Darunavir Krka d.d.

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Darunavir Krka d.d. 400 mg film-coated tablets
Darunavir Krka d.d. 800 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Darunavir Krka d.d. 400 mg film-coated tablets:

Each film-coated tablet contains 400 mg darunavir.

Darunavir Krka d.d. 800 mg film-coated tablets:

Each film-coated tablet contains 800 mg darunavir.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Darunavir Krka d.d. 400 mg film-coated tablets:

Yellowish brown, oval, biconvex film-coated tablets, engraved with a mark S1 on one side. Tablet 
dimension: 17 x 8.5 mm.

Darunavir Krka d.d. 800 mg film-coated tablets:

Brownish red, oval, biconvex film-coated tablets, engraved with a mark S3 on one side. Tablet 
dimension: 20 x 10 mm.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Darunavir Krka d.d., co-administered with low dose ritonavir is indicated in combination with other 
antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus 
(HIV-1) infection.

Darunavir Krka d.d., co-administered with cobicistat is indicated in combination with other 
antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus 
(HIV-1) infection in adult patients (see section 4.2).

Darunavir Krka d.d. 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the 
treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg 
body weight who are:
- antiretroviral therapy (ART)-naïve (see section 4.2).
- ART-experienced with no 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. In 
deciding to initiate treatment with darunavir in such ART-experienced patients, genotypic 
testing should guide the use of darunavir (see sections 4.2, 4.3, 4.4 and 5.1).

4.2 Posology and method of administration



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Therapy should be initiated by a health care provider experienced in the management of HIV 
infection. After therapy with darunavir has been initiated, patients should be advised not to alter the 
dosage, dose form or discontinue therapy without discussing with their health care provider.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as 
pharmacokinetic enhancer. Darunavir may therefore have different contraindications and 
recommendations for concomitant medications depending on whether the compound is boosted with 
ritonavir or cobicistat (see sections 4.3, 4.4 and 4.5).

Posology
Darunavir must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic 
enhancer and in combination with other antiretroviral medicinal products. The Summary of Product 
Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation 
of therapy with darunavir. Cobicistat is not indicated for use in twice daily regimens or for use in the 
paediatric population.

This product is only available as film coated tablets and is thus not suitable for patients who are unable 
to swallow intact tablets, for example young children. For use in these patients, more suitable 
formulations containing darunavir should be checked for their availability.

ART-naïve adult patients
The recommended dose regimen is 800 mg once daily with cobicistat 150 mg once daily or ritonavir 
100 mg once daily taken with food. Darunavir Krka d.d. 400 mg and 800 mg tablets can be used to 
construct the once daily 800 mg regimen.

ART-experienced adult patients
The recommended dose regimens are as follows:
- In ART-experienced patients with no 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) a regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 
100 mg once daily taken with food may be used. Darunavir Krka d.d. 400 mg and 800 mg 
tablets can be used to construct the once daily 800 mg regimen.

- In all other ART-experienced patients or if HIV-1 genotype testing is not available, the 
recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken 
with food. See the Summary of Product Characteristics for Darunavir Krka d.d. 600 mg tablets.

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

ART-naïve paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken with 
food. The dose of cobicistat to be used with darunavir in children less than 18 years of age has not 
been established.

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The dose of cobicistat to be used with darunavir in children less than 18 years of age has not been 
established.

The recommended dose regimens are as follows:
- In ART-experienced patients without 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) a regimen of 800 
mg once daily with ritonavir 100 mg once daily taken with food may be used. Darunavir Krka 
d.d. 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.

- In all other ART-experienced patients or if HIV-1 genotype testing is not available, the 
recommended dose regimen is described in the Summary of Product Characteristics for 
Darunavir Krka d.d. 600 mg tablets.

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

Advice on missed doses



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If a once daily dose of darunavir and/or cobicistat or ritonavir is missed within 12 hours of the time it 
is usually taken, patients should be instructed to take the prescribed dose of darunavir and cobicistat or 
ritonavir with food as soon as possible. If this is noticed later than 12 hours after the time it is usually 
taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.

This guidance is based on the half-life of darunavir in the presence of cobicistat or ritonavir and the 
recommended dosing interval of approximately 24 hours.

Special populations

Elderly
Limited information is available in this population, and therefore, darunavir should be used with 
caution in this age group (see sections 4.4 and 5.2).

Hepatic impairment
Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with 
mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, darunavir 
should be used with caution in these patients. No pharmacokinetic data are available in patients with 
severe hepatic impairment. Severe hepatic impairment could result in an increase of darunavir 
exposure and a worsening of its safety profile. Therefore, darunavir 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
No dose adjustment is required for darunavir/ritonavir in patients with renal impairment (see sections 
4.4 and 5.2). Cobicistat has not been studied in patients receiving dialysis, and, therefore, no 
recommendation can be made for the use of darunavir/cobicistat in these patients.
Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum 
creatinine and modest declines in creatinine clearance. Hence, the use of creatinine clearance as an 
estimate of renal elimination capacity may be misleading. Cobicistat as a pharmacokinetic enhancer of 
darunavir should, therefore, not be initiated in patients with creatine clearance less than 70 ml/min if 
any co-administered agent requires dose adjustment based on creatinine clearance: e.g. emtricitabine, 
lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate) or adefovir dipovoxil.
For information on cobicistat, consult the cobicistat Summary of Product Characteristics.

Paediatric population
Darunavir should not be used in paediatric patients below 3 years of age or less than 15 kg body 
weight (see sections 4.4 and 5.3).

ART-naïve paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken with 
food.

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)
In ART-experienced patients without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 
copies/ml and CD4+ cell count ≥ 100 cells x 106/l, a regimen of 800 mg once daily with ritonavir 100 
mg once daily taken with food may be used.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

For dosage recommendations in children, see the Summary of Product Characteristics for Darunavir 
Krka d.d. 600 mg tablets.

The dose of cobicistat to be used with darunavir has not been established in this patient population.

Pregnancy and postpartum
No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. 
Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential 
risk (see sections 4.4, 4.6 and 5.2).



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Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure 
(see sections 4.4 and 5.2). Therefore, therapy with darunavir/cobicistat should not be initiated during 
pregnancy, and women who become pregnant during therapy with darunavir/cobicistat 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

Patients should be instructed to take darunavir with cobicistat or low dose ritonavir within 30 minutes 
after completion of a meal. The type of food does not affect the exposure to darunavir (see sections 
4.4, 4.5 and 5.2).

4.3 Contraindications

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

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

Concomitant treatment with any of the following medicinal products given the expected decrease in 
plasma concentrations of darunavir, ritonavir and cobicistat and the potential for loss of therapeutic 
effect (see sections 4.4 and 4.5).

Applicable to darunavir boosted with either ritonavir or cobicistat: 
 The combination product lopinavir/ritonavir (see section 4.5).
 The strong CYP3A inducers rifampicin and herbal preparations containing St John’s wort 

(Hypericum perforatum). Co-administration is expected to reduce plasma concentrations of 
darunavir, ritonavir and cobicistat, which could lead to loss of therapeutic effect and possible 
development of resistance (see sections 4.4 and 4.5).

Applicable to darunavir boosted with cobicistat, not when boosted with ritonavir:
 Darunavir boosted with cobicistat is more sensitive for CYP3A induction than darunavir 

boosted with ritonavir. Concomitant use with strong CYP3A inducers is contraindicated, since 
these may reduce the exposure to cobicistat and darunavir leading to loss of therapeutic effect.
Strong CYP3A inducers include e.g. carbamazepine, phenobarbital and phenytoin (see sections 
4.4 and 4.5).

Darunavir boosted with either ritonavir or cobicistat inhibits the elimination of active substances that 
are highly dependent on CYP3A for clearance, which results in increased exposure to the co-
administered medicinal product. Therefore, concomitant treatment with such medicinal products for 
which elevated plasma concentrations are associated with serious and/or life-threatening events is 
contraindicated (applies to darunavir boosted with either ritonavir or cobicistat). These active 
substances include e.g.:
 alfuzosin 
 amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
 astemizole, terfenadine 
 colchicine when used in patients with renal and/or hepatic impairment (see section
 4.5)
 ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
 elbasvir/grazoprevir 
 cisapride 
 dapoxetine
 domperidone
 naloxegol
 lurasidone, pimozide, quetiapine, sertindole (see section 4.5)
 triazolam, midazolam administered orally (for caution on parenterally administered midazolam, 



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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 (see section 4.5).

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 must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic 
enhancer and in combination with other antiretroviral medicinal products (see section 5.2). The 
Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be 
consulted prior to initiation of therapy with darunavir.

Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect 
darunavir concentrations. It is not recommended to alter the dose of cobicistat or ritonavir.

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 – once daily dosing

Darunavir used in combination with cobicistat or low dose ritonavir once daily in ART-experienced 
patients 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 section 
4.2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIs have not been 
studied in this population. Limited data are available in patients with HIV-1 clades other than B (see 
section 5.1).

Paediatric population

Darunavir is not recommended for use in paediatric patients below 3 years of age or less than 15 kg 
body weight (see sections 4.2 and 5.3).

Pregnancy
Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential
risk.
Caution should be used in pregnant women with concomitant medications which may further decrease 
darunavir exposure (see sections 4.5 and 5.2).

Treatment with darunavir/cobicistat 800/150 mg once daily 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 darunavir/cobicistat should not be 
initiated during pregnancy, and women who become pregnant during therapy with darunavir/cobicistat 
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



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As limited information is available on the use of darunavir in patients aged 65 and over, caution 
should be exercised in the administration of darunavir in elderly patients, 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. Darunavir 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 by 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 (see section 4.8).

Darunavir contains a sulphonamide moiety. Darunavir 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. 
During the darunavir/ritonavir 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 darunavir used in 
combination with cobicistat or low dose ritonavir 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 darunavir used in combination with cobicistat or low dose ritonavir 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 darunavir used in combination with cobicistat or low dose 
ritonavir, interruption or discontinuation of treatment should be considered promptly.

Patients with coexisting conditions

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

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



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not been studied in patients receiving dialysis, therefore, no recommendation can be made for the use 
of darunavir/cobicistat in these patients (see section 4.2).

Cobicistat decreases the estimated creatinine clearance due to inhibition of tubular secretion of 
creatinine. This should be taken into consideration if darunavir with cobicistat is administered to 
patients in whom the estimated creatinine clearance is used to adjust doses of co-administered 
medicinal products (see section 4.2 and cobicistat SmPC).

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 PIs. In some patients additional 
factor VIII was given. In more than half of the reported cases, treatment with 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.

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 
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 studies 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
Several of the interaction studies have been performed with darunavir at lower than recommended 
doses. The effects on co-administered medicinal products may thus be underestimated and clinical 
monitoring of safety may be indicated. For full information on interactions with other medicinal 
products see section 4.5.



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Pharmacokinetic enhancer and concomitant medications
Darunavir has different interaction profiles depending on whether the compound is boosted with 
ritonavir or cobicistat:
 Darunavir boosted with cobicistat is more sensitive for CYP3A induction: concomitant use of

darunavir/cobicistat and strong CYP3A inducers is therefore contraindicated (see section 
4.3),and concomitant use with weak to moderate CYP3A inducers is not recommended (see 
section 4.5). Concomitant use of darunavir/ritonavir and darunavir/cobicistat with 
lopinavir/ritonavir, rifampicin and herbal products containing St John’s wort, Hypericum 
perforatum, is contraindicated (see section 4.5).

 Unlike ritonavir, cobicistat does not have inducing effects on enzymes or transport proteins (see
section 4.5). If switching the pharmacoenhancer from ritonavir to cobicistat, caution is required
during the first two weeks of treatment with darunavir/cobicistat, particularly if doses of any
concomitantly administered medicinal products have been titrated or adjusted during use of
ritonavir as a pharmacoenhancer. A dose reduction of the co-administered drug may be needed
in these cases.

Efavirenz in combination with darunavir may result in sub-optimal darunavir Cmin. If efavirenz is to be 
used in combination with darunavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be 
used. See the Summary of Product Characteristics for Darunavir Krka d.d. 600 mg tablets (see section 
4.5).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and 
strong inhibitors of CYP3A and P-glycoprotein (P-gp; see sections 4.3 and 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

The interaction profile of darunavir may differ depending on whether ritonavir or cobicistat is used as 
pharmacoenhancer. The recommendations given for concomitant use of darunavir and other medicinal 
products may therefore differ depending on whether darunavir is boosted with ritonavir or cobicistat 
(see sections 4.3 and 4.4), and caution is also required during the first time of treatment if switching 
the pharmacoenhancer from ritonavir to cobicistat (see section 4.4).

Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer)

Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity 
would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma 
concentrations of these compounds and consequently that of darunavir, leading to loss of therapeutic 
effect and possible development of resistance (see sections 4.3 and 4.4). CYP3A inducers that are 
contraindicated include rifampicin, St John’s wort and lopinavir.

Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may 
decrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrations 
of darunavir and ritonavir. Co-administration with strong CYP3A4 inhibitors is not recommended and 
caution is warranted, these interactions are described in the interaction table below (e.g. indinavir, 
azole antifungals like clotrimazole).

Medicinal products that affect darunavir exposure (cobicistat as pharmacoenhancer)

Darunavir and cobicistat are metabolised by CYP3A, and co-administration with CYP3A inducers 
may therefore result in subtherapeutic plasma exposure to darunavir. Darunavir boosted with 
cobicistat is more sensitive to CYP3A induction than ritonavir-boosted darunavir: co-administration of 
darunavir/cobicistat with medicinal products that are strong inducers of CYP3A (e.g. St John’s wort, 
rifampicin, carbamazepine, phenobarbital, and phenytoin) is contraindicated (see section 4.3). Co-
administration of darunavir/cobicistat with weak to moderate CYP3A inducers (e.g. efavirenz, 
etravirine, nevirapine, boceprevir, fluticasone, and bosentan) is not recommended (see interaction 
table below).



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For co-administration with strong CYP3A4 inhibitors, the same recommendations apply independent 
of whether darunavir is boosted with ritonavir or with cobicistat (see section above).

Medicinal products that may be affected by darunavir boosted with ritonavir

Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of 
darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or 
transported by P-gp may result in increased systemic exposure to such medicinal products, which 
could increase or prolong their therapeutic effect and adverse reactions.

Darunavir co-administered with low dose ritonavir must 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).

The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in 
the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in 
combination with ritonavir at 100 mg twice daily. Therefore, darunavir must only be used in 
combination with a pharmacokinetic enhancer (see sections 4.4 and 5.2).

A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes 
CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and 
inhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to the 
presence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal products 
which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result 
in increased plasma concentrations of these medicinal products, which could increase or prolong their 
therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir and medicinal 
products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) 
may result in decreased systemic exposure to such medicinal products, which could decrease or 
shorten their therapeutic effect.

Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir and 
ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone, 
repaglinide) may result in decreased systemic exposure to such medicinal products, which could 
decrease or shorten their therapeutic effect.

Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration 
with substrates of these transporters can result in increased plasma concentrations of these compounds 
(e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).

Medicinal products that may be affected by darunavir boosted with cobicistat

The recommendations for darunavir boosted with ritonavir are adequate also for darunavir boosted 
with cobicistat with regard to substrates of CYP3A4, CYP2D6, P-glycoprotein, OATP1B1 and 
OATP1B3 (see contraindications and recommendations presented in the section above). Cobicistat 
150 mg given with darunavir 800 mg once daily enhances darunavir pharmacokinetic parameters in a 
comparable way to ritonavir (see section 5.2).

Unlike ritonavir, cobicistat does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or 
UGT1A1. For further information on cobicistat, consult the cobicistat Summary of Product 
Characteristics.

Interaction table

Interaction studies have only been performed in adults.

Several of the interaction studies (indicated by # in the table below) have been performed at lower than 
recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). The 



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effects on co-administered medicinal products may thus be underestimated and clinical monitoring o 
safety may be indicated.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as 
pharmacokinetic enhancer. Darunavir may therefore have different recommendations for concomitant 
medications depending on whether the compound is boosted with ritonavir or cobicistat. No 
interaction studies presented in the table have been performed with darunavir boosted with cobicistat. 
The same recommendations apply, unless specifically indicated. For further information on cobicistat, 
consult the cobicistat Summary of Product Characteristics.

Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products 
are listed in the table below. The direction of the arrow for each pharmacokinetic parameter is based 
on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) 
the 80-125% range (not determined as “ND”).

In the table below the specific pharmacokinetic enhancer is specified when recommendations differ. 
When the recommendation is the same for darunavir when co-administered with a low dose ritonavir 
or cobicistat, the term “boosted darunavir” is used.

The below list of examples of drug drug interactions is not comprehensive and therefore the label of 
each drug that is co-administered with darunavir 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 
Geometric mean change (%) 

Recommendations concerning co-
administration 

HIV ANTIRETROVIRALS 

Integrase strand transfer inhibitors

Dolutegravir dolutegravir AUC ↓ 22%
dolutegravir C24h ↓38%
dolutegravir Cmax ↓ 11%
darunavir ↔*
* Using cross-study comparisons to 
historical pharmacokinetic data

Boosted darunavir and dolutegravir 
can be used without dose adjustment.

Raltegravir Some clinical studies 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. 
Boosted darunavir and raltegravir can 
be used without dose adjustments.

Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)

Didanosine
400 mg once daily

didanosine AUC ↓ 9%
didanosine Cmin ND
didanosine Cmax ↓ 16%
darunavir AUC ↔
darunavir Cmin ↔
darunavir Cmax ↔

Boosted darunavir and didanosine 
can be used without dose 
adjustments.
Didanosine is to be administered on 
an empty stomach, thus it should be 
administered 1 hour before or 2 hours 
after boosted darunavir given with 
food.

Tenofovir disoproxil
245 mg once daily

tenofovir AUC ↑ 22%
tenofovir Cmin ↑ 37%
tenofovir Cmax ↑ 24%
#darunavir AUC ↑ 21%
#darunavir Cmin ↑ 24%
#darunavir Cmax ↑ 16%
(↑ tenofovir from effect on MDR-1 
transport in the renal tubules)

Monitoring of renal function may be 
indicated when boosted darunavir is 
given in combination with tenofovir
disoproxil, particularly in patients 
with underlying systemic or renal 
disease, or in patients taking 
nephrotoxic agents.
Darunavir co-administered with 



12

cobicistat lowers the creatinine 
clearance. Refer to section 4.4 if 
creatinine clearance is used for dose 
adjustment of tenofovir disoproxil.

Emtricitabine/tenofovir 
alafenamide 

Tenofovir alafenamide ↔
Tenofovir ↑

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

Abacavir
Emtricitabine
Lamivudine
Stavudine
Zidovudine

Not studied. Based on the different 
elimination pathways of the other NRTIs 
zidovudine, emtricitabine, stavudine, 
lamivudine, that are primarily renally 
excreted, and abacavir for which 
metabolism is not mediated by CYP450, no 
interactions are expected for these 
medicinal compounds and boosted 
darunavir.

Boosted darunavir can be used with 
these NRTIs without dose 
adjustment.
Darunavir co-administered with 
cobicistat lowers the creatinine 
clearance. Refer to section 4.4 if 
creatinine clearance is used for dose 
adjustment of emtricitabine or 
lamivudine.

Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs) 

Efavirenz
600 mg once daily

efavirenz AUC ↑ 21%
efavirenz Cmin ↑ 17%
efavirenz Cmax ↑ 15%
#darunavir AUC ↓ 13%
#darunavir Cmin ↓ 31%
#darunavir Cmax ↓ 15%
(↑ efavirenz from CYP3A inhibition)
(↓ darunavir from CYP3A induction)

Clinical monitoring for central 
nervous system toxicity associated 
with increased exposure to efavirenz 
may be indicated when darunavir co-
administered with low dose ritonavir 
is given in combination with 
efavirenz.
Efavirenz in combination with 
darunavir /ritonavir 800/100 mg once 
daily may result in sub-optimal 
darunavir Cmin. If efavirenz is to be 
used in combination with darunavir 
/ritonavir, the darunavir/ritonavir 
600/100 mg twice daily regimen 
should be used (see section 4.4).
Co-administration with darunavir co-
administered with cobicistat is not 
recommended (see section 4.4).

Etravirine
100 mg twice daily

etravirine AUC ↓ 37%
etravirine Cmin ↓ 49%
etravirine Cmax ↓ 32%
darunavir AUC ↑ 15%
darunavir Cmin ↔
darunavir Cmax ↔

Darunavir co-administered with low 
dose ritonavir and etravirine 200 mg 
twice daily can be used without dose 
adjustments.
Co-administration with darunavir co-
administered with cobicistat is not 
recommended (see section 4.4).

Nevirapine
200 mg twice daily

nevirapine AUC ↑ 27%
nevirapine Cmin ↑ 47%
nevirapine Cmax ↑ 18%
#darunavir: concentrations were consistent 
with historical data
(↑ nevirapine from CYP3A inhibition)

Darunavir co-administered with low 
dose ritonavir and nevirapine can be 
used without dose adjustments.
Co-administration with darunavir co-
administered with cobicistat is not 
recommended (see section 4.4).

Rilpivirine
150 mg once daily

rilpivirine AUC ↑ 130%
rilpivirine Cmin ↑ 178%
rilpivirine Cmax ↑ 79%
darunavir AUC ↔
darunavir Cmin ↓ 11%
darunavir Cmax ↔

Boosted darunavir and rilpivirine can 
be used without dose adjustments.

HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir† 

Atazanavir
300 mg once daily

atazanavir AUC ↔
atazanavir Cmin ↑ 52%
atazanavir Cmax ↓ 11%
#darunavir AUC ↔

Darunavir co-administered with low 
dose ritonavir and atazanavir can be 
used without dose adjustments.
Darunavir co-administered with 



13

#darunavir Cmin ↔
#darunavir Cmax ↔
Atazanavir: comparison of 
atazanavir/ritonavir 300/100 mg once daily 
vs. atazanavir 300 mg once daily in 
combination with darunavir/ritonavir 
400/100 mg twice daily.
Darunavir: comparison of 
darunavir/ritonavir 400/100 mg twice daily 
vs. darunavir/ritonavir 400/100 mg twice 
daily in combination with atazanavir 300 
mg once daily.

cobicistat should not be used in 
combination with another 
antiretroviral agent that requires 
pharmacoenhancement by means of 
co-administration with an inhibitor of 
CYP3A4 (see section 4.5).

