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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 10 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 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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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 components of Symtuza, darunavir and cobicistat 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).
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
- 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, 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)
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- 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
and lovastatin (see section 4.5)
- 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 or with
HIV-1 RNA ≥ 100,000 copies/ml or CD4+ cell count < 100 cells x 106
/l (see section 5.1).
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.
Patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since
post-treatment exacerbation of hepatitis may lead to hepatic decompensation.
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.
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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.
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.
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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
(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) 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
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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).
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. systemic azoles like ketoconazole and 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
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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.
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 theoritical consideration
DRV/COBI is expected to
increase alfusozin concentrations
(CYP3A4 inhibition)
The concomitante use of Symtuza
with alfusozin is contra-indicated
(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
consideration.
Symtuza and antacids can be
used concomitantly without dose
adjustment.
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ANTIANGINA/ANTIARRHYTHMIC
Disopyramide
Flecainide
Mexiletine
Propafenone
Lidocaine (systemic)
Amiodarone
Dronedarone
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,
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.
ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban
Dabigatran etexilate
Rivaroxaban
Based on theoretical
considerations co-administration of
DRV/COBI with these
anticoagulants may increase
concentrations of the
anticoagulant.
(CYP3A and/or P-glycoprotein
inhibition)
Co-administration of Symtuza
and these anticoagulants is not
recommended.
Ticagrelor Based on theoretical
considerations co-administration of
DRV/COBI with ticagrelor may
increase concentrations of the
anticoagulant.
(CYP3A and/or P-glycoprotein
inhibition).
Concomitant administration of
Symtuza with 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.
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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.
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)
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.
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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).
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).
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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
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
and Symtuza is not
recommended.
ANTIPSYCHOTICS/NEUROLEPTICS
Perphenazine
Risperidone
Thioridazine
Lurasidone
Pimozide
Quetiapine
Sertindole
Based on theoretical
considerations DRV/COBI is
expected to increase these
neuroleptic plasma concentrations.
(CYP2D6 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).
13
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.
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).
14
HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A inhibitors
Boceprevir
Telaprevir
Based on theoretical
considerations these antivirals may
decrease darunavir and/or
cobicistat plasma concentrations
and adversely affect the
intracellular activation and clinical
antiviral efficacy of tenofovir
alafenamide. Symtuza may
decrease these antiviral plasma
concentrations.
It is not recommended to
co-administer Symtuza with
boceprevir or telaprevir.
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 theoritical 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 contra-indicated (see
section 4.3).
HMG CO-A REDUCTASE INHIBITORS
Atorvastatin
Fluvastatin
Pitavastatin
Pravastatin
Rosuvastatin
Lovastatin
Simvastatin
Based on theoretical
considerations DRV/COBI is
expected to increase these
HMG Co-A reductase inhibitor
plasma concentrations.
(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).
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.
15
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 analgesic plasma
concentrations.
(CYP2D6 and/or CYP3A
inhibition)
Clinical monitoring is
recommended when
co-administering Symtuza with
these analgesics.
OESTROGEN-BASED CONTRACEPTIVES
Ethinyl estradiol
Norethindrone
Based on theoretical
considerations DRV/COBI may
alter ethinyl estradiol and/or
norethindrone plasma
concentrations.
No dosing recommendations can
be made on the use of Symtuza
with oral contraceptives.
Alternative forms of
contraception should be
considered.
16
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.
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.
17
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).
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). Symtuza should be used during pregnancy only if the potential benefit
justifies the potential risk.
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.
18
4.7 Effects on ability to drive and use machines
Symtuza has no or negligible influence on the 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 randomized, double-blinded,
comparative Phase II trial, GS-US-299-0102, 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 adverse reactions reported were diarrhoea (28%), nausea (23%), fatigue (14%),
headache (12%), and rash (16%).
Tabulated list of adverse reactions
Adverse reactions are listed by system organ class (SOC) and frequency category. 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).
