of these protease mutations.

The resistance profile of REZOLSTA is driven by darunavir. Cobicistat does not select any HIV
resistance mutations, due to its lack of antiviral activity. The resistance profile of REZOLSTA is 
supported by two Phase III trials conducted with darunavir/ritonavir in treatment-naïve (ARTEMIS) 
and treatment-experienced (ODIN) patients and the analysis of 48 week data from trial
GS-US-216-130 in treatment-naïve and treatment-experienced patients.

Low rates of developing resistant HIV-1 virus were observed in ART-naïve patients who are treated 
for the first time with REZOLSTA or darunavir/ritonavir 800/100 mg once daily in combination with 
other ART, and in ART-experienced patients with no darunavir RAMs receiving REZOLSTA or 
darunavir/ritonavir 800/100 mg once daily in combination with other ART. The table below shows the 
development of HIV-1 protease mutations and loss of susceptibility to HIV PIs in virologic failures at 
endpoint in the GS-US-216-130, ARTEMIS and ODIN trials.

GS-US-216-130
a

ARTEMIS
b

ODIN
b

Treatment-naïve
darunavir/cobicistat 

800/150 mg
once daily

N = 295

Treatment-experienced
darunavir/cobicistat 

800/150 mg
once daily

N = 18

Treatment-naïve
darunavir/ritonavir

800/100 mg
once daily

N = 343

Treatment-experienced
darunavir/ritonavir

800/100 mg
once daily

N = 294

Treatment-experienced
darunavir/ritonavir

600/100 mg
twice daily

N = 296

Number of subjects with virologic failure and genotype data that develop mutations
c

at endpoint, n/N

Primary
(major) PI 
mutations

0/8 1/7 0/43 1/60 0/42

PI RAMs 2/8 1/7 4/43 7/60 4/42

Number of subjects with virologic failure and phenotype data that show a loss of susceptibility to PIs at endpoint compared to baseline
d
, n/N

HIV PI
darunavir 0/8 0/7 0/39 1/58 0/41
amprenavir 0/8 0/7 0/39 1/58 0/40
atazanavir 0/8 0/7 0/39 2/56 0/40
indinavir 0/8 0/7 0/39 2/57 0/40
lopinavir 0/8 0/7 0/39 1/58 0/40
saquinavir 0/8 0/7 0/39 0/56 0/40
tipranavir 0/8 0/7 0/39 0/58 0/41



25

a
Virologic failures selected for resistance testing were defined as: never suppressed: HIV-1 RNA < 1 log10 reduction from baseline and ≥ 50 copies/mL at week 8, 
confirmed at the following visit; rebound: HIV-1 RNA < 50 copies/mL followed by confirmed HIV-1 RNA to ≥ 400 copies/mL or confirmed > 1 log10
HIV-1 RNA increase from the nadir; discontinuations with HIV-1 RNA ≥ 400 copies/mL at last visit

b
Virologic failures based on TLOVR non-VF censored algorithm (HIV-1 RNA > 50 copies/mL)

c
IAS-USA lists

d
In GS-US-216-130 baseline phenotype was not available

Cross-resistance

In the virologic failures of the GS-US-216-130 trial no cross-resistance with other HIV PIs was 
observed. Refer to the table above for information on ARTEMIS and ODIN.

Clinical results

The antiretroviral effect of REZOLSTA is due to the darunavir component. The activity of cobicistat 
as a pharmacokinetic enhancer to darunavir has been demonstrated in pharmacokinetic trials. In these 
pharmacokinetic trials, the exposure of darunavir 800 mg boosted with cobicistat 150 mg was 
consistent with that observed when boosted with ritonavir 100 mg. Darunavir as a component of 
REZOLSTA is bioequivalent to darunavir 800 mg once daily in combination with cobicistat 150 mg 
once daily co-administered as single medicinal products (see section 5.2).

The evidence of efficacy of REZOLSTA once daily is based on the analysis of 48 week data from trial
GS-US-216-130 in ART-naïve and ART-experienced patients, trial TMC114FD2HTX3001 in 
ART-naïve patients, and two Phase III trials ARTEMIS and ODIN conducted with darunavir/ritonavir 
800/100 mg q.d. in ART-naïve and ART-experienced patients, respectively.

Description of clinical studies of REZOLSTA in adults

Efficacy of darunavir 800 mg once daily co-administered with 150 mg cobicistat once daily in 
ART-naïve and ART-experienced patients
GS-US-216-130 is a single-arm, open-label, Phase III trial evaluating the pharmacokinetics, safety, 
tolerability, and efficacy of darunavir with cobicistat in 313 HIV-1 infected adult patients 
(295 treatment-naïve and 18 treatment-experienced). These patients received darunavir 800 mg once 
daily in combination with cobicistat 150 mg once daily with an investigator selected optimised 
background regimen (OBR) consisting of 2 active NRTIs.

HIV-1 infected patients who were eligible for this trial had a screening genotype showing no darunavir 
RAMs and plasma HIV-1 RNA ≥ 1,000 copies/mL. The table below shows the efficacy data of the 
48 week analyses from the GS-US-216-130 trial:

GS-US-216-130

Outcomes at week 48

Treatment-naïve
darunavir/cobicistat 

800/150 mg once daily
+ OBR
N = 295

Treatment-experienced
darunavir/cobicistat 

800/150 mg once daily
+ OBR
N = 18

All subjects
darunavir/cobicistat 

800/150 mg once daily
+ OBR
N = 313

HIV-1 RNA

< 50 copies/mL
a

245 (83.1%) 8 (44.4%) 253 (80.8%)

mean HIV-1 RNA log 
change from baseline 
(log10 copies/mL)

-3.01 -2.39 -2.97

CD4+ cell count mean 

change from baseline
b

+174 +102 +170

a
Imputations according to the TLOVR algorithm

b
Last Observation Carried Forward imputation



26

Efficacy of darunavir/cobicistat fixed-dose combination 800/150 mg once daily in ART-naïve patients
TMC114FD2HTX3001 is a randomized, active-controlled, double blind, Phase III trial to evalate the
efficacy and safety of darunavir/cobicistat/emtricitabine/tenofovir alafenamide versus 
darunavir/cobicistat fixed-dose combination + emtricitabine/tenofovir disoproxil fumarate. In the 
darunavir/cobicistat fixed-dose combination treament arm, 363 HIV-1 infected, adult, treatment-naïve
patients were treated.