Indinavir
800 mg twice daily

indinavir AUC ↑ 23%
indinavir Cmin ↑ 125%
indinavir Cmax ↔
#darunavir AUC ↑ 24%
#darunavir Cmin ↑ 44%
#darunavir Cmax ↑ 11%
Indinavir: comparison of 
indinavir/ritonavir 800/100 mg twice daily 
vs. indinavir/darunavir/ritonavir 
800/400/100 mg twice daily.
Darunavir: comparison of 
darunavir/ritonavir 400/100 mg twice daily 
vs. darunavir/ritonavir 400/100 mg in 
combination with indinavir 800 mg twice 
daily.

When used in combination with 
darunavir co-administered with low 
dose ritonavir, dose adjustment of 
indinavir from 800 mg twice daily to 
600 mg twice daily may be warranted 
in case of intolerance.
Darunavir co-administered with 
cobicistat should not be used in 
combination with another 
antiretroviral agent that requires 
pharmacoenhancement by means of 
co-administration with an inhibitor of 
CYP3A4 (see section 4.5).

Saquinavir
1,000 mg twice daily

#darunavir AUC ↓ 26%
#darunavir Cmin ↓ 42%
#darunavir Cmax ↓ 17%
saquinavir AUC ↓ 6%
saquinavir Cmin ↓ 18%
saquinavir Cmax ↓ 6%
Saquinavir: comparison of 
saquinavir/ritonavir 1,000/100 mg twice 
daily vs. saquinavir/darunavir/ritonavir 
1,000/400/100 mg twice daily
Darunavir: comparison of 
darunavir/ritonavir 400/100 mg twice daily 
vs. darunavir/ritonavir 400/100 mg in 
combination with saquinavir 1,000 mg 
twice daily.

It is not recommended to combine 
darunavir co-administered with low 
dose ritonavir with saquinavir.
Darunavir co-administered with 
cobicistat should not be used in 
combination with another 
antiretroviral agent that requires 
pharmacoenhancement by means of 
co-administration with an inhibitor of 
CYP3A4 (see section 4.5).

HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavir† 

Lopinavir/ritonavir
400/100 mg twice daily

Lopinavir/ritonavir
533/133.3 mg twice daily

lopinavir AUC ↑ 9%
lopinavir Cmin ↑ 23%
lopinavir Cmax ↓ 2%
darunavir AUC ↓ 38%‡

darunavir Cmin ↓ 51%‡

darunavir Cmax ↓ 21%‡

lopinavir AUC ↔
lopinavir Cmin ↑ 13%
lopinavir Cmax ↑ 11%
darunavir AUC ↓ 41%
darunavir Cmin ↓ 55%
darunavir Cmax ↓ 21%
‡ based upon non dose normalised values

Due to a decrease in the exposure 
(AUC) of darunavir by 40%, 
appropriate doses of the combination 
have not been established. Hence, 
concomitant use of boosted darunavir 
and the combination product 
lopinavir/ritonavir is contraindicated 
(see section 4.3).

CCR5 ANTAGONIST 

Maraviroc
150 mg twice daily

maraviroc AUC ↑ 305%
maraviroc Cmin ND
maraviroc Cmax ↑ 129%
darunavir, ritonavir concentrations were 

The maraviroc dose should be 150 
mg twice daily when co-administered 
with boosted darunavir.



14

consistent with historical data

α1-ADRENORECEPTOR ANTAGONIST

Alfuzosin Based on theoretical considerations 
darunavir is expected to increase alfuzosin 
plasma concentrations.
(CYP3A inhibition)

Co-administration of boosted 
darunavir and alfuzosin is 
contraindicated (see section 4.3).

ANAESTHETIC 

Alfentanil Not studied. The metabolism of alfentanil 
is mediated via CYP3A, and may as such 
be inhibited by boosted darunavir.

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

ANTIANGINA/ANTIARRHYTHMIC 

Disopyramide
Flecainide
Lidocaine (systemic)
Mexiletine
Propafenone

Amiodarone
Bepridil
Dronedarone
Ivabradine
Quinidine
Ranolazine

Not studied. Boosted darunavir 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 boosted darunavir.

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

Digoxin
0.4 mg single dose

digoxin AUC ↑ 61%
digoxin Cmin ND
digoxin Cmax ↑ 29%
(↑ digoxin from probable inhibition of P-
gp)

Given that digoxin has a narrow 
therapeutic index, it is recommended 
that the lowest possible dose of 
digoxin should initially be prescribed 
in case digoxin is given to patients on 
boosted darunavir therapy. The 
digoxin dose should be carefully 
titrated to obtain the desired clinical 
effect while assessing the overall 
clinical state of the subject.

ANTIBIOTIC 

Clarithromycin
500 mg twice daily

clarithromycin AUC ↑ 57%
clarithromycin Cmin ↑ 174%
clarithromycin Cmax ↑ 26%
#darunavir AUC ↓ 13%
#darunavir Cmin ↑ 1%
#darunavir Cmax ↓ 17%
14-OH-clarithromycin concentrations were 
not detectable when combined with 
darunavir/ritonavir.
(↑ clarithromycin from CYP3A inhibition 
and possible P-gp inhibition)

Caution should be exercised when 
clarithromycin is combined with 
boosted darunavir.
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

Not studied. Co-administration of boosted 
darunavir with these anticoagulants may 
increase concentrations of the 
anticoagulant, which may lead to an 
increased bleeding risk.
(CYP3A and/or P-gp inhibition)

The use of boosted darunavir and 
these anticoagulants is not 
recommended.

Dabigatran
Ticagrelor

Not studied. Co-administration with 
boosted darunavir may lead to a substantial 
increase in exposure to dabigatran or 
ticagrelor.

Concomitant administration of 

boosted darunavir with dabigatran or 

ticagrelor is contraindicated (see 

I I



15

section 4.3).

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

Warfarin Not studied. Warfarin concentrations may 
be affected when co-administered with 
boosted darunavir.

It is recommended that the 
international normalised ratio (INR) 
be monitored when warfarin is 
combined with boosted darunavir.

ANTICONVULSANTS 

Phenobarbital
Phenytoin

Not studied. Phenobarbital and phenytoin 
are expected to decrease plasma 
concentrations of darunavir and its 
pharmacoenhancer.
(induction of CYP450 enzymes)

Darunavir co-administered with low 
dose ritonavir should not be used in 
combination with these medicines.
The use of these medicines with 
darunavir/cobicistat is 
contraindicated (see section 4.3).

Carbamazepine
200 mg twice daily

carbamazepine AUC ↑ 45%
carbamazepine Cmin ↑ 54%
carbamazepine Cmax ↑ 43%
darunavir AUC ↔
darunavir Cmin ↓ 15%
darunavir Cmax ↔

No dose adjustment for darunavir 
/ritonavir is recommended. If there is 
a need to combine darunavir/ritonavir 
and carbamazepine, patients should 
be monitored for potential 
carbamazepine-related adverse 
events. Carbamazepine 
concentrations should be monitored 
and its dose should be titrated for 
adequate response. Based upon the 
findings, the carbamazepine dose 
may need to be reduced by 25% to 
50% in the presence of 
darunavir/ritonavir.
The use of carbamazepine with 
darunavir co-administered with 
cobicistat is contraindicated (see 
section 4.3).

Clonazepam Not studied. Co-administration of boosted 
darunavir with clonazepam may increase 
concentrations of clonazepam. (CYP3A 
inhibition)

Clinical monitoring is recommended 
when co-administering boosted 
darunavir and clonazepam.

ANTIDEPRESSANTS 

Paroxetine
20 mg once daily

Sertraline
50 mg once daily

Amitriptyline
Desipramine
Imipramine
Nortriptyline

paroxetine AUC ↓ 39%
paroxetine Cmin ↓ 37%
paroxetine Cmax ↓ 36%
#darunavir AUC ↔
#darunavir Cmin ↔
#darunavir Cmax ↔
sertraline AUC ↓ 49%
sertraline Cmin ↓ 49%
sertraline Cmax ↓ 44%
#darunavir AUC ↔
#darunavir Cmin ↓ 6%
#darunavir Cmax ↔

In contrast to these data with darunavir 
/ritonavir, darunavir/cobicistat may 
increase these antidepressant plasma 
concentrations (CYP2D6 and/or CYP3A 
inhibition).

Concomitant use of boosted darunavir and 
these antidepressants may increase 

If antidepressants are co-administered 
with boosted darunavir, the 
recommended approach is a dose 
titration of the antidepressant based 
on a clinical assessment of 
antidepressant response. In addition, 
patients on a stable dose of these 
antidepressants who start treatment 
with boosted darunavir should be 
monitored for antidepressant 
response.

Clinical monitoring is recommended 
when co-administering boosted 
darunavir with these antidepressants 



16

Trazodone concentrations of the antidepressant.
(CYP2D6 and/or CYP3A inhibition)

and a dose adjustment of the 
antidepressant may be needed.

ANTI-DIABETICS

Metformin Not studied. Based on theoretical 
considerations darunavir co-administered 
with cobicistat is expected to increase 
metformin plasma concentrations.
(MATE1 inhibition)

Careful patient monitoring and dose 
adjustment of metformin is 
recommended in patients who are 
taking darunavir co-administered 
with cobicistat.
(not applicable for darunavir co-
administered with ritonavir)

ANTIEMETICS

Domperidone Not studied. Co-administration of domperidone 
with boosted darunavir is 
contraindicated. 

ANTIFUNGALS 

Voriconazole Not studied. Ritonavir may decrease 
plasma concentrations of voriconazole.
(induction of CYP450 enzymes)
Concentrations of voriconazole may 
increase or decrease when co-administered 
with darunavir co-administered with 
cobicistat.
(inhibition of CYP450 enzymes)

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

Fluconazole
Isavuconazole
Itraconazole
Posaconazole

Clotrimazole

Not studied. Boosted darunavir may 
increase antifungal plasma concentrations 
and posaconazole, isavuconazole, 
itraconazole or fluconazole may increase 
darunavir concentrations.
(CYP3A and/or P-gp inhibition)

Not studied. Concomitant systemic use of 
clotrimazole and boosted darunavir may 
increase plasma concentrations of 
darunavir and/or clotrimazole.
darunavir AUC24h ↑ 33% (based on 
population pharmacokinetic model)

Caution is warranted and clinical 
monitoring is recommended.
When co-administration is required 
the daily dose of itraconazole should 
not exceed 200 mg.

ANTIGOUT MEDICINES

Colchicine Not studied. Concomitant use of colchicine 
and boosted darunavir may increase the 
exposure to colchicine.
(CYP3A and/ or P-gp 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 boosted darunavir is 
required. For patients with renal or 
hepatic impairment colchicine with 
boosted darunavir is contraindicated 
(see sections 4.3 and 4.4).

ANTIMALARIALS

Artemether/Lumefantrine
80/480 mg, 6 doses at 0, 8, 
24, 36, 48, and 60 hours

artemether AUC ↓ 16%
artemether Cmin ↔
artemether Cmax ↓ 18%
dihydroartemisinin AUC ↓ 18%
dihydroartemisinin Cmin ↔
dihydroartemisinin Cmax ↓ 18%
lumefantrine AUC ↑ 175%
lumefantrine Cmin ↑ 126%
lumefantrine Cmax ↑ 65%
darunavir AUC ↔
darunavir Cmin ↓ 13%

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



17

darunavir Cmax ↔

ANTIMYCOBACTERIALS 

Rifampicin
Rifapentine

Not studied. Rifapentine and rifampicin are 
strong CYP3A inducers and have been 
shown to cause profound decreases in 
concentrations of other protease inhibitors, 
which can result in virological failure and 
resistance development (CYP450 enzyme 
induction). During attempts to overcome 
the decreased exposure by increasing the 
dose of other protease inhibitors with low 
dose ritonavir, a high frequency of liver 
reactions was seen with rifampicin.

The combination of rifapentine and 
boosted darunavir is not 
recommended.
The combination of rifampicin and 
boosted darunavir is contraindicated 
(see section 4.3).

Rifabutin
150 mg once every other day

rifabutin AUC** ↑ 55%
rifabutin Cmin** ↑ ND
rifabutin Cmax** ↔
darunavir AUC ↑ 53%
darunavir Cmin ↑ 68%
darunavir Cmax ↑ 39%
** sum of active moieties of rifabutin 
(parent drug + 25-O-desacetyl metabolite)
The interaction trial showed a comparable 
daily systemic exposure for rifabutin 
between treatment at 300 mg once daily 
alone and 150 mg once every other day in 
combination with darunavir/ritonavir 
(600/100 mg twice daily) with an about 10-
fold increase in the daily exposure to the 
active metabolite 25-O-desacetylrifabutin. 
Furthermore, AUC of the sum of active 
moieties of rifabutin (parent drug + 25-O-
desacetyl metabolite) was increased 1.6-
fold, while Cmax remained comparable.
Data on comparison with a 150 mg once 
daily reference dose is lacking.
(Rifabutin is an inducer and substrate of 
CYP3A.) An increase of systemic exposure 
to darunavir was observed when darunavir 
co-administered with 100 mg ritonavir was 
co-administered with rifabutin (150 mg 
once every other day).

A dosage reduction of rifabutin by 
75% of the usual dose of 300 mg/day 
(i.e. rifabutin 150 mg once every 
other day) and increased monitoring 
for rifabutin related adverse events is 
warranted in patients receiving the 
combination with darunavir co-
administered with ritonavir. In case 
of safety issues, a further increase of 
the dosing interval for rifabutin 
and/or monitoring of rifabutin levels 
should be considered.
Consideration should be given to 
official guidance on the appropriate 
treatment of tuberculosis in HIV 
infected patients.
Based upon the safety profile of 
darunavir/ritonavir, the increase in 
darunavir exposure in the presence of 
rifabutin does not warrant a dose 
adjustment for darunavir/ritonavir.
Based on pharmacokinetic modeling, 
this dosage reduction of 75% is also 
applicable if patients receive rifabutin 
at doses other than 300 mg/day.
Co-administration of darunavir co-
administered with cobicistat and 
rifabutin is not recommended.

ANTINEOPLASTICS 

Dasatinib
Nilotinib
Vinblastine
Vincristine

Everolimus
Irinotecan

Not studied. Boosted darunavir is expected 
to increase these antineoplastic plasma 
concentrations.
(CYP3A inhibition)

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

Concominant use of everolimus or 
irinotecan and boosted darunavir is 
not recommended.

ANTIPSYCHOTICS/NEUROLEPTICS 

Quetiapine Not studied. Boosted darunavir is expected 
to increase these antipsychotic plasma 
concentrations.
(CYP3A inhibition)

Concomitant administration of 
boosted darunavir and quetiapine is 
contraindicated as it may increase 
quetiapine-related toxicity. Increased 

I I



18

concentrations of quetiapine may lead 
to coma (see section 4.3).

Perphenazine
Risperidone
Thioridazine

Lurasidone
Pimozide
Sertindole

Not studied. Boosted darunavir is expected 
to increase these antipsychotic plasma 
concentrations.
(CYP3A, CYP2D6 and/or P-gp inhibition)

A dose decrease may be needed for 
these drugs when co-administered 
with boosted darunavir.

Concominant administration of 
boosted darunavir and lurasidone, 
pimozide or sertindole is 
contraindicated (see section 4.3).

β-BLOCKERS 

Carvedilol
Metoprolol
Timolol

Not studied. Boosted darunavir is expected 
to increase these β-blocker plasma 
concentrations.
(CYP2D6 inhibition)

Clinical monitoring is recommended 
when co-administering boosted 
darunavir with β-blockers. A lower
dose of the β-blocker should be 
considered.

CALCIUM CHANNEL BLOCKERS 

Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil

Not studied. Boosted darunavir can be 
expected to increase the plasma 
concentrations of calcium channel 
blockers.
(CYP3A and/or CYP2D6 inhibition)

Clinical monitoring of therapeutic 
and adverse effects is recommended 
when these medicines are 
concomitantly administered with 
boosted darunavir.

CORTICOSTEROIDS 

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

Fluticasone: in a clinical study where 
ritonavir 100 mg capsules twice daily were 
co-administered with 50 μg intranasal 
fluticasone propionate (4 times daily) for 7 
days in healthy subjects, fluticasone 
propionate plasma concentrations increased 
significantly, whereas the intrinsic cortisol 
levels decreased by approximately 86% 
(90% CI 82-89%). Greater effects may be 
expected when fluticasone is inhaled. 
Systemic corticosteroid effects including 
Cushing's syndrome and adrenal 
suppression have been reported in patients 
receiving ritonavir and inhaled or 
intranasally administered fluticasone. The 
effects of high fluticasone systemic 
exposure on ritonavir plasma levels are 
unknown.
Other corticosteroids: interaction not 
studied. Plasma concentrations of these 
medicinal products may be increased when 
co-administered with boosted darunavir, 
resulting in reduced serum cortisol 
concentrations.

Concomitant use of boosted 
darunavir 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) Not studied. Dexamethasone may decrease 
plasma concentrations of darunavir.
(CYP3A induction)

Systemic dexamethasone should be 
used with caution when combined 
with boosted darunavir.

ENDOTHELIN RECEPTOR ANTAGONISTS 

Bosentan Not studied. Concomitant use of bosentan 
and boosted darunavir may increase plasma 
concentrations of bosentan.
Bosentan is expected to decrease plasma 
concentrations of darunavir and/or its 
pharmacoenhancer.
(CYP3A induction)

When administered concomitantly 
with darunavir and low dose 
ritonavir, the patient's tolerability of 
bosentan should be monitored.
Co administration of darunavir co-
administered with cobicistat and 
bosentan is not recommended.



19

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS 

NS3-4A protease inhibitors

Elbasvir/grazoprevir Boosted darunavir may increase the 
exposure to grazoprevir.
(CYP3A and OATP1B inhibition)

Concomitant use of boosted 
darunavir and elbasvir/grazoprevir is 
contraindicated (see section 4.3).

Boceprevir
800 mg three times daily

boceprevir AUC ↓ 32%
boceprevir Cmin ↓ 35%
boceprevir Cmax ↓ 25%
darunavir AUC ↓ 44%
darunavir Cmin ↓ 59%
darunavir Cmax ↓ 36%

It is not recommended to co-
administer boosted darunavir and 
boceprevir.

Glecaprevir/pibrentasvir Based on theoretical considerations 

boosted darunavir may increase the 

exposure to glecaprevir and pibrentasvir.
(P-gp, BCRP and/or OATP1B1/3 
inhibition)

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

Simeprevir simeprevir AUC ↑ 159%
simeprevir Cmin ↑ 358%
simeprevir Cmax ↑ 79%
darunavir AUC ↑ 18%
darunavir Cmin ↑ 31%
darunavir Cmax ↔
The dose of simeprevir in this interaction 
study was 50 mg when co-administered in 
combination with darunavir/ritonavir, 
compared to 150 mg in the simeprevir 
alone treatment group.

It is not recommended to co-
administer boosted darunavir and 
simeprevir.

HERBAL PRODUCTS 

St John's wort (Hypericum 
perforatum)

Not studied. St John's wort is expected to 
decrease the plasma concentrations of 
darunavir or its pharmacoenhancers.
(CYP450 induction)

Boosted darunavir must not be used 
concomitantly with products 
containing St John's wort (Hypericum 
perforatum) (see section 4.3). If a 
patient is already taking St John's 
wort, stop St John's wort and if 
possible check viral levels. Darunavir 
exposure (and also ritonavir 
exposure) may increase on stopping 
St John's wort. The inducing effect 
may persist for at least 2 weeks after 
cessation of treatment with St John's 
wort.

HMG CO-A REDUCTASE INHIBITORS 

Lovastatin
Simvastatin

Not studied. Lovastatin and simvastatin are 
expected to have markedly increased 
plasma concentrations when co-
administered with boosted darunavir.
(CYP3A inhibition)

Increased plasma concentrations of 
lovastatin or simvastatin may cause 
myopathy, including rhabdomyolysis. 
Concomitant use of boosted 
darunavir with lovastatin and 
simvastatin is therefore 
contraindicated (see section 4.3).

Atorvastatin
10 mg once daily

atorvastatin AUC ↑ 3-4 fold
atorvastatin Cmin ↑ ≈5.5-10 fold
atorvastatin Cmax ↑ ≈2 fold
#darunavir/ritonavir

atorvastatin AUC ↑ 290% Ω

atorvastatin Cmax ↑ 319% Ω

atorvastatin Cmin ND Ω
Ω with darunavir/cobicistat 800/150 mg

When administration of atorvastatin 
and boosted darunavir is desired, it is 
recommended to start with an 
atorvastatin dose of 10 mg once 
daily. A gradual dose increase of 
atorvastatin may be tailored to the 
clinical response.



20

Pravastatin
40 mg single dose

pravastatin AUC ↑ 81%¶

pravastatin Cmin ND
pravastatin Cmax ↑ 63%
¶ an up to five-fold increase was seen in a 
limited subset of subjects

When administration of pravastatin 
and boosted darunavir is required, it 
is recommended to start with the 
lowest possible dose of pravastatin 
and titrate up to the desired clinical 
effect while monitoring for safety.

Rosuvastatin
10 mg once daily

rosuvastatin AUC ↑ 48%║

rosuvastatin Cmax ↑ 144%║
║ based on published data with darunavir/ritonavir

rosuvastatin AUC ↑ 93%§

rosuvastatin Cmax ↑ 277%§

rosuvastatin Cmin ND§
§ with darunavir/cobicistat 800/150 mg

When administration of rosuvastatin 
and boosted darunavir is required, it 
is recommended to start with the 
lowest possible dose of rosuvastatin 
and titrate up to the desired clinical 
effect while monitoring for safety.

