4.1. Therapeutic indications

Symtuza is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and adolescents (aged 12 years and older with body weight at least 40 kg).

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

4.2. Posology and method of administration

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

Posology

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

Antiretroviral Therapy (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.

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

Special populations

Elderly

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

Hepatic impairment

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

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

Renal impairment

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

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

Symtuza should be discontinued in patients with eGFRCG that declines below 30 mL/min during treatment (see sections 5.1 and 5.2).

Paediatric population

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

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

Pregnancy and postpartum

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

Method of administration

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

4.3. Contraindications

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

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

Co-administration with strong CYP3A inducers such as the medicinal products listed below 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 medicinal products such as those products listed below due to the potential for serious and/or life-threatening adverse reactions (see section 4.5):

- alfuzosin

- amiodarone, dronedarone, ivabradine, quinidine, ranolazine

- colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)

- rifampicin

- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)

- dapoxetine

- domperidone

- naloxegol

- pimozide, quetiapine, sertindole, lurasidone (see section 4.5)

- elbasvir/grazoprevir

- triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5)

- sildenafil when used for the treatment of pulmonary arterial hypertension, avanafil

- simvastatin, lovastatin and lomitapide (see section 4.5)

- ticagrelor

4.4. Special warnings and precautions for use

ART-experienced patients

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

Pregnancy

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

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

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

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

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

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

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

Mitochondrial dysfunction

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

Elderly

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

Hepatotoxicity

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

Post-marketing cases of renal impairment, including acute renal failure and proximal renal tubulopathy have been reported with tenofovir alafenamide-containing products. 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). It is recommended that renal function is assessed in all patients prior to, or when, initiating therapy with Symtuza and that it is also monitored during therapy in all patients as clinically appropriate. In patients who develop clinically significant decreases in renal function or evidence of proximal renal tubulopathy, discontinuation of Symtuza should be considered.

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.

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 reconstitution inflammatory syndrome (IRIS)

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 and autoimmune hepatitis) have also been reported to occur in the setting of IRIS; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).

Opportunistic infections

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

Interactions with medicinal products

Co-administration of other medicinal products

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

Paediatric population

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

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

No 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. 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 or transported by P-gp, BCRP, MATE1, OATP1B1 and OATP1B3 may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions (see section 4.3 or table below).

Symtuza 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).

Co-administration of Symtuza and medicinal products that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s) potentially leading to loss of their therapeutic effect. These interactions are described in the interaction 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. azole antifungals like clotrimazole). These interactions are described in the interaction table below.

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

Emtricitabine

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

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

Tenofovir alafenamide

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

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

Interaction table

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

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

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

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

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

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

Medicinal product examples by therapeutic area

Interaction

Recommendations concerning co-administration

ALPHA ADRENORECEPTOR ANTAGONISTS

Alfusozin

Based on theoretical considerations DRV/COBI is expected to increase alfusozin concentrations

(CYP3A4 inhibition)

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

ANAESTHETIC

Alfentanil

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

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

ANTACIDS

Aluminium/magnesium hydroxide

Calcium carbonate

No mechanistic interaction expected based on theoretical considerations.

Symtuza and antacids can be used concomitantly without dose adjustment.

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide

Flecainide

Mexiletine

Propafenone

Lidocaine (systemic)

Amiodarone

Dronedarone

Ivabradine

Quinidine

Ranolazine

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

(CYP3A inhibition)

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

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

Digoxin

Based on theoretical considerations DRV/COBI is expected to increase digoxin plasma concentrations.

(P-glycoprotein inhibition)

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

ANTIBIOTIC

Clarithromycin

Based on theoretical considerations clarithromycin is expected to increase darunavir and/or cobicistat plasma concentrations.

(CYP3A inhibition)

Concentrations of clarithromycin may be increased upon co-administration with DRV/COBI.

(CYP3A inhibition)

Caution should be exercised when clarithromycin is combined with Symtuza.

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

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR

Apixaban

Rivaroxaban

Based on theoretical considerations co-administration of Symtuza with these anticoagulants may increase concentrations of the anticoagulant.

(CYP3A and/or P-glycoprotein inhibition)

Co-administration of Symtuza with a direct oral anticoagulant (DOAC) that is metabolised by CYP3A4 and transported by P-gp is not recommended as this may lead to an increased bleeding risk.

Dabigatran etexilate

Edoxaban

Ticagrelor

Clopidogrel

dabigatran etexilate (150 mg):

darunavir/cobicistat 800/150 mg single dose:

dabigatran AUC ↑ 164%

dabigatran Cmax ↑ 164%

darunavir/cobicistat 800/150 mg once daily:

dabigatran AUC ↑ 88%

dabigatran Cmax ↑ 99%

Based on theoretical considerations co-administration of DRV/COBI with ticagrelor may increase concentrations of ticagrelor.

(CYP3A and/or P-glycoprotein inhibition).

Based on theoretical considerations co-administration of Symtuza with clopidogrel is expected to decrease clopidogrel active metabolite plasma concentration, which may reduce the antiplatelet activity of clopidogrel.

