Symtuza

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Symtuza 800 mg/150 mg/200 mg/10 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 800 mg of darunavir (as ethanolate), 150 mg of cobicistat, 200 mg of
emtricitabine, and 10 mg of tenofovir alafenamide (as fumarate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Yellow to yellowish-brown capsule shaped tablet of 22 mm x 11 mm, debossed with “8121” on one 
side and “JG” on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Symtuza is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in 
adults and adolescents (aged 12 years and older with body weight at least 40 kg).
Genotypic testing should guide the use of Symtuza (see sections 4.2, 4.4, and 5.1).

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV-1 infection.

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

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

ART-experienced patients
One film-coated tablet of Symtuza once daily taken with food may be used in patients with prior 
exposure to antiretroviral medicinal products but without darunavir resistance associated mutations 
(DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/mL and CD4+ cell count 
≥ 100 cells x 106/L (see section 5.1).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V.

Advice on missed doses
If a dose of Symtuza is missed within 12 hours of the time it is usually taken, patients should be 
instructed to take the prescribed dose of Symtuza with food as soon as possible. If a missed dose is 
noticed later than 12 hours of the time it is usually taken, it should not be taken and the patient should 
resume the usual dosing schedule.



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In case a patient vomits within 1 hour of taking the medicine, another dose of Symtuza should be 
taken with food as soon as possible. If a patient vomits more than 1 hour after taking the medicine, the 
patient does not need to take another dose of Symtuza until the next regularly scheduled time.

Special populations

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

Hepatic impairment
No dose adjustment of Symtuza is required in patients with mild (Child-Pugh Class A) or moderate 
(Child-Pugh Class B) hepatic impairment, however, Symtuza should be used with caution in these 
patients, as the darunavir and cobicistat components of Symtuza are metabolised by the hepatic 
system.

Symtuza has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), 
therefore, Symtuza must not be used in patients with severe hepatic impairment (see sections 4.3, 4.4 
and 5.2).

Renal impairment
No dose adjustment of Symtuza is required in patients with estimated glomerular filtration rate 
according to the Cockcroft-Gault formula (eGFRCG) ≥ 30 mL/min.

Symtuza should not be initiated in patients with eGFRCG < 30 mL/min, as there are no data available 
regarding the use of Symtuza in this population (see sections 5.1 and 5.2).
Symtuza should be discontinued in patients with eGFRCG that declines below 30 mL/min during 
treatment (see sections 5.1 and 5.2).

Paediatric population
The safety and efficacy of Symtuza in children aged 3-11 years, or weighing < 40 kg, have not yet 
been established. No data are available.

Symtuza should not be used in paediatric patients below 3 years of age because of safety concerns (see 
sections 4.4 and 5.3).

Pregnancy and postpartum
Treatment with darunavir/cobicistat (two of the components of Symtuza) during pregnancy results in 
low darunavir exposure (see sections 4.4 and 5.2). Therefore, therapy with Symtuza should not be 
initiated during pregnancy, and women who become pregnant during therapy with Symtuza should be 
switched to an alternative regimen (see sections 4.4 and 4.6).

Method of administration

Symtuza should be taken orally, once daily with food (see section 5.2). The tablet should not be 
crushed.

4.3 Contraindications

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

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

Co-administration with the following medicinal products due to the potential for loss of therapeutic 
effect (see section 4.5):
- carbamazepine, phenobarbital, phenytoin
- rifampicin



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- lopinavir/ritonavir
- St. John’s wort (Hypericum perforatum)

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

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy (ART) 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.

ART-experienced patients
Symtuza should not be used in treatment-experienced patients with one or more DRV-RAMs (see 
section 5.1) or with HIV-1 RNA ≥ 100,000 copies/mL or CD4+ cell count < 100 cells x 106/L.

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

Patients co-infected with HIV and hepatitis B or C virus

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for 
severe and potentially fatal hepatic adverse reactions.

The safety and efficacy of Symtuza in patients co-infected with HIV-1 and hepatitis C virus (HCV) 
have not been established. Tenofovir alafenamide is active against hepatitis B virus (HBV).

In case of concomitant antiviral therapy for hepatitis C, please refer also to the relevant Summary of 
Product Characteristics for these medicinal products.

Discontinuation of Symtuza therapy in patients co-infected with HIV and HBV may be associated 
with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue 
Symtuza should be closely monitored with both clinical and laboratory follow-up for at least several 
months after stopping treatment. If appropriate, initiation of hepatitis B therapy may be warranted. In 
patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since 
post-treatment exacerbation of hepatitis may lead to hepatic decompensation.



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Symtuza should not be administered concomitantly with medicinal products containing tenofovir 
disoproxil (e.g. fumarate, phosphate, or succinate), lamivudine, or adefovir dipivoxil used for the 
treatment of HBV infection.

Mitochondrial dysfunction

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable 
degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV
negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse 
reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders 
(hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological 
disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological 
disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside 
and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up 
and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or 
symptoms. These findings do not affect current national recommendations to use antiretroviral therapy 
in pregnant women to prevent vertical transmission of HIV.

Elderly

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

Hepatotoxicity

Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with 
darunavir/ritonavir. 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 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 Symtuza 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 Symtuza 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 Symtuza, interruption or discontinuation of treatment 
should be considered promptly (see section 5.3).

Nephrotoxicity

A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to 
dosing with tenofovir alafenamide cannot be excluded (see section 5.3).

Renal impairment

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



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Patients with co-existing conditions

Hepatic impairment
The safety and efficacy of Symtuza or its components have not been established in patients with 
severe underlying liver disorders. Symtuza is, therefore, contraindicated in patients with severe hepatic 
impairment. Due to an increase in the unbound darunavir plasma concentrations, Symtuza should be 
used with caution in patients with mild or moderate hepatic impairment (see sections 4.2, 4.3 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 HIV PIs. In some patients 
additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was 
continued or reintroduced if treatment had been discontinued. A causal relationship has been 
suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should, 
therefore, be made aware of the possibility of increased bleeding.

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. Symtuza should be 
discontinued immediately if signs or symptoms of severe skin reactions develop. These can include, 
but are not limited to, severe rash or rash accompanied with fever, general malaise, fatigue, muscle or 
joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.

Sulphonamide allergy

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

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 Reactivation Syndrome

In HIV infected patients treated with CART, immune reactivation syndrome has been reported. In HIV 
infected patients with severe immune deficiency at the time of initiation of 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 include cytomegalovirus retinitis, 
generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii



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(formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and 
treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has 
been observed in clinical trials with darunavir co-administered with low dose ritonavir.
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment (see section 4.8).

Opportunistic infections

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

Interactions with medicinal products

Co-administration of other medicinal products
Symtuza is indicated for use as a complete regimen for the treatment of HIV-1 infection and should
not be administered with other antiretroviral products (see section 4.5). Symtuza should not be 
administered concomitantly with medicinal products requiring pharmacokinetic enhancement with 
ritonavir or cobicistat. Symtuza should not be administered concomitantly with medicinal products 
containing tenofovir disoproxil (as fumarate, phosphate or succinate), lamivudine, or adefovir 
dipivoxil used for the treatment of HBV infection.

Paediatric population

Symtuza should not be used in paediatric patients below 3 years of age (see sections 4.2 and 5.3).

4.5 Interaction with other medicinal products and other forms of interaction

No drug interaction trials have been performed using Symtuza. Interactions that have been identified 
in studies with individual components of Symtuza, i.e. with darunavir (in combination with low dose 
ritonavir), cobicistat, emtricitabine or tenofovir alafenamide, determine the interactions that may occur 
with Symtuza.

Darunavir and cobicistat

Darunavir is an inhibitor of CYP3A, a weak inhibitor of CYP2D6 and an inhibitor of P-gp. Cobicistat 
is a mechanism based inhibitor of CYP3A, and a weak CYP2D6 inhibitor. Cobicistat inhibits the 
transporters p-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Co-administration of 
cobicistat with medicinal products that are substrates of these transporters can result in increased 
plasma concentrations of the co-administered medicinal products. Cobicistat is not expected to inhibit 
CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Cobicistat is not expected to induce CYP1A2, 
CYP3A4, CYP2C9, CYP2C19, UGT1A1, or P-gp (MDR1).

Co-administration of Symtuza and medicinal products primarily metabolised by CYP3A may result in 
increased systemic exposure to such medicinal products, which could increase or prolong their
therapeutic effect and adverse reactions. Symtuza, therefore, 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 or table below).

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



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

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

Emtricitabine

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for 
CYP-mediated interactions involving emtricitabine with other medicinal products is low.