MedDRA system organ class
Frequency category
Adverse reaction
Blood and lymphatic system disorders
uncommon anaemia
Immune system disorders
common (drug) hypersensitivity
uncommon immune reconstitution inflammatory syndromea
Metabolism and nutrition disorders
common anorexia, diabetes mellitus,
hypercholesterolaemia, hypertriglyceridaemia,
hyperlipidaemia
Psychiatric disorders
common abnormal dreams
Nervous system disorders
very common headache
common dizziness
Gastrointestinal disorders
very common diarrhoea, nausea
common vomiting, abdominal pain, abdominal distension,
dyspepsia, flatulence, pancreatic enzymes
increaseda
uncommon pancreatitis acutea
Hepatobiliary disorders
common hepatic enzyme increaseda
uncommon acute hepatitisb
, cytolytic hepatitisb
19
Skin and subcutaneous tissue disorders
very common rash (including macular, maculopapular,
papular, erythematous, pruritic rash, generalised
rash, and allergic dermatitis)
common angioedema, pruritus, urticaria
rare drug reaction with eosinophilia and systemic
symptomsb
, Stevens-Johnson syndromeb
not known toxic epidermal necrolysisb
, acute generalised
exanthematous pustulosisb
Musculoskeletal and connective tissue disorders
common arthralgia, myalgia
uncommon osteonecrosisb
Reproductive system and breast disorders
uncommon gynaecomastiab
General disorders and administration site conditions
very common fatigue
common astheniaa
Investigations
common increased blood creatinine
a
Adverse drug reactions that have not been reported in clinical trial experience with Symtuza but have been reported
for darunavir/cobicistat in the GS-US-216-0130 study
b
Additional adverse drug reactions only seen in 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 comparative Phase II trial investigating Symtuza as a single tablet regimen,
11.7% of patients receiving Symtuza (N = 103) experienced rash (most of which were grade 1), of
which 1% of patients discontinued treatment due to grade 3 hypersensitivity and rash.
Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see
section 4.4).
In the Phase II 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
Weeks 24 and 48. The median increase from baseline was greater in the D/C/F/TAF group compared
with the DRV+COBI+F/TDF group at both Week 24 and Week 48.
The median change in total cholesterol was 1.04 mmol/L with D/C/F/TAF and 5 mg/dL
(0.13 mmol/L) with D/C/F/TDF (p < 0.001). Changes from baseline at week 48 were observed in
direct LDL cholesterol (0.67 mmol/L with D/C/F/TAF vs 0.10 mmol/L with DRV+COBI+F/TDF,
p < 0.001) HDL cholesterol (0.18 mmol/L with D/C/F/TAF vs 0.08 mmol/L with
DRV+COBI+F/TDF, p = 0.009), and triglycerides (0.33 mmol/L with D/C/F/TAF vs -0.06 mmol/L
with DRV+COBI+F/TDF, p = 0.007).
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.
20
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) 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 II 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 48 weeks. At Week 48 changes from baseline were smaller with darunavir/ cobicistat/
emtricitabine /tenofovir alafenamide (D/C/F/TAF) than with darunavir+cobicistat+ emtricitabine/
tenofovir disoproxil fumarate (D+C+F/TDF). The median change in eGFRCG was -2.9 mL/min with
D/C/F/TAF and -10.6 mL/min with D+C+F/TDF (p = 0.017). 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 6.7 mL/min/1.73 m² and 0.3 mL/min/1.73 m² (p = 0.029).
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).
21
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. If indicated, elimination of unabsorbed active substance is to be achieved
by emesis.
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: not yet assigned
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.
22
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).
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.
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.
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.
The clinical resistance profile of Symtuza is driven by darunavir, emtricitabine, and tenofovir
alafenamide. Cobicistat does not select any HIV resistance mutations, due to its lack of antiviral
activity.
In the comparative Phase II trial GS-US-299-0102 in HIV-1 infected treatment-naïve patients, no
patient developed any darunavir resistance-associated or primary protease mutations from baseline
through Week 48. One patient, receiving Symtuza, had an NRTI-resistance mutation emerging at the
unblinding visit after Week 48 with the emergence of a mutant/wild-type mixture at position K65
(K65K/R) and a mutant/wild-type mixture at position M184 (M184M/I). These mutations are
23
associated with resistance to tenofovir disoproxil /tenofovir alafenamide and emtricitabine,
respectively. However, phenotypic susceptibilities to both emtricitabine and tenofovir disoproxil were
in the sensitive range despite the presence of those mutations. The patient had a viral load increase
above 50 copies/mL at Week 40 followed by re-suppression of HIV-1 RNA < 50 copies/mL,
suggesting improper treatment compliance.