HIV-1 infected patients who were eligible for this trial had a plasma HIV-1 RNA ≥ 1,000 copies/mL. 
The table below shows the 48-week efficacy data of the darunavir/cobicistat arm of the 
TMC114FD2HTX3001 trial:

TMC114FD2HTX3001 (darunavir/cobicistat arm)

Outcomes at week 48

Treatment-naïve
darunavir/cobicistat 800/150 mg once daily

+ emtricitabine/tenofovir disoproxil fumarate
N = 363

HIV-1 RNA < 50 copies/mL
a 321 (88.4%)

Virologic failure
a 12 (3.3%)

No virologic data in 48-week 

window
a

30 (8.3%)

CD4+ cell count mean 

change from baseline
b

+173.8

a
Imputations according to the Snapshot algorithm.

b
Non completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0

Description of clinical studies of darunavir/ritonavir in adults

Efficacy of darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in 
ART-naïve patients
The evidence of efficacy of darunavir/ritonavir 800/100 mg once daily is based on the analyses of 
192 week data from the randomised, controlled, open-label Phase III trial ARTEMIS in antiretroviral 
treatment-naïve HIV-1 infected patients comparing darunavir/ritonavir 800/100 mg once daily with 
lopinavir/ritonavir 800/200 mg per day (given as a twice-daily or as a once-daily regimen). Both arms 
used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily and 
emtricitabine 200 mg once daily.

The table below shows the efficacy data of the 48 week and 96 week analyses from the ARTEMIS 
trial:

ARTEMIS

Week 48
a

Week 96
b

Outcomes darunavir/
ritonavir

800/100 mg 
once daily

N = 343

lopinavir/ 
ritonavir

800/200 mg 
per day
N = 346

Treatment 
difference 
(95% CI 

of 
difference)

darunavir/
ritonavir

800/100 mg 
once daily

N = 343

lopinavir/ 
ritonavir

800/200 mg 
per day
N = 346

Treatment 
difference 

(95% CI of 
difference)

HIV-1 RNA 
< 50 copies/mLc

All patients

83.7%
(287)

78.3%
(271)

5.3%
(-0.5; 
11.2)d

79.0%
(271)

70.8% 
(245)

8.2%
(1.7; 14.7)d

With baseline 
HIV-RNA 
< 100,000

85.8%
(194/226)

84.5%
(191/226)

1.3%
(-5.2; 7.9)d

80.5%
(182/226)

75.2%
(170/226)

5.3%
(-2.3; 13.0)d

With baseline 
HIV-RNA 
≥ 100,000

79.5%
(93/117)

66.7%
(80/120)

12.8%
(1.6; 24.1)d

76.1%
(89/117)

62.5%
(75/120)

13.6%
(1.9; 25.3)d

With baseline 
CD4+ cell 
count < 200

79.4%
(112/141)

70.3%
(104/148)

9.2%
(-0.8; 
19.2)d

78.7%
(111/141)

64.9%
(96/148)

13.9%
(3.5; 24.2)d



27

With baseline 
CD4+ cell 
count ≥ 200

86.6%
(175/202)

84.3%
(167/198)

2.3%
(-4.6; 9.2)d

79.2%
(160/202)

75.3%
(149/198)

4.0%
(-4.3; 12.2)d

median 
CD4+ cell count 
change from 
baseline 
(x 106/L)e

+137 +141 +171 +188

a
Data based on analyses at week 48

b
Data based on analyses at week 96

c
Imputations according to the TLOVR algorithm

d
Based on normal approximation to the difference in % response

e
Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0

Non-inferiority in virologic response to the darunavir/ritonavir treatment, defined as the percentage of 
patients with plasma HIV-1 RNA level < 50 copies/mL, was demonstrated (at the pre-defined 12% 
non-inferiority margin) for both Intent-To-Treat (ITT) and On Protocol (OP) populations in the 
48 week analysis. These results were confirmed in the analyses of data at 96 weeks of treatment in the 
ARTEMIS trial. These results were sustained up to 192 weeks of treatment in the ARTEMIS trial.

Efficacy of darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in 
ART-experienced patients
ODIN is a Phase III, randomised, open-label trial comparing darunavir/ritonavir 800/100 mg once 
daily versus darunavir/ritonavir 600/100 mg twice daily in ART-experienced HIV-1 infected patients 
with screening genotype resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V, 
I50V, I54M, I54L, T74P, L76V, I84V, L89V) and a screening HIV-1 RNA > 1,000 copies/mL. 
Efficacy analysis is based on 48 weeks of treatment (see table below). Both arms used an optimised 
background regimen (OBR) of ≥ 2 NRTIs.