Emtricitabine did not inhibit the glucuronidation reaction of a non-specific UGT substrate in vitro. 
Co-administration of emtricitabine with medicinal products that are eliminated by active tubular 
secretion may increase concentrations of emtricitabine, and/or the co-administered medicinal product. 
Medicinal products that decrease renal function may increase concentrations of emtricitabine.

Tenofovir alafenamide

Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein 
(BCRP). Medicinal products that strongly affect P-gp activity and BCRP may lead to changes in 
tenofovir alafenamide absorption. Medicinal products that induce P-gp activity (e.g., rifampicin, 
rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofovir 
alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead to 
loss of therapeutic effect of tenofovir alafenamide and development of resistance. Co-administration 
of tenofovir alafenamide with other medicinal products that inhibit P-gp (e.g., cobicistat, ritonavir, 
ciclosporin) are expected to increase the absorption and plasma concentration of tenofovir 
alafenamide. It is not known whether the co-administration of tenofovir alafenamide and xanthine 
oxidase inhibitors (e.g. febuxostat) would increase systemic exposure to tenofovir.

Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or 
CYP2D6 in vitro. It is not an inhibitor of CYP3A4 in vivo. Tenofovir alafenamide is a substrate of 
OATP1B1 and OATP1B3 in vitro. The distribution of tenofovir alafenamide in the body may be 
affected by the activity of OATP1B1 and OATP1B3.

Interaction table

Expected interactions between Symtuza with potential concomitant medicinal products are listed in 
Table 1 below and are based on the studies conducted with the components of Symtuza, as individual 
agents or combined, or are potential drug interactions that may occur.

Interaction trials with the components of Symtuza have only been performed in adults.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as a 
pharmacokinetic enhancer; therefore, there may be different recommendations for the use of darunavir 
with concomitant medicines. Refer to the prescribing information for darunavir for further 
information.

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



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Table 1: Interactions between the individual components of Symtuza and other medicinal 
products

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

Interaction Recommendations concerning 
co-administration

ALPHA ADRENORECEPTOR ANTAGONISTS
Alfusozin Based on theoretical 

considerations
DRV/COBI is expected to 
increase alfusozin concentrations
(CYP3A4 inhibition)

The concomitant use of Symtuza
with alfusozin is contraindicated 
(see section 4.3).

ANAESTHETIC
Alfentanil Based on theoretical 

considerations DRV/COBI is 
expected to increase alfentanil 
plasma concentrations.

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

ANTACIDS
Aluminium/magnesium 
hydroxide
Calcium carbonate

No mechanistic interaction 
expected based on theoretical 
considerations.

Symtuza and antacids can be 
used concomitantly without dose 
adjustment.

ANTIANGINA/ANTIARRHYTHMIC
Disopyramide
Flecainide
Mexiletine
Propafenone
Lidocaine (systemic)

Amiodarone
Dronedarone
Ivabradine
Quinidine
Ranolazine

Based on theoretical 
considerations DRV/COBI is 
expected to increase these 
antiarrhythmic plasma 
concentrations.
(CYP3A inhibition)

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

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

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

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

ANTIBIOTIC
Clarithromycin Based on theoretical 

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

Caution should be exercised 
when clarithromycin is combined 
with Symtuza.

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



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ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban
Edoxaban
Rivaroxaban

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

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

Dabigatran
Ticagrelor

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

Concomitant administration of 
Symtuza 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 Based on theoretical 
considerations DRV/COBI may 
alter warfarin plasma 
concentrations.

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

ANTICONVULSANTS
Carbamazepine
Phenobarbital
Phenytoin

Oxcarbazepine

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

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

Co-administration of Symtuza
with oxcarbazepine is not 
recommended. Alternative 
anticonvulsants should be 
considered.

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

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

ANTI-DEPRESSANTS 
Herbal supplements
St. John’s wort

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

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



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Paroxetine
Sertraline

Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone

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

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

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

ANTI-DIABETICS 
Metformin Based on theoretical considerations 

DRV/COBI is expected to increase 
metformin plasma concentrations.
(MATE1 inhibition)

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

ANTIEMETICS
Domperidone Not studied. Co-administration of 

domperidone with Symtuza is 
contraindicated. 

ANTIFUNGALS
Clotrimazole
Fluconazole
Itraconazole

Isavuconazole
Posaconazole

Voriconazole

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

Concentrations of voriconazole 
may increase or decrease when 
co-administered with DRV/COBI.

Caution is warranted and clinical 
monitoring is recommended.

Therapeutic drug monitoring of 
voriconazole, posaconazole or 
itraconazole is recommended.

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

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

ANTIGOUT MEDICINES
Colchicine Based on theoretical considerations 

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

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



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ANTIMALARIALS
Artemether/Lumefantrine Based on theoretical considerations 

DRV/COBI is expected to increase 
lumefantrine plasma 
concentrations.
(CYP3A inhibition)

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

ANTIMYCOBACTERIALS
Rifampicin Based on theoretical considerations 

rifampicin is expected to decrease 
darunavir and/or cobicistat and/or 
tenofovir alafenamide plasma 
concentrations.
(CYP3A and/or P-gp induction)

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

Rifabutin
Rifapentine

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

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

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

ANTI-NEOPLASTICS
Dasatinib
Nilotinib
Vinblastine
Vincristine

Everolimus
Irinotecan

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

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

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



13

ANTIPSYCHOTICS/NEUROLEPTICS
Perphenazine
Risperidone
Thioridazine

Lurasidone
Pimozide
Quetiapine
Sertindole

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

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

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

β-BLOCKERS
Carvedilol
Metoprolol
Timolol

Based on theoretical considerations 
DRV/COBI is expected to increase 
these beta-blocker plasma 
concentrations.
(CYP2D6 inhibition)

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

CALCIUM CHANNEL BLOCKERS
Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil

Based on theoretical considerations 
DRV/COBI is expected to increase 
these calcium channel blocker 
plasma concentrations.
(CYP3A inhibition)

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

CORTICOSTEROIDS
Budesonide
Fluticasone

Prednisone

Based on theoretical considerations 
DRV/COBI is expected to increase 
these corticosteroid plasma 
concentrations.
(CYP3A inhibition)

Co-administration of Symtuza 
and budesonide or fluticasone is 
not recommended unless the 
potential benefit of treatment 
outweighs the risk of systemic 
corticosteroid side effects.

Concomitant use of Symtuza may 
increase the risk for development 
of systemic corticosteroid effects, 
including Cushing’s syndrome 
and adrenal suppression. Clinical 
monitoring is recommended 
when co-administering Symtuza 
with corticosteroids.

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

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

ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan Based on theoretical considerations 

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

Co-administration of Symtuza 
and bosentan is not 
recommended.



14

ERGOT DERIVATIVES
e.g.
Dihydroergotamine
Ergometrine
Ergotamine
Methylergonovine

Based on theoretical considerations 
DRV/COBI may increase ergot 
derivative exposure. 

Co-administration of Symtuza 
and ergot derivatives is 
contraindicated (see section 4.3).

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

Boceprevir Based on theoretical considerations 
boceprevir may decrease darunavir 
and/or cobicistat plasma 
concentrations and adversely affect 
the intracellular activation and 
clinical antiviral efficacy of 
tenofovir alafenamide. Symtuza 
may decrease boceprevir plasma 
concentrations.

It is not recommended to 
co-administer Symtuza with 
boceprevir.

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

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

Simeprevir Based on theoretical considerations 
DRV/COBI is expected to increase 
simeprevir plasma concentrations. 
Simeprevir may increase darunavir 
and/or cobicistat plasma 
concentrations.

It is not recommended to 
co-administer Symtuza with 
simeprevir.

Daclatasvir
Ledipasvir
Sofosbuvir

Based on theoretical 
considerations, no clinically 
relevant interaction is expected.

Symtuza and sofosbuvir, 
sofosbuvir/ledipasvir, or 
daclatasvir can be used 
concomitantly without dose 
adjustment 

Herbal products
St. John’s wort (Hypericum
Perforatum)

Based on theoretical consideration, 
St. John’s wort may substantially 
decrease DRV/COBI (CYP3A4 
induction) and TAF exposures.
(P-gp induction)

The concomitante use of Symtuza 
with these medicinal products is 
contraindicated (see section 4.3).

HMG CO-A REDUCTASE INHIBITORS
Atorvastatin
Fluvastatin
Pitavastatin
Pravastatin
Rosuvastatin

Lovastatin
Simvastatin

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

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

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

Concomitant use of a HMG CoA 
reductase inhibitor and Symtuza 
may increase plasma 
concentrations of the lipid 
lowering agent, which may lead 
to adverse reactions such as 
myopathy.
When administration of 
HMG CoA reductase inhibitors 
and Symtuza is desired, it is 
recommended to start with the 
lowest dose and titrate up to the 
desired clinical effect while 
monitoring for safety.