OTHER LIPID MODIFYING AGENTS

Lomitapide Based on theoretical considerations 
boosted darunavir is expected to increase 
the exposure of lomitapide when co-
administered. 
(CYP3A inhibition)

Co-administration is contraindicated 
(see section 4.3)

H2-RECEPTOR ANTAGONISTS 

Ranitidine
150 mg twice daily

#darunavir AUC ↔
#darunavir Cmin ↔
#darunavir Cmax ↔

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

IMMUNOSUPPRESSANTS 

Ciclosporin
Sirolimus
Tacrolimus

Everolimus

Not studied. Exposure to these 
immunosuppressants will be increased 
when co-administered with boosted 
darunavir.
(CYP3A inhibition)

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

Concomitant use of everolimus and 
boosted darunavir is not 
recommended.

INHALED BETA AGONISTS 

Salmeterol Not studied. Concomitant use of salmeterol 
and boosted darunavir may increase plasma 
concentrations of salmeterol.

Concomitant use of salmeterol and 
boosted darunavir 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 

Methadone
individual dose ranging from 
55 mg to 150 mg once daily

R(-) methadone AUC ↓ 16%
R(-) methadone Cmin ↓ 15%
R(-) methadone Cmax ↓ 24%
darunavir /cobicistat may, in contrast, 
increase methadone plasma concentrations 
(see cobicistat SmPC).

No adjustment of methadone dosage 
is required when initiating co-
administration with boosted 
darunavir. However, adjustment of 
the methadone dose may be 
necessary when concomitantly 
administered for a longer period of 
time. Therefore, clinical monitoring 
is recommended, as maintenance 
therapy may need to be adjusted in 
some patients.

Buprenorphine/naloxone
8/2 mg–16/4 mg once daily

buprenorphine AUC ↓ 11%
buprenorphine Cmin ↔
buprenorphine Cmax ↓ 8%
norbuprenorphine AUC ↑ 46%
norbuprenorphine Cmin ↑ 71%

The clinical relevance of the increase 
in norbuprenorphine pharmacokinetic 
parameters has not been established. 
Dose adjustment for buprenorphine 
may not be necessary when co-



21

norbuprenorphine Cmax ↑ 36%
naloxone AUC ↔
naloxone Cmin ND
naloxone Cmax ↔

administered with boosted darunavir 
but a careful clinical monitoring for 
signs of opiate toxicity is 
recommended.

Fentanyl
Oxycodone
Tramadol

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

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

OESTROGEN-BASED CONTRACEPTIVES 

Drospirenone 
Ethinylestradiol 
(3 mg/0.02 mg once daily)

Ethinylestradiol
Norethindrone
35 μg/1 mg once daily

drospirenone AUC ↑ 58%€

drospirenone Cmin ND€

drospirenone Cmax ↑ 15%€

ethinylestradiol AUC  30%€

ethinylestradiol Cmin ND€

ethinylestradiol Cmax  14%€
€ with darunavir/cobicistat

ethinylestradiol AUC ↓ 44% β

ethinylestradiol Cmin ↓ 62% β

ethinylestradiol Cmax ↓ 32% β

norethindrone AUC ↓ 14% β

norethindrone Cmin ↓ 30% β

norethindrone Cmax ↔ β
β with darunavir/ritonavir

When darunavir is coadministered 
with a drospirenone-containing 
product, clinical monitoring is 
recommended due to the potential for 
hyperkalaemia. 

Alternative or additional 
contraceptive measures are 
recommended when oestrogen-based 
contraceptives are co-administered 
with boosted darunavir. Patients 
using oestrogens as hormone 
replacement therapy should be 
clinically monitored for signs of 
oestrogen deficiency.

OPIOID ANTAGONIST

Naloxegol Not studied. Co-administration of boosted 
darunavir and naloxegol is 
contraindicated. 

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS 

For the treatment of erectile 
dysfunction
Avanafil
Sildenafil
Tadalafil
Vardenafil

In an interaction study #, a comparable 
systemic exposure to sildenafil was 
observed for a single intake of 100 mg 
sildenafil alone and a single intake of 25 
mg sildenafil co-administered with 
darunavir and low dose ritonavir.

The combination of avanafil and 
boosted darunavir is contraindicated 
(see section 4.3).
Concomitant use of other PDE-5 
inhibitors for the treatment of erectile 
dysfunction with boosted darunavir 
should be done with caution. If 
concomitant use of boosted darunavir 
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.

For the treatment of 
pulmonary arterial 
hypertension
Sildenafil
Tadalafil

Not studied. Concomitant use of sildenafil 
or tadalafil for the treatment of pulmonary 
arterial hypertension and boosted darunavir 
may increase plasma concentrations of 
sildenafil or tadalafil.
(CYP3A inhibition)

A safe and effective dose of sildenafil 
for the treatment of pulmonary 
arterial hypertension co-administered 
with boosted darunavir 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 boosted darunavir 
and sildenafil when used for the 
treatment of pulmonary arterial 
hypertension is contraindicated (see 
section 4.3).



22

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

PROTON PUMP INHIBITORS 

Omeprazole
20 mg once daily

#darunavir AUC ↔
#darunavir Cmin ↔
#darunavir Cmax ↔

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

SEDATIVES/HYPNOTICS 

Buspirone
Clorazepate
Diazepam
Estazolam
Flurazepam
Midazolam (parenteral)
Zoldipem

Midazolam (oral)
Triazolam

Not studied. Sedative/hypnotics are 
extensively metabolised by CYP3A. Co-
administration with boosted darunavir may 
cause a large increase in the concentration 
of these medicines.

If parenteral midazolam is co-administered 
with boosted darunavir it may cause a large 
increase in the concentration of this 
benzodiazepine. Data from concomitant 
use of parenteral midazolam with other 
protease inhibitors suggest a possible 3-4 
fold increase in midazolam plasma levels.

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

If parenteral midazolam is co-
administered with boosted darunavir, 
it should be done in an intensive care 
unit (ICU) 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.

Boosted darunavir with triazolam or 
oral midazolam is contraindicated 
(see section 4.3)

TREATMENT FOR PREMATURE EJACULATION

Dapoxetine Not studied. Co-administration of boosted 
darunavir 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.

#
Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2
Posology).

† The efficacy and safety of the use of darunavir with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavir, nelfinavir and 
tipranavir) has not been established in HIV patients. According to current treatment guidelines, dual therapy with protease inhibitors is 
generally not recommended.

‡ Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.

4.6 Fertility, pregnancy and lactation

Pregnancy

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

There are no adequate and well controlled studies on pregnancy outcome with darunavir 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).



23

Darunavir co-administered or low dose ritonavir should be used during pregnancy only if the potential 
benefit justifies the potential risk.

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 darunavir/cobicistat should not be initiated during 
pregnancy, and women who become pregnant during therapy with darunavir/cobicistat should be 
switched to an alternative regimen (see sections 4.2 and 4.4).

Breast-feeding

It is not known whether darunavir is 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. 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 Darunavir Krka 
d.d..

Fertility

No human data on the effect of darunavir on fertility are available. There was no effect on mating or 
fertility with darunavir treatment in rats (see section 5.3).

4.7 Effects on ability to drive and use machines

Darunavir in combination with cobicistat or ritonavir has no or negligible influence on the ability to 
drive and use machines. However, dizziness has been reported in some patients during treatment with 
regimens containing darunavir co-administered with cobicistat or low dose ritonavir and should be 
borne in mind when considering a patient's ability to drive or operate machinery (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

During the clinical development program (N=2,613 treatment-experienced subjects who initiated 
therapy with darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one
adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent 
adverse reactions reported in clinical trials 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. No new safety findings were identified in the 192 
week analysis of the treatment-naïve subjects in which the mean treatment duration of 
darunavir/ritonavir 800/100 mg once daily was 162.5 weeks.

During the Phase III clinical trial GS-US-216-130 with darunavir/cobicistat (N=313 treatment-naïve 
and treatment-experienced subjects), 66.5% of subjects experienced at least one adverse reaction. The 
mean treatment duration was 58.4 weeks. The most frequent adverse reactions reported were diarrhoea 
(28%), nausea (23%), and rash (16%). Serious adverse reactions are diabetes mellitus, (drug) 
hypersensitivity, immune reconstitution inflammatory syndrome, rash and vomiting.

For information on cobicistat, consult the cobicistat Summary of Product Characteristics.



24

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).

Adverse reactions observed with darunavir/ritonavir in clinical trials and post-marketing

MedDRA system organ class
Frequency category

Adverse reaction

Infections and infestations

uncommon herpes simplex

Blood and lymphatic system disorders

uncommon thrombocytopenia, neutropenia, anaemia, leukopenia

rare increased eosinophil count

Immune system disorders

uncommon immune reconstitution inflammatory syndrome, (drug) 
hypersensitivity

Endocrine disorders

uncommon hypothyroidism, increased blood thyroid stimulating 
hormone

Metabolism and nutrition disorders

common diabetes mellitus, hypertriglyceridaemia, 
hypercholesterolaemia, hyperlipidaemia

uncommon gout, anorexia, decreased appetite, decreased weight, 
increased weight, hyperglycaemia, insulin resistance, 
decreased high density lipoprotein, increased appetite, 
polydipsia, increased blood lactate dehydrogenase

Psychiatric disorders

common insomnia

uncommon depression, disorientation, anxiety, sleep disorder, 
abnormal dreams, nightmare, decreased libido

rare confusional state, altered mood, restlessness

Nervous system disorders

common headache, peripheral neuropathy, dizziness

uncommon lethargy, paraesthesia, hypoaesthesia, dysgeusia, 
disturbance in attention, memory impairment, 
somnolence

rare syncope, convulsion, ageusia, sleep phase rhythm 
disturbance

Eye disorders

uncommon conjunctival hyperaemia, dry eye

rare visual disturbance

Ear and labyrinth disorders

uncommon vertigo

Cardiac disorders

uncommon myocardial infarction, angina pectoris, prolonged 
electrocardiogram QT, tachycardia

rare acute myocardial infarction, sinus bradycardia, 
palpitations



25

Vascular disorders

uncommon hypertension, flushing

Respiratory, thoracic and mediastinal disorders

uncommon dyspnoea, cough, epistaxis, throat irritation

rare rhinorrhoea

Gastrointestinal disorders

very common diarrhoea

common vomiting, nausea, abdominal pain, increased blood 
amylase, dyspepsia, abdominal distension, flatulence

uncommon pancreatitis, gastritis, gastrooesophageal reflux disease, 
aphthous stomatitis, retching, dry mouth, abdominal 
discomfort, constipation, increased lipase, eructation, 
oral dysaesthesia

rare stomatitis, haematemesis, cheilitis, dry lip, coated 
tongue

Hepatobiliary disorders

common increased alanine aminotransferase

uncommon hepatitis, cytolytic hepatitis, hepatic steatosis, 
hepatomegaly, increased transaminase, increased 
aspartate aminotransferase, increased blood bilirubin, 
increased blood alkaline phosphatase, increased 
gamma-glutamyltransferase

Skin and subcutaneous tissue disorders

common rash (including macular, maculopapular, papular, 
erythematous and pruritic rash), pruritus

uncommon angioedema, generalised rash, allergic dermatitis, 
urticaria, eczema, erythema, hyperhidrosis, night 
sweats, alopecia, acne, dry skin, nail pigmentation

rare DRESS, Stevens-Johnson syndrome, erythema 
multiforme, dermatitis, seborrhoeic dermatitis, skin 
lesion, xeroderma

not known toxic epidermal necrolysis, acute generalised 
exanthematous pustulosis

Musculoskeletal and connective tissue disorders

uncommon myalgia, osteonecrosis, muscle spasms, muscular 
weakness, arthralgia, pain in extremity, osteoporosis, 
increased blood creatine phosphokinase

rare musculoskeletal stiffness, arthritis, joint stiffness

Renal and urinary disorders

uncommon acute renal failure, renal failure, nephrolithiasis, 
increased blood creatinine, proteinuria, bilirubinuria, 
dysuria, nocturia, pollakiuria

rare decreased creatinine renal clearance

Reproductive system and breast disorders

uncommon erectile dysfunction, gynaecomastia

General disorders and administration site conditions

common asthenia, fatigue

uncommon pyrexia, chest pain, peripheral oedema, malaise, feeling 
hot, irritability, pain

rare chills, abnormal feeling, xerosis

Adverse reactions observed with darunavir/cobicistat in adult patients



26

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, diabetes mellitus, 
hypercholesterolaemia, hypertriglyceridaemia, 
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, pancreatic enzymes 
increased

uncommon pancreatitis acute

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 angioedema, pruritus, urticaria

rare drug reaction with eosinophilia and systemic 
symptoms*, Stevens-Johnson syndrome*

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

uncommon asthenia

Investigations

common increased blood creatinine
* 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.

Description of selected adverse reactions 

Rash
In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of 



27

treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in 
section 4.4. In a single arm trial investigating darunavir 800 mg once daily in combination with 
cobicistat 150 mg once daily and other antiretrovirals 2.2% of patients discontinued treatment due to 
rash.

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

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 
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).

Paediatric population 
The safety assessment in paediatric patients is based on the 48-week analysis of safety data from three 
Phase II trials. The following patient populations were evaluated (see section 5.1):
 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at 

least 20 kg who received darunavir tablets with low dose ritonavir twice daily in combination 
with other antiretroviral agents.

 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 
10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received darunavir oral suspension 
with low dose ritonavir twice daily in combination with other antiretroviral agents.

 12 ART-naïve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 
40 kg who received darunavir tablets with low dose ritonavir once daily in combination with 
other antiretroviral agents (see section 5.1).

Overall, the safety profile in these paediatric patients was similar to that observed in the adult 
population.

Other special populations 
Patients co-infected with hepatitis B and/or hepatitis 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 



28

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 darunavir co-administered with cobicistat or low dose 
ritonavir 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 darunavir. Treatment of overdose with darunavir 
consists of general supportive measures including monitoring of vital signs and observation of the 
clinical status of the patient. 

Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of 
the active substance.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE10.

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.

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.

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 clinical trial data from ART-experienced patients (TITAN trial and the pooled analysis of the 



29

POWER 1, 2 and 3 and DUET 1 and 2 trials) showed that virologic response to darunavir co-
administered with low dose ritonavir was decreased when 3 or more darunavir RAMs (V11I, V32I, 
L33F, I47V, I50V, I54L or M, T74P, L76V, I84V and L89V) were present at baseline or when these 
mutations developed during treatment.

Increasing baseline darunavir fold change in EC50 (FC) was associated with decreasing virologic 
response. A lower and upper clinical cut-off of 10 and 40 were identified. Isolates with baseline FC ≤ 
10 are susceptible; isolates with FC > 10 to 40 have decreased susceptibility; isolates with FC > 40 are 
resistant (see Clinical results).

Viruses isolated from patients on darunavir/ritonavir 600/100 mg twice daily experiencing virologic 
failure by rebound that were susceptible to tipranavir at baseline remained susceptible to tipranavir 
after treatment in the vast majority of cases.

The lowest rates of developing resistant HIV virus are observed in ART-naïve patients who are treated 
for the first time with darunavir in combination with other ART.

The table below shows the development of HIV-1 protease mutations and loss of susceptibility to PIs 
in virologic failures at endpoint in the ARTEMIS, ODIN and TITAN trials.

ARTEMIS
Week 192

ODIN
Week 48

TITAN
Week 48

Darunavir/ritonavir
800/100 mg
once daily

N=343

Darunavir/ritonavir
800/100 mg
once daily

N=294

darunavir/ritonavir
600/100 mg
twice daily

N=296

darunavir/ritonavir
600/100 mg
twice daily

N=298

Total number of virologic 
failuresa, n (%)

55 (16.0%) 65 (22.1%) 54 (18.2%) 31 (10.4%)

Rebounders 39 (11.4%) 11 (3.7%) 11 (3.7%) 16 (5.4%)

Never suppressed subjects 16 (4.7%) 54 (18.4%) 43 (14.5%) 15 (5.0%)

Number of subjects with virologic failure and paired baseline/endpoint genotypes, developing mutationsb at 
endpoint, n/N

Primary (major) PI 
mutations

0/43 1/60 0/42 6/28

PI RAMs 4/43 7/60 4/42 10/28

Number of subjects with virologic failure and paired baseline/endpoint phenotypes, showing loss of 
susceptibility to PIs at endpoint compared to baseline, n/N

PI

darunavir 0/39 1/58 0/41 3/26

amprenavir 0/39 1/58 0/40 0/22

atazanavir 0/39 2/56 0/40 0/22

indinavir 0/39 2/57 0/40 1/24

lopinavir 0/39 1/58 0/40 0/23

saquinavir 0/39 0/56 0/40 0/22

tipranavir 0/39 0/58 0/41 1/25
a TLOVR non-VF censored algorithm based on HIV-1 RNA < 50 copies/ml, except for TITAN (HIV-1 RNA < 400 
copies/ml)
b IAS-USA lists

Low rates of developing resistant HIV-1 virus were observed in ART-naïve patients who are treated 
for the first time with darunavir/cobicistat once daily in combination with other ART, and in ART-
experienced patients with no darunavir RAMs receiving darunavir/cobicistat in combination with 
other ART. The table below shows the development of HIV-1 protease mutations and resistance to PIs 
in virologic failures at endpoint in the GS-US-216-130 trial.



30

GS-US-216-130
Week 48

Treatment-naïve
darunavir/cobicistat 800/150 mg

once daily
N=295

Treatment-experienced
darunavir/cobicistat 800/150 mg

once daily
N=18

Number of subjects with virologic failurea and genotype data that develop mutationsb at endpoint, n/N

Primary (major) PI 
mutations

0/8 1/7

PI RAMs 2/8 1/7

Number of subjects with virologic failurea and phenotype data that show resistance to PIs at endpointc, n/N

HIV PI

darunavir 0/8 0/7

amprenavir 0/8 0/7

atazanavir 0/8 0/7

indinavir 0/8 0/7

lopinavir 0/8 0/7

saquinavir 0/8 0/7

tipranavir 0/8 0/7
a Virogic failures were defined as: never suppressed: confirmed HIV-1 RNA < 1 log10 reduction from baseline and ≥ 50 
copies/ml at the week-8; 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 IAS-USA lists
c In GS-US216-130 baseline phenotype was not available

Cross-resistance
Darunavir FC was less than 10 for 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir, 
indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to 
most PIs remain susceptible to darunavir.

In the virologic failures of the ARTEMIS trial no cross-resistance with other PIs was observed.
In the virologic failures of the GS-US-216-130 trial no cross-resistance with other HIV PIs was 
observed.

Clinical results
The pharmacokinetic enhancing effect of cobicistat on darunavir was evaluated in a Phase I study in 
healthy subjects that were administered darunavir 800 mg with either cobicistat at 150 mg or ritonavir 
at 100 mg once daily. The steady-state pharmacokinetic parameters of darunavir were comparable 
when boosted with cobicistat versus ritonavir. For information on cobicistat, consult the cobicistat 
Summary of Product Characteristics.

Adult patients

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 background regimen 
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:



31

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/mla 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 baselineb

+174 +102 +170

a Imputations according to the TLOVR algorithm
b Last Observation Carried Forward imputation

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 48a Week 96b

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

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



32

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

Outcomes Darunavir/ritonavir
800/100 mg once daily + 

OBR
N=294

Darunavir/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 
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.

Darunavir/ritonavir 800/100 mg once daily in ART-experienced patients 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 section 4.2 and 4.4). Limited data is available in 
patients with HIV-1 clades other than B.

Paediatric patients

ART-naïve paediatric patients from the age of 12 years to < 18 years, and weighing at least 40 kg
DIONE is an open-label, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and 



33

efficacy of darunavir with low dose ritonavir in 12 ART-naïve HIV-1 infected paediatric patients aged 
12 to less than 18 years and weighing at least 40 kg. These patients received darunavir/ritonavir
800/100 mg once daily in combination with other antiretroviral agents. Virologic response was defined 
as a decrease in plasma HIV-1 RNA viral load of at least 1.0 log10 versus baseline.

DIONE

Outcomes at week 48
Darunavir/ritonavir

N=12

HIV-1 RNA < 50 copies/mla 83.3% (10)

CD4+ percent change from baselineb 14

CD4+ cell count mean change from baselineb 221

≥ 1.0 log10 decrease from baseline in plasma viral load 100%
a Imputations according to the TLOVR algorithm.
b Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0.

For additional clinical study results in ART-experienced adults and paediatric patients, refer to the 
Summary of Product Characteristics for Darunavir Krka d.d. 600 mg tablets.

Pregnancy and postpartum
Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a 
background regimen was evaluated in a clinical trial of 36 pregnant women (18 in each arm) during 
the second and third trimesters, and postpartum. Virologic response was preserved throughout the 
study period in both arms. No mother to child transmission occurred in the infants born to the 31
subjects who stayed on the antiretroviral treatment through delivery. There were no new clinically 
relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1 
infected adults (see sections 4.2, 4.4 and 5.2).

5.2 Pharmacokinetic properties

The pharmacokinetic properties of darunavir, co-administered with cobicistat or ritonavir, have been 
evaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher 
in HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 
infected patients compared to healthy subjects may be explained by the higher concentrations of α1-
acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma 
AAG and, therefore, higher plasma concentrations.

Darunavir is primarily metabolised by CYP3A. Cobicistat and ritonavir inhibit CYP3A, thereby 
increasing the plasma concentrations of darunavir considerably.

For information on cobicistat pharmacokinetic properties, consult the cobicistat Summary of Product 
Characteristics.

Absorption
Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of 
darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.

The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% 
and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The overall 
pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic 
exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with 
ritonavir at 100 mg twice daily (see section 4.4).

When administered without food, the relative bioavailability of darunavir in the presence of cobicistat 
or low dose ritonavir is lower as compared to intake with food. Therefore, darunavir tablets should be 
taken with cobicistat or ritonavir and with food. The type of food does not affect exposure to 
darunavir.



34

Distribution
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.

Biotransformation
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.

Elimination
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.