These data are in line with the low level of resistance development observed in historical studies
investigating: (1) darunavir once daily, boosted with either ritonavir or cobicistat, in combination with
other antiretroviral products (primarily emtricitabine/tenofovir disoproxil) in treatment-naïve patients
and treatment experienced patients with no darunavir resistance-associated mutations, and (2)
emtricitabine and tenofovir alafenamide in treatment-naïve patients and virologically suppressed
patients.
Cross-resistance in HIV-1 infected, treatment-naïve or virologically suppressed patients
In treatment-naïve virologic failures on boosted darunavir no cross-resistance with other HIV PIs has
been observed.
Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but
retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.
The K65R and K70E mutations result in reduced susceptibility to abacavir, didanosine, lamivudine,
emtricitabine, and tenofovir, but retain sensitivity to zidovudine.
Clinical data
The evidence of efficacy of Symtuza once daily in HIV-1 infected patients is based on the established
efficacy of the constituents (refer to the prescribing information for darunavir, darunavir/cobicistat and
emtricitabine/ tenofovir alafenamide for more details) supported by the analysis of 24 week and
48 week data from the randomized, double-blinded, comparative Phase II trial GS-US-299-0102,
conducted with emtricitabine and tenofovir alafenamide (10 mg) when given with darunavir (800 mg)
and cobicistat as a fixed-dose combination tablet (darunavir/cobicistat/emtricitabine/ tenofovir
alafenamide).
In study GS-US-299-0102, treatment-naïve patients were randomized to receive either Symtuza
(N = 103) or cobicistat-boosted darunavir (as single agents) plus emtricitabine/tenofovir disoproxil
fumarate fixed-dose combination (N = 50) once daily. HIV-1 infected patients who were eligible for
this trial had plasma HIV-1 RNA levels ≥ 5,000 copies/mL and CD4+ cell count > 50 cells/μL at
screening. Virologic response was defined as confirmed plasma HIV-1 RNA viral load
< 50 copies/mL.
The 153 patients in total had a median age of 33 years (range 18-68), 92.8% were male, 60.1% White,
34.6% Black, 2% Asian, and 1.3% Native Hawaiian or other Pacific Islander. The mean baseline
plasma HIV-1 RNA and the median baseline CD4+ cell count were 4.68 log10 copies/mL (SD = 0.515)
and 384 x 10
6
cells/L (range 7 – 1,463 x 10
6
cells/L), respectively.
Table 2 shows the efficacy data of the 24 week and 48 week analyses from the GS-US-299-0102 trial.
Table 2: Virologic outcomes of study GS-US-299-0102 at Week 24 and 48 a
Week 24 Week 48
D/C/F/TAF
(N = 103)
D+C+F/TDF
(N = 50)
D/C/F/TAF
(N = 103)
D+C+F/TDF
(N = 50)
Virologic Response (Snapshot Analysis) % (N)
HIV-1 RNA < 50 copies/mLb
75% (77) 74% (37) 77% (79) 84% (42)
Treatment difference (95% CI) c
3.3% (-11.4% to 18.1%) -6.2% (-19.9% to 7.4%)
HIV-1 RNA < 50 copies/mL-PPd
85% (77) 79% (37) 93% (79) 91% (42)
Treatment difference (95% CI)c
8.3% (-5.3% to 22%) 2.4% (-8.8% to 13.7%)
Virologic Failure 20% (21) 24% (12) 16% (16) 12% (6)
HIV-1 RNA ≥ 50 copies/mL 14% (14) 22% (11) 7% (7) 8% (4)
24
Discontinued study drug due to other
reasons and last available HIV-1 RNA
≥ 50 copies/mLe
7% (7) 2% (1) 9% (9) 4% (2)
No virologic data 5% (5) 2% (1) 8% (8) 4% (2)
Discontinued study drug due to AE or
deathf
1% (1) 0 1% (1) 2% (1)
Discontinued study drug due to other
reasons and last available HIV-1 RNA
< 50 copies/mLe
4% (4) 2% (1) 7% (7) 2% (1)
CD4+ cell count mean change from
baseline
186 139 231 212
D/C/F/TAF = fixed-dose combination of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
D+C+F/TDF = cobicistat-boosted darunavir plus emtricitabine/tenofovir disoproxil fumarate fixed-dose combination
a Week 24 and 48 window was between Day 140 and 195 (inclusive), and Day 294 and 377 (inclusive), respectively.