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



15

OTHER LIPID MODIFYING AGENTS
Lomitapide Based on theoretical 

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

Co-administration is 
contraindicated (see section 4.3)

H2-RECEPTOR ANTAGONISTS
Cimetidine
Famotidine
Nizatidine
Ranitidine

Based on theoretical 
considerations, no mechanistic 
interaction is expected.

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

IMMUNOSUPPRESSANTS
Ciclosporin
Sirolimus
Tacrolimus

Everolimus

Based on theoretical considerations 
DRV/COBI is expected to increase 
these immunosuppressant plasma 
concentrations.
(CYP3A inhibition)
Co-administration of ciclosporin is 
expected to increase plasma 
concentrations of tenofovir 
alafenamide.
(P-gp inhibition)

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

Concomitant use of everolimus 
and Symtuza is not 
recommended.

INHALED BETA AGONISTS
Salmeterol Based on theoretical considerations 

DRV/COBI is expected to increase 
salmeterol plasma concentrations.
(CYP3A inhibition)

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

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

DRV/COBI may increase 
buprenorphine and/or 
norbuprenorphine plasma 
concentrations.

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

Methadone Based on theoretical considerations 
DRV/COBI may increase 
methadone plasma concentrations.

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

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

Fentanyl
Oxycodone
Tramadol

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

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



16

OESTROGEN-BASED CONTRACEPTIVES
Drospirenone Ethinylestradiol 
(3 mg/0.02 mg once daily)

Ethinyl estradiol

Norethindrone

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

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

Based on theoretical considerations 
DRV/COBI may alter 
norethindrone plasma 
concentrations.

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

OPIOID ANTAGONIST
Naloxegol Not studied. Co-administration of Symtuza

and naloxegol is contraindicated. 
PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of erectile 
dysfunction

Sildenafil
Tadalafil
Vardenafil

Avanafil

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

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

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

For the treatment of pulmonary 
arterial hypertension

Sildenafil
Tadalafil

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

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



17

PROTON PUMP INHIBITORS
Dexlansoprazole
Esomeprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole

Based on theoretical 
considerations, no mechanistic 
interaction is expected.

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

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

Midazolam (oral)
Triazolam

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

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

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

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

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

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

with dapoxetine is 
contraindicated.

UROLOGICAL DRUGS
Fesoterodine
Solifenacin

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

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Treatment with darunavir/cobicistat (two of the components of Symtuza) 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. Therefore, therapy with Symtuza should 



18

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

Breast-feeding

Emtricitabine is excreted in human milk. It is not known whether darunavir, cobicistat, or tenofovir 
alafenamide are excreted in human milk. Studies in animals have demonstrated that darunavir, 
cobicistat and tenofovir are excreted in milk.

Because of both the potential for HIV transmission and the potential for adverse reactions in breast-fed 
infants, mothers should be instructed not to breast-feed if they are receiving Symtuza.

Fertility

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

4.7 Effects on ability to drive and use machines

Patients should be informed that dizziness may occur when treated with Symtuza (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile
The overall safety profile of Symtuza is based on data from a randomised, double-blinded, 
comparative Phase 2 trial, GS-US-299-0102 (N = 103 on darunavir/cobicistat/emtricitabine/tenofovir 
alafenamide [D/C/F/TAF]), data from 2 Phase 3 trials TMC114FD2HTX3001 (AMBER, N = 362 on 
D/C/F/TAF) and TMC114IFD3013 (EMERALD, N = 763 on D/C/F/TAF), and on all available 
clinical trial and post-marketing data of its components. As Symtuza contains darunavir, cobicistat, 
emtricitabine, and tenofovir alafenamide, the adverse reactions associated with each of the individual 
compounds may be expected.

The most frequent (> 5%) adverse reactions reported in treatment-naïve patients in the Phase 2 (GS-
US-299-0102) and Phase 3 Study (AMBER, TMC114FD2HTX3001, Week 96 analysis) were 
diarrhoea (22.6%), headache (13.1%), rash (12.7%), nausea (9.7%), fatigue (8.0%), and abdominal 
pain (5.8%).

The most frequent (> 5%) adverse reactions reported in suppressed treatment-experienced patients 
(EMERALD Study TMC114IFD3013, Week 96 analysis) were diarrhoea (10.5%), headache (10.4%), 
arthralgia (7.7%), abdominal pain (7.5%), fatigue (5.9%), and rash (5.1%).

Tabulated list of adverse reactions

Adverse reactions are listed by system organ class (SOC) and frequency category in Table 2. 
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)

Table 2
MedDRA system organ class
Frequency category

Adverse reaction

Blood and lymphatic system disorders
common anaemia
Immune system disorders
common (drug) hypersensitivity
uncommon immune reconstitution inflammatory syndrome



19

Metabolism and nutrition disorders
common diabetes mellitus, anorexia, 

hypercholesterolaemia, low density lipoprotein
increased, hypertriglyceridaemia, 
hyperlipidaemia, dyslipidaemia

uncommon hyperglycaemia
Psychiatric disorders
common abnormal dreams
Nervous system disorders
very common headache
common dizziness
Gastrointestinal disorders
very common diarrhoea
common vomiting, nausea, abdominal pain, abdominal 

distension, dyspepsia, flatulence
uncommon pancreatitis acute, pancreatic enzymes increased
Hepatobiliary disorders
common hepatic enzyme increased
uncommon acute hepatitisa, cytolytic hepatitisa

Skin and subcutaneous tissue disorders
very common rash (including macular, maculopapular, 

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

common pruritus, urticaria
uncommon angioedema
rare drug reaction with eosinophilia and systemic 

symptomsa, Stevens-Johnson syndromea

not known toxic epidermal necrolysisa, acute generalised 
exanthematous pustulosisa

Musculoskeletal and connective tissue disorders
common arthralgia, myalgia
uncommon osteonecrosis
Reproductive system and breast disorders
uncommon gynaecomastiaa

General disorders and administration site conditions
common asthenia, fatigue
Investigations
common increased blood creatinine
a

Additional adverse drug reactions only seen with darunavir/ritonavir in other trials or postmarketing experience

Description of selected adverse reactions

Rash
Rash is a common adverse drug reaction in patients treated with darunavir. Rash was mostly mild to 
moderate, often occurring within the first four weeks of treatment and resolving with continued dosing 
(see section 4.4). In the Phase 2/3 trials in treatment-naïve patients, 12.7% (59/465) of patients 
receiving Symtuza experienced rash (most of which were grade 1), 1.5% (7/465) of patients 
discontinued treatment due to rash, of whom one for rash and hypersensitivity. In the Phase 3 trial in 
suppressed treatment-experienced patients (EMERALD Study TMC114IFD3013), 5.1% (39/763) of 
patients receiving Symtuza experienced rash (most of which were grade 1), none discontinued 
treatment due to rash.

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



20

In the Phase 3 trial of Symtuza in treatment-naïve patients, increases from baseline were observed in 
the fasting lipid parameters total cholesterol, direct LDL and HDL cholesterol, and triglycerides at 
Week 48 and 96 (see Table 3). The median increases from baseline were greater in the D/C/F/TAF 
group compared with the DRV/ cobicistat (COBI)+F/ tenofovir disoproxil fumarate (TDF) group at
Week 48.

Table 3

Lipid Parameter Baseline Median
Median Increase From Baseline at

Week 48 
D/C/F/TAF

Week 48
D/C + F/TDF

Week 96*
D/C/F/TAF

Total cholesterol 
(mmol/L)

4.22 0.74 0.27 0.88

LDL cholesterol 
(mmol/L)

2.49 0.45 0.13 0.56

HDL cholesterol 
(mmol/L)

1.08 0.12 0.04 0.13

Triglycerides 
(mmol/L)

1.09 0.28 0.16 0.33

p < 0.001 for all 4 lipid parameters when comparing D/C/F/TAF versus D/C + F/TDF at Week 48
* No comparator data available beyond Week 48

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

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

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

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

Decrease estimated creatinine clearance
Cobicistat increases serum creatinine due to inhibition of tubular secretion of creatinine without 
affecting renal glomerular function as assessed, for instance, by using Cystatin C (Cyst C) as filtration 
marker.