Special populations

Paediatric population
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 74 treatment-
experienced paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that the 
administered weight-based doses of darunavir /ritonavir resulted in darunavir exposure comparable to 
that in adults receiving darunavir /ritonavir 600/100 mg twice daily (see section 4.2).

The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 14 treatment-
experienced paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to < 20 kg, showed 
that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in 
adults receiving darunavir /ritonavir 600/100 mg twice daily (see section 4.2).

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naïve 
paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that darunavir /ritonavir 
800/100 mg once daily results in darunavir exposure that was comparable to that achieved in adults 
receiving darunavir /ritonavir 800/100 mg once daily. Therefore the same once daily dosage may be 
used in treatment-experienced adolescents aged 12 to < 18 years and weighing at least 40 kg 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 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment-
experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to < 20 kg, showed 
that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in 
adults receiving darunavir/ritonavir 800/100 mg once daily (see section 4.2). In addition, 
pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages 
of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed 
the identification of weight-based darunavir/ritonavir once daily dosing regimens for paediatric 
patients weighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patients 



35

without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 
100 cells x 106/l (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

Elderly
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) (see section 4.4). However, only limited data were available in patients above the age 
of 65 year.

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

Renal impairment
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).

Hepatic impairment
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with darunavir
co-administered with 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 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).

Pregnancy and postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice 
daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally 
lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the 
pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an 
increase in the unbound fraction of darunavir during pregnancy compared to postpartum.

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg twice 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=12)a

Third trimester of 
pregnancy 
(n=12) 

Postpartum (6-12 weeks)

(n=12) 

Cmax, ng/ml 4,668 ± 1,097 5,328 ± 1,631 6,659 ± 2,364

AUC12h, ng.h/ml 39,370 ± 9,597 45,880 ± 17,360 56,890 ± 26,340

Cmin, ng/ml 1,922 ± 825 2,661 ± 1,269 2,851 ± 2,216
a n=11 for AUC12h

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 800/100 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=17) 

Third Trimester of 
pregnancy 
(n=15) 

Postpartum (6-12 weeks)

(n=16) 

Cmax, ng/ml 4,964 ± 1,505 5,132 ± 1,198 7,310 ± 1,704



36

AUC24h, ng.h/ml 62,289 ± 16,234 61,112 ± 13,790 92,116 ± 29,241

Cmin, ng/ml 1,248 ± 542 1,075 ± 594 1,473 ± 1,141

In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of 
pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and 
26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total 
darunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, as 
compared with postpartum.

In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of 
pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and 
30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total 
darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared 
with postpartum.

Treatment with darunavir/cobicistat 800/150 mg once daily during pregnancy results in low darunavir 
exposure. In women receiving darunavir/cobicistat 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 
pregnancy, cobicistat Cmax, AUC24h, and Cmin, were 27%, 49%, and 83% lower, respectively, as 
compared with postpartum.

5.3 Preclinical safety data

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 



37

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, darunavir with low dose ritonavir 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 
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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Cellulose, microcrystalline
Crospovidone
Hydroxypropylcellulose
Silica, colloidal anhydrous



38

Silicified microcrystalline cellulose (Cellulose, microcrystalline; Silica, colloidal anhydrous)
Magnesium stearate (E470b)

Film coating:

Poly(vinyl alcohol)
Macrogol
Titanium dioxide (E171)
Talc (E553b)
Iron oxide, yellow (E172) – only for 400 mg film-coated tablets
Iron oxide, red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

Shelf life after first opening: 3 months.

6.4 Special precautions for storage

Keep the bottle tightly closed in order to protect from moisture.

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

6.5 Nature and contents of container

400 mg film-coated tablets:
Bottle (HDPE), child resistant temper evident PP closure with a desiccant:
- 30 tablets: 1 bottle of 30 film-coated tablets,
- 60 tablets: 2 bottles of 30 film-coated tablets,
- 90 tablets: 3 bottles of 30 film-coated tablets,
- 180 tablets: 6 bottles of 30 film-coated tablets.

800 mg film-coated tablets:
Bottle (HDPE), child resistant temper evident PP closure with a desiccant:
- 30 tablets: 1 bottle of 30 film-coated tablets,
- 90 tablets: 3 bottles of 30 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

400 mg film-coated tablets:



39

30 film-coated tablets: EU/1/17/1248/001
60 film-coated tablets: EU/1/17/1248/002
90 film-coated tablets: EU/1/17/1248/003
180 film-coated tablets: EU/1/17/1248/004

800 mg film-coated tablets:

30 film-coated tablets: EU/1/17/1248/009
90 film-coated tablets: EU/1/17/1248/010

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18 January 2018

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.



40

1. NAME OF THE MEDICINAL PRODUCT

Darunavir Krka d.d. 600 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 600 mg darunavir.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Orangish brown, oval, biconvex film-coated tablets, engraved with a mark S2 on one side. Tablet 
dimension: 19.5 x 10 mm.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Darunavir Krka d.d., co-administered with low dose ritonavir is indicated in combination with other 
antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus 
(HIV-1) infection (see section 4.2).

Darunavir Krka d.d. 600 mg tablets may be used to provide suitable dose regimens (see section 4.2):
 For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adult 

patients, including those that have been highly pre-treated.
 For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least 

15 kg body weight.

In deciding to initiate treatment with darunavir co-administered with low dose ritonavir, careful 
consideration should be given to the treatment history of the individual patient and the patterns of 
mutations associated with different agents. Genotypic or phenotypic testing (when available) and 
treatment history should guide the use of darunavir (see sections 4.2, 4.4 and 5.1).

4.2 Posology and method of administration

Therapy should be initiated by a health care provider experienced in the management of HIV 
infection. After therapy with darunavir has been initiated, patients should be advised not to alter the 
dosage, dose form or discontinue therapy without discussing with their health care provider.

Posology
Darunavir must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in 
combination with other antiretroviral medicinal products. The Summary of Product Characteristics of 
ritonavir must, therefore, be consulted prior to initiation of therapy with darunavir.

Darunavir Krka d.d. 600 mg film coated tablets must not be chewed or crushed. This strength is not 
suitable for dosages below 600 mg.  It is not possible to administer all paediatric dosages with this 
product. Other tablet strengths and formulations of darunavir are available.

ART-experienced adult patients
The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken 
with food. Darunavir Krka d.d. 600 mg tablets can be used to construct the twice daily 600 mg 



41

regimen.

ART-naïve adult patients
For dosage recommendations in ART-naïve patients see the Summary of Product Characteristics for 
Darunavir Krka d.d. 400 mg and 800 mg tablets.

ART-naïve paediatric patients (3 to 17 years of age and weighing at least 15 kg)
The weight-based dose of darunavir and ritonavir in paediatric patients is provided in the table below.

Recommended dose for treatment-naïve paediatric patients (3 to 17 years) with darunavir
tablets and ritonavira

Body weight (kg) Dose (once daily with food)

≥ 15 kg to < 30 kg 600 mg darunavir/100 mg ritonavir once daily

≥ 30 kg to < 40 kg 675 mg darunavir/100 mg ritonavir once daily

≥ 40 kg 800 mg darunavir/100 mg ritonavir once daily
a ritonavir oral solution: 80 mg/ml

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 15 kg)
Darunavir twice daily taken with ritonavir taken with food is usually recommended.

A once daily dose regimen of darunavir taken with ritonavir 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.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

The recommended dose of darunavir with low dose ritonavir for paediatric patients is based on body 
weight and should not exceed the recommended adult dose (600/100 mg twice daily or 800/100 mg 
once daily).

Recommended dose for treatment-experienced paediatric patients (3 to 17 years) with darunavir
tablets and ritonavira

Body weight (kg) Dose (once daily with food) Dose(twice daily with food)

≥ 15 kg–< 30 kg 600 mg darunavir/100 mg ritonavir
once daily

375 mg darunavir/50 mg ritonavir
twice daily

≥ 30 kg–< 40 kg 675 mg darunavir/100 mg ritonavir
once daily

450 mg darunavir/60 mg ritonavir
twice daily

≥ 40 kg 800 mg darunavir/100 mg ritonavir
once daily

600 mg darunavir/100 mg ritonavir
twice daily

a ritonavir oral solution: 80 mg/ml

For ART-experienced paediatric patients HIV genotypic testing is recommended. However, when HIV 
genotypic testing is not feasible, the darunavir/ritonavir once daily dosing regimen is recommended in 
HIV protease inhibitor-naïve paediatric patients and the twice daily dosing regimen is recommended 
in HIV protease inhibitor-experienced patients.

Advice on missed doses
In case a dose of darunavir and/or ritonavir is missed within 6 hours of the time it is usually taken, 
patients should be instructed to take the prescribed dose of darunavir and ritonavir with food as soon 
as possible. If this is noticed later than 6 hours after the time it is usually taken, the missed dose should 
not be taken and the patient should resume the usual dosing schedule.

This guidance is based on the 15 hour half-life of darunavir in the presence of ritonavir and the 
recommended dosing interval of approximately 12 hours.

Special populations



42

Elderly
Limited information is available in this population, and therefore, darunavir should be used with
caution in this age group (see sections 4.4 and 5.2).

Hepatic impairment
Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with 
mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, darunavir 
should be used with caution in these patients. No pharmacokinetic data are available in patients with 
severe hepatic impairment. Severe hepatic impairment could result in an increase of darunavir 
exposure and a worsening of its safety profile. Therefore, darunavir 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
No dose adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).

Paediatric population
Darunavir/ritonavir should not be used in children with a body weight of less than 15 kg as the dose 
for this population has not been established in a sufficient number of patients (see section 5.1). 
Darunavir/ritonavir should not be used in children below 3 years of age because of safety concerns 
(see sections 4.4 and 5.3). 

The weight-based dose regimen for darunavir and ritonavir is provided in the tables above.

Pregnancy and postpartum
No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. 
Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential 
risk (see sections 4.4, 4.6 and 5.2).

Method of administration

Patients should be instructed to take darunavir with low dose ritonavir within 30 minutes after
completion of a meal. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5 
and 5.2).

4.3 Contraindications

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

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

Combination of rifampicin with darunavir with concomitant low dose ritonavir (see section 4.5).

Co-administration with the combination product lopinavir/ritonavir (see section 4.5).

Co-administration with herbal preparations containing St John's wort (Hypericum perforatum) (see 
section 4.5).

Co-administration of darunavir with low dose ritonavir, with active substances that are highly 
dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with
serious and/or life-threatening events. These active substances include e.g.:
 alfuzosin 
 amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
 astemizole, terfenadine 
 colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)
 ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
 elbasvir/grazoprevir 



43

 cisapride 
 dapoxetine
 domperidone
 naloxegol
 lurasidone, pimozide, quetiapine, sertindole (see section 4.5)
 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 (see section 4.5).

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 must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in 
combination with other antiretroviral medicinal products (see section 5.2). The Summary of Product 
Characteristics of ritonavir as appropriate, must therefore be consulted prior to initiation of therapy 
with darunavir.

Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect 
darunavir concentrations . It is not recommended to alter the dose of ritonavir.

Darunavir binds predominantly to α1-acid glycoprotein. This protein binding is concentration-
dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products 
highly bound to α1-acid glycoprotein cannot be ruled out (see section 4.5).

ART-experienced patients – once daily dosing

Darunavir used in combination with cobicistat or low dose ritonavir once daily in ART-experienced 
patients 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 section 
4.2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIs have not been 
studied in this population. Limited data are available in patients with HIV-1 clades other than B (see 
section 5.1).

Paediatric population

Darunavir is not recommended for use in paediatric patients below 3 years of age or less than 15 kg 
body weight (see sections 4.2 and 5.3).

Pregnancy
Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential
risk. Caution should be used in pregnant women with concomitant medications which may further 
decrease darunavir exposure (see sections 4.5 and 5.2).

Elderly

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



44

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. Darunavir 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 by 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 (see section 4.8).

Darunavir contains a sulphonamide moiety. Darunavir 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. 
During the darunavir/ritonavir 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 darunavir/ritonavir 
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 darunavir/ritonavir 
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 darunavir/ritonavir, interruption or discontinuation of 
treatment should be considered promptly.

Patients with coexisting conditions

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

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

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 PIs. In some patients additional 



45

factor VIII was given. In more than half of the reported cases, treatment with 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.

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 
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 studies 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

Several of the interaction studies have been performed with darunavir at lower than recommended 
doses. The effects on co-administered medicinal products may thus be underestimated and clinical 
monitoring of safety may be indicated. For full information on interactions with other medicinal 
products see section 4.5.
Efavirenz in combination with boosted darunavir once daily may result in sub-optimal darunavir Cmin. 
If efavirenz is to be used in combination with darunavir, the darunavir/ritonavir 600/100 mg twice 
daily regimen should be used (see section 4.5).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and 
strong inhibitors of CYP3A and P-glycoprotein (P-gp; see sections 4.3 and 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Medicinal products that may be affected by darunavir boosted with ritonavir
Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of 
darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or 
transported by P-gp may result in increased systemic exposure to such medicinal products, which 
could increase or prolong their therapeutic effect and adverse reactions.



46

Darunavir co-administered with low dose ritonavir must 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).

The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in 
the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in 
combination with ritonavir at 100 mg twice daily. Therefore, darunavir must only be used in
combination with low dose ritonavir as a pharmacokinetic enhancer (see sections 4.4 and 5.2).

A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes 
CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and 
inhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to the 
presence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal products 
which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result 
in increased plasma concentrations of these medicinal products, which could increase or prolong their 
therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir with medicinal 
products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) 
may result in decreased systemic exposure to such medicinal products, which could decrease or 
shorten their therapeutic effect.

Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir and 
ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone, 
repaglinide) may result in decreased systemic exposure to such medicinal products, which could 
decrease or shorten their therapeutic effect.

Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration 
with substrates of these transporters can result in increased plasma concentrations of these compounds 
(e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).

Medicinal products that affect darunavir/ritonavir exposure
Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity 
would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma 
concentrations of darunavir and ritonavir (e.g. rifampicin, St John's wort, lopinavir). Co-administration 
of darunavir and ritonavir and other medicinal products that inhibit CYP3A may decrease the 
clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir 
and ritonavir (e.g. indinavir azole antifungals like clotrimazole). These interactions are described in 
the interaction table below.

Interaction table 

Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products
are listed in the table below. The direction of the arrow for each pharmacokinetic parameter is based 
on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) 
the 80-125% range (not determined as “ND”).

Several of the interaction studies (indicated by # in the table below) have been performed at lower than 
recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). The 
effects on co-administered medicinal products may thus be underestimated and clinical monitoring of 
safety may be indicated.

The below list of examples of drug drug interactions is not comprehensive and therefore the label of 
each drug that is co-administered with darunavir 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 I I



47

Medicinal products by 
therapeutic areas 

Interaction 
Geometric mean change (%) 

Recommendations concerning co-
administration 

HIV ANTIRETROVIRALS 

Integrase strand transfer inhibitors

Dolutegravir dolutegravir AUC ↓ 22%
dolutegravir C24h ↓38%
dolutegravir Cmax ↓ 11%
darunavir ↔*
* Using cross-study comparisons to 
historical pharmacokinetic data

Darunavir co-administered with low 
dose ritonavir and dolutegravir can be 
used without dose adjustment.

Raltegravir Some clinical studies 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. 
Darunavir co-administered with low 
dose ritonavir and raltegravir can be 
used without dose adjustments.

Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)

Didanosine
400 mg once daily

didanosine AUC ↓ 9%
didanosine Cmin ND
didanosine Cmax ↓ 16%
darunavir AUC ↔
darunavir Cmin ↔
darunavir Cmax ↔

Darunavir co-administered with low 
dose ritonavir and didanosine can be 
used without dose adjustments.
Didanosine is to be administered on 
an empty stomach, thus it should be 
administered 1 hour before or 2 hours 
after darunavir/ritonavir given with 
food.

Tenofovir disoproxil 
245 mg once daily

tenofovir AUC ↑ 22%
tenofovir Cmin ↑ 37%
tenofovir Cmax ↑ 24%
#darunavir AUC ↑ 21%
#darunavir Cmin ↑ 24%
#darunavir Cmax ↑ 16%
(↑ tenofovir from effect on MDR-1 
transport in the renal tubules)

Monitoring of renal function may be 
indicated when darunavir co-
administered with low dose ritonavir 
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 darunavir with low dose 
ritonavir.

Abacavir
Emtricitabine
Lamivudine
Stavudine
Zidovudine

Not studied. Based on the different 
elimination pathways of the other NRTIs 
zidovudine, emtricitabine, stavudine, 
lamivudine, that are primarily renally 
excreted, and abacavir for which 
metabolism is not mediated by CYP450, no 
interactions are expected for these 
medicinal compounds and darunavir co-
administered with low dose ritonavir.

Darunavir co-administered with low 
dose ritonavir can be used with these 
NRTIs without dose adjustment.

Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)

Efavirenz
600 mg once daily

efavirenz AUC ↑ 21%
efavirenz Cmin ↑ 17%
efavirenz Cmax ↑ 15%
#darunavir AUC ↓ 13%
#darunavir Cmin ↓ 31%
#darunavir Cmax ↓ 15%
(↑ efavirenz from CYP3A inhibition)
(↓ darunavir from CYP3A induction)

Clinical monitoring for central 
nervous system toxicity associated 
with increased exposure to efavirenz 
may be indicated when darunavir co-
administered with low dose ritonavir 
is given in combination with 
efavirenz.
Efavirenz in combination with 
darunavir /ritonavir 800/100 mg once 
daily may result in sub-optimal 
darunavir Cmin. If efavirenz is to be 



48

used in combination with darunavir
/ritonavir, the darunavir/ritonavir 
600/100 mg twice daily regimen 
should be used (see section 4.4).

Etravirine
100 mg twice daily

etravirine AUC ↓ 37%
etravirine Cmin ↓ 49%
etravirine Cmax ↓ 32%
darunavir AUC ↑ 15%
darunavir Cmin ↔
darunavir Cmax ↔

Darunavir co-administered with low 
dose ritonavir and etravirine 200 mg 
twice daily can be used without dose 
adjustments.

Nevirapine
200 mg twice daily

nevirapine AUC ↑ 27%
nevirapine Cmin ↑ 47%
nevirapine Cmax ↑ 18%
#darunavir: concentrations were consistent 
with historical data
(↑ nevirapine from CYP3A inhibition)

Darunavir co-administered with low 
dose ritonavir and nevirapine can be 
used without dose adjustments.

Rilpivirine
150 mg once daily

rilpivirine AUC ↑ 130%
rilpivirine Cmin ↑ 178%
rilpivirine Cmax ↑ 79%
darunavir AUC ↔
darunavir Cmin ↓ 11%
darunavir Cmax ↔

Darunavir co-administered with low 
dose ritonavir and rilpivirine can be
used without dose adjustments.

HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir† 

Atazanavir
300 mg once daily

atazanavir AUC ↔
atazanavir Cmin ↑ 52%
atazanavir Cmax ↓ 11%
#darunavir AUC ↔
#darunavir Cmin ↔
#darunavir Cmax ↔
Atazanavir: comparison of 
atazanavir/ritonavir 300/100 mg once daily 
vs. atazanavir 300 mg once daily in 
combination with darunavir/ritonavir 
400/100 mg twice daily.
Darunavir: comparison of 
darunavir/ritonavir 400/100 mg twice daily 
vs. darunavir/ritonavir 400/100 mg twice 
daily in combination with atazanavir 300 
mg once daily.

Darunavir co-administered with low 
dose ritonavir and atazanavir can be 
used without dose adjustments.

Indinavir
800 mg twice daily

indinavir AUC ↑ 23%
indinavir Cmin ↑ 125%
indinavir Cmax ↔
#darunavir AUC ↑ 24%
#darunavir Cmin ↑ 44%
#darunavir Cmax ↑ 11%
Indinavir: comparison of 
indinavir/ritonavir 800/100 mg twice daily 
vs. indinavir/darunavir/ritonavir 
800/400/100 mg twice daily.
Darunavir: comparison of 
darunavir/ritonavir 400/100 mg twice daily 
vs. darunavir/ritonavir 400/100 mg in 
combination with indinavir 800 mg twice 
daily.

When used in combination with 
darunavir co-administered with low 
dose ritonavir, dose adjustment of 
indinavir from 800 mg twice daily to 
600 mg twice daily may be warranted 
in case of intolerance.

Saquinavir
1,000 mg twice daily

#darunavir AUC ↓ 26%
#darunavir Cmin ↓ 42%
#darunavir Cmax ↓ 17%
saquinavir AUC ↓ 6%
saquinavir Cmin ↓ 18%
saquinavir Cmax ↓ 6%

It is not recommended to combine 
darunavir co-administered with low 
dose ritonavir with saquinavir.



49

Saquinavir: comparison of 
saquinavir/ritonavir 1,000/100 mg twice 
daily vs. saquinavir/darunavir/ritonavir 
1,000/400/100 mg twice daily
Darunavir: comparison of 
darunavir/ritonavir 400/100 mg twice daily 
vs. darunavir/ritonavir 400/100 mg in 
combination with saquinavir 1,000 mg 
twice daily.

HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavir† 

Lopinavir/ritonavir
400/100 mg twice daily

Lopinavir/ritonavir
533/133.3 mg twice daily

lopinavir AUC ↑ 9%
lopinavir Cmin ↑ 23%
lopinavir Cmax ↓ 2%
darunavir AUC ↓ 38%‡

darunavir Cmin ↓ 51%‡

darunavir Cmax ↓ 21%‡

lopinavir AUC ↔
lopinavir Cmin ↑ 13%
lopinavir Cmax ↑ 11%
darunavir AUC ↓ 41%
darunavir Cmin ↓ 55%
darunavir Cmax ↓ 21%
‡ based upon non dose normalised values

Due to a decrease in the exposure 
(AUC) of darunavir by 40%, 
appropriate doses of the combination 
have not been established. Hence, 
concomitant use of darunavir co-
administered with low dose ritonavir 
and the combination product 
lopinavir/ritonavir is contraindicated 
(see section 4.3).