b
The primary analysis set for the efficacy analysis was the Full Analysis Set, which included all subjects who (1) were randomized
into the study and (2) received ≥ 1 dose of study medication.
c Treatment difference (D/C/F/TAF versus D+C+F/TDF) and 95% CI based on baseline HIV-1 RNA and race stratum-adjusted
Mantel-Haenszel proportions.
d
The Per-Protocol (PP) analysis set was defined as all subjects who (1) were randomized into the study, (2) received ≥ 1 dose of study
drug, and (3) did not commit any major protocol violation (such as having an adherence rate for study drug up to Week 48 visit
below the 2.5th percentile, or discontinued for reasons other than lack of efficacy with no Week 48 data)
e
Included patients who discontinued for reasons other than an AE, death, or lack or loss of efficacy (eg, withdrew consent, loss to
follow-up).
f
Included patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no
virologic data on treatment during the specified window.
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 II 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.
Table 3: 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/mL
a
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/mm3
(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
25
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.
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.
26
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%.
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.
27
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.
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.
28
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).
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.
29
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).
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.
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
30
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
2 years
After first opening: 6 weeks
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
31
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
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.
32
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
33
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.
34
ANNEX III
LABELLING AND PACKAGE LEAFLET
35
A. LABELLING
36
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
9. SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture. Keep the bottle tightly closed.
37
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:
38
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.
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
17. UNIQUE IDENTIFIER – 2D BARCODE
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA
40
B. PACKAGE LEAFLET
41
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.
Medicine Purpose of the medicine
Alfuzosin to treat enlarged prostate
42
Amiodarone, dronedarone, 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 or simvastatin 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
Ticagrelor to help stop the clumping of platelets in the
treatment of patients with a history of a heart
attack
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
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.
43
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, telaprevir (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, dabigatran etexilate, rivaroxaban (to reduce clotting of the blood) as their
therapeutic effect or side effects may be altered;.
- Oestrogen-based hormonal contraceptives and hormone replacement therapy. Symtuza might
reduce its effectiveness. When used for birth control, non-hormonal contraception methods are
recommended.
- 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 opioiddependence)
- Salmeterol (medicine to treat asthma)
- Artemether/lumefantrine (a combination medicine to treat malaria)
- Dasatinib, nilotinib, vinblastine, vincristine (medicines to treat cancer)
- Prednisone (corticosteroid)
44
- Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder
called pulmonary arterial hypertension)
- Simeprevir, boceprevir, telaprevir (to treat hepatitis C virus infection).
- Fentanyl, oxycodone, tramadol (to treat pain).
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 muscledamage 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
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor for advice before taking this medicine.
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.
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.
45
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.
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.
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
46
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, feeling sick (nausea)
tiredness (fatigue)
rash
Common side effects (may affect up to 1 in 10 people)
allergic reactions such as nettle rash (urticaria), itching, severe swelling of the skin and other
tissues (most often the lips or the eyes)
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 pancreas or kidney.Your doctor will
explain these to you.
dizziness
joint pain
muscle pain, muscle cramps or weakness
weakness
Uncommon side effects (may affect up to 1 in 100 people)
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)
low red blood cell count (anaemia)
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.
47
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.
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.
Film coating:
The film-coating contains polyethylene glycol (macrogol), polyvinyl alcohol (partially hydrolyzed),
talc, titanium dioxide and yellow ferric oxide.
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
48
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
Antwerpseweg 15-17
B-2340 Beerse
Tel/Tél: +32 14 64 94 11
Lietuva
UAB "JOHNSON & JOHNSON"
Geležinio Vilko g. 18A
LT-08104 Vilnius
Tel: +370 5 278 68 88
България
„Джонсън & Джонсън България” ЕООД
ж.к. Младост 4
Бизнес Парк София, сграда 4
София 1766
Тел.: +359 2 489 94 00
Luxembourg/Luxemburg
Janssen-Cilag NV
Antwerpseweg 15-17
B-2340 Beerse
Belgique/Belgien
Tél/Tel: +32 14 64 94 11
Česká republika
Janssen-Cilag s.r.o.