ODIN
Week 48

Outcomes darunvir/ritonavir 
800/100 mg once daily 

+ OBR
N = 294

darunvir/ritonavir 
600/100 mg twice 

daily + OBR
N = 296

Treatment difference
(95% CI of difference)

HIV-1 RNA < 50 copies/mLa 72.1% (212) 70.9% (210) 1.2% (-6.1; 8.5)b

With Baseline 
HIV-1 RNA (copies/mL)
< 100,000

≥ 100,000
77.6% (198/255)

35.9% (14/39)
73.2% (194/265)

51.6% (16/31)
4.4% (-3.0; 11.9)

-15.7% (-39.2; 7.7)
With Baseline CD4+ cell 
count (x 106/L)
≥ 100
< 100

75.1% (184/245)
57.1% (28/49)

72.5% (187/258)
60.5% (23/38)

2.6% (-5.1; 10.3)
-3.4% (-24.5; 17.8)

With HIV-1 clade
Type B
Type AE
Type C
Otherc

70.4% (126/179)
90.5% (38/42)
72.7% (32/44)
55.2% (16/29)

64.3% (128/199)
91.2% (31/34)
78.8% (26/33)
83.3% (25/30)

6.1% (-3.4; 15.6)
-0.7% (-14.0; 12.6)
-6.1% (-2.6; 13.7)

-28.2% (-51.0; -5.3)
mean CD4+ cell count 
change from baseline
(x 106/L)e

+108 +112 -5d (-25; 16)

a
Imputations according to the TLOVR algorithm

b
Based on a normal approximation of the difference in % response

c
Clades A1, D, F1, G, K, CRF02_AG, CRF12_BF, and CRF06_CPX

d
Difference in means

e
Last Observation Carried Forward imputation

At 48 weeks, virologic response, defined as the percentage of patients with plasma HIV-1 RNA level 
< 50 copies/mL, with darunavir/ritonavir 800/100 mg once daily treatment was demonstrated to be 



28

non-inferior (at the pre-defined 12% non-inferiority margin) compared to darunavir/ritonavir 
600/100 mg twice daily for both ITT and OP populations.

REZOLSTA should not be used in patients with one or more darunavir resistance associated mutations 
(DRV-RAMs) or HIV-1 RNA ≥ 100,000 copies/mL or CD4+ cell count < 100 cells x 106/L (see 
sections 4.2 and 4.4). Limited data is available in patients with HIV-1 clades other than B.

Paediatric population

The use of REZOLSTA in adolescent patients from the age of 12 years to less than 18 years, and 
weighing at least 40 kg is supported by adult trials and by trial GS-US-216-0128 in HIV-1 infected 
adolescents evaluating components of REZOLSTA. For additional supportive information, refer to the 
Summary of Product Characteristics of darunavir and cobicistat.

In the open-label, Phase II/III trial GS-US-216-0128, the efficacy, safety, and pharmacokinetics of 
darunavir 800 mg and cobicistat 150 mg (administered as separate tablets) and at least 2 NRTIs were 
evaluated in 7 HIV-1 infected, treatment-experienced, virologically suppressed adolescents (see 
section 5.2). Patients were on a stable antiretroviral regimen (for at least 3 months), consisting of 
darunavir adminstered with ritonavir, combined with 2 NRTIs. They were switched from ritonavir to 
cobicistat 150 mg once daily and continued darunavir (N = 7) and 2 NRTIs.

Virologic outcome in ART-experienced, virologically suppressed adolescents at week 48
GS-US-216-0128

Outcomes at week 48 Darunavir/cobicistat + at least 2 NRTIs
(N = 7)

HIV-1 RNA < 50 copies/mL per FDA Snapshot
Approach

85.7% (6)

CD4+ percent median change from baseline -6.1%
CD4+ cell count median change from baseline -342 cells/mm³

The European Medicines Agency has deferred the obligation to submit the results of studies with 
REZOLSTA in one or more subsets of the paediatric population in the condition of treatment of HIV-1 
infection.

5.2 Pharmacokinetic properties

Darunavir exposure was shown to be comparable in a bioavailability trial between REZOLSTA and
darunavir/ritonavir 800/100 mg q.d. at steady-state and fed conditions in healthy subjects.
The bioequivalence between REZOLSTA and darunavir/cobicistat 800/150 mg co-administered as
single agents was established under fed and fasted conditions in healthy subjects.

Absorption

Darunavir
The absolute oral bioavailability of a single 600 mg dose of darunavir alone is approximately 37%.

Darunavir was rapidly absorbed following oral administration of REZOLSTA in healthy volunteers. 
Maximum plasma concentration of darunavir in the presence of cobicistat is generally achieved within 
3 to 4.5 hours. Following oral administration of REZOLSTA in healthy volunteers, maximum plasma 
concentrations of cobicistat were observed 2 to 5 hours post-dose.

When administered with food, the relative exposure of darunavir is 1.7-fold higher as compared to 
intake without food. Therefore, REZOLSTA tablets should be taken with food. The type of food does
not affect exposure to REZOLSTA.



29

Distribution

Darunavir
Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma α1-acid 
glycoprotein.
Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 L
(Mean ± SD) and increased to 131 ± 49.9 L (Mean ± SD) in the presence of 100 mg twice-daily 
ritonavir.

Cobicistat
Cobicistat is 97 to 98% bound to human plasma proteins and the mean plasma to blood-drug 
concentration ratio was approximately 2.

Biotransformation

Darunavir
In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily 
undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and 
almost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a 
majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due 
to the parent active substance. At least 3 oxidative metabolites of darunavir have been identified in 
humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild 
type HIV.

Cobicistat
Cobicistat is metabolised via CYP3A (major)- and CYP2D6 (minor)-mediated oxidation and does not 
undergo glucuronidation. Following oral administration of 14C-cobicistat, 99% of circulating 
radioactivity in plasma was unchanged cobicistat. Low levels of metabolites are observed in urine and 
feces and do not contribute to the CYP3A inhibitory activity of cobicistat.

Elimination

Darunavir
After a 400/100 mg 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the 
administered dose of 14C-darunavir could be retrieved in faeces and urine, respectively. Unchanged 
darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, 
respectively. The terminal elimination half-life of darunavir was approximately 15 hours when 
combined with ritonavir.
The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 
32.8 L/h and 5.9 L/h, respectively.