CCR5 ANTAGONIST 

Maraviroc
150 mg twice daily

maraviroc AUC ↑ 305%
maraviroc Cmin ND
maraviroc Cmax ↑ 129%
darunavir, ritonavir concentrations were 
consistent with historical data

The maraviroc dose should be 150 
mg twice daily when co-administered 
with darunavir with low dose 
ritonavir.

α1-ADRENORECEPTOR ANTAGONIST 

Alfuzosin Based on theoretical considerations 
darunavir is expected to increase alfuzosin 
plasma concentrations.
(CYP3A inhibition)

Co-administration of darunavir with 
low dose ritonavir and alfuzosin is 
contraindicated (see section 4.3).

ANAESTHETIC 

Alfentanil Not studied. The metabolism of alfentanil 
is mediated via CYP3A, and may as such 
be inhibited by darunavir co-administered 
with low dose ritonavir.

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

ANTIANGINA/ANTIARRHYTHMIC 

Disopyramide
Flecainide
Lidocaine (systemic)
Mexiletine
Propafenone

Amiodarone
Bepridil
Dronedarone
Ivabradine
Quinidine
Ranolazine

Not studied. Darunavir 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 darunavir with low 
dose ritonavir.
Darunavir co-administered with low 
dose ritonavir and amiodarone, 
bepridil, dronedarone, ivabradine,
quinidine, or ranolazine is 
contraindicated (see section 4.3).

Digoxin
0.4 mg single dose

digoxin AUC ↑ 61%
digoxin Cmin ND

Given that digoxin has a narrow 
therapeutic index, it is recommended 



50

digoxin Cmax ↑ 29%
(↑ digoxin from probable inhibition of P-
gp)

that the lowest possible dose of 
digoxin should initially be prescribed 
in case digoxin is given to patients on 
darunavir/ritonavir therapy. The 
digoxin dose should be carefully 
titrated to obtain the desired clinical 
effect while assessing the overall 
clinical state of the subject.

ANTIBIOTIC 

Clarithromycin
500 mg twice daily

clarithromycin AUC ↑ 57%
clarithromycin Cmin ↑ 174%
clarithromycin Cmax ↑ 26%
#darunavir AUC ↓ 13%
#darunavir Cmin ↑ 1%
#darunavir Cmax ↓ 17%
14-OH-clarithromycin concentrations were 
not detectable when combined with 
darunavir/ritonavir.
(↑ clarithromycin from CYP3A inhibition 
and possible P-gp inhibition)

Caution should be exercised when 
clarithromycin is combined with 
darunavir co-administered with low 
dose ritonavir.

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

Not studied. Co-administration of 
darunavir with these anticoagulants may 
increase concentrations of the 
anticoagulant, which may lead to an 
increased bleeding risk.
(CYP3A and/or P-gp inhibition).

The use of darunavir co-administered 
with low dose ritonavir and these 
anticoagulants is not recommended.

Dabigatran
Ticagrelor

Not studied. Co-administration with 
boosted darunavir may lead to a substantial 
increase in exposure to dabigatran or 
ticagrelor.

Concomitant administration of 

boosted darunavir with dabigatran or 

ticagrelor is contraindicated (see 

section 4.3).

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

Warfarin Not studied. Warfarin concentrations may 
be affected when co-administered with 
darunavir with low dose ritonavir.

It is recommended that the 
international normalised ratio (INR) 
be monitored when warfarin is 
combined with darunavir co-
administered with low dose ritonavir.

ANTICONVULSANTS 

Phenobarbital
Phenytoin

Not studied. Phenobarbital and phenytoin 
are expected to decrease plasma 
concentrations of darunavir and its 
pharmacoenhancer.
(induction of CYP450 enzymes)

Darunavir co-administered with low 
dose ritonavir should not be used in 
combination with these medicines.

Carbamazepine
200 mg twice daily

carbamazepine AUC ↑ 45%
carbamazepine Cmin ↑ 54%
carbamazepine Cmax ↑ 43%
darunavir AUC ↔
darunavir Cmin ↓ 15%
darunavir Cmax ↔

No dose adjustment for darunavir
/ritonavir is recommended. If there is 
a need to combine darunavir/ritonavir 
and carbamazepine, patients should 
be monitored for potential 
carbamazepine-related adverse 
events. Carbamazepine 
concentrations should be monitored 
and its dose should be titrated for 
adequate response. Based upon the 
findings, the carbamazepine dose 
may need to be reduced by 25% to 
50% in the presence of 



51

darunavir/ritonavir.

Clonazepam Not studied. Co-administration of boosted 
darunavir with clonazepam may increase 
concentrations of clonazepam. (CYP3A 
inhibition)

Clinical monitoring is recommended 
when co-administering darunavir 
with low dose ritonavir and
clonazepam.

ANTIDEPRESSANTS 

Paroxetine
20 mg once daily

Sertraline
50 mg once daily

Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone

paroxetine AUC ↓ 39%
paroxetine Cmin ↓ 37%
paroxetine Cmax ↓ 36%
#darunavir AUC ↔
#darunavir Cmin ↔
#darunavir Cmax ↔
sertraline AUC ↓ 49%
sertraline Cmin ↓ 49%
sertraline Cmax ↓ 44%
#darunavir AUC ↔
#darunavir Cmin ↓ 6%
#darunavir Cmax ↔
Concomitant use of darunavir co-
administered wirth low dose ritonavir and 
these antidepressants may increase 
concentrations of the antidepressant.
(CYP2D6 and/or CYP3A inhibition).

If antidepressants are co-administered 
with darunavir with low dose 
ritonavir, the recommended approach 
is a dose titration of the 
antidepressant based on a clinical 
assessment of antidepressant 
response. In addition, patients on a 
stable dose of these antidepressants 
who start treatment with darunavir
with low dose ritonavir should be 
monitored for antidepressant 
response.

Clinical monitoring is recommended 
when co-administering darunavir
with low dose ritonavir with these 
antidepressants and a dose adjustment 
of the antidepressant may be needed.

ANTIEMETICS

Domperidone Not studied. Co-administration of domperidone 
with boosted darunavir is 
contraindicated. 

ANTIFUNGALS 

Voriconazole Not studied. Ritonavir may decrease 
plasma concentrations of voriconazole.
(induction of CYP450 enzymes)

Voriconazole should not be combined 
with darunavir co-administered with 
low dose ritonavir unless an 
assessment of the benefit/risk ratio 
justifies the use of voriconazole.

Fluconazole
Isavuconazole
Itraconazole
Posaconazole

Clotrimazole

Not studied. Darunavir may increase 
antifungal plasma concentrations and 
posaconazole, isavuconazole, itraconazole, 
or fluconazole may increase darunavir 
concentrations.
(CYP3A and/or P-gp inhibition)

Not studied. Concomitant systemic use of 
clotrimazole and darunavir co-administered 
with low dose ritonavir may increase 
plasma concentrations of darunavir and/or 
clotrimazole.
darunavir AUC24h ↑ 33% (based on 
population pharmacokinetic model)

Caution is warranted and clinical 
monitoring is recommended. When 
co-administration is required the 
daily dose of itraconazole should not 
exceed 200 mg.

ANTIGOUT MEDICINES 

Colchicine Not studied. Concomitant use of colchicine 
and darunavir co-administered with low 
dose ritonavir may increase the exposure to 
colchicine.

A reduction in colchicine dosage or 
an interruption of colchicine 
treatment is recommended in patients 
with normal renal or hepatic function 



52

(CYP3A and/ or P-gp inhibition) if treatment with darunavir co-
administered with low dose ritonavir 
is required. For patients with renal or 
hepatic impairment colchicine with 
darunavir co-administered with low 
dose ritonavir is contraindicated (see 
sections 4.3 and 4.4).

ANTIMALARIALS 

Artemether/Lumefantrine
80/480 mg, 6 doses at 0, 8, 
24, 36, 48, and 60 hours

artemether AUC ↓ 16%
artemether Cmin ↔
artemether Cmax ↓ 18%
dihydroartemisinin AUC ↓ 18%
dihydroartemisinin Cmin ↔
dihydroartemisinin Cmax ↓ 18%
lumefantrine AUC ↑ 175%
lumefantrine Cmin ↑ 126%
lumefantrine Cmax ↑ 65%
darunavir AUC ↔
darunavir Cmin ↓ 13%
darunavir Cmax ↔

The combination of darunavir 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
Rifapentine

Not studied. Rifapentine and rifampicin are 
strong CYP3A inducers and have been 
shown to cause profound decreases in 
concentrations of other protease inhibitors, 
which can result in virological failure and 
resistance development (CYP450 enzyme 
induction). During attempts to overcome 
the decreased exposure by increasing the 
dose of other protease inhibitors with low 
dose ritonavir, a high frequency of liver 
reactions was seen with rifampicin.

The combination of rifapentine and 
darunavir with concomitant low dose 
ritonavir is not recommended.
The combination of rifampicin and 
darunavir with concomitant low dose 
ritonavir is contraindicated (see 
section 4.3).

Rifabutin
150 mg once every other day

rifabutin AUC** ↑ 55%
rifabutin Cmin** ↑ ND
rifabutin Cmax** ↔
darunavir AUC ↑ 53%
darunavir Cmin ↑ 68%
darunavir Cmax ↑ 39%
** sum of active moieties of rifabutin 
(parent drug + 25-O-desacetyl metabolite)
The interaction trial showed a comparable 
daily systemic exposure for rifabutin 
between treatment at 300 mg once daily 
alone and 150 mg once every other day in 
combination with darunavir/ritonavir 
(600/100 mg twice daily) with an about 10-
fold increase in the daily exposure to the 
active metabolite 25-O-desacetylrifabutin. 
Furthermore, AUC of the sum of active 
moieties of rifabutin (parent drug + 25-O-
desacetyl metabolite) was increased 1.6-
fold, while Cmax remained comparable.
Data on comparison with a 150 mg once 
daily reference dose is lacking.
(Rifabutin is an inducer and substrate of 
CYP3A.) An increase of systemic exposure 
to darunavir was observed when darunavir 
co-administered with 100 mg ritonavir was 
co-administered with rifabutin (150 mg 
once every other day).

A dosage reduction of rifabutin by 
75% of the usual dose of 300 mg/day 
(i.e. rifabutin 150 mg once every 
other day) and increased monitoring 
for rifabutin related adverse events is 
warranted in patients receiving the 
combination with darunavir
co-administered with ritonavir. In 
case of safety issues, a further 
increase of the dosing interval for 
rifabutin and/or monitoring of 
rifabutin levels should be considered.
Consideration should be given to 
official guidance on the appropriate 
treatment of tuberculosis in HIV 
infected patients.
Based upon the safety profile of 
darunavir/ritonavir, the increase in 
darunavir exposure in the presence of 
rifabutin does not warrant a dose 
adjustment for darunavir/ritonavir.
Based on pharmacokinetic modeling, 
this dosage reduction of 75% is also 
applicable if patients receive rifabutin 
at doses other than 300 mg/day.

ANTINEOPLASTICS 



53

Dasatinib
Nilotinib
Vinblastine
Vincristine

Everolimus
Irinotecan

Not studied. Darunavir is expected to 
increase these antineoplastic plasma 
concentrations.
(CYP3A inhibition)

Concentrations of these medicinal 
products may be increased when co-
administered with darunavir with low 
dose ritonavir resulting in the 
potential for increased adverse events 
usually associated with these agents.
Caution should be exercised when 
combining one of these antineoplastic 
agents with darunavir with low dose 
ritonavir.

Concominant use of everolimus or 
irinotecan and darunavir co-
administered with low dose ritonavir 
is not recommended.

ANTIPSYCHOTICS/NEUROLEPTICS 

Quetiapine Not studied. Darunavir is expected to 
increase these antipsychotic plasma 
concentrations.
(CYP3A inhibition)

Concomitant administration of 
darunavir with low dose ritonavir and 
quetiapine is contraindicated as it 
may increase quetiapine-related 
toxicity. Increased concentrations of 
quetiapine may lead to coma (see 
section 4.3).

Perphenazine
Risperidone
Thioridazine

Lurasidone
Pimozide
Sertindole

Not studied. Darunavir is expected to 
increase these antipsychotic plasma 
concentrations.
(CYP3A, CYP2D6 and/or P-gp inhibition)

A dose decrease may be needed for 
these drugs when co-administered 
with darunavir co-administered with 
low dose ritonavir.

Concominant administration of 
darunavir with low dose ritonavir and 
lurasidone, pimozide or sertindole is 
contraindicated (see section 4.3).

β-BLOCKERS 

Carvedilol
Metoprolol
Timolol

Not studied. Darunavir is expected to 
increase these β-blocker plasma 
concentrations.
(CYP2D6 inhibition)

Clinical monitoring is recommended 
when co-administering darunavir 
with β-blockers. A lower dose of the 
β-blocker should be considered.

CALCIUM CHANNEL BLOCKERS 

Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil

Not studied. Darunavir co-administered 
with low dose ritonavir can be expected to 
increase the plasma concentrations of 
calcium channel blockers.
(CYP3A and/or CYP2D6 inhibition)

Clinical monitoring of therapeutic 
and adverse effects is recommended 
when these medicines are 
concomitantly administered with 
darunavir with low dose ritonavir.

CORTICOSTEROIDS 

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

Fluticasone: in a clinical study where 
ritonavir 100 mg capsules twice daily were 
co-administered with 50 μg intranasal 
fluticasone propionate (4 times daily) for 7 
days in healthy subjects, fluticasone 
propionate plasma concentrations increased 
significantly, whereas the intrinsic cortisol 
levels decreased by approximately 86% 
(90% CI 82-89%). Greater effects may be 
expected when fluticasone is inhaled. 
Systemic corticosteroid effects including 
Cushing's syndrome and adrenal 
suppression have been reported in patients 
receiving ritonavir and inhaled or 
intranasally administered fluticasone. The 

Concomitant use of darunavir with 
low dose ritonavir 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 



54

effects of high fluticasone systemic 
exposure on ritonavir plasma levels are 
unknown.
Other corticosteroids: interaction not 
studied. Plasma concentrations of these 
medicinal products may be increased when 
co-administered with darunavir with low 
dose ritonavir, resulting in reduced serum 
cortisol concentrations.

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) Not studied. Dexamethasone may decrease 
plasma concentrations of darunavir.
(CYP3A induction)

Systemic dexamethasone should be 
used with caution when combined 
with darunavir co-administered with 
low dose ritonavir.

ENDOTHELIN RECEPTOR ANTAGONISTS 

Bosentan Not studied. Concomitant use of bosentan 
and darunavir co-administered with low 
dose ritonavir may increase plasma 
concentrations of bosentan.
Bosentan is expected to decrease plasma 
concentrations of darunavir and/or its 
pharmacoenhancer.
(CYP3A induction)

When administered concomitantly
with darunavir A and low dose 
ritonavir, the patient's tolerability of 
bosentan should be monitored.

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS 

NS3-4A protease inhibitors

Elbasvir/grazoprevir Darunavir with low dose ritonavir may 
increase the exposure to grazoprevir.
(CYP3A and OATP1B inhibition)

Concomitant use of darunavir with 
low dose ritonavir and 
elbasvir/grazoprevir is 
contraindicated (see section 4.3).

Boceprevir
800 mg three times daily

boceprevir AUC ↓ 32%
boceprevir Cmin ↓ 35%
boceprevir Cmax ↓ 25%
darunavir AUC ↓ 44%
darunavir Cmin ↓ 59%
darunavir Cmax ↓ 36%

It is not recommended to co-
administer darunavir with low dose 
ritonavir and boceprevir.

Glecaprevir/pibrentasvir Based on theoretical considerations 

boosted darunavir may increase the 

exposure to glecaprevir and pibrentasvir.
(P-gp, BCRP and/or OATP1B1/3 
inhibition)

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

Simeprevir simeprevir AUC ↑ 159%
simeprevir Cmin ↑ 358%
simeprevir Cmax ↑ 79%
darunavir AUC ↑ 18%
darunavir Cmin ↑ 31%
darunavir Cmax ↔
The dose of simeprevir in this interaction 
study was 50 mg when co-administered in 
combination with darunavir/ritonavir, 
compared to 150 mg in the simeprevir 
alone treatment group.

It is not recommended to co-
administer darunavir with low dose 
ritonavir and simeprevir.

HERBAL PRODUCTS 

St John's wort (Hypericum 
perforatum)

Not studied. St John's wort is expected to 
decrease the plasma concentrations of 
darunavir and ritonavir.
(CYP450 induction)

Darunavir co-administered with low 
dose ritonavir must not be used 
concomitantly with products 
containing St John's wort (Hypericum 
perforatum) (see section 4.3). If a 
patient is already taking St John's 
wort, stop St John's wort and if 



55

possible check viral levels. Darunavir 
exposure (and also ritonavir 
exposure) may increase on stopping 
St John's wort. The inducing effect 
may persist for at least 2 weeks after 
cessation of treatment with St John's 
wort.

HMG CO-A REDUCTASE INHIBITORS 

Lovastatin
Simvastatin

Not studied. Lovastatin and simvastatin are 
expected to have markedly increased 
plasma concentrations when co-
administered with darunavir co-
administered with low dose ritonavir.
(CYP3A inhibition)

Increased plasma concentrations of 
lovastatin or simvastatin may cause 
myopathy, including rhabdomyolysis. 
Concomitant use of darunavir co-
administered with low dose ritonavir 
with lovastatin and simvastatin is 
therefore contraindicated (see section 
4.3).

Atorvastatin
10 mg once daily

atorvastatin AUC ↑ 3-4 fold
atorvastatin Cmin ↑ ≈5.5-10 fold
atorvastatin Cmax ↑ ≈2 fold
#darunavir/ritonavir

When administration of atorvastatin 
and darunavir co-administered with 
low dose ritonavir is desired, it is 
recommended to start with an 
atorvastatin dose of 10 mg once 
daily. A gradual dose increase of 
atorvastatin may be tailored to the 
clinical response.

Pravastatin
40 mg single dose

pravastatin AUC ↑ 81%¶

pravastatin Cmin ND
pravastatin Cmax ↑ 63%
¶ an up to five-fold increase was seen in a 
limited subset of subjects

When administration of pravastatin 
and darunavir co-administered with 
low dose ritonavir is required, it is 
recommended to start with the lowest 
possible dose of pravastatin and 
titrate up to the desired clinical effect 
while monitoring for safety.

Rosuvastatin
10 mg once daily

rosuvastatin AUC ↑ 48%║

rosuvastatin Cmax ↑ 144%║
║ based on published data with darunavir/ritonavir

When administration of rosuvastatin 
and darunavir co-administered with 
low dose ritonavir is required, it is 
recommended to start with the lowest 
possible dose of rosuvastatin and 
titrate up to the desired clinical effect 
while monitoring for safety.

OTHER LIPID MODIFYING AGENTS

Lomitapide Based on theoretical considerations 
boosted darunavir is expected to increase 
the exposure of lomitapide when co-
administered. 
(CYP3A inhibition)

Co-administration is contraindicated 
(see section 4.3)

H2-RECEPTOR ANTAGONISTS 

Ranitidine
150 mg twice daily

#darunavir AUC ↔
#darunavir Cmin ↔
#darunavir Cmax ↔

Darunavir co-administered with low 
dose ritonavir can be co-administered 
with H2-receptor antagonists without 
dose adjustments.

IMMUNOSUPPRESSANTS

Ciclosporin
Sirolimus
Tacrolimus
Everolimus

Not studied. Exposure to these 
immunosuppressants will be increased 
when co-administered with darunavir co-
administered with low dose ritonavir.
(CYP3A inhibition)

Therapeutic drug monitoring of the 
immunosuppressive agent must be 
done when co-administration occurs.
Concomitant use of everolimus and 
darunavir co-administered with low 
dose ritonavir is not recommended.

INHALED BETA AGONISTS 

Salmeterol Not studied. Concomitant use of salmeterol Concomitant use of salmeterol and I I



56

and darunavir co-administered with low 
dose ritonavir may increase plasma 
concentrations of salmeterol.

darunavir co-administered with low 
dose ritonavir 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 

Methadone
individual dose ranging from 
55 mg to 150 mg once daily

R(-) methadone AUC ↓ 16%
R(-) methadone Cmin ↓ 15%
R(-) methadone Cmax ↓ 24%

No adjustment of methadone dosage 
is required when initiating co-
administration with darunavir 
/ritonavir. However, increased 
methadone dose may be necessary 
when concomitantly administered for 
a longer period of time due to 
induction of metabolism by ritonavir. 
Therefore, clinical monitoring is 
recommended, as maintenance 
therapy may need to be adjusted in 
some patients.

Buprenorphine/naloxone
8/2 mg–16/4 mg once daily

buprenorphine AUC ↓ 11%
buprenorphine Cmin ↔
buprenorphine Cmax ↓ 8%
norbuprenorphine AUC ↑ 46%
norbuprenorphine Cmin ↑ 71%
norbuprenorphine Cmax ↑ 36%
naloxone AUC ↔
naloxone Cmin ND
naloxone Cmax ↔

The clinical relevance of the increase 
in norbuprenorphine pharmacokinetic 
parameters has not been established. 
Dose adjustment for buprenorphine 
may not be necessary when co-
administered with darunavir/ritonavir 
but a careful clinical monitoring for 
signs of opiate toxicity is 
recommended.

Fentanyl
Oxycodone
Tramadol

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

Clinical monitoring is recommended 
when co-administering darunavir
with low dose ritonavir with these 
analgesics.

OESTROGEN-BASED CONTRACEPTIVES 

Drospirenone 
Ethinylestradiol (3 mg/0.02 
mg once daily)

Ethinylestradiol
Norethindrone
35 μg/1 mg once daily

Not studied with darunavir/ritonavir.

ethinylestradiol AUC ↓ 44% β

ethinylestradiol Cmin ↓ 62% β

ethinylestradiol Cmax ↓ 32% β

norethindrone AUC ↓ 14% β

norethindrone Cmin ↓ 30% β

norethindrone Cmax ↔ β
β with darunavir/ritonavir

When darunavir is coadministered 
with a drospirenone-containing 
product, clinical monitoring is 
recommended due to the potential for 
hyperkalaemia. 