Karla Engliše 3201/06
CZ-150 00 Praha 5 - Smíchov
Tel.: +420 227 012 227
Magyarország
Janssen-Cilag Kft.
Nagyenyed u. 8-14
H-Budapest, 1123
Tel.: +36 1 884 2858
Danmark
Janssen-Cilag A/S
Bregnerødvej 133
DK-3460 Birkerød
Tlf: +45 45 94 82 82
Malta
AM MANGION LTD.
Mangion Building, Triq Ġdida fi Triq Valletta
MT-Ħal-Luqa LQA 6000
Tel: +356 2397 6000
Deutschland
Janssen-Cilag GmbH
Johnson & Johnson Platz 1
D-41470 Neuss
Tel: +49 2137 955 955
Nederland
Janssen-Cilag B.V.
Graaf Engelbertlaan 75
NL-4837 DS Breda
Tel: +31 76 711 1111
Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Lõõtsa 2
EE-11415 Tallinn
Tel: +372 617 7410
Norge
Janssen-Cilag AS
Postboks 144
NO-1325-Lysaker
Tlf: +47 24 12 65 00
Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Λεωφόρος Ειρήνης 56
GR-151 21 Πεύκη, Αθήνα
Tηλ: +30 210 80 90 000
Österreich
Janssen-Cilag Pharma GmbH
Vorgartenstraße 206B
A-1020 Wien
Tel: +43 1 610 300
España
Janssen-Cilag, S.A.
Paseo de las Doce Estrellas, 5-7
E-28042 Madrid
Tel: +34 91 722 81 00
Polska
Janssen-Cilag Polska Sp. z o.o.
ul. Iłżecka 24
PL-02-135 Warszawa
Tel.: +48 22 237 60 00
49
France
Janssen-Cilag
1, rue Camille Desmoulins, TSA 91003
F-92787 Issy Les Moulineaux, Cedex 9
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
Portugal
Janssen-Cilag Farmacêutica, Lda.
Estrada Consiglieri Pedroso, 69 A
Queluz de Baixo
PT-2734-503 Barcarena
Tel: +351 21 43 68 835
Hrvatska
Johnson & Johnson S.E. d.o.o.
Oreškovićeva 6h
10010 Zagreb
Tel: +385 1 6610 700
România
Johnson & Johnson România SRL
Str. Tipografilor nr. 11-15
Clădirea S-Park, Corp B3-B4, Etaj 3
013714 Bucureşti, ROMÂNIA
Tel: +40 21 207 1800
Ireland
Janssen-Cilag Ltd.
50-100 Holmers Farm Way
High Wycombe
Buckinghamshire HP12 4EG
United Kingdom
Tel: +44 1 494 567 444
Slovenija
Johnson & Johnson d.o.o.
Šmartinska cesta 53
SI-1000 Ljubljana
Tel: +386 1 401 18 30
Ísland
Janssen-Cilag AB
c/o Vistor hf.
Hörgatúni 2
IS-210 Garðabær
Sími: +354 535 7000
Slovenská republika
Johnson & Johnson, s.r.o.
CBC III, Karadžičova 12
SK-821 08 Bratislava
Tel: +421 232 408 400
Italia
Janssen-Cilag SpA
Via M.Buonarroti, 23
I-20093 Cologno Monzese MI
Tel: +39 02 2510 1
Suomi/Finland
Janssen-Cilag Oy
Vaisalantie/Vaisalavägen 2
FI-02130 Espoo/Esbo
Puh/Tel: +358 207 531 300
Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Λεωφόρος Γιάννου Κρανιδιώτη 226
Λατσιά
CY-2234 Λευκωσία
Τηλ: +357 22 207 700
Sverige
Janssen-Cilag AB
Box 4042
SE-16904 Solna
Tel: +46 8 626 50 00
Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Mūkusalas iela 101
Rīga, LV-1004
Tel: +371 678 93561
United Kingdom
Janssen-Cilag Ltd.
50-100 Holmers Farm Way
High Wycombe
Buckinghamshire HP12 4EG - UK
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.