In the Phase 3 trial of Symtuza in treatment-naïve patients, increases in serum creatinine and decreases 
in eGFRCG occurred at the first on-treatment assessment (Week 2) and remained stable through 
96 weeks. At Week 48 changes from baseline were smaller with D/C/F/TAF than D/C+F/TDF. The 
median change in eGFRCG was -5.5 mL/min with D/C/F/TAF and -12.0 mL/min with D/C+F/TDF 
(p < 0.001). Using Cyst C as filtration marker, the median changes in estimated glomerular filtration 
rate calculated using the CKD-EPI (eGFRCKD-EPI CystC) formula were respectively 4.0 mL/min/1.73 m² 
and 1.6 mL/min/1.73 m² (p<0.001). At Week 96, the median change in eGFRCG was -5.2 mL/min with 
D/C/F/TAF. Using Cyst C as filtration marker, the median change in estimated glomerular filtration 
rate calculated using the CKD-EPI (eGFRCKD-EPI Cyst C) formula (N=22) was +4.4 mL/min/1.73 m² with 
D/C/F/TAF. 



21

Paediatric population

The safety of Symtuza in paediatric patients has not been investigated. However,the safety of 
components of Symtuza was evaluated through the clinical study TMC114-C230 (N = 12) for 
darunavir with ritonavir and GS-US-292-0106 (N = 50) for a fixed dose combination containing
elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide. The data from these studies showed 
that the overall safety profile of components of Symtuza in paediatric patients aged 12 to < 18 years 
and weighing at least 40 kg was similar to that observed in the adult population (see section 5.1).

Other special populations

Patients co-infected with hepatitis B and/or hepatitis C virus
Limited information is available on the use of Symtuza components in patients co-infected with 
hepatitis B and/or C virus.

Among 1,968 treatment-experienced patients receiving darunavir co-administered with ritonavir 
600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were 
more likely to have baseline and treatment emergent hepatic transaminase elevations than those 
without chronic viral hepatitis. The safety of emtricitabine and tenofovir alafenamide in combination 
with elvitegravir and cobicistat as a fixed-dose combination tablet was evaluated in approximately 70 
HIV/HBV co-infected patients currently receiving treatment for HIV in an open-label clinical study 
(GS-US-292-1249). Based on this limited experience, the safety profile of emtricitabine/tenofovir 
alafenamide in patients with HIV/HBV co-infection appears to be similar to that in patients with
HIV-1 monoinfection (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 Symtuza is limited.
If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8).

There is no specific antidote for overdose with Symtuza. Treatment of overdose with Symtuza consists 
of general supportive measures, including monitoring of vital signs as well as observation of the 
clinical status of the patient.

Since darunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be 
significantly removed by haemodialysis or peritoneal dialysis. Emtricitabine can be removed by 
haemodialysis, which removes approximately 30% of the emtricitabine dose over a 3 hour dialysis 
period starting within 1.5 hours of emtricitabine dosing. Tenofovir is efficiently removed by 
haemodialysis with an extraction coefficient of approximately 54%. It is not known whether 
emtricitabine or tenofovir can be removed by peritoneal dialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infection,
combinations ATC code: J05AR22

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


22

Mechanism of action

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

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

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

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and nucleoside analogue of
2’-deoxycytidine. Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 
triphosphate. Emtricitabine triphosphate inhibits HIV replication through incorporation into viral DNA 
by the HIV reverse transcriptase (RT), which results in DNA chain-termination.

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and phosphonoamidate 
prodrug of tenofovir (2’-deoxyadenosine monophosphate analogue). Tenofovir alafenamide is 
permeable into cells and due to increased plasma stability and intracellular activation through 
hydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovir disoproxil in 
concentrating tenofovir in peripheral blood mononuclear cells (PBMC) (including lymphocytes and 
other HIV target cells) and macrophages. Intracellular tenofovir is subsequently phosphorylated to the 
pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV 
replication through incorporation into viral DNA by the HIV RT, which results in DNA 
chain-termination.

Antiviral activity in vitro

Darunavir, emtricitabine and tenofovir alafenamide demonstrated additive to synergistic antiviral 
effects in two-drug combination studies in cell culture.

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

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

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in 
lymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs. The EC50 values for emtricitabine 
were in the range of 0.0013 to 0.64 μM. Emtricitabine displayed antiviral activity in cell culture 
against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 μM) and 
showed strain specific activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 μM).

The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV-1 
subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells 
and CD4+-T lymphocytes. The EC50 values for tenofovir alafenamide were in the range of 2.0 to 
14.7 nM. Tenofovir alafenamide displayed antiviral activity in cell culture against all HIV-1 groups 
(M, N, and O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) 
and showed strain specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM).



23

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.

In vivo, darunavir resistance-associated mutations (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, 
L76V, I84V and L89V) in HIV-1 protease were derived from clinical trial data of ART-experienced 
patients, all of whom were protease inhibitor experienced.

Reduced susceptibility to emtricitabine is associated with M184V/I mutations in HIV-1 RT.

HIV-1 isolates with reduced susceptibility to tenofovir alafenamide express a K65R mutation in
HIV-1 RT; in addition, a K70E mutation in HIV-1 RT has been transiently observed. HIV-1 isolates 
with the K65R mutation have low-level reduced susceptibility to abacavir, emtricitabine, tenofovir, 
and lamivudine.

Emerging resistance in HIV-1 infected, treatment-naïve and virologically suppressed patients

Over 96 weeks of treatment in the Phase 3 studies TMC114FD2HTX3001 (AMBER) in treatment-
naïve patients and TMC114IFD3013 (EMERALD) in virologically suppressed treatment-experienced 
patients, resistance testing was performed on samples from patients experiencing protocol-defined 
virologic failure (PDVF) and who had HIV-1 RNA ≥400 copies/mL at failure or at later time points. 
Emerging resistance in the Symtuza groups is shown in Table 4. No DRV, primary PI, or TDF/TAF 
resistance-associated mutations were observed.

Table 4: Emerging Resistance in AMBER and EMERALD Trial (Week 96)

Study
Treatment 

group
Subjects,

n

Subjects 
with 

PDVF, 
n (%)

Subjects 
with PDVF 
evaluated 

for 
resistance, 

n (%)

Subjects with ≥1 emergent RAM, n (%)

Protease Reverse transcriptase

Primary 
PI/DRV

TDF/
TAF FTC

TMC114FD2HTX3001 Symtuza 362 15 (4.1) 9 (2.5) 0 0
1

(M184I/V)a

TMC114IFD3013 Symtuza 763 24 (3.1) 4 (0.5) 0 0 0

Total Phase 3 Symtuza 1,125 39 (3.5) 13 (1.2) 0 0 1 (0.1)
a At Week 36 M184M/I/V observed, conferring resistance to FTC. This subject harbored a K103N mutation at 
  screening, indicating transmitted NNRTI resistance.
DRV = darunavir; FTC = emtricitabine; PDVF = protocol-defined virologic failure; PI = protease inhibitor; RAM = resistance-
associated mutation; TDF = tenofovir disoproxil fumarate; TAF = tenofovir alafenamide 

Cross-resistance in HIV-1 infected, treatment-naïve and virologically suppressed patients

The emtricitabine-resistant virus with the M184M/I/V mutation was cross-resistant to lamivudine, but 
retained sensitivity to abacavir, stavudine, tenofovir, and zidovudine.

Clinical data

HIV-1 Treatment naïve Patients

In double-blind Phase 3 Trial TMC114FD2HTX3001 (AMBER), treatment-naïve patients were 
randomised to receive either Symtuza (N = 362) or a combination of fixed-dose combination of 
darunavir and cobicistat and fixed-dose combination of emtricitabine and tenofovir disoproxil 



24

fumarate (F/TDF) (N = 363) once daily. Virologic response was defined as < 50 copies/mL  using the 
snapshot approach (see Table 5).

The 725 patients in total had a median age of 34 years (range 18-71), 88.3% were male, 83.2% White, 
11.1% Black, 1.5% Asian. The mean baseline plasma HIV-1 RNA and the median baseline CD4+ cell 
count were 4.48 log10 copies/mL (SD = 0.61) and 453 x 10

6 cells/L (range 38 – 1,456 x 106 cells/L), 
respectively.