Alternative or additional 
contraceptive measures are 
recommended when oestrogen-based 
contraceptives are co-administered 
with darunavir and low dose 
ritonavir. 

Patients using oestrogens as hormone 
replacement therapy should be 
clinically monitored for signs of 
oestrogen deficiency.

OPIOID ANTAGONIST

Naloxegol Not studied. Co-administration of boosted 
darunavir and naloxegol is 
contraindicated. 

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS 

For the treatment of erectile 
dysfunction
Avanafil

In an interaction study #, a comparable 
systemic exposure to sildenafil was 
observed for a single intake of 100 mg 

The combination of avanafil and 
darunavir with low dose ritonavir is 
contraindicated (see section 4.3). 



57

Sildenafil
Tadalafil
Vardenafil

sildenafil alone and a single intake of 25 
mg sildenafil co-administered with 
darunavir and low dose ritonavir.

Concomitant use of other PDE-5 
inhibitors for the treatment of erectile 
dysfunction with darunavir co-
administered with low dose ritonavir
should be done with caution. If 
concomitant use of darunavir co-
administered with low dose ritonavir 
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.

For the treatment of 
pulmonary arterial 
hypertension
Sildenafil
Tadalafil

Not studied. Concomitant use of sildenafil 
or tadalafil for the treatment of pulmonary 
arterial hypertension and darunavir co-
administered with low dose ritonavir may 
increase plasma concentrations of sildenafil 
or tadalafil.
(CYP3A inhibition)

A safe and effective dose of sildenafil 
for the treatment of pulmonary 
arterial hypertension co-administered 
with darunavir and low dose ritonavir 
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 
darunavir with low dose ritonavir 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 darunavir and low 
dose ritonavir is not recommended.

PROTON PUMP INHIBITORS 

Omeprazole
20 mg once daily

#darunavir AUC ↔
#darunavir Cmin ↔
#darunavir Cmax ↔

Darunavir co-administered with low 
dose ritonavir can be co-administered 
with proton pump inhibitors without 
dose adjustments.

SEDATIVES/HYPNOTICS 

Buspirone
Clorazepate
Diazepam
Estazolam
Flurazepam
Midazolam (parenteral)
Zoldipem

Midazolam (oral)
Triazolam

Not studied. Sedative/hypnotics are 
extensively metabolised by CYP3A. Co-
administration with darunavir/ritonavir 
may cause a large increase in the 
concentration of these medicines.

If parenteral midazolam is co-administered 
with darunavir co-administered with low 
dose ritonavir it may cause a large increase 
in the concentration of this benzodiazepine. 
Data from concomitant use of parenteral 
midazolam with other protease inhibitors 
suggest a possible 3-4 fold increase in 
midazolam plasma levels.

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

If parenteral midazolam is co-
administered with darunavir with a 
low dose ritonavir, it should be done 
in an intensive care unit (ICU) 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.

Darunavir with low dose ritonavir 
with triazolam or oral midazolam is 
contraindicated (see section 4.3)



58

TREATMENT FOR PREMATURE EJACULATION

Dapoxetine Not studied. Co-administration of boosted 
darunavir 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.

# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2
Posology).

† The efficacy and safety of the use of darunavir with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavir, 
nelfinavir and tipranavir) has not been established in HIV patients. According to current treatment guidelines, dual 
therapy with protease inhibitors is generally not recommended.

‡ Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.

4.6 Fertility, pregnancy and lactation

Pregnancy

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

There are no adequate and well controlled studies on pregnancy outcome with darunavir 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).

Darunavir co-administered with low dose ritonavir should be used during pregnancy only if the 
potential benefit justifies the potential risk.

Breast-feeding

It is not known whether darunavir is 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. 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 Darunavir Krka 
d.d..

Fertility

No human data on the effect of darunavir on fertility are available. There was no effect on mating or 
fertility with darunavir treatment in rats (see section 5.3).

4.7 Effects on ability to drive and use machines

Darunavir in combination with ritonavir has no or negligible influence on the ability to drive and use 
machines. However, dizziness has been reported in some patients during treatment with regimens 
containing darunavir co-administered with low dose ritonavir and should be borne in mind when 
considering a patient's ability to drive or operate machinery (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

During the clinical development program (N=2,613 treatment-experienced subjects who initiated 
therapy with darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one



59

adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent 
adverse reactions reported in clinical trials 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. No new safety findings were identified in the 192 
week analysis of the treatment-naïve subjects in which the mean treatment duration of 
darunavir/ritonavir 800/100 mg once daily was 162.5 weeks.

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).

Adverse reactions observed with darunavir/ritonavir in clinical trials and post-marketing

MedDRA system organ class
Frequency category

Adverse reaction

Infections and infestations

uncommon herpes simplex

Blood and lymphatic system disorders

uncommon thrombocytopenia, neutropenia, anaemia, leukopenia

rare increased eosinophil count

Immune system disorders

uncommon immune reconstitution inflammatory syndrome, (drug) 
hypersensitivity

Endocrine disorders

uncommon hypothyroidism, increased blood thyroid stimulating 
hormone

Metabolism and nutrition disorders

common diabetes mellitus, hypertriglyceridaemia, 
hypercholesterolaemia, hyperlipidaemia

uncommon gout, anorexia, decreased appetite, decreased weight, 
increased weight, hyperglycaemia, insulin resistance, 
decreased high density lipoprotein, increased appetite, 
polydipsia, increased blood lactate dehydrogenase

Psychiatric disorders

common insomnia

uncommon depression, disorientation, anxiety, sleep disorder, 
abnormal dreams, nightmare, decreased libido

rare confusional state, altered mood, restlessness

Nervous system disorders

common headache, peripheral neuropathy, dizziness

uncommon lethargy, paraesthesia, hypoaesthesia, dysgeusia, 
disturbance in attention, memory impairment, 
somnolence

rare syncope, convulsion, ageusia, sleep phase rhythm 



60

disturbance

Eye disorders

uncommon conjunctival hyperaemia, dry eye

rare visual disturbance

Ear and labyrinth disorders

uncommon vertigo

Cardiac disorders

uncommon myocardial infarction, angina pectoris, prolonged 
electrocardiogram QT, tachycardia

rare acute myocardial infarction, sinus bradycardia, 
palpitations

Vascular disorders

uncommon hypertension, flushing

Respiratory, thoracic and mediastinal disorders

uncommon dyspnoea, cough, epistaxis, throat irritation

rare rhinorrhoea

Gastrointestinal disorders

very common diarrhoea

common vomiting, nausea, abdominal pain, increased blood 
amylase, dyspepsia, abdominal distension, flatulence

uncommon pancreatitis, gastritis, gastrooesophageal reflux disease, 
aphthous stomatitis, retching, dry mouth, abdominal 
discomfort, constipation, increased lipase, eructation, 
oral dysaesthesia

rare stomatitis, haematemesis, cheilitis, dry lip, coated 
tongue

Hepatobiliary disorders

common increased alanine aminotransferase

uncommon hepatitis, cytolytic hepatitis, hepatic steatosis, 
hepatomegaly, increased transaminase, increased 
aspartate aminotransferase, increased blood bilirubin, 
increased blood alkaline phosphatase, increased 
gamma-glutamyltransferase

Skin and subcutaneous tissue disorders

common rash (including macular, maculopapular, papular, 
erythematous and pruritic rash), pruritus

uncommon angioedema, generalised rash, allergic dermatitis, 
urticaria, eczema, erythema, hyperhidrosis, night 
sweats, alopecia, acne, dry skin, nail pigmentation

rare DRESS, Stevens-Johnson syndrome, erythema 
multiforme, dermatitis, seborrhoeic dermatitis, skin 
lesion, xeroderma

not known toxic epidermal necrolysis, acute generalised 
exanthematous pustulosis

Musculoskeletal and connective tissue disorders

uncommon myalgia, osteonecrosis, muscle spasms, muscular 
weakness, arthralgia, pain in extremity, osteoporosis, 
increased blood creatine phosphokinase

rare musculoskeletal stiffness, arthritis, joint stiffness

Renal and urinary disorders

uncommon acute renal failure, renal failure, nephrolithiasis, 
increased blood creatinine, proteinuria, bilirubinuria, 



61

dysuria, nocturia, pollakiuria

rare decreased creatinine renal clearance

Reproductive system and breast disorders

uncommon erectile dysfunction, gynaecomastia

General disorders and administration site conditions

common asthenia, fatigue

uncommon pyrexia, chest pain, peripheral oedema, malaise, feeling 
hot, irritability, pain

rare chills, abnormal feeling, xerosis

Description of selected adverse reactions

Rash
In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of 
treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in 
section 4.4.

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

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 
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).

Paediatric population
The safety assessment in paediatric patients is based on the 48-week analysis of safety data from three 
Phase II trials. The following patient populations were evaluated (see section 5.1):
 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at 

least 20 kg who received darunavir tablets with low dose ritonavir twice daily in combination 
with other antiretroviral agents.



62

 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 
10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received darunavir oral suspension 
with low dose ritonavir twice daily in combination with other antiretroviral agents.

 12 ART-naïve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 
40 kg who received darunavir tablets with low dose ritonavir once daily in combination with 
other antiretroviral agents (see section 5.1).

Overall, the safety profile in these paediatric patients was similar to that observed in the adult
population.

Other special populations
Patients co-infected with hepatitis B and/or hepatitis 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 darunavir co-administered with low dose ritonavir 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 darunavir. Treatment of overdose with darunavir 
consists of general supportive measures including monitoring of vital signs and observation of the 
clinical status of the patient. 

Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of
the active substance.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE10.

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.

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.



63

These EC50 values are well below the 50% cellular toxicity concentration range of 87 µM to > 100 
µM.

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 clinical trial data from ART-experienced patients (TITAN trial and the pooled analysis of the 
POWER 1, 2 and 3 and DUET 1 and 2 trials) showed that virologic response to darunavir co-
administered with low dose ritonavir was decreased when 3 or more darunavir RAMs (V11I, V32I, 
L33F, I47V, I50V, I54L or M, T74P, L76V, I84V and L89V) were present at baseline or when these 
mutations developed during treatment.

Increasing baseline darunavir fold change in EC50 (FC) was associated with decreasing virologic 
response. A lower and upper clinical cut-off of 10 and 40 were identified. Isolates with baseline FC ≤ 
10 are susceptible; isolates with FC > 10 to 40 have decreased susceptibility; isolates with FC > 40 are 
resistant (see Clinical results).

Viruses isolated from patients on darunavir/ritonavir 600/100 mg twice daily experiencing virologic 
failure by rebound that were susceptible to tipranavir at baseline remained susceptible to tipranavir 
after treatment in the vast majority of cases.

The lowest rates of developing resistant HIV virus are observed in ART-naïve patients who are treated 
for the first time with darunavir in combination with other ART.

The table below shows the development of HIV-1 protease mutations and loss of susceptibility to PIs 
in virologic failures at endpoint in the ARTEMIS, ODIN and TITAN trials.

ARTEMIS
Week 192

ODIN
Week 48

TITAN
Week 48

Darunavir/ritonavir
800/100 mg
once daily

N=343

darunavir/ritonavir
800/100 mg
once daily

N=294

darunavir/ritonavir
600/100 mg
twice daily

N=296

darunavir/ritonavir
600/100 mg
twice daily

N=298

Total number of virologic 
failuresa, n (%)

55 (16.0%) 65 (22.1%) 54 (18.2%) 31 (10.4%)

Rebounders 39 (11.4%) 11 (3.7%) 11 (3.7%) 16 (5.4%)

Never suppressed subjects 16 (4.7%) 54 (18.4%) 43 (14.5%) 15 (5.0%)

Number of subjects with virologic failure and paired baseline/endpoint genotypes, developing mutationsb at 
endpoint, n/N

Primary (major) PI 
mutations

0/43 1/60 0/42 6/28

PI RAMs 4/43 7/60 4/42 10/28

Number of subjects with virologic failure and paired baseline/endpoint phenotypes, showing loss of 
susceptibility to PIs at endpoint compared to baseline, n/N

PI

darunavir 0/39 1/58 0/41 3/26

amprenavir 0/39 1/58 0/40 0/22

atazanavir 0/39 2/56 0/40 0/22



64

indinavir 0/39 2/57 0/40 1/24

lopinavir 0/39 1/58 0/40 0/23

saquinavir 0/39 0/56 0/40 0/22

tipranavir 0/39 0/58 0/41 1/25
a TLOVR non-VF censored algorithm based on HIV-1 RNA < 50 copies/ml, except for TITAN (HIV-1 RNA < 400 
copies/ml)
b IAS-USA lists

Cross-resistance
Darunavir FC was less than 10 for 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir, 
indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to 
most PIs remain susceptible to darunavir.

In the virologic failures of the ARTEMIS trial no cross-resistance with other PIs was observed.

Clinical results
Adult patients
For clinical trial results in ART-naïve adult patients, refer to the Summary of Product Characteristics 
for Darunavir Krka d.d. 400 mg and 800 mg tablets.

Efficacy of darunavir 600 mg twice daily co-administered with 100 mg ritonavir twice daily in ART-
experienced patients
The evidence of efficacy of darunavir co-administered with ritonavir (600/100 mg twice daily) in 
ART-experienced patients is based on the 96 weeks analysis of the Phase III trial TITAN in ART-
experienced lopinavir naïve patients, on the 48 week analysis of the Phase III trial ODIN in ART-
experienced patients with no DRV-RAMs, and on the analyses of 96 weeks data from the Phase IIb 
trials POWER 1 and 2 in ART-experienced patients with high level of PI resistance.

TITAN is a randomised, controlled, open-label Phase III trial comparing darunavir co-administered 
with ritonavir (600/100 mg twice daily) versus lopinavir/ritonavir (400/100 mg twice daily) in ART-
experienced, lopinavir naïve HIV-1 infected adult patients. Both arms used an Optimised Background 
Regimen (OBR) consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).

The table below shows the efficacy data of the 48 week analysis from the TITAN trial.

TITAN

Outcomes Darunavir/ritonavir
600/100 mg twice daily + 

OBR
N=298

Lopinavir/ritonavir
400/100 mg twice daily + 

OBR
N=297

Treatment difference
(95% CI of difference)

HIV-1 RNA < 50 
copies/mla

70.8% (211) 60.3% (179) 10.5% (2.9; 18.1)b

median CD4+ cell 
count change from 
baseline (x 106/l)c

88 81

a Imputations according to the TLOVR algorithm
b Based on a normal approximation of the difference in % response
c NC=F

At 48 weeks non-inferiority in virologic response to the darunavir/ritonavir treatment, defined as the 
percentage of patients with plasma HIV-1 RNA level < 400 and < 50 copies/ml, was demonstrated (at 
the pre-defined 12% non-inferiority margin) for both ITT and OP populations. These results were 
confirmed in the analysis of data at 96 weeks of treatment in the TITAN trial, with 60.4% of patients in 
the darunavir/ritonavir arm having HIV-1 RNA < 50 copies/ml at week 96 compared to 55.2% in the 
lopinavir/ritonavir arm [difference: 5.2%, 95% CI (-2.8; 13.1)].

ODIN is a Phase III, randomised, open-label trial comparing darunavir/ritonavir 800/100 mg once 



65

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

Outcomes Darunavir/ritonavir
800/100 mg once daily + 

OBR
N=294

darunavir/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 
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.

Darunavir/ritonavir 800/100 mg once daily in ART-experienced patients 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 section 4.2 and 4.4). Limited data is available in 
patients with HIV-1 clades other than B.

POWER 1 and POWER 2 are randomised, controlled trials comparing darunavir co-administered with 
ritonavir (600/100 mg twice daily) with a control group receiving an investigator-selected PI(s) 
regimen in HIV-1 infected patients who had previously failed more than 1 PI containing regimen. An 
OBR consisting of at least 2 NRTIs with or without enfuvirtide (ENF) was used in both trials.

The table below shows the efficacy data of the 48-week and 96-week analyses from the pooled 
POWER 1 and POWER 2 trials.

POWER 1 and POWER 2 pooled data

Week 48 Week 96

Outcomes darunavir/ritonavir
600/100 mg twice 

Control 
n=124

Treatment 
difference

darunavir/ritonavir
600/100 mg twice 

Control 
n=124

Treatment 
difference



66

daily n=131 daily n=131

HIV RNA < 50 
copies/mla

45.0%
(59)

11.3%
(14)

33.7%
(23.4%; 44.1%)c

38.9%
(51)

8.9%
(11)

30.1%
(20.1; 40.0)c

CD4+ cell count 
mean change from 
baseline (x 106/l)b

103 17 86
(57; 114)c

133 15 118
(83.9; 153.4)c

a Imputations according to the TLOVR algorithm
b Last Observation Carried Forward imputation
c 95% confidence intervals.

Analyses of data through 96 weeks of treatment in the POWER trials demonstrated sustained 
antiretroviral efficacy and immunologic benefit.

Out of the 59 patients who responded with complete viral suppression (< 50 copies/ml) at week 48, 47 
patients (80% of the responders at week 48) remained responders at week 96.

Baseline genotype or phenotype and virologic outcome
Baseline genotype and darunavir FC (shift in susceptibility relative to reference) were shown to be a 
predictive factor of virologic outcome.

Proportion (%) of patients with response (HIV-1 RNA < 50 copies/ml at week 24) to darunavir co-
administered with ritonavir (600/100 mg twice daily) by baseline genotypea, and baseline darunavir 
FC and by use of enfuvirtide (ENF): As treated analysis of the POWER and DUET trials.

Number of baseline mutationsa Baseline DRV FCb

Response (HIV-1 
RNA < 50 
copies/ml at week 
24)
%, n/N

All 
ranges

0-2 3 ≥ 4
All 

ranges
≤ 10 10-40 > 40

All patients
45%

455/1,014
54%

359/660
39%

67/172
12%

20/171
45%

455/1,014
55%

364/659
29%

59/203
8%

9/118

Patients with 
no/non-naïve use of 
ENFc

39%
290/741

50%
238/477

29%
35/120

7%
10/135

39%
290/741

51%
244/477

17%
25/147

5%
5/94

Patients with naïve 
use of ENFd

60%
165/273

66%
121/183

62%
32/52

28%
10/36

60%
165/273

66%
120/182

61%
34/56

17%
4/24

a Number of mutations from the list of mutations associated with a diminished response to darunavir/ritonavir (V11I, V32I, 
L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V)
b fold change in EC50
c “Patients with no/non-naïve use of ENF” are patients who did not use ENF or who used ENF but not for the first time
d “Patients with naïve use of ENF” are patients who used ENF for the first time

Paediatric patients
For clinical trial results in ART-naïve paediatric patients aged 12 to 17 years, refer to the Summary of 
Product Characteristics for Darunavir Krka d.d. 400 mg and 800 mg tablets.

ART-experienced paediatric patients from the age of 6 to < 18 years and weighing at least 20 kg
DELPHI is an open-label, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and 
efficacy of darunavir with low dose ritonavir in 80 ART-experienced HIV-1 infected paediatric 
patients aged 6 to 17 years and weighing at least 20 kg. These patients received darunavir/ritonavir
twice daily in combination with other antiretroviral agents (see section 4.2 for dosage 
recommendations per body weight). Virologic response was defined as a decrease in plasma HIV-1 
RNA viral load of at least 1.0 log10 versus baseline.
In the study, patients who were at risk of discontinuing therapy due to intolerance of ritonavir oral 
solution (e.g. taste aversion) were allowed to switch to the capsule formulation. Of the 44 patients 
taking ritonavir oral solution, 27 switched to the 100 mg capsule formulation and exceeded the weight-



67

based ritonavir dose without changes in observed safety.

DELPHI

Outcomes at week 48
Darunavir/ritonavir

N=80

HIV-1 RNA < 50 copies/mla 47.5% (38)

CD4+ cell count mean change from baselineb 147
a Imputations according to the TLOVR algorithm.
b Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0.

According to the TLOVR non-virologic failure censored algorithm 24 (30.0%) patients experienced 
virological failure, of which 17 (21.3%) patients were rebounders and 7 (8.8%) patients were non-
responders.

ART-experienced paediatric patients from the age of 3 to < 6 years
The pharmacokinetics, safety, tolerability and efficacy of darunavir/ritonavir twice daily in 
combination with other antiretroviral agents in 21 ART-experienced HIV-1 infected paediatric patients 
aged 3 to < 6 years and weighing 10 kg to < 20 kg was evaluated in an open-label, Phase II trial, 
ARIEL. Patients received a weight-based twice daily treatment regimen, patients weighing 10 kg to < 
15 kg received darunavir/ritonavir 25/3 mg/kg twice daily, and patients weighing 15 kg to < 20 kg 
received darunavir/ritonavir 375/50 mg twice daily. At week 48, the virologic response, defined as the 
percentage of patients with confirmed plasma viral load < 50 HIV-1 RNA copies/ml, was evaluated in 
16 paediatric patients 15 kg to < 20 kg and 5 paediatric patients 10 kg to < 15 kg receiving 
darunavir/ritonavir in combination with other antiretroviral agents (see section 4.2 for dosage 
recommendations per body weight).

ARIEL

Outcomes at week 48 Darunavir/ritonavir

10 kg to < 15 kg
N=5

15 kg to < 20 kg
N=16

HIV-1 RNA < 50 copies/mla 80.0% (4) 81.3% (13)

CD4+ percent change from baselineb 4 4

CD4+ cell count mean change from baselineb 16 241
a Imputations according to the TLOVR algorithm.
b NC=F

Limited efficacy data are available in paediatric patients below 15 kg and no recommendation on a 
posology can be made.

Pregnancy and postpartum
Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a 
background regimen was evaluated in a clinical trial of 36 pregnant women (18 in each arm) during 
the second and third trimesters, and postpartum. Virologic response was preserved throughout the 
study period in both arms. No mother to child transmission occurred in the infants born to the 31
subjects who stayed on the antiretroviral treatment through delivery. There were no new clinically 
relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1 
infected adults (see sections 4.2, 4.4 and 5.2).