Cobicistat
Following oral administration of 14C-cobicistat, 86% and 8.2% of the dose were recovered in feces and 
urine, respectively. The median terminal plasma half-life of cobicistat following administration of 
REZOLSTA is approximately 3-4 hours.

Special populations

Paediatric population
Available pharmacokinetic data for the different components of REZOLSTA indicate there were no 
clinically relevant differences in exposure between adults and adolescents. In addition, the 
pharmacokinetics of darunavir 800 mg co-administered with cobicistat 150 mg in paediatric patients 
have been studied in 7 adolescents aged 12 to less than 18 years, weighing at least 40 kg who received 
darunavir 800 mg co-administered with cobicistat 150 mg in Study GS-US-216-0128. The geometric 
mean adolescent exposure (AUCtau) was similar for darunavir and increased 19% for cobicistat
compared to exposures achieved in adults who received darunavir 800 mg co-administered with 



30

cobicistat 150 mg in Study GS-US-216-0130. The difference observed for cobicistat was not 
considered clinically relevant.
DRV PK 
Parameter

Adults in Study 
GS-US-216-0130, week 24

(Reference)
Mean (%CV)

GLSM

Adolescents in Study 
GS-US-216-0128, day 10

(Test)a

Mean (%CV)
GLSM

% GLSM Ratio
(90% CI)

(Test/Reference)

N 60b 7
AUCtau (h.ng/mL)

c 81,646 (32.2)
77,534

80,877 (29.5)
77,217

1.00 (0.79-1.26)

Cmax (ng/mL) 7,663 (25.1)
7,422

7,506 (21.7)
7,319

0.99 (0.83-1.17)

Ctau (ng/mL)
c 1,311 (74.0)

947
1,087 (91.6)

676
0.71 (0.34-1.48)

COBI PK 
Parameter
AUCtau (h.ng/mL)

c 7,596 (48.1)
7,022

8,741 (34.9)
8,330

1.19 (0.95-1.48)

Cmax (ng/mL) 991 (33.4)
945

1,116 (20.0)
1,095

1.16 (1.00-1.35)

Ctau (ng/mL)
c 32.8 (289.4)

17.2
28.3 (157.2)

22.0
1.28 (0.51-3.22)

a
PK parameters for the test group were from day 10 intensive PK assessment when DRV was boosted by COBI.

b
N = 59 for AUCtau and Ctau.

c
Concentration at predose (0 hours) was used as surrogate for concentration at 24 hours for the purposes of estimating 
AUCtau and Ctau.

Elderly
Darunavir
Limited information is available in this population. Population pharmacokinetic analysis in HIV 
infected patients showed that darunavir pharmacokinetics are not considerably different in the age 
range (18 to 75 years) evaluated in HIV infected patients (n = 12, age  65 years) (see section 4.4). 
However, only limited data were available in patients above the age of 65 years.

Cobicistat
Pharmacokinetics of cobicistat have not been fully evaluated in older people (65 years of age and
older).

Gender
Darunavir
Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV 
infected females compared to males. This difference is not clinically relevant.

Cobicistat
No clinically relevant pharmacokinetic differences due to gender have been identified for cobicistat.

Renal impairment
REZOLSTA has not been investigated in patients with renal impairment.

Darunavir
Results from a mass balance study with 14C-darunavir with ritonavir showed that approximately 7.7% 
of the administered dose of darunavir is excreted in the urine unchanged.

Although darunavir has not been studied in patients with renal impairment, population 
pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly
affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 mL/min, 
n = 20) (see sections 4.2 and 4.4).



31

Cobicistat
A trial of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with 
severe renal impairment (estimated creatinine clearance below 30 mL/min). No meaningful 
differences in cobicistat pharmacokinetics were observed between subjects with severe renal 
impairment and healthy subjects, consistent with low renal clearance of cobicistat.

Hepatic impairment
REZOLSTA has not been investigated in patients with hepatic impairment.

Darunavir
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose trial with
darunavir/ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrations 
of darunavir in subjects with mild (Child-Pugh Class A, n = 8) and moderate (Child-Pugh Class B, 
n = 8) hepatic impairment were comparable with those in healthy subjects. However, unbound 
darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh 
Class B) higher, respectively. The clinical relevance of this increase is unknown, therefore,
darunavir/ritonavir should be used with caution. The effect of severe hepatic impairment on the 
pharmacokinetics of darunavir has not been studied (see sections 4.2, 4.3 and 4.4).

Cobicistat
Cobicistat is primarily metabolised and eliminated by the liver. A trial of the pharmacokinetics of 
cobicistat was performed in non-HIV-1 infected subjects with moderate hepatic impairment 
(Child-Pugh Class B). No clinically relevant differences in cobicistat pharmacokinetics were observed 
between subjects with moderate impairment and healthy subjects. No dosage adjustment of 
REZOLSTA is necessary for patients with mild to moderate hepatic impairment. The effect of severe 
hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied.

Hepatitis B and/or hepatitis C virus co-infection
There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B
and/or C virus infection on the pharmacokinetics of darunavir and cobicistat (refer to sections 4.4 and
4.8).

Pregnancy and postpartum
Treatment with REZOLSTA during pregnancy results in low darunavir exposure. In women receiving 
REZOLSTA during the second trimester of pregnancy, mean intra-individual values for total
darunavir Cmax, AUC24h and Cmin were 49%, 56% and 92% lower, respectively, as compared with 
postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 
37%, 50% and 89% lower, respectively, as compared with postpartum. The unbound fraction was also 
substantially reduced, including around 90% reductions of Cmin levels. The main cause of these low 
exposures is a marked reduction in cobicistat exposure as a consequence of pregnancy-associated 
enzyme induction (see below).