Table 5: Virologic Outcomes in AMBER at Week 48 and 96 (FDA Snapshot)
Week 48 Week 96*

Symtuza
N = 362

DRV/COBI +F/TDF
N = 363

Symtuza
N = 362

Virologic Response, % 
HIV-1 RNA < 50 copies/mL 91.4% 88.4% 85.1%

Treatment differencea 2.7 (95% CI: -1.6; 7.1) -
Virologic Failureb 4.4% 3.3% 5.5%

HIV-1 RNA ≥ 50 copies/mL 2.5% 2.5% 1.7%
Virologic Failure Leading to Discontinuation 0.3%d 0 1.4%d

Discontinued study drug due to other reasons 
and last available HIV-1 RNA 
≥ 50 copies/mLe

1.7% 0.8% 2.5%

No virologic datac 4.1% 8.3% 9.4%
Reasons

Discontinued trial due to adverse event or 
death

2.2% 4.4% 2.2%

Discontinued study drug due to other reasons 
and last available HIV-1 RNA < 50 copies/mL

1.1% 2.5% 5.8%

Missing data during window but on trialf 0.8% 1.4% 1.4%
Virologic response (HIV-1-RNA 
< 50 copies/mL; Snapshot Analysis) by 
subgroup, n/N (%)
Age

< 50 years
≥ 50 years

299/326 (91.7%)
32/36 (88.9%)

293/331 (88.5%)
28/32 (87.5%)

276/326 (84.7%)
32/36 (88.9%)

Sex
Male
Female

292/318 (91.8%)
39/44 (88.6%)

289/322 (89.8%)
32/41 (78.0%)

270/318 (84.9%)
38/44 (86.4%)

Race
Black
Non-black

34/40 (85.0%)
281/305 (92.1%)

34/40 (85.0%)
275/309 (89.0%)

28/40 (70.0%)
266/305 (87.2%)

Baseline viral load
≤ 100,000 copies/mL
> 100,000 copies/mL

278/303 (91.7%)
53/59 (89.8%)

265/293 (90.4%)
56/70 (80.0%)

260/303 (85.8%)
48/59 (81.4%)

Baseline CD4+ cell count
< 200 cells/mm3

≥ 200 cells/mm3
16/22 (72.7%)

315/340 (92.6%)
25/29 (86.2%)

296/334 (88.6%)
16/22 (72.7%)

292/340 (85.9%)
CD4+ cell count mean change from baseline 188.7 173.8 228.8
a

Based on stratum adjusted MH test where stratification factors are HIV-1 RNA level (≤ 100,000 or > 100,000 copies/mL) 
and CD4+ cell count (< 200 or ≥ 200 cells/µL).

b
Included subjects who had HIV-1 RNA ≥ 50 copies/mL in the Week 48/96 window; subjects who discontinued early due to 
lack or loss of efficacy per investigator’s assessment; subjects who discontinued for reasons other than an adverse event (AE), 
death or lack or loss of efficacy and at the time of discontinuation had a HIV-1 RNA ≥ 50 copies/mL.

c
Week 48 window: Day 295 – Day 378; Week 96 window: Day 631 – Day 714

d Five subjects were discontinued from the study due to efficacy related reasons per investigator’s assessment (physician 
decision), of which 3 had last on treatment HIV-1 RNA <50 copies/mL.

*
No comparator data available beyond Week 48

Changes in measures of bone mineral density

In the Phase 3 study TMC114FD2HTX3001in treatment-naïve patients, Symtuza was associated with 
no or smaller reductions in bone mineral density (BMD) compared DRV/COBI+F/TDF as measured 



25

by DXA analysis of hip (LS means percent change: 0.17% vs -2.69%, p < 0.001) and lumbar spine 
(LS means percent change: -0.68% vs -2.38%, p =0.004) after 48 weeks of treatment. After 96 weeks 
of treatment with Symtuza, the (95% CI) percent changes from baseline in BMD at the hip and spine 
region were respectively: -0.26 (-0.96; 0.45) % and -0.93 (-1.82; -0.05) %.

Changes in measures of renal function

In studies in treatment-naïve patients, Symtuza was associated with a lower impact on the estimated 
glomerular filtration rate by Cockcroft-Gault method compared to control group 
(DRV/COBI+F/TDF).

HIV-1 Treatment experienced Patients

Phase 3 trial TMC114IFD3013 (EMERALD) evaluated the efficacy of Symtuza in virologically-
suppressed (HIV-1 RNA less than 50 copies/mL) HIV-1 infected patients. Patients were virologically 
suppressed for at least 2 months and no more than once had a viral load elevation above 50 HIV-1 
RNA copies/mL during the year prior to enrollment. Patients were allowed in the study if they had 
previous failure on any non-darunavir ARV regimen. Patients had no history of virologic failure on 
darunavir-based regimens, and if historical genotypes were available, absence of darunavir RAMs. 
Patients were on a stable ARV regimen (for at least 6 months), consisting of a boosted protease 
inhibitor [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or 
lopinavir with ritonavir] combined with emtricitabine and TDF. They either switched to Symtuza 
(N = 763) or continued their treatment regimen (N = 378) (randomised 2:1).

Patients had a median age of 46 years (range 19-78), 82% were male, 75.5% White, 20.9% Black, and 
2.3% Asian. The median baseline CD4+ cell count was 628 x 106 cells/mm3 (range 
111-1921 x 106 cells/mm3). Week 48 and 96 virologic outcomes in the EMERALD trial are provided 
in Table 6.

Table 6: Week 48 and 96 Virologic Outcomes in EMERALD Trial
Week 48 Week 96*

Symtuza
N = 763

bPI+F/TDF
N = 378

Symtuza
N = 763

Cumulative Protocol-Defined Virologic Rebounda, %
Protocol Defined Rebound Rate 2.5% 2.1% 3.1%
(95% CI)b (1.5; 3.9) (0.9; 4.1) (2.0 ; 4.6)
Difference in Proportions 0.4 (95% CI: -1.5; 2.2) -
FDA Snapshot Outcome 
HIV-1 RNA < 50 copies/mL 94.9% 93.7% 90.7%
Virologic Failurec 0.8% 0.5% 1.2%

Treatment differenced 0.3 (95% CI: -0.7; 1.2) -
HIV-1 RNA ≥ 50 copies/mL 0.5% 0.5% 0.7%f

Virologic failure - leading to discontinuation 0 0 0
Virologic failure - discontinued due to other reason 
and last available HIV-1 RNA ≥ 50 copies/mL

0.3% 0 0.5%

No virologic datae 4.3% 5.8% 8.1%
Reasons
Discontinued trial due to adverse event or death 1.4% 1.1% 2.4%
Discontinued trial for other reasons 2.5% 4.2% 5.0%
Missing data during window but on trial 0.4% 0.5% 0.8%

Cumulative Protocol-Defined Virologic Rebound by subgroup, %
Age

< 50 years
≥ 50 years

13/507 (2.6%)
6/256 (2.3%)

7/252 (2.8%)
1/126 (0.8%)

18/507 (3.6%) 
6/256 (2.3%)

Sex
Male
Female

14/623 (2.2%)
5/140 (3.6%)

7/313 (2.2%)
1/65 (1.5%)

20/623 (3.2%) 
4/140 (2.9%)



26

Race
Black
Non-black

6/155 (3.9%)
13/597 (2.2%)

1/82 (1.2%)
7/293 (2.4%)

7/155 (4.5%) 
17/597 (2.8%)

Previous ARV Failure
0
≥ 1

16/647 (2.5%)
3/116 (2.6%)

8/325 (2.5%)
0/53 (0%)

19/647 (2.9%) 
5/116 (4.3%)

a
2 consecutive HIV-1 RNA ≥ 50 copies/mL, or in case of discontinuation or at Week 48/96 for any reason, (single) HIV-1 
RNA ≥ 50 copies/mL as of baseline (included)

b
Two-sided Exact Clopper-Pearson 95% CI

c
Included subjects who had ≥ 50 copies/mL in the Week 48/96 window; subjects who discontinued early due to lack or loss of 
efficacy per investigator’s assessment; subjects who discontinued for reasons other than an adverse event (AE), death or lack 
or loss of efficacy and at the time of discontinuation had a viral value ≥ 50 copies/mL.

d
Based on MH test adjusting for bPI at screening (ATV with rtv or COBI, DRV with rtv or COBI, LPV with rtv)

e
Week 48 window: Day 295 – Day 378; Week 96 window: Day 631 – Day 714

f The following viral load values were observed for these subjects at Week 96: 54 copies/mL, 78 copies/mL, 111 
copies/mL, 152 copies/mL, and 210 copies/mL.

*
    No comparator data available beyond Week 48

Paediatric population

The use of Symtuza in ART-naïve adolescent patients from the age of 12 years to < 18 years, and 
weighing at least 40 kg is supported by two trials in HIV-1 infected paediatric patients
(TMC114-C230 and GS-US-292-0106). For more details, refer to the prescribing information of 
darunavir and emtricitabine/ tenofovir alafenamide.

An open-label, Phase 2 trial (TMC114-C230) was conducted for evaluating the pharmacokinetics, 
safety, tolerability, and 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 (see Table 7).

Table 7: Virologic Outcome in ART- naïve Adolescents at Week 48 (TLOVR algorithm)
TMC114-C230

Outcomes at Week 48 Darunavir/ritonavir
(N = 12)

HIV-1 RNA < 50 copies/mLa 83.3% (10)
CD4+ percent median change from baseline 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.