5.2 Pharmacokinetic properties

The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in 
healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 
infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infected 
patients compared to healthy subjects may be explained by the higher concentrations of α1-acid 
glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG 
and, therefore, higher plasma concentrations.



68

Darunavir is primarily metabolised by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the 
plasma concentrations of darunavir considerably.

Absorption
Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of 
darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.

The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% 
and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The overall 
pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic 
exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with 
ritonavir at 100 mg twice daily (see section 4.4).

When administered without food, the relative bioavailability of darunavir in the presence of low dose 
ritonavir is 30% lower as compared to intake with food. Therefore, darunavir tablets should be taken 
with ritonavir and with food. The type of food does not affect exposure to darunavir.

Distribution
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.

Biotransformation
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.

Elimination
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.

Special populations

Paediatric population
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 74 treatment-
experienced paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that the 
administered weight-based doses of darunavir/ritonavir resulted in darunavir exposure comparable to 
that in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).

The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 14 treatment-
experienced paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to < 20 kg, showed 
that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in 
adults receiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).



69

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naïve 
paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that darunavir/ritonavir 
800/100 mg once daily results in darunavir exposure that was comparable to that achieved in adults 
receiving darunavir/ritonavir 800/100 mg once daily. Therefore the same once daily dosage may be 
used in treatment-experienced adolescents aged 12 to < 18 years and weighing at least 40 kg 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 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment-
experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to < 20 kg, showed 
that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in 
adults receiving darunavir/ritonavir 800/100 mg once daily (see section 4.2). In addition, 
pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages 
of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed 
the identification of weight-based darunavir/ritonavir once daily dosing regimens for paediatric 
patients weighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patients 
without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 
100 cells x 106/l (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

Elderly
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) (see section 4.4). However, only limited data were available in patients above the age 
of 65 year.

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

Renal impairment
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).

Hepatic impairment
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with darunavir
co-administered with 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 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).

Pregnancy and postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice 
daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally 
lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the 
pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an 
increase in the unbound fraction of darunavir during pregnancy compared to postpartum.

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg I I



70

twice 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=12)a

Third trimester of 
pregnancy 
(n=12) 

Postpartum (6-12 weeks) 
(n=12) 

Cmax, ng/ml 4,668 ± 1,097 5,328 ± 1,631 6,659 ± 2,364

AUC12h, ng.h/ml 39,370 ± 9,597 45,880 ± 17,360 56,890 ± 26,340

Cmin, ng/ml 1,922 ± 825 2,661 ± 1,269 2,851 ± 2,216
a n=11 for AUC12h

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 800/100 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=17) 

Third Trimester of 
pregnancy 
(n=15) 

Postpartum (6-12 weeks) 
(n=16) 

Cmax, ng/ml 4,964 ± 1,505 5,132 ± 1,198 7,310 ± 1,704

AUC24h, ng.h/ml 62,289 ± 16,234 61,112 ± 13,790 92,116 ± 29,241

Cmin, ng/ml 1,248 ± 542 1,075 ± 594 1,473 ± 1,141

In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of 
pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and 
26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total 
darunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, as 
compared with postpartum.

In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of 
pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and 
30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total 
darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared 
with postpartum.

5.3 Preclinical safety data

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 



71

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, darunavir with low dose ritonavir 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 
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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Cellulose, microcrystalline
Crospovidone
Hydroxypropylcellulose
Silica, colloidal anhydrous
Silicified microcrystalline cellulose (Cellulose, microcrystalline; Silica, colloidal anhydrous)
Magnesium stearate (E470b)

Film coating:

Poly(vinyl alcohol)
Macrogol
Titanium dioxide (E171)



72

Talc (E553b)
Iron oxide, yellow (E172)
Iron oxide, red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

Shelf life after first opening: 3 months.

6.4 Special precautions for storage

Keep the bottle tightly closed in order to protect from moisture.

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

6.5 Nature and contents of container

Bottle (HDPE), child resistant temper evident PP closure with a desiccant:
- 30 tablets: 1 bottle of 30 film-coated tablets,
- 60 tablets : 2 bottles of 30 film-coated tablets,
- 90 tablets: 3 bottles of 30 film-coated tablets,
- 180 tablets: 6 bottles of 30 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

30 film-coated tablets: EU/1/17/1248/005
60 film-coated tablets: EU/1/17/1248/006
90 film-coated tablets: EU/1/17/1248/007
180 film-coated tablets: EU/1/17/1248/008

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18 January 2018

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 



73

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



74

ANNEX II

A. MANUFACTURERS 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



75

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturers responsible for batch release

KRKA d.d., Novo mesto
Šmarješka cesta 6
8501 Novo mesto
Slovenia

TAD Pharma GmbH
Heinz-Lohmann-Straβe 5
27472 Cuxhaven
Germany

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

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 (PSURs)

The requirements for submission of PSURs 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 marketing authorisation holder (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. 



76

ANNEX III

LABELLING AND PACKAGE LEAFLET



77

A. LABELLING



78

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

BOX

1. NAME OF THE MEDICINAL PRODUCT

Darunavir Krka d.d. 400 mg film-coated tablets

darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 400 mg darunavir.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

film-coated tablet

30 film-coated tablets
60 film-coated tablets
90 film-coated tablets
180 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

Shelf life after first opening: 3 months.

Date of opening:___________



79

9. SPECIAL STORAGE CONDITIONS

Keep the bottle tightly closed in order to protect from moisture.

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

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1248/001 30 film-coated tablets
EU/1/17/1248/002 60 film-coated tablets
EU/1/17/1248/003 90 film-coated tablets
EU/1/17/1248/004 180 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Darunavir Krka d.d. 400 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN



80

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

LABEL for bottle

1. NAME OF THE MEDICINAL PRODUCT

Darunavir Krka d.d. 400 mg film-coated tablets

darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 400 mg darunavir.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

film-coated tablet

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

Shelf life after first opening: 3 months.

Date of opening:___________

9. SPECIAL STORAGE CONDITIONS



81

Keep the bottle tightly closed in order to protect from moisture.

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

KRKA

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1248/001 30 film-coated tablets
EU/1/17/1248/002 60 film-coated tablets
EU/1/17/1248/003 90 film-coated tablets
EU/1/17/1248/004 180 film-coated tablets

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

I



82

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

BOX

1. NAME OF THE MEDICINAL PRODUCT

Darunavir Krka d.d. 600 mg film-coated tablets

darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 600 mg darunavir.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

film-coated tablet

30 film-coated tablets
60 film-coated tablets
90 film-coated tablets
180 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

Shelf life after first opening: 3 months.

Date of opening:___________



83

9. SPECIAL STORAGE CONDITIONS

Keep the bottle tightly closed in order to protect from moisture.

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

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1248/005 30 film-coated tablets
EU/1/17/1248/006 60 film-coated tablets
EU/1/17/1248/007 90 film-coated tablets
EU/1/17/1248/008 180 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Darunavir Krka d.d. 600 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN



84

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

LABEL for bottle

1. NAME OF THE MEDICINAL PRODUCT

Darunavir Krka d.d. 600 mg film-coated tablets

darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 600 mg darunavir.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

film-coated tablet

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

Shelf life after first opening: 3 months.

Date of opening:___________

9. SPECIAL STORAGE CONDITIONS

Keep the bottle tightly closed in order to protect from moisture.



85

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

KRKA

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1248/005 30 film-coated tablets
EU/1/17/1248/006 60 film-coated tablets
EU/1/17/1248/007 90 film-coated tablets
EU/1/17/1248/008 180 film-coated tablets

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

I



86

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

BOX

1. NAME OF THE MEDICINAL PRODUCT

Darunavir Krka d.d. 800 mg film-coated tablets

darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 800 mg darunavir.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

film-coated tablet

30 film-coated tablets
90 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

Shelf life after first opening: 3 months.

Date of opening:___________

9. SPECIAL STORAGE CONDITIONS



87

Keep the bottle tightly closed in order to protect from moisture.

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

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1248/009 30 film-coated tablets
EU/1/17/1248/010 90 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Darunavir Krka d.d. 800 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN



88

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

LABEL for bottle

1. NAME OF THE MEDICINAL PRODUCT

Darunavir Krka d.d. 800 mg film-coated tablets

darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 800 mg darunavir.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

film-coated tablet

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

Shelf life after first opening: 3 months.

Date of opening:___________

9. SPECIAL STORAGE CONDITIONS

Keep the bottle tightly closed in order to protect from moisture.



89

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

KRKA

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1248/009 30 film-coated tablets
EU/1/17/1248/010 90 film-coated tablets

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



90

B. PACKAGE LEAFLET



91

Package leaflet: Information for the patient

Darunavir Krka d.d. 400 mg film-coated tablets
Darunavir Krka d.d. 800 mg film-coated tablets

darunavir

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 or pharmacist.
- 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 or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

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

1. What Darunavir Krka d.d. is and what it is used for

What is Darunavir Krka d.d.? 
Darunavir Krka d.d. contains the active substance darunavir. Darunavir Krka d.d. is an antiretroviral 
medicine used in the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a 
group of medicines called protease inhibitors. Darunavir Krka d.d. works by reducing the amount of 
HIV in your body. This will improve your immune system and reduces the risk of developing illnesses 
linked to HIV infection. 

What it is used for? 
The Darunavir Krka d.d. 400 and 800 milligram tablets are used to treat adults and children (3 years of 
age and above, at least 40 kilograms body weight) who are infected by HIV and 
 who have not used antiretroviral medicines before. 
 in certain patients who have used antiretroviral medicines before (your doctor will determine 

this). 

Darunavir Krka d.d. must be taken in combination with a low dose of cobicistat or ritonavir and other 
anti-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 Darunavir Krka d.d.

Do not take Darunavir Krka d.d.
 if you are allergic to active substance 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 Darunavir Krka d.d. 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 



92

Avanafil to treat erectile dysfunction 
Astemizole or terfenadine to treat allergy symptoms 
Triazolam and oral (taken by mouth) 
midazolam 

to help you sleep and/or relieve anxiety 

Cisapride to treat some stomach conditions 
Colchicine (if you have kidney and/or liver 
problems) 

to treat gout or familial Mediterranean 
fever 

Lurasidone, pimozide, quetiapine or 
sertindole 

to treat psychiatric conditions 

Ergot alkaloids like ergotamine, 
dihydroergotamine, ergometrine and 
methylergonovine 

to treat migraine headaches 

Amiodarone, bepridil, dronedarone,
ivabradine, quinidine, ranolazine 

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

Lovastatin, simvastatin and lomitapide to lower cholesterol levels 
Rifampicin to treat some infections such as 

tuberculosis 
The combination product 
lopinavir/ritonavir 

this anti-HIV medicine belongs to the 
same class as Darunavir Krka d.d.

Elbasvir/grazoprevir to treat hepatitis C infection 
Alfuzosin to treat enlarged prostate 
Sildenafil to treat high blood pressure in the 

pulmonary circulation 
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

Do not combine Darunavir Krka d.d. with products that contain St John’s wort (Hypericum 
perforatum). 

Warnings and precautions 
Talk to your doctor, pharmacist or nurse before taking Darunavir Krka d.d.. 

Darunavir Krka d.d. is not a cure for HIV infection. 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 Darunavir Krka d.d. may still develop infections or other illnesses associated with HIV 
infection. You must keep in regular contact with your doctor. 

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

Tell your doctor about your situation BEFORE and DURING your treatment 
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 Darunavir Krka d.d.. 

 Tell your doctor if you have diabetes. Darunavir Krka d.d. might increase sugar levels in the 
blood. 



93

 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 
opportunistic infection, signs and symptoms of inflammation from previous infections may 
occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an 
improvement in the body’s immune response, enabling the body to fight infections that may 
have been present with no obvious symptoms. 

 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 to seek 
necessary treatment. 

 Tell your doctor if you have haemophilia. Darunavir Krka d.d. 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). The length of combination 
antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, 
higher body mass index, among others, may be some of the many risk factors for developing 
this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, 
knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your doctor. 

Elderly
Darunavir Krka d.d. 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 Darunavir Krka d.d..

Children and adolescents 
The Darunavir Krka d.d. 400 or 800 milligram tablet is not for use in children younger than 3 years of 
age or weighing less than 40 kilograms. 

Other medicines and Darunavir Krka d.d.
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 Darunavir Krka d.d.. These are mentioned 
above under the heading ‘Do not combine Darunavir Krka d.d. with any of the following medicines:’ 

In most cases, Darunavir Krka d.d. can be combined with anti-HIV medicines belonging to another 
class [e.g. NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse 
transcriptase inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. Darunavir Krka d.d. with 
cobicistat or ritonavir has not been tested with all PIs (protease inhibitors) and must not be used with 
other HIV PIs. 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 Darunavir Krka d.d. might be reduced if you take any of the following products. Tell 
your doctor if you take: 
 Phenobarbital, phenytoin (to prevent seizures) 
 Dexamethasone (corticosteroid) 
 Efavirenz (HIV infection) 
 Boceprevir (hepatitis C infection) 
 Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis) 
 Saquinavir (HIV infection). 



94

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

mexiletine, nifedipine, nicardipine, 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. 

 Oestrogen-based hormonal contraceptives and hormonal replacement therapy. Darunavir Krka
d.d. might reduce its effectiveness. When used for birth control, alternative methods of non-
hormonal contraception are recommended. 

 Ethinylestradiol/drospirenone. Darunavir Krka d.d. might increase the risk for elevated 
potassium levels by drospirenone.

 Atorvastatin, 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. 

 Clarithromycin (antibiotic) 
 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 (medicines to treat opioid dependence) 
 Salmeterol (medicine to treat asthma) 
 Artemether/lumefantrine (a combination medicine to treat malaria) 
 Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine (to treat cancer) 
 Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder 

called pulmonary arterial hypertension) 
 Glecaprevir/pibrentasvir, simeprevir (to treat hepatitis C infection)
 Fentanyl, oxycodone, tramadol (to treat pain)
 Fesoterodine, solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or Darunavir Krka
d.d.’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) 
 Itraconazole, isavuconazole, fluconazole, posaconazole, clotrimazole (to treat fungal 

infections). Voriconazole should only be taken after medical evaluation. 
 Rifabutin (against bacterial infections) 
 Sildenafil, vardenafil, tadalafil (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) 
 Methadone (to treat opiate dependance) 
 Carbamazepine, clonazepam (to prevent seizures or to treat certain types of nerve pain) 
 Colchicine (to treat gout or familial Mediterranean fever) 
 Bosentan (to treat high blood pressure in the pulmonary circulation) 
 Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam when used as injection, 

zoldipem (sedative agents) 
 Perphenazine, risperidone, thioridazine (to treat psychiatric conditions) 



95

 Metformin (to treat type 2 diabetes). 

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

Darunavir Krka d.d. with food and drink 
See section 3 ‘How to take Darunavir Krka d.d..’

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 Darunavir Krka d.d. with ritonavir unless 
specifically directed by the doctor. Pregnant or breast feeding mothers should not take darunavir with 
cobicistat.

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 Darunavir Krka d.d..

3. How to take Darunavir Krka d.d.

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has 
told you. Check with your doctor, pharmacist or nurse if you are not sure. 
Even if you feel better, do not stop taking Darunavir Krka d.d. and cobicistat or ritonavir without 
talking to your doctor. 

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be 
stopped without instruction of the doctor. 

Darunavir Krka d.d. 400 and 800 milligram tablets are only to be used to construct the once daily 800 
milligram regimen. 

This product is only available as film coated tablets and is thus not suitable for patients who are unable 
to swallow intact tablets, for example young children. For use in these patients, more suitable 
formulations containing darunavir should be checked for their availability.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine 
this) 
The usual dose of Darunavir Krka d.d. is 800 milligram (2 tablets containing 400 milligram of 
Darunavir Krka d.d. or 1 tablet containing 800 milligram of Darunavir Krka d.d.) once daily. 
You must take Darunavir Krka d.d. every day and always in combination with 150 milligram of 
cobicistat or 100 milligram of ritonavir and with food. Darunavir Krka d.d. cannot work properly 
without cobicistat or ritonavir and food. You must eat a meal or a snack within 30 minutes prior to 
taking your Darunavir Krka d.d. and cobicistat or ritonavir. The type of food is not important. Even if 
you feel better, do not stop taking Darunavir Krka d.d. and cobicistat or ritonavir without talking to 
your doctor. 

Instructions for adults 
 Take two 400 milligram tablets at the same time or one 800 miligram tablet, once a day, every 

day. 
 Take Darunavir Krka d.d. always together with 150 milligram of cobicistat or100 milligram of 

ritonavir.
 Take Darunavir Krka d.d. with food. 
 Swallow the tablets with a drink such as water or milk. 



96

 Take your other HIV medicines used in combination with Darunavir Krka d.d. and cobicistat or 
ritonavir as recommended by your doctor. 

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this) 
Maybe you will require a different dose of Darunavir Krka d.d. which cannot be administered with 
these 400 or 800 milligram tablets. Other strengths of Darunavir Krka d.d. are available.
The dose is either: 
 800 milligram Darunavir Krka d.d. (2 tablets containing 400 milligram of Darunavir Krka d.d.

or 1 tablet containing 800 milligram of Darunavir Krka d.d.) together with 150 milligram 
cobicistat or 100 milligram ritonavir once daily. 

OR
 600 milligram Darunavir Krka d.d. (1 tablet containing 600 milligram of Darunavir Krka d.d.) 

together with 100 milligram ritonavir twice daily. 

Please discuss with your doctor which dose is right for you. 

Dose for children 3 years of age and above, weighing more than 40 kilograms who have not 
taken antiretroviral medicines before (your child’s doctor will determine this) 
 The usual dose of Darunavir Krka d.d. is 800 milligram (2 tablets containing 400 milligram of 

Darunavir Krka d.d. or 1 tablet containing 800 milligram of Darunavir Krka d.d.) together with 
100 milligram ritonavir once daily. 

Dose for children 3 years of age and above, weighing more than 40 kilograms who have taken 
antiretroviral medicines before (your child’s doctor will determine this) 
The dose is either: 
 800 milligram Darunavir Krka d.d. (2 tablets containing 400 milligram of Darunavir Krka d.d.

or 1 tablet containing 800 milligram of Darunavir Krka d.d.) together with 100 milligram 
ritonavir once daily. 

OR
 600 milligram Darunavir Krka d.d. (1 tablet containing 600 milligram of Darunavir Krka d.d.)

together with 100 milligram ritonavir twice daily. 

Please discuss with your doctor which dose is right for you. 

Instructions for children 3 years of age and above, weighing more than 40 kilograms 
 Take 800 milligram Darunavir Krka d.d. (2 tablets containing 400 milligram of Darunavir Krka

d.d. or 1 tablet containing 800 milligram of Darunavir Krka d.d.) at the same time, once a day, 
every day. 

 Take Darunavir Krka d.d. always together with 100 milligram of ritonavir.
 Take Darunavir Krka d.d. with food. 
 Swallow the tablets with a drink such as water or milk. 
 Take your other HIV medicines used in combination with Darunavir Krka d.d. and ritonavir as 

recommended by your doctor. 

If you take more Darunavir Krka d.d. than you should 
Contact your doctor, pharmacist or nurse immediately. 

If you forget to take Darunavir Krka d.d.
If you notice within 12 hours, you must take the tablets immediately. Always take with cobicistat or 
ritonavir and 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. 

Do not stop taking Darunavir Krka d.d. without talking to your doctor first 
Anti-HIV medicines may make you feel better. Even when you feel better, do not stop taking 
Darunavir Krka d.d.. Talk to your doctor first. 



97

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. 

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 Darunavir Krka d.d.. 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. 

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 important to talk to your 
doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms or whether 
Darunavir Krka d.d. must be stopped.

Other severe side effectswere diabetes (common) and inflammation of the pancreas (uncommon). 

Very common side effects (may affect more than 1 in 10 people) 
 diarrhoea. 

Common side effects (may affect up to 1 in 10 people) 
 vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence 
 headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of 

strength, difficulty falling asleep. 

Uncommon side effects (may affect up to 1 in 100 people) 
 chest pain, changes in electrocardiogram, rapid heart beating 
 decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory,

problems with your balance 
 difficulty breathing, cough, nosebleed, throat irritation 
 inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the 

abdomen, constipation, belching 
 kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of 

urine, sometimes at night 
 urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema, 

excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails 
 muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis 
 slowing down of the thyroid gland function. This can be seen in a blood test. 
 high blood pressure, flushing 
 red or dry eyes 
 fever, swelling of lower limbs due to fluids, malaise, irritability, pain 
 symptoms of infection, herpes simplex 
 erectile dysfunction, enlargement of breasts 
 sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive 

Rare side effects (may affect up to 1 in 1,000 people) 



98

 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] 

 heart attack, slow heart beating, palpitations 
 visual disturbance 
 chills, feeling abnormal 
 a feeling of confusion or disorientation, altered mood, restlessness 
 fainting, epileptic fits, changes or loss of taste 
 mouth sores, vomiting blood, inflamation of the lips, dry lips, coated tongue 
 running nose 
 skin lesions, dry skin 
 stiffness of muscles or joints, joint pain with or without inflammation 
 changes in some values of your blood cells or chemistry. These can be seen in the results of 

blood and/or urine tests. Your doctor will explain these to you. Examples are: increase in some 
white blood cells. 

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

serious. 

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. 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 Darunavir Krka d.d.

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 packaging after EXP. The expiry 
date refers to the last day of that month.

Keep the bottle tightly closed in order to protect from moisture.
Shelf life after first opening: 3 months.