Pharmacokinetic results of total darunavir after administration of darunavir/cobicistat 
800/150 mg once daily as part of an antiretroviral regimen, during the second trimester of 

pregnancy, the third trimester of pregnancy, and postpartum
Pharmacokinetics of 
total darunavir
(mean ± SD)

Second trimester 
of pregnancy

N = 7

Third trimester 
of pregnancy

N = 6

Postpartum 
(6-12 weeks)

N = 6
Cmax, ng/mL 4,340 ± 1,616 4,910 ± 970 7,918 ± 2,199
AUC24h, ng.h/mL 47,293 ± 19,058 47,991 ± 9,879 99,613 ± 34,862
Cmin, ng/mL 168 ± 149 184 ± 99 1,538 ± 1,344

The exposure to cobicistat was lower during pregnancy, potentially leading to suboptimal boosting of 
darunavir. During the second trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin were 50%, 
63%, and 83% lower, respectively, as compared with postpartum. During the third trimester of 



32

pregnancy, cobicistat Cmax, AUC24h, and Cmin, were 27%, 49%, and 83% lower, respectively, as 
compared with postpartum.

5.3 Preclinical safety data

Darunavir

Animal toxicology studies have been conducted at exposures up to clinical exposure levels with 
darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.

In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment 
with darunavir. In rodents the target organs identified were the haematopoietic system, the blood 
coagulation system, liver and thyroid. A variable but limited decrease in red blood cell-related 
parameters was observed, together with increases in activated partial thromboplastin time.

Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and 
thyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a small 
increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the 
pancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicity 
findings or target organs were identified up to exposures equivalent to clinical exposure at the 
recommended dose.

In a study conducted in rats, the number of corpora lutea and implantations were decreased in the 
presence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavir 
treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the 
clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in 
rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The 
exposure levels were lower than those with the recommended clinical dose in humans. In a pre- and 
postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient 
reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening 
of eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pups 
that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation. 
These effects may be secondary to pup exposure to the active substance via the milk and/or maternal 
toxicity. No post weaning functions were affected with darunavir alone or in combination with 
ritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed with 
convulsions in some animals. Exposure in plasma, liver and brain was considerably higher than in 
adult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, the 
exposure was comparable to that in adult rats. The increased exposure was likely at least partly due to 
immaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalities 
were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at 
500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were
comparable to those observed in adult rats.

Due to uncertainties regarding the rate of development of the human blood brain barrier and liver 
enzymes REZOLSTA should not be used in paediatric patients below 3 years of age.

Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up 
to 104 weeks. Daily doses of 150, 450 and 1,000 mg/kg were administered to mice and doses of 50,
150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences of
hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid 
follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a 
statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or 
rats. The observed hepatocellular and thyroid tumours in rodents are considered to be of limited 
relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme
induction and increased thyroid hormone elimination, which predispose rats, but not humans, to 
thyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavir 



33

when co-administered with ritonavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), 
relative to those observed in humans at the recommended therapeutic doses.

After 2 years administration of darunavir at exposures at or below the human exposure, kidney 
changes were observed in mice (nephrosis) and rats (chronic progressive nephropathy).

Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including 
bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivo
micronucleus test in mice.

Cobicistat

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose
toxicity, genotoxicity, and toxicity to reproduction and development. No teratogenic effects were
observed in rats and rabbit developmental toxicity studies. In rats, ossification changes in the spinal
column and sternebrae of fetuses occurred at a dose that produced significant maternal toxicity.

Ex vivo rabbit studies and in vivo dog studies suggest that cobicistat has a low potential for QT
prolongation, and may slightly prolong the PR interval and decrease left ventricular function at mean
concentrations at least 10-fold higher than the human exposure at the recommended 150 mg daily 
dose.

A long term carcinogenicity study of cobicistat in rats revealed tumourigenic potential specific for this
species, that is regarded as of no relevance for humans. A long term carcinogenicity study in mice did
not show any carcinogenic potential.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Hypromellose
Colloidal silicon dioxide
Silicified microcrystalline cellulose
Crospovidone
Magnesium stearate

Tablet film-coat

Polyvinyl alcohol– partially hydrolysed
Macrogol 3350
Titanium dioxide
Talc
Iron oxide red
Iron oxide black

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years
6 weeks after opening the bottle.



34

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

White, high density polyethylene (HDPE) bottle containing 30 tablets, fitted with polypropylene (PP) 
child resistant closure with induction seal.
Pack size of one bottle.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/967/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 November 2014
Date of latest renewal: 31 July 2019

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.

http://www.ema.europa.eu/


35

ANNEX II

A. MANUFACTURER(S) 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



36

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

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

Janssen-Cilag SpA
Via C. Janssen
Borgo San Michele
04100 Latina
Italy

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 requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates 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.



37

ANNEX III

LABELLING AND PACKAGE LEAFLET



38

A. LABELLING



39

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

REZOLSTA 800 mg/150 mg film-coated tablets
darunavir/cobicistat

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 800 mg darunavir (as ethanolate) and 150 mg cobicistat.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 film-coated tablets

5. METHOD AND ROUTE(S) 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
Do not use after 6 weeks of first opening the bottle.

9. SPECIAL STORAGE CONDITIONS



40

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

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/967/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

rezolsta

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



41

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

REZOLSTA 800 mg/150 mg tablets
darunavir/cobicistat

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 800 mg darunavir (as ethanolate) and 150 mg cobicistat.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 tablets

5. METHOD AND ROUTE(S) 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



42

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

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/967/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA



43

B. PACKAGE LEAFLET



44

Package leaflet: Information for the user

REZOLSTA 800 mg/150 mg - film-coated tablets
darunavir/cobicistat

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- 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 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 REZOLSTA is and what it is used for
2. What you need to know before you take REZOLSTA
3. How to take REZOLSTA
4. Possible side effects
5. How to store REZOLSTA
6. Contents of the pack and other information

1. What REZOLSTA is and what it is used for

What is REZOLSTA?
REZOLSTA contains the active substances darunavir and cobicistat.
Darunavir belongs to a group of HIV medicines called ‘protease inhibitors’ which work by reducing 
the amount of HIV in your body to a very low level. It is given with cobicistat, which increases the 
amount of darunavir in your blood. 
Treatment with REZOLSTA will improve your immune system (your body’s natural defences) and 
reduce the risk of developing illnesses linked to HIV infection, but REZOLSTA is not a cure for HIV 
infection.