In the study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of emtricitabine and 
tenofovir alafenamide were evaluated in an open-label study in which 50 HIV-1 infected, 
treatment-naïve adolescents received emtricitabine and tenofovir alafenamide (10 mg) given with 
elvitegravir and cobicistat as a fixed-dose combination tablet. Patients had a median age of 15 years 
(range: 12-17), and 56% were female, 12% were Asian, and 88% were Black. At baseline, median 
plasma HIV-1 RNA was 4.7 log10 copies/mL, median CD4+ cell count was 456 cells/mm

3 (range: 
95-1,110), and median CD4+ % was 23% (range: 7-45%). Overall, 22% had baseline plasma HIV-1 
RNA > 100,000 copies/mL. At 48 weeks, 92% (46/50) achieved HIV-1 RNA < 50 copies/mL, similar 
to response rates in studies of treatment-naïve HIV-1 infected adults. The mean increase from baseline 
in CD4+ cell count at Week 48 was 224 cells/mm3. No emergent resistance to E/C/F/TAF 
(elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) was detected through Week 48.



27

The European Medicines Agency has deferred the obligation to submit the results of studies with 
Symtuza in one or more subsets of the paediatric population in the treatment of HIV-1 infection (see 
section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The bioavailability of all components of Symtuza was comparable to that when darunavir 800 mg, 
cobicistat 150 mg, and emtricitabine/tenofovir alafenamide 200/10 mg were co-administered as 
separate formulations; bioequivalence was established following single-dose administration under fed 
conditions in healthy subjects (N = 96).

Absorption

The absolute 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 absolute 
bioavailability of the emtricitabine 200 mg capsule was 93%.

All components were rapidly absorbed following oral administration of Symtuza in healthy subjects. 
Maximum plasma concentrations of darunavir, cobicistat, emtricitabine and tenofovir alafenamide
were achieved at 4.00, 4.00, 2.00, and 1.50 hours after dosing, respectively. The bioavailability of the 
components of Symtuza was not affected when administered orally as a split tablet compared to 
administration as a tablet swallowed whole.

The exposure to darunavir and cobicistat administered as the Symtuza was 30-45% lower and 16-29% 
lower, respectively, in fasted compared to fed condition. For emtricitabine, the Cmax was 1.26-fold 
higher in a fasted condition, while the AUC was comparable in fed and fasted condition. For tenofovir 
alafenamide, the Cmax was 1.82-fold higher in fasted condition, while the AUC was 20% lower to 
comparable in a fasted compared to fed condition. Symtuza tablets should be taken with food. The 
type of food does not affect exposure to Symtuza.

Distribution

Darunavir
Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma α1-acid 
glycoprotein.

Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 L 
(mean ± SD) and increased to 131 ± 49.9 L (mean ± SD) in the presence of 100 mg twice-daily 
ritonavir.

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

Emtricitabine
In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of 
concentration over the range of 0.02-200 mcg/mL. At peak plasma concentration, the mean plasma to 
blood drug concentration ratio was approximately 1.0 and the mean semen to plasma drug 
concentration ratio was approximately 4.0.

Tenofovir alafenamide
In vitro binding of tenofovir to human plasma proteins is < 0.7% and is independent of concentration 
over the range of 0.01-25 mcg/mL. Ex vivo binding of tenofovir alafenamide to human plasma 
proteins in samples collected during clinical studies was approximately 80%.



28

Biotransformation

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

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

Emtricitabine
In vitro studies indicate that emtricitabine is not an inhibitor of human CYP enzymes. Following 
administration of [14C]-emtricitabine, complete recovery of the emtricitabine dose was achieved in 
urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the dose was 
recovered in the urine as three putative metabolites. The biotransformation of emtricitabine includes 
oxidation of the thiol moiety to form the 3’-sulfoxide diastereomers (approximately 9% of dose) and 
conjugation with glucuronic acid to form 2’-O-glucuronide (approximately 4% of dose). No other 
metabolites were identifiable.

Tenofovir alafenamide
Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for 
> 80% of an oral dose. In vitro studies have shown that tenofovir alafenamide is metabolised to 
tenofovir (major metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV target 
cells) and macrophages; and by carboxylesterase-1 in hepatocytes. In vivo, tenofovir alafenamide is 
hydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the active 
metabolite tenofovir diphosphate.

In vitro, tenofovir alafenamide is not metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or 
CYP2D6. Tenofovir alafenamide is minimally metabolised by CYP3A4. Upon co-administration with 
the moderate CYP3A inducer probe efavirenz, tenofovir alafenamide exposure was not significantly 
affected. Following administration of tenofovir alafenamide, plasma [14C]-radioactivity showed a 
time-dependent profile with tenofovir alafenamide as the most abundant species in the initial few 
hours and uric acid in the remaining period.

Elimination

Darunavir
After a 400/100 mg [14C]-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the 
administered dose of [14C]-darunavir could be retrieved in faeces and urine, respectively. Unchanged 
darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, 
respectively.

The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose (100 mg)
ritonavir was 32.8 l/h and 5.9 l/h, respectively. The median terminal plasma half-life of darunavir 
following administration of Symtuza is 5.5 hours.

Cobicistat
Following oral administration of [14C]-cobicistat, 86% and 8.2% of the dose were recovered in feces 
and urine, respectively. The median terminal plasma half-life of cobicistat following administration of 
Symtuza is 3.6 hours.



29

Emtricitabine
Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in 
urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabine 
dose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged 
307 mL/min. Following oral administration of Symtuza, the median terminal elimination half-life of 
emtricitabine is 17.2 hours.

Tenofovir alafenamide
Tenofovir alafenamide is mainly eliminated following metabolism to tenofovir. The median terminal 
elimination half–life of tenofovir alafenamide was 0.3 hours when administered as Symtuza. 
Tenofovir is eliminated from the body by the kidneys by both glomerular filtration and active tubular 
secretion. Tenofovir has a median plasma half-life of approximately 32 hours. Renal excretion of 
intact tenofovir alafenamide is a minor pathway with less than 1% of the dose eliminated in urine. The 
pharmacologically active metabolite, tenofovir diphosphate, has a half-life of 150-180 hours within 
PBMCs.

Special populations

Paediatric population
The pharmacokinetics of Symtuza have not been investigated in paediatric patients. However, there 
are pharmacokinetic data for the different components of Symtuza, indicating that doses of 800 mg
darunavir, 150 mg cobicistat, 200 mg emtricitabine and 10 mg tenofovir alafenamide result in similar 
exposures in adults and adolescents aged 12 years and older, weighing at least 40 kg.

Elderly
Limited PK information is available in the elderly (age ≥ 65 years of age) for Symtuza as well as its 
individual components.

Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics 
are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients 
(N = 12, age ≥ 65 years) (see section 4.4).
No clinically relevant pharmacokinetic differences due to age have been identified for cobicistat, 
emtricitabine or tenofovir alafenamide in the age range ≤ 65 years.

Gender
Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV-1
infected females compared to males. This difference is not clinically relevant.

No clinically relevant pharmacokinetic differences due to gender have been identified for cobicistat, 
emtricitabine or tenofovir alafenamide.

Renal impairment
Symtuza has not been investigated in patients with renal impairment. There are pharmacokinetic data 
for the (individual) components of Symtuza.

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

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



30

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

Emtricitabine
Mean systemic emtricitabine exposure was higher in patients with severe renal impairment 
(eGFRCG < 30 mL/min) (33.7 mcg•h/mL) than in subjects with normal renal function 
(11.8 mcg•h/mL).

Tenofovir alafenamide
No clinically relevant differences in tenofovir alafenamide, or tenofovir pharmacokinetics were 
observed between healthy subjects and patients with severe renal impairment (eGFRCG > 15 but 
< 30 mL/min) in studies of tenofovir alafenamide. There are no pharmacokinetic data on tenofovir 
alafenamide in patients with eGFRCG < 15 mL/min.

Hepatic impairment
Symtuza has not been investigated in patients with hepatic impairment. There are pharmacokinetic 
data for the (individual) components of Symtuza.

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

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

Emtricitabine
The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment; 
however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver 
impairment should be limited.

Tenofovir alafenamide
Clinically relevant changes in tenofovir pharmacokinetics in patients with hepatic impairment were 
not observed in patients with mild to moderate hepatic impairment. The effect of severe hepatic 
impairment (Child-Pugh Class C) on the pharmacokinetics of tenofovir alafenamide has not been 
studied.

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

Pregnancy and postpartum
Treatment with darunavir/cobicistat 800/150 mg once daily during pregnancy results in low darunavir 
exposure (see Table 8). In women receiving darunavir/cobicistat during the second trimester of 



31

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).

Table 8
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.