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

6. Contents of the pack and other information

What Darunavir Krka d.d. contains
- The active substance is darunavir. Each film-coated tablet contains 400 mg or 800 mg 

darunavir.
- The other ingredients are cellulose, microcrystalline; crospovidone, hydroxypropylcellulose;

silica, colloidal anhydrous; silicified microcrystalline cellulose (cellulose, microcrystalline; 
silica, colloidal anhydrous) and magnesium stearate (E470b) in the tablet core and poly(vinyl 
alcohol), macrogol, titanium dioxide (E171), talc (E553b), yellow iron oxide (E172) – only for 
400 mg film-coated tablets and red iron oxide (E172) in film coating.

What Darunavir Krka d.d. looks like and contents of the pack
Darunavir Krka d.d. 400 mg film-coated tablets (tablets):
Yellowish brown, oval, biconvex film-coated tablets (tablets), engraved with a mark S1 on one side. 



99

Tablet dimension: 17 x 8.5 mm.
Darunavir Krka d.d. 800 mg film-coated tablets (tablets):
Brownish red, oval, biconvex film-coated tablets (tablets), engraved with a mark S3 on one side. 
Tablet dimension: 20 x 10 mm.

Darunavir Krka d.d. 400 mg film-coated tablets are available in bottles containing 30 film-coated 
tablets (1 bottle of 30 film-coated tablets), 60 film-coated tablets (2 bottles of 30 film-coated tablets), 
90 film-coated tablets (3 bottles of 30 film-coated tablets) and 180 film-coated tablets (6 bottles of 30 
film-coated tablets) in a box.
Darunavir Krka d.d. 800 mg film-coated tablets are available in bottles containing 30 film-coated 
tablets (1 bottle of 30 film-coated tablets) and 90 film-coated tablets (3 bottles of 30 film-coated 
tablets) in a box.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
TAD Pharma GmbH, Heinz-Lohmann-Straβe 5, 27472 Cuxhaven, Germany

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

België/Belgique/Belgien
KRKA Belgium, SA.
Tél/Tel: +32 (0) 487 50 73 62

Lietuva
UAB KRKA Lietuva
Tel: + 370 5 236 27 40

България
КРКА България ЕООД
Teл.: + 359 (02) 962 34 50

Luxembourg/Luxemburg
KRKA Belgium, SA.
Tél/Tel: +32 (0) 487 50 73 62 (BE)

Česká republika
KRKA ČR, s.r.o.
Tel: + 420 (0) 221 115 150

Magyarország
KRKA Magyarország Kereskedelmi Kft.
Tel.: + 36 (1) 355 8490

Danmark
KRKA Sverige AB
Tlf: + 46 (0)8 643 67 66 (SE)

Malta
E. J. Busuttil Ltd.
Tel: + 356 21 445 885

Deutschland
TAD Pharma GmbH
Tel: + 49 (0) 4721 606-0

Nederland
KRKA Belgium, SA.
Tel: +32 (0) 487 50 73 62 (BE)

Eesti
KRKA, d.d., Novo mesto Eesti filiaal
Tel: + 372 (0) 6 671 658

Norge
KRKA Sverige AB
Tlf: + 46 (0)8 643 67 66 (SE)

Ελλάδα
QUALIA PHARMA S.A.
Τηλ: +30 210 6256177

Österreich
KRKA Pharma GmbH, Wien
Tel: + 43 (0)1 66 24 300

España
KRKA Farmacéutica, S.L.
Tel: + 34 911 61 03 81

Polska
KRKA-POLSKA Sp. z o.o.
Tel.: + 48 (0)22 573 7500

France Portugal



100

KRKA France Eurl
Tél: + 33 (0)1 57 40 82 25

KRKA Farmacêutica, Sociedade Unipessoal Lda.
Tel: + 351 (0)21 46 43 650

Hrvatska
KRKA - FARMA d.o.o.
Tel: + 385 1 6312 100

România
KRKA Romania S.R.L., Bucharest
Tel: + 4 021 310 66 05

Ireland
KRKA Pharma Dublin, Ltd.
Tel: + 353 1 293 91 80

Slovenija
KRKA, d.d., Novo mesto
Tel: + 386 (0) 1 47 51 100

Ísland
LYFIS ehf.
Sími: + 354 534 3500

Slovenská republika
KRKA Slovensko, s.r.o.
Tel: + 421 (0) 2 571 04 501

Italia
KRKA Farmaceutici Milano S.r.l.
Tel: + 39 02 3300 8841

Suomi/Finland
KRKA Finland Oy
Puh/Tel: +358 20 754 5330

Κύπρος
KI.PA. (PHARMACAL) LIMITED
Τηλ: + 357 24 651 882

Sverige
KRKA Sverige AB
Tel: + 46 (0)8 643 67 66 (SE)

Latvija
KRKA Latvija SIA
Tel: + 371 6 733 86 10

United Kingdom
Krka UK Ltd.
Tel: +44 (0)207 400 3352

This leaflet was last revised in

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



101

Package leaflet: Information for the patient

Darunavir Krka d.d. 600 mg film-coated tablets
darunavir

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 or pharmacist.
- 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 or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

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

1. What Darunavir Krka d.d. is and what it is used for

What is Darunavir Krka d.d.? 
Darunavir Krka d.d. contains the active substance darunavir. Darunavir Krka d.d. is an antiretroviral 
medicine used in the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a 
group of medicines called protease inhibitors. Darunavir Krka d.d. works by reducing the amount of 
HIV in your body. This will improve your immune system and reduces the risk of developing illnesses 
linked to HIV infection. 

What it is used for? 
Darunavir Krka d.d. is used to treat adults and children of 3 years of age and above, and at least 15 
kilogram body weight who are infected by HIV and who have already used other antiretroviral 
medicines. 

Darunavir Krka d.d. must be taken in combination with a low dose of ritonavir and other anti-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 Darunavir Krka d.d.

Do not take Darunavir Krka d.d.
 if you are allergic to active substance 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 Darunavir Krka d.d. 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 
Avanafil to treat erectile dysfunction 
Astemizole or terfenadine to treat allergy symptoms 
Triazolam and oral (taken by mouth)
midazolam 

to help you sleep and/or relieve anxiety 



102

Cisapride to treat some stomach conditions 
Colchicine (if you have kidney and/or liver 
problems) 

to treat gout or familial Mediterranean fever 

Lurasidone, pimozide, quetiapine or 
sertindole 

to treat psychiatric conditions 

Ergot alkaloids like ergotamine, 
dihydroergotamine, ergometrine and 
methylergonovine 

to treat migraine headaches 

Amiodarone, bepridil, dronedarone,
ivabradine, quinidine, ranolazine 

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

Lovastatin, simvastatin and lomitapide to lower cholesterol levels 
Rifampicin to treat some infections such as tuberculosis 
The combination product lopinavir/ritonavir this anti-HIV medicine belongs to the same 

class as Darunavir Krka d.d.
Elbasvir/grazoprevir to treat hepatitis C infection
Alfuzosin to treat enlarged prostate 
Sildenafil to treat high blood pressure in the pulmonary 

circulation 
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

Do not combine Darunavir Krka d.d. with products that contain St John’s wort (Hypericum 
perforatum). 

Warnings and precautions 
Talk to your doctor, pharmacist or nurse before taking Darunavir Krka d.d.. 

Darunavir Krka d.d. is not a cure for HIV infection. 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 Darunavir Krka d.d. may still develop infections or other illnesses associated with HIV 
infection. You must keep in regular contact with your doctor. 

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

Tell your doctor about your situation BEFORE and DURING your treatment 
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 Darunavir Krka d.d.. 

 Tell your doctor if you have diabetes. Darunavir Krka d.d.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 
opportunistic infection, signs and symptoms of inflammation from previous infections may 
occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an 
improvement in the body’s immune response, enabling the body to fight infections that may 



103

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 to seek 
necessary treatment. 

 Tell your doctor if you have haemophilia. Darunavir Krka d.d. 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). The length of combination 
antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, 
higher body mass index, among others, may be some of the many risk factors for developing 
this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, 
knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your doctor. 

Elderly
Darunavir Krka d.d. 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 Darunavir Krka d.d.. 

Children and adolescents
Darunavir Krka d.d. is not for use in children younger than 3 years of age or weighing less than 15 
kilograms. 

Other medicines and Darunavir Krka d.d.
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 Darunavir Krka d.d.. These are mentioned 
above under the heading ‘Do not combine Darunavir Krka d.d. with any of the following medicines:’ 

In most cases, Darunavir Krka d.d. can be combined with anti-HIV medicines belonging to another 
class [e.g. NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse 
transcriptase inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. Darunavir Krka d.d. with 
ritonavir has not been tested with all PIs (protease inhibitors) and must not be used with other HIV 
PIs. 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 Darunavir Krka d.d. might be reduced if you take any of the following products. Tell 
your doctor if you take: 
 Phenobarbital, phenytoin (to prevent seizures) 
 Dexamethasone (corticosteroid) 
 Efavirenz (HIV infection) 
 Boceprevir (hepatitis C infection) 
 Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis) 
 Saquinavir (HIV infection). 

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

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



104

 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. 

 Oestrogen-based hormonal contraceptives and hormonal replacement therapy. Darunavir Krka
d.d. might reduce its effectiveness. When used for birth control, alternative methods of non-
hormonal contraception are recommended. 

 Ethinylestradiol/drospirenone. Darunavir Krka d.d. might increase the risk for elevated 
potassium levels by drospirenone.

 Atorvastatin, 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. 

 Clarithromycin (antibiotic) 
 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 bethametasone, 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 (medicines to treat opioid dependence) 
 Salmeterol (medicine to treat asthma) 
 Artemether/lumefantrine (a combination medicine to treat malaria) 
 Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine (to treat cancer) 
 Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder 

called pulmonary arterial hypertension) 
 Glecaprevir/pibrentasvir, simeprevir (to treat hepatitis C infection)
 Fentanyl, oxycodone, tramadol (to treat pain)
 Fesoterodine, solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or Darunavir Krka d.d.
d.d.’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) 
 Itraconazole, isavuconazole, fluconazole, posaconazole, clotrimazole (to treat fungal 

infections). Voriconazole should only be taken after medical evaluation. 
 Rifabutin (against bacterial infections) 
 Sildenafil, vardenafil, tadalafil (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) 
 Methadone (to treat opiate dependance) 
 Carbamazepine, clonazepam (to prevent seizures or to treat certain types of nerve pain) 
 Colchicine (to treat gout or familial Mediterranean fever) 
 Bosentan (to treat high blood pressure in the pulmonary circulation) 
 Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam when used as injection, 

zoldipem (sedative agents) 
 Perphenazine, risperidone, thioridazine (to treat psychiatric conditions). 

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

Darunavir Krka d.d. with food and drink 



105

See section 3 ‘How to take Darunavir Krka d.d..’ 

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 Darunavir Krka d.d. with ritonavir unless 
specifically directed by the doctor. Pregnant or breast feeding mothers should not take darunavir with 
cobicistat.

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 Darunavir Krka d.d..

3. How to take Darunavir Krka d.d.

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has 
told you. Check with your doctor, pharmacist or nurse if you are not sure. 
Even if you feel better, do not stop taking Darunavir Krka d.d. and ritonavir without talking to your 
doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be 
stopped without instruction of the doctor. 

Darunavir Krka d.d. 600 mg film coated tablets must not be chewed or crushed. This strength is not 
suitable for dosages below 600 mg.  It is not possible to administer all paediatric dosages with this 
product. Other tablet strengths and formulations of darunavir are available.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine 
this) 
You will require a different dose of Darunavir Krka d.d. which cannot be administered with these 600 
milligram tablets. Other strengths of Darunavir Krka d.d. are available.

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this) 
The dose is either: 
 600 milligram Darunavir Krka d.d. (1 tablet containing 600 milligram of Darunavir Krka d.d.) 

together with 100 milligram ritonavir twice daily. 
OR 
 800 milligram Darunavir Krka d.d. (2 tablets containing 400 milligram of Darunavir Krka d.d.

or 1 tablet containing 800 milligram of Darunavir Krka d.d.) together with 100 milligram 
ritonavir once daily. Darunavir Krka d.d. 400 milligram and 800 milligram tablets are only to be 
used to construct the once daily 800 milligram regimen.

Please discuss with your doctor which dose is right for you. 

Instructions for adults 
 Take Darunavir Krka d.d. always together with ritonavir. Darunavir Krka d.d. cannot work 

properly without ritonavir.
 In the morning, take one 600 milligram Darunavir Krka d.d. tablet together with 100 milligram 

ritonavir. 
 In the evening, take one 600 milligram Darunavir Krka d.d. tablet together with 100 milligram 

ritonavir. 
 Take Darunavir Krka d.d. with food. Darunavir Krka d.d. cannot work properly without food. 

The type of food is not important. 
 Swallow the tablets with a drink such as water or milk. 



106

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have not taken 
antiretroviral medicines before (your child’s doctor will determine this) 
The doctor will work out the right once daily dose based on the weight of the child (see table below). 
This dose must not exceed the recommended adult dose, which is 800 milligram Darunavir Krka d.d.
together with 100 milligram ritonavir once a day.
The doctor will inform you on how much Darunavir Krka d.d. tablets the child must take.

Weight Darunavir dose is One ritonavira dose is
between 15 and 30 kilograms 600 milligram 100 milligram
between 30 and 40 kilograms 675 milligram 100 milligram
more than 40 kilograms 800 milligram 100 milligram
a ritonavir oral solution: 80 milligram per millilitre

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have taken 
antiretroviral medicines before (your child’s doctor will determine this) 
The doctor will work out the right dose based on the weight of the child (see table below). The doctor 
will determine if once daily dosing or twice daily dosing is appropriate for the child. This dose must 
not exceed the recommended adult dose, which is 600 milligram Darunavir Krka d.d. together with 
100 miligran of ritonavir two times per day or 800 milligram Darunavir Krka d.d. together with 100 
miligran of ritonavir once a day. The doctor will inform you on how many Darunavir Krka d.d. tablets 
and how much ritonavir (capsules, tablets or solution) the child must take. Tablets of lower strengths 
are available to construct the appropriate dosing regimen. 
Your doctor will determine whether Darunavir Krka d.d. tablets is right for the child.

Twice daily dosing
Weight One dose is 
between 15 and 30 kilograms 375 milligram darunavir + 50 milligram ritonavir 

twice a day 
between 30 and 40 kilograms 450 milligram darunavir + 60 milligram ritonavir 

twice a day 
more than 40 kilograms* 600 milligram darunavir + 100 milligram 

ritonavir twice a day 
* For children aged 12 or more and weighing at least 40 kilograms, your child’s doctor will determine if Darunavir Krka d.d.
800 milligram once daily dosing may be used. This cannot be administered with these 600 milligram tablets. Other strengths 
of Darunavir Krka d.d. are available.

Once daily dosing
Weight Darunavir dose is One ritonavira dose is
between 15 and 30 kilograms 600 milligram 100 milligram
between 30 and 40 kilograms 675 milligram 100 milligram
more than 40 kilograms 800 milligram 100 milligram
a ritonavir oral solution: 80 milligram per millilitre

Instructions for children 
 The child must take Darunavir Krka d.d. always together with ritonavir. Darunavir Krka d.d. 

cannot work properly without ritonavir.
 The child must take the appropriate doses of Darunavir Krka d.d. and ritonavir two times per 

day or once a day. If prescribed Darunavir Krka d.d. twice daily the child must take one dose in 
the morning, and one dose in the evening. Your child’s doctor will determine the appropriate 
dosing regimen for your child. 

 The child must take Darunavir Krka d.d. with food. Darunavir Krka d.d. cannot work properly 
without food. The type of food is not important. 

 The child must swallow the tablets with a drink such as water or milk. 

If you take more Darunavir Krka d.d. than you should 
Contact your doctor, pharmacist or nurse immediately. 



107

If you forget to take Darunavir Krka d.d.
If you notice within 6 hours, you must take your missed dose immediately. Always take with 
ritonavir and food. If you notice after 6 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. 

Do not stop taking Darunavir Krka d.d. without talking to your doctor first 
Anti-HIV medicine may make you feel better. Even when you feel better, do not stop taking Darunavir 
Krka d.d.. 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. 

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 Darunavir Krka d.d.. 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. 

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 Darunavir Krka d.d. must be stopped. 

Other severe side effectswere diabetes (common) and inflammation of the pancreas (uncommon).

Very common side effects (may affect more than 1 in 10 people) 
 diarrhoea. 

Common side effects (may affect up to 1 in 10 people) 
 vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence 
 headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of 

strength, difficulty falling asleep. 

Uncommon side effects (may affect up to 1 in 100 people) 
 chest pain, changes in electrocardiogram, rapid heart beating 
 decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory, 

problems with your balance 
 difficulty breathing, cough, nosebleed, throat irritation 
 inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the 

abdomen, constipation, belching 
 kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of 

urine, sometimes at night 
 urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema, 

excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails 



108

 muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis 
 slowing down of the thyroid gland function. This can be seen in a blood test. 
 high blood pressure, flushing 
 red or dry eyes 
 fever, swelling of lower limbs due to fluids, malaise, irritability, pain 
 symptoms of infection, herpes simplex 
 erectile dysfunction, enlargement of breasts 
 sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive 

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] 

 heart attack, slow heart beating, palpitations 
 visual disturbance 
 chills, feeling abnormal 
 a feeling of confusion or disorientation, altered mood, restlessness 
 fainting, epileptic fits, changes or loss of taste 
 mouth sores, vomiting blood, inflamation of the lips, dry lips, coated tongue 
 running nose 
 skin lesions, dry skin 
 stiffness of muscles or joints, joint pain with or without inflammation 
 changes in some values of your blood cells or chemistry. These can be seen in the results of 

blood and/or urine tests. Your doctor will explain these to you. Examples are: increase in some 
white blood cells. 

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

serious. 

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. 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 Darunavir Krka d.d.

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 packaging after EXP. The expiry 
date refers to the last day of that month.

Keep the bottle tightly closed in order to protect from moisture.
Shelf life after first opening: 3 months.

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

6. Contents of the pack and other information

What Darunavir Krka d.d. contains
- The active substance is darunavir. Each film-coated tablet contains 600 mg darunavir.



109

- The other ingredients are cellulose, microcrystalline; crospovidone, hydroxypropylcellulose;
silica, colloidal anhydrous; silicified microcrystalline cellulose (cellulose, microcrystalline; 
silica, colloidal anhydrous) and magnesium stearate (E470b) in the tablet core and poly(vinyl 
alcohol), macrogol, titanium dioxide (E171), talc (E553b), yellow iron oxide (E172) and red 
iron oxide (E172) in film coating.

What Darunavir Krka d.d. looks like and contents of the pack
Film-coated tablets (tablets) are orangish brown, oval, biconvex, engraved with a mark S2 on one side. 
Tablet dimension: 19.5 x 10 mm.

Darunavir Krka d.d. is available in bottles containing 30 film-coated tablets (1 bottle of 30 film-coated 
tablets), 60 film-coated tablets (2 bottles of 30 film-coated tablets), 90 film-coated tablets (3 bottles of 
30 film-coated tablets) and 180 film-coated tablets (6 bottles of 30 film-coated tablets) in a boxes.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
TAD Pharma GmbH, Heinz-Lohmann-Straβe 5, 27472 Cuxhaven, Germany

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

België/Belgique/Belgien
KRKA Belgium, SA.
Tél/Tel: +32 (0) 487 50 73 62

Lietuva
UAB KRKA Lietuva
Tel: + 370 5 236 27 40

България
КРКА България ЕООД
Teл.: + 359 (02) 962 34 50

Luxembourg/Luxemburg
KRKA Belgium, SA.
Tél/Tel: +32 (0) 487 50 73 62 (BE)

Česká republika
KRKA ČR, s.r.o.
Tel: + 420 (0) 221 115 150

Magyarország
KRKA Magyarország Kereskedelmi Kft.
Tel.: + 36 (1) 355 8490

Danmark
KRKA Sverige AB
Tlf: + 46 (0)8 643 67 66 (SE)

Malta
E. J. Busuttil Ltd.
Tel: + 356 21 445 885

Deutschland
TAD Pharma GmbH
Tel: + 49 (0) 4721 606-0

Nederland
KRKA Belgium, SA.
Tel: +32 (0) 487 50 73 62 (BE)

Eesti
KRKA, d.d., Novo mesto Eesti filiaal
Tel: + 372 (0) 6 671 658

Norge
KRKA Sverige AB
Tlf: + 46 (0)8 643 67 66 (SE)

Ελλάδα
QUALIA PHARMA S.A.
Τηλ: +30 210 6256177

Österreich
KRKA Pharma GmbH, Wien
Tel: + 43 (0)1 66 24 300

España
KRKA Farmacéutica, S.L.
Tel: + 34 911 61 03 81

Polska
KRKA-POLSKA Sp. z o.o.
Tel.: + 48 (0)22 573 7500



110

France
KRKA France Eurl
Tél: + 33 (0)1 57 40 82 25

Portugal
KRKA Farmacêutica, Sociedade Unipessoal Lda.
Tel: + 351 (0)21 46 43 650

Hrvatska
KRKA - FARMA d.o.o.
Tel: + 385 1 6312 100

România
KRKA Romania S.R.L., Bucharest
Tel: + 4 021 310 66 05

Ireland
KRKA Pharma Dublin, Ltd.
Tel: + 353 1 293 91 80

Slovenija
KRKA, d.d., Novo mesto
Tel: + 386 (0) 1 47 51 100

Ísland
LYFIS ehf.
Sími: + 354 534 3500

Slovenská republika
KRKA Slovensko, s.r.o.
Tel: + 421 (0) 2 571 04 501

Italia
KRKA Farmaceutici Milano S.r.l.
Tel: + 39 02 3300 8841

Suomi/Finland
KRKA Finland Oy
Puh/Tel: +358 20 754 5330

Κύπρος
KI.PA. (PHARMACAL) LIMITED
Τηλ: + 357 24 651 882

Sverige
KRKA Sverige AB
Tel: + 46 (0)8 643 67 66 (SE)

Latvija
KRKA Latvija SIA
Tel: + 371 6 733 86 10

United Kingdom
Krka UK Ltd.
Tel: +44 (0)207 400 3352

This leaflet was last revised in

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


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS 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