What it is used for?
REZOLSTA is used to treat adults and adolescents aged 12 years and older who weigh at least 
40 kilograms and who are infected by HIV (see How to take REZOLSTA).

REZOLSTA must be taken in combination with other HIV medicines. Your doctor will discuss with 
you which combination of medicines is best for you.

2. What you need to know before you take REZOLSTA

Do not take REZOLSTA
- if you are allergic to darunavir, cobicistat or any of the other ingredients of this medicine (listed 

in section 6).
- if you have severe liver problems. Ask your doctor if you are unsure about the severity of your 

liver disease. Some additional tests might be necessary.

Do not combine REZOLSTA with any of the following medicines
If you are taking any of these, ask your doctor about switching to another medicine.

Medicine Purpose of the medicine
Alfuzosin to treat enlarged prostate
Amiodarone, bepridil, dronedarone, ivabradine,
quinidine, ranolazine

to treat certain heart disorders e.g. abnormal 
heart beat



45

Carbamazepine, phenobarbital and phenytoin to prevent seizures 
Astemizole or terfenadine to treat allergy symptoms 
Colchicine (if you have kidney/liver problems) to treat gout or familial Mediterranean fever
The combination product lopinavir/ritonavir anti-HIV medicine
Rifampicin to treat some infections such as tuberculosis
Lurasidone, pimozide, quetiapine or sertindole to treat psychiatric conditions
Ergot alkaloids like ergotamine, 
dihydroergotamine, ergometrine and 
methylergonovine

to treat migraine headaches

Cisapride to treat some stomach conditions
St John’s wort (Hypericum perforatum) a herbal product used for depression
Elbasvir/grazoprevir to treat hepatitis C infection
Lovastatin, simvastatin, and lomitapide to lower cholesterol levels
Triazolam or oral (taken by mouth) midazolam to help you sleep and/or relieve anxiety
Sildenafil to treat a heart and lung disorder called 

pulmonary arterial hypertension. There are other 
uses for sildenafil. Please see section ‘Other 
medicines and REZOLSTA’.

Avanafil to treat erectile dysfunction
Dabigatran, ticagrelor to help stop the clumping of platelets in the 

treatment of patients with a history of a heart 
attack

Naloxegol to treat opioid induced constipation
Dapoxetine to treat premature ejaculation
Domperidone to treat nausea and vomiting

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking REZOLSTA.

You can still pass on HIV when taking this medicine, although the risk is lowered by effective 
antiretroviral therapy. Discuss with your physician the precautions needed to avoid infecting other 
people.
People taking REZOLSTA may still develop infections or other illnesses associated with HIV 
infection. You must keep in regular contact with your doctor.

People taking REZOLSTA may develop a skin rash. Infrequently a rash may become severe or 
potentially life-threatening. Please contact your doctor whenever you develop a rash.

In patients taking REZOLSTA and raltegravir (for HIV infection), rashes (generally mild or moderate) 
may occur more frequently than in patients taking either medicine separately.

REZOLSTA has only been used in limited numbers of patients 65 years or older. If you belong to this 
age group, please discuss with your doctor if you can use REZOLSTA.

Make sure that you check the following points and tell your doctor if any of these apply to you.
- Tell your doctor if you have had problems with your liver before, including hepatitis B or C

infection. Your doctor may evaluate how severe your liver disease is before deciding if you can 
take REZOLSTA.

- Tell your doctor if you have had problems with your kidneys. Your doctor will carefully 
consider whether to treat you with REZOLSTA.

- Tell your doctor if you have diabetes. REZOLSTA might increase sugar levels in the blood.
- Tell your doctor immediately if you notice any symptoms of infection (for example enlarged 

lymph nodes and fever). In some patients with advanced HIV infection and a history of unusual 
infections due to a weakened immune system (opportunistic infection), signs and symptoms of 
inflammation from previous infections may occur soon after HIV treatment is started. It is 



46

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. 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, please inform your doctor immediately 
so you can be given the necessary treatment.

- Tell your doctor if you have haemophilia. REZOLSTA might increase the risk of bleeding.
- Tell your doctor if you are allergic to sulphonamides (e.g. used to treat certain infections).
- Tell your doctor if you notice any musculoskeletal problems. Some patients taking 

combination antiretroviral therapy 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. Signs of osteonecrosis are joint stiffness, aches and pains 
(especially of the hip, knee and shoulder) and difficulty in movement. If you notice any of these 
symptoms please inform your doctor.

Children and adolescents
REZOLSTA is not for use in children younger than 12 years, or weighing less than 
40 kilograms.

Other medicines and REZOLSTA
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

There are some medicines that you must not combine with REZOLSTA. These are mentioned above 
under the heading ‘Do not combine REZOLSTA with any of the following medicines:’

REZOLSTA must not be used with another antiviral medicine that contains a booster or another 
antiviral that requires boosting. In some cases dosage of other medicines might need to be changed. 
Therefore, always tell your doctor if you take other anti-HIV medicines and follow your doctor’s 
instruction carefully on which medicines can be combined.

The effects of REZOLSTA might be reduced if you take any of the following products. Tell your 
doctor if you take:
- Bosentan (to treat heart disease)
- Dexamethasone (injectable) (corticosteroid)
- Efavirenz, etravirine, nevirapine (to treat HIV infection)
- Rifapentine, rifabutin (to treat bacterial infections).