No pharmacokinetic data are available for emtricitabine and tenofovir alafenamide during pregnancy.

5.3 Preclinical safety data

Darunavir

Non-clinical data on darunavir reveal no special hazard for humans based on conventional studies of 
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. Darunavir has no 
effect on fertility or early embryonic development and DRV shows no teratogenic potential, at 
exposure levels below those at the recommended clinical dose in humans.

In juvenile rats receiving darunavir up to days 23-26 (equivalent to less than 2 years of age in 
humans), increased mortality was observed with convulsions in some animals. These findings were 
attributed to the immaturity of the liver enzymes and of the blood brain barrier. Due to uncertainties 
regarding the rate of development of the human blood brain barrier and liver enzymes Symtuza should 
not be used in paediatric patients below 3 years of age.

Cobicistat

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

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

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



32

Emtricitabine

Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies 
of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to 
reproduction and development.

Emtricitabine had demonstrated low carcinogenic potential in mice and rats.

Tenofovir alafenamide

Non-clinical studies of tenofovir alafenamide in rats and dogs revealed bone and kidney as the primary 
target organs of toxicity. Bone toxicity was observed as reduced bone mineral density in rats and dogs 
at tenofovir exposures at least four times greater than those expected after administration of Symtuza. 
A minimal infiltration of histiocytes was present in the eye in dogs at tenofovir alafenamide and 
tenofovir exposures of approximately 15 and 40 times greater, respectively, than those expected after 
administration of Symtuza.

Tenofovir alafenamide was not mutagenic or clastogenic in conventional genotoxicity assays.

Because there is a lower tenofovir exposure in rats and mice after the administration of tenofovir 
alafenamide compared to tenofovir disoproxil, carcinogenicity studies and a rat peri-postnatal study 
were conducted only with tenofovir disoproxil. No special hazard for humans was revealed in 
conventional studies of carcinogenic potential and toxicity to reproduction and development. 
Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or 
fetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in a 
peri-postnatal toxicity study at maternally toxic doses.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core
Croscarmellose sodium
Magnesium stearate
Cellulose, microcrystalline
Silica, colloidal anhydrouse

Tablet coating
Macrogol 4000
Poly (vinyl alcohol)– partially hydrolysed
Talc
Titanium dioxide
Iron oxide yellow

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years
After first opening: 6 weeks



33

6.4 Special precautions for storage

Store in the original package with desiccant inside the bottle in order to protect the tablets from 
moisture. Keep the bottle tightly closed.

6.5 Nature and contents of container

White, high density polyethylene (HDPE) bottle with a silica gel desiccant (contained in a separate 
sachet or canister) fitted with polypropylene (PP) child resistant closure with induction seal.

Each bottle contains 30 tablets.
Pack size of one bottle or three bottles per carton.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

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

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1225/001- 30 film-coated tablets
EU/1/17/1225/002- 90 film-coated tablets (3 x 30)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 September 2017

10. DATE OF REVISION OF THE TEXT

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

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


34

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

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



35

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release
Janssen-Cilag SpA
Via C. Janssen, Borgo San Michele
04100
Latina
Italy

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

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

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic safety update reports

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

The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation.

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

 Risk Management Plan (RMP)

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

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

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



36

ANNEX III

LABELLING AND PACKAGE LEAFLET



37

A. LABELLING



38

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Symtuza 800 mg/150 mg/200 mg/10 mg film-coated tablets
darunavir/cobicistat/emtricitabine/tenofovir alafenamide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 800 mg darunavir (as ethanolate), 150 mg cobicistat, 200 mg 
emtricitabine, and 10 mg tenofovir alafenamide (as fumarate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 film-coated tablets
90 film-coated tablets (3 bottles containing 30 tablets each)
The bottles are not to be distributed individually.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

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

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

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

9. SPECIAL STORAGE CONDITIONS

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



39

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

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

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1225/001- 30 film-coated tablets
EU/1/17/1225/002- 90 film-coated tablets (3 x 30)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

symtuza

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:



40

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

Symtuza 800 mg/150 mg/200 mg/10 mg tablets
darunavir/cobicistat/emtricitabine/tenofovir alafenamide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 800 mg darunavir (as ethanolate), 150 mg cobicistat, 200 mg 
emtricitabine, and 10 mg tenofovir alafenamide (as fumarate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 tablets
90 film-coated tablets (3 bottles containing 30 tablets each)
The bottles are not to be distributed individually.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

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

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



41

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

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

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1225/001- 30 film-coated tablets
EU/1/17/1225/002- 90 film-coated tablets (3 x 30)

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



42

B. PACKAGE LEAFLET



43

Package leaflet: Information for the user

Symtuza 800 mg/150 mg/200 mg/10 mg - film-coated tablets
darunavir/cobicistat/emtricitabine/tenofovir alafenamide

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects.

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

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

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

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

1. What Symtuza is and what it is used for

Symtuza is an antiretroviral medicine used to treat infection with human immunodeficiency virus 1
(HIV-1). It is used in adults and adolescents aged 12 years and older who weigh at least 40 kg. 
Symtuza contains four active substances:
 darunavir, an anti-HIV medicine known as a protease inhibitor
 cobicistat, a booster (enhancer) of darunavir
 emtricitabine, an anti-HIV medicine known as a nucleoside reverse transcriptase inhibitor
 tenofovir alafenamide, an anti-HIV medicine known as a nucleotide reverse transcriptase 

inhibitor

Symtuza reduces HIV-1 in your body and this will improve your immune system (your body’s natural 
defences) and reduce the risk of developing illnesses linked to HIV infection but Symtuza is not a cure 
for HIV infection.

2. What you need to know before you take Symtuza

Do not take Symtuza
- if you are allergic (hypersensitive) to darunavir, cobicistat, emtricitabine, tenofovir 

alafenamide, or any of the other ingredients of Symtuza (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 Symtuza with any of the following medicines
If you are taking any of these, ask your doctor about switching to another medicine.



44

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

to treat certain heart disorders (e.g. abnormal 
heart rhythm)

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

to treat migraine headaches

St. John’s wort (Hypericum perforatum) a herbal product used for depression
Lovastatin, simvastatin and lomitapide to lower cholesterol levels
Triazolam or midazolam (taken by mouth) to help you sleep and/or relieve anxiety
Sildenafil to treat a heart and lung disorder called 

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

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

treatment of patients with a history of a heart 
attack

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

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

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 Symtuza may still develop infections or other illnesses associated with HIV infection. 
You must keep in regular contact with your doctor.

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

Talk to your doctor before taking Symtuza. Tell your doctor immediately, if any of these apply to you.
 if you have had problems with your liver, including hepatitis B or C infection. Your doctor 

may evaluate how severe your liver disease is before deciding if you can take Symtuza.
 If you have hepatitis B infection, your liver problems may become worse after you stop taking 

Symtuza. It is important not to stop taking Symtuza without talking to your doctor first.
 if you have had problems with your kidneys. Your doctor will consider if Symtuza is the right 

medicine for you.
 if you have diabetes. Symtuza might increase sugar levels in the blood.
 if you notice any symptoms of infection (e.g. swollen lymph nodes and fever). In some patients 

with advanced HIV infection and who had unusual infections due to a weakened immune 
system (opportunistic infection), signs and symptoms of inflammation from previous infections 
may occur soon after you start HIV treatment. 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.

 if you notice 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, tell your doctor 



45

immediately. In addition to the opportunistic infections, autoimmune disorders (when the 
immune system attacks healthy body tissue) may also occur after you start taking medicines for 
the treatment of your HIV infection, due to an improvement in the body’s immune response. 
Autoimmune disorders may occur many months after the start of treatment.

 if you have haemophilia. Symtuza might increase the risk of bleeding.
 if you are allergic to sulphonamides (e.g. used to treat certain infections).
 if you notice any muscle or bone problems. Some patients taking anti-HIV medicines may 

develop a bone disease called osteonecrosis (bone damage caused by loss of blood supply to the 
bone). This may be more likely with long-term HIV treatment, more severe damage to the 
immune system, being overweight, or the use of alcohol or medicines called corticosteroids. 
Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and 
shoulder) and difficulty in movement. If you notice any of these symptoms tell your doctor.

Elderly
Symtuza 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 Symtuza.

Children and adolescents
Symtuza is not for use in children younger than 12 years, or weighing less than 40 kg, as it has 
not been studied in children under 12 years.

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

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

You should also not take Symtuza with medicines that contain tenofovir disoproxil (e.g. as fumarate, 
phosphate, or succinate), lamivudine or adefovir dipivoxil, or medicines that require boosting with 
ritonavir or cobicistat.

The effects of Symtuza might be reduced if you take any of the following products. Tell your doctor if 
you take:
- Bosentan (to treat high blood pressure in the pulmonary circulation)
- Dexamethasone (injection) (corticosteroid)
- Boceprevir (to treat hepatitis C virus infection)
- Rifapentine, rifabutin (to treat bacterial infections)
- Oxcarbazepine (to prevent seizures).

The effects of other medicines might be influenced if you take Symtuza. Tell your doctor if you take:
- Amlodipine, diltiazem, disopyramide, felodipine, flecainide, mexiletine, nicardipine, nifedipine, 

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

- Bosentan (to treat high blood pressure in the pulmonary circulation)
- Apixaban, edoxaban, rivaroxaban (to reduce clotting of the blood) as their therapeutic effect or 

side effects may be altered.
- Clonazepam (to prevent seizures).
- Oestrogen-based hormonal contraceptives and hormone replacement therapy. Symtuza might 

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

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



46

- Budesonide, fluticasone (to control asthma). Its use should only take place after medical
evaluation and under close monitoring by your doctor for corticosteroid side effects.

- Buprenorphine/naloxone, methadone (medicines to treat opioid dependence)
- Salmeterol (medicine to treat asthma)
- Artemether/lumefantrine (a combination medicine to treat malaria)
- Dasatinib, irinotecan, nilotinib, vinblastine, vincristine (medicines to treat cancer)
- Prednisone (corticosteroid)
- Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder

called pulmonary arterial hypertension)
- Glecaprevir/pibrentasvir, simeprevir, boceprevir (to treat hepatitis C virus 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 Symtuza’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)
- Carvedilol, metoprolol, timolol (for heart disease)
- Warfarin (to reduce clotting of the blood) as its therapeutic effect or side effects may be altered; 

your doctor may have to check your blood.
- Digoxin (to treat certain heart disorders)
- Clarithromycin (antibiotic)
- Clotrimazole, fluconazole, Isavuconazole, itraconazole, posaconazole, (for treating fungal

infections). Voriconazole should only be taken after medical evaluation.
- Atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin (to lower cholesterol levels). 

The risk of muscle damage might be increased. Your doctor will evaluate which cholesterol 
lowering regimen is best for your specific situation.

- Rifabutin (against bacterial infections)
- Tadalafil, sildenafil, vardenafil (for erectile dysfunction or high blood pressure in the

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

depression and anxiety)
- Perphenazine, risperidone, thioridazine (psychiatric medicines)
- 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.

- Colchicine (antigout). If you have kidney or liver problems see section ‘Do not combine
Symtuza with any of the following medicines’.

- Buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem, midazolam when used as
an injection (medicines to treat trouble with sleeping or anxiety)

- 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.

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 Symtuza.

It is recommended that women with HIV do not breast-feed their infants because of the possibility of 
the baby becoming infected with HIV through breast milk and because the medicine may affect the
baby.

Driving and using machines
Symtuza can cause dizziness. Do not operate machines or drive if you feel dizzy after taking Symtuza.



47

3. How to take Symtuza

Always take Symtuza exactly as your doctor or pharmacist has told you. Check with your doctor or
pharmacist if you are not sure.

The recommended dose for adults and adolescents 12 years of age and older, who weigh at least 
40 kg is one tablet each day with food.

You must take Symtuza every day and always with food. You must eat a meal or a snack within 
30 minutes before taking your Symtuza. The type of food is not important.

 The tablet should not be crushed, but swallowed whole. The tablet can be taken with a drink 
such as water, milk or any nutritional drink. Take Symtuza at around the same time each day.

Removing the child resistant cap

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

If you take more Symtuza than you should
Contact your doctor or nearest emergency department immediately for advice. Keep the tablet bottle 
with you so that you can show what you have taken.

If you forget to take Symtuza
It is important not to miss a dose of Symtuza.

If you do miss a dose:
 If you notice within 12 hours of the time you usually take Symtuza, you must take the tablet 

immediately, with food. Then take the next dose at your usual time.
 If you notice 12 hours or more after the time you usually take Symtuza, then do not take the 

missed dose and take the next doses with food at your usual time. Do not take a double dose to 
make up for a forgotten dose.

If you vomit within 1 hour of taking the medicine, another dose of Symtuza should be taken with food 
as soon as possible. If you vomit more than 1 hour after taking the medicine, then you do not need to 
take another dose of Symtuza until the next regularly scheduled time.

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

Do not stop taking Symtuza without talking to your doctor first

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

When your supply of Symtuza starts to run low, get more from your doctor or pharmacist. This is 
very important because the amount of virus may start to increase if the medicine is stopped for even a 
short time. The disease may then become harder to treat.

If you have both HIV infection and hepatitis B, it is very important not to stop taking Symtuza
without talking to your doctor first. You may require blood tests for several months after stopping 
treatment with Symtuza. In some patients with advanced liver disease or cirrhosis, stopping treatment 
may lead to worsening of hepatitis, which may be life-threatening.
Tell your doctor immediately about new or unusual symptoms after you stop treatment, particularly 
symptoms you associate with hepatitis B infection.



48

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

4. Possible side effects

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 Symtuza. 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 may affect more than 1 in 10 patients receiving Symtuza. Although most rashes are mild and 
disappear after a while as treatment is continued, a rash can occasionally be severe or potentially 
life-threatening. 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 Symtuza must be stopped.

Other severe side effects, seen up to 1 patient in 10, were diabetes, increased blood fat levels and 
symptoms of infection. Inflammation of the pancreas (pancreatitis) has been reported in up to 1 patient 
in 100.

Very common side effects (may affect more than 1 in 10 people)
 headache
 diarrhoea
 rash

Common side effects (may affect up to 1 in 10 people)
 low red blood cell count (anaemia)
 allergic reactions such as nettle rash (urticaria), itching, decreased appetite (anorexia)
 abnormal dreams
 vomiting, pain or swelling of the belly, indigestion, flatulence (wind)
 abnormal blood test results such as some tests for your kidney. Your doctor will explain these to 

you.
 dizziness
 joint pain
 muscle pain, muscle cramps or weakness
 weakness
 tiredness (fatigue)
 feeling sick (nausea)

Uncommon side effects (may affect up to 1 in 100 people)
 severe swelling of the skin and other tissues (most often the lips or the eyes)
 symptoms of infection or of autoimmune disorders (immune reconstitution inflammatory 

syndrome)
 enlargement of breasts
 osteonecrosis (bone damage caused by loss of blood supply to the bone)
 abnormal blood test results such as some tests for your pancreas. Your doctor will explain these 

to you.



49

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].

Some side effects are typical for anti-HIV medicines similar to Symtuza. These are:
- raised blood sugar and worsening of diabetes
- muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been 

serious.
- immune reconstitution inflammatory syndrome. In some patients with advanced HIV infection 

(AIDS) and a history of opportunistic infection (unusual infections due to a weakened immune 
system), signs and symptoms of inflammation from previous infections may occur soon after 
HIV treatment is started, including Symtuza. 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 of these symptoms tell your doctor.
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.

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

5. How to store Symtuza

Keep Symtuza out of the sight and reach of children.

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

Do not use this medicine after 6 weeks of first opening the bottle.
Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

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

6. Contents of the pack and other information

What Symtuza contains

The active substances are darunavir, cobicistat, emtricitabine, and tenofovir alafenamide. Each 
film-coated tablet contains 800 mg darunavir (as ethanolate), 150 mg cobicistat, 200 mg emtricitabine, 
and 10 mg tenofovir alafenamide (as fumarate).

The other ingredients are
Tablet core:
The tablet core contains croscarmellose sodium, magnesium stearate, microcrystalline cellulose and
colloidal silicon dioxide.

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


50

Film coating:
The film-coating contains polyethylene glycol (macrogol), polyvinyl alcohol (partially hydrolyzed), 
talc, titanium dioxide and yellow ferric oxide.

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

What Symtuza looks like and contents of the pack
Yellow to yellowish-brown capsule shaped film-coated tablet, mentioning “8121” on one side and 
“JG” on the other side.

Symtuza comes in bottles of 30 tablets (with a silica gel desiccant that must be kept in the bottle to 
help protect your tablets). The silica gel desiccant is contained in a separate sachet or canister and 
should not be swallowed.
The Symtuza tablets are available in packs containing one bottle or three bottles per carton.
Not all pack sizes may be marketed.

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

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

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

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

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

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

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

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

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858

Danmark
Janssen-Cilag A/S
Tlf: +45 45 94 82 82
jacdk@its.jnj.com

Malta
AM MANGION LTD.
Tel: +356 2397 6000

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

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

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

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

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

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

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

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



51

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

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

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

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

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

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

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

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

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

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

Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700

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

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

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

This leaflet was last revised in {MM/YYYY}.

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

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

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