The effects of other medicines might be influenced if you take REZOLSTA. Tell your doctor if you 
take:
- Amlodipine, carvedilol, diltiazem, disopyramide, felodipine, flecainide, lidocaine, metoprolol, 

mexiletine, nicardipine, nifedipine, propafenone, timolol, verapamil (for heart disease) as the 
therapeutic effect or side effects of these medicines may be increased.

- Apixaban, edoxaban, rivaroxaban, warfarin (to reduce clotting of the blood) as their therapeutic 
effect or side effects may be altered; your doctor may have to check your blood.

- Clonazepam (to prevent seizures).
- Oestrogen-based hormonal contraceptives and hormone replacement therapy. REZOLSTA

might reduce its effectiveness. When used for birth control, alternative methods of 
non-hormonal contraception are recommended.

- Ethinylestradiol/drospirenone. REZOLSTA might increase the risk for elevated potassium 
levels by drospirenone.

- Atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin (to lower cholesterol levels). 
The risk of muscle damage might be increased. Your doctor will evaluate which cholesterol 
lowering regimen is best for your specific situation.



47

- Ciclosporin, everolimus, tacrolimus, sirolimus (for dampening down your immune system) as 
the therapeutic effect or side effects of these medicines might be increased. Your doctor might 
want to do some additional tests.

- Corticosteroids including betamethasone, budesonide, fluticasone, mometasone, prednisone, 
triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel 
diseases, inflammatory conditions of the eyes, joints and muscles and other inflammatory 
conditions. If alternatives cannot be used, its use should only take place after medical evaluation 
and under close monitoring by your doctor for corticosteroid side effects.

- Buprenorphine/naloxone, methadone (medicines to treat opioid dependence)
- Salmeterol (medicine to treat asthma)
- Artemether/lumefantrine (a combination medicine to treat malaria)
- Dasatinib, irinotecan, nilotinib, vinblastine, vincristine (medicines to treat cancer)
- Perphenazine, risperidone, thioridazine (psychiatric medicines)
- Clorazepate, diazepam, estazolam, flurazepam (medicines to treat sleeping disorders or anxiety)
- Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder 

called pulmonary arterial hypertension)
- Glecaprevir/pibrentasvir (to treat hepatitis C infection)
- Fesoterodine, solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or REZOLSTA’s 
therapeutic effect or side effects may be influenced when combined.
Tell your doctor if you take:
- Alfentanil (injectable, strong and short-acting, painkiller that is used for surgical procedures)
- Digoxin (to treat certain heart disorders)
- Clarithromycin (antibiotic)
- Clotrimazole, fluconazole, itraconazole, isavuconazole, posaconazole (against fungal 

infections). Voriconazole should only be taken after medical evaluation.
- Rifabutin (against bacterial infections)
- Tadalafil, sildenafil, vardenafil (for erectile dysfunction or high blood pressure in the 

pulmonary circulation)
- Amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone (to treat 

depression and anxiety)
- Maraviroc (to treat HIV infection)
- Colchicine (to treat gout or familial Mediterranean fever). If you have renal and/or hepatic 

impairment see section ‘Do not combine REZOLSTA with any of the following medicines’.
- Bosentan (to treat high blood pressure in the pulmonary circulation)
- Buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem, midazolam when used as 

injection (medicines to treat trouble with sleeping and/or anxiety)
- Metformin (to treat type 2 diabetes)
- Fentanyl, oxycodone, tramadol (to treat pain).

This is not a complete list of medicines. Tell your healthcare provider about all medicines that you are
taking.

Pregnancy and breast-feeding
Tell your doctor immediately if you are pregnant, planning to become pregnant or if you are 
breast-feeding. Pregnant or breast-feeding mothers should not take REZOLSTA. It is recommended 
that HIV infected women must not breast-feed their infants because of both the possibility of your 
baby becoming infected with HIV through your breast milk and because of the unknown effects of the 
medicine on your baby.

Driving and using machines
Do not operate machines or drive if you feel dizzy after taking REZOLSTA.



48

3. How to take REZOLSTA

Always use this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your 
doctor, pharmacist or nurse if you are not sure.

You must take REZOLSTA every day and always with food. REZOLSTA cannot work properly 
without food. You must eat a meal or a snack within 30 minutes prior to taking your REZOLSTA. The 
type of food is not important.

- Swallow the tablet whole with a drink such as water or milk. If you have difficulty swallowing 
REZOLSTA, tell your doctor. The tablet may be split using a tablet-cutter. After splitting the 
tablet, the entire dose (both halves) should then be taken right away with a drink such as water 
or milk.

- Take your other HIV medicines used in combination with REZOLSTA as recommended by 
your doctor.

Removing the child resistant cap

The plastic bottle comes with a child resistant cap and must be opened as follows:
- Push the plastic screw cap down while turning it counter clockwise.
- Remove the unscrewed cap.

If you take more REZOLSTA than you should
Contact your doctor, pharmacist or nurse immediately.

If you forget to take REZOLSTA
If you notice within 12 hours, you must take the tablet immediately. Always take with food. If you 
notice after 12 hours, then skip the intake and take the next doses as usual. Do not take a double dose
to make up for a forgotten dose.

If you vomit after taking REZOLSTA
If you vomit within 4 hours of taking the medicine, another dose of REZOLSTA should be taken with 
food as soon as possible. If you vomit more than 4 hours after taking the medicine, then you do not 
need to take another dose of REZOLSTA until the next regularly scheduled time.

Contact your doctor if you are uncertain about what to do if you miss a dose or vomit.

Do not stop taking REZOLSTA without talking to your doctor first
After therapy has started, it must not be stopped without instruction of the doctor.

Anti-HIV medicines may make you feel better. Even when you feel better, do not stop taking 
REZOLSTA. Talk to your doctor first.

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

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

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



49

Tell your doctor if you develop any of the following side effects
Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests 
before you start REZOLSTA. If you have chronic hepatitis B or C infection, your doctor should check 
your blood tests more often because you have an increased chance of developing liver problems. Talk 
to your doctor about the signs and symptoms of liver problems. These may include yellowing of your 
skin or whites of your eyes, dark (tea coloured) urine, pale coloured stools (bowel movements), 
nausea, vomiting, loss of appetite, or pain, aching, or pain and discomfort on your right side below 
your ribs.

A common side effect of REZOLSTA is skin rash (more often when used in combination with 
raltegravir), itching. The rash is usually mild to moderate. A skin rash might also be a symptom of a 
rare severe situation. It is, therefore, important to talk to your doctor if you develop a rash. Your 
doctor will advise you how to deal with your symptoms or whether REZOLSTA must be stopped.

Other severe side effects, seen up to 1 patient in 10, were diabetes. Inflammation of the pancreas
(pancreatitis) has been reported in up to 1 patient in 100.

Very common side effects (may affect more than 1 in 10 people)
- headache
- diarrhoea, nausea.

Common side effects (may affect up to 1 in 10 people)
- allergic reactions such as itching
- decreased appetite
- abnormal dreams
- vomiting, pain or swelling of the belly, indigestion, flatulence
- muscle pain
- tiredness
- abnormal blood test results such as some tests for your liver or kidney. Your doctor will explain

these to you.
- weakness.

Uncommon side effects (may affect up to 1 in 100 people)
- symptoms of infection or of autoimmune disorders (immune reconstitution inflammatory 

syndrome)
- osteonecrosis (death of bone tissue caused by loss of blood supply to the bone)
- enlargement of breasts
- abnormal blood test results such as some tests for your pancreas, high level of sugar, abnormal 

levels of ‘lipids’ (fats). Your doctor will explain these to you.
- allergic reactions such as nettle rash (urticaria), severe swelling of the skin and other tissues 

(most often the lips or the eyes)
- severe rash with blisters and peeling skin, particularly around the mouth, nose, eyes and 

genitals.

Rare side effects (may affect up to 1 in 1,000 people)
- a reaction called DRESS [severe rash, which may be accompanied by fever, fatigue, swelling of 

the face or lymph glands, increase of eosinophils (type of white blood cells), effects on liver, 
kidney or lung].

Side effects with unknown frequency: a rash may become severe or potentially life-threatening: 
- rash with blisters and peeling skin over much of the body
- red rash covered with small pus-filled bumps that can spread over the body, sometimes with a 

fever.

Some side effects are typical for HIV medicines in the same family as REZOLSTA. These are:
- muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been 

serious.



50

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 REZOLSTA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the bottle after 
EXP. The expiry date refers to the last day of that month.

Do not use this medicine after 6 weeks of first opening the bottle.

REZOLSTA does not require any special storage conditions.

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

6. Contents of the pack and other information

What REZOLSTA contains
- The active substances are darunavir and cobicistat. Each tablet contains 800 mg of darunavir (as 

ethanolate) and 150 mg cobicistat.
- The other ingredients are hypromellose, silicified microcrystalline cellulose, colloidal silicon

dioxide, crospovidone and magnesium stearate. The film-coating contains polyvinyl alcohol -
partially hydrolyzed, titanium dioxide, polyethylene glycol (macrogol), talc, iron oxide red, and 
iron oxide black.

- This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially ‘sodium-free’.

What REZOLSTA looks like and contents of the pack
Film-coated, pink, oval shaped tablet, mentioning TG on one side, 800 on the other side.
30 tablets in a plastic bottle.

Marketing Authorisation Holder
Janssen-Cilag International NV, Turnhoutseweg 30, 2340 Beerse, Belgium

Manufacturer
Janssen-Cilag SpA, Via C. Janssen, Borgo San Michele, 04100 Latina, Italy

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

België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: +32 14 64 94 11
janssen@jacbe.jnj.com

Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88
lt@its.jnj.com

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


51

България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00
jjsafety@its.jnj.com

Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: +32 14 64 94 11
janssen@jacbe.jnj.com

Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858
janssenhu@its.jnj.com

Danmark
Janssen-Cilag A/S
Tlf: +45 4594 8282
jacdk@its.jnj.com

Malta
AM MANGION LTD
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Tel: +49 2137 955 955
jancil@its.jnj.com

Nederland
Janssen-Cilag B.V.
Tel: +31 76 711 1111
janssen@jacnl.jnj.com

Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410
ee@its.jnj.com

Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00
jacno@its.jnj.com

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000

Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300

España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00
contacto@its.jnj.com

Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.: +48 22 237 60 00

France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
medisource@its.jnj.com

Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600

Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700
jjsafety@JNJCR.JNJ.com

România
Johnson & Johnson România SRL
Tel: +40 21 207 1800

Ireland
Janssen Sciences Ireland UC
Tel: +353 1 800 709 122

Slovenija
Johnson & Johnson d.o.o.
Tel: +386 1 401 18 00
Janssen_safety_slo@its.jnj.com

Ísland
Janssen-Cilag AB
c/o Vistor hf.
Sími: +354 535 7000
janssen@vistor.is

Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400



52

Italia
Janssen-Cilag SpA
Tel: 800.688.777 / +39 02 2510 1
janssenita@its.jnj.com

Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300
jacfi@its.jnj.com

Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700

Sverige
Janssen-Cilag AB
Tfn: +46 8 626 50 00
jacse@its.jnj.com

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
lv@its.jnj.com

United Kingdom
Janssen-Cilag Ltd.
Tel: +44 1 494 567 444

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.

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) 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