Clinical monitoring and dose reduction is required when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with Symtuza.

Concomitant administration of Symtuza with ticagrelor is contraindicated (see section 4.3).

Co-administration of Symtuza with clopidogrel is not recommended. Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended (see section 4.3).

Warfarin

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

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

ANTICONVULSANTS

Carbamazepine

Phenobarbital

Phenytoin

Oxcarbazepine

Based on theoretical considerations these anticonvulsants are expected to decrease darunavir and/or cobicistat and/or tenofovir alafenamide plasma concentrations.

(CYP3A and/or P-gp induction).

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

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

Clonazepam

Based on theoretical considerations Symtuza is expected to increase concentrations of clonazepam

(inhibition of CYP3A)

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

ANTI-DEPRESSANTS

Herbal supplements

St. John's Wort

Based on theoretical considerations St. John's Wort is expected to decrease darunavir and/or cobicistat and/or tenofovir alafenamide plasma concentrations.

(CYP3A and/or P-gp induction)

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

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

ANTIEMETICS

Domperidone

Not studied.

Co-administration of domperidone with Symtuza is contraindicated.

ANTIFUNGALS

Clotrimazole

Fluconazole

Itraconazole

Isavuconazole

Posaconazole

Voriconazole

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

(CYP3A and/or P-gp inhibition)

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

Caution is warranted and clinical monitoring is recommended.

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 dose 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).

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 dose reduction of rifabutin has not been studied. It should be kept in mind that the twice weekly dose of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifamycin resistance and a treatment failure. Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV infected patients.

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

ANTI-NEOPLASTICS

Dasatinib

Nilotinib

Vinblastine

Vincristine

Everolimus

Irinotecan

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

(CYP3A inhibition)

Concentrations of these medicinal products may be increased when co-administered with Symtuza resulting in the potential for increased adverse events usually associated with these medicinal products.

Caution should be exercised when combining one of these anti-neoplastic agents with Symtuza.

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

ANTIPSYCHOTICS/NEUROLEPTICS

Perphenazine

Risperidone

Thioridazine

Lurasidone

Pimozide

Quetiapine

Sertindole

Based on theoretical considerations DRV/COBI is expected to increase these neuroleptic plasma concentrations.

(CYP3A, CYP2D6 and/or P-gp inhibition)

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

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

β-BLOCKERS

Carvedilol

Metoprolol

Timolol

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

(CYP2D6 inhibition)

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

CALCIUM CHANNEL BLOCKERS

Amlodipine

Diltiazem

Felodipine

Nicardipine

Nifedipine

Verapamil

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

(CYP3A inhibition)

Clinical monitoring is recommended when these medicinal products are co administered with Symtuza.

CORTICOSTEROIDS

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

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

Concomitant use of Symtuza and corticosteroids (all routes of administration) that are metabolised by CYP3A may increase the risk for development of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.

Co-administration with CYP3A-metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects.

Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone should be considered, particularly for long-term use.

Dexamethasone (systemic)

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

(CYP3A induction)

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

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

NS3-4A inhibitors

Elbasvir/grazoprevir

Based on theoretical considerations SYMTUZA may increase the exposure to grazoprevir.

(OATP1B and CYP3A inhibition)

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

Glecaprevir/pibrentasvir

Based on theoretical considerations DRV/COBI may increase the exposure to glecaprevir and pibrentasvir.

(P-gp, BCRP and/or OATP1B1/3 inhibition)

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

Daclatasvir

Ledipasvir

Sofosbuvir

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

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

Herbal products

St. John's Wort (Hypericum perforatum)

Based on theoretical consideration, St. John's Wort may substantially decrease DRV/COBI (CYP3A4 induction) and TAF exposures.

(P-gp induction)

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

HMG CO-A REDUCTASE INHIBITORS

Atorvastatin

Fluvastatin

Pitavastatin

Pravastatin

Rosuvastatin

Lovastatin

Simvastatin

Atorvastatin (10 mg once daily):

atorvastatin AUC ↑ 290%

atorvastatin Cmax ↑ 319%

atorvastatin Cmin ND

Rosuvastatin (10 mg once daily):

rosuvastatin AUC ↑ 93%

rosuvastatin Cmax ↑ 277%

rosuvastatin Cmin ND

Based on theoretical considerations DRV/COBI is expected to increase the plasma concentrations of fluvastatin, pitavastatin, pravastatin, lovastatin and simvastatin.

(CYP3A inhibition and/or transport)

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

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

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

OTHER LIPID MODIFYING AGENTS

Lomitapide

Based on theoretical considerations, Symtuza is expected to increase the exposure of lomitapide when co-administered.

(CYP3A inhibition)

Co-administration is contraindicated (see section 4.3).

H2-RECEPTOR ANTAGONISTS

Cimetidine

Famotidine

Nizatidine

Ranitidine

Based on theoretical considerations, no mechanistic interaction is expected.

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

IMMUNOSUPPRESSANTS

Ciclosporin

Sirolimus

Tacrolimus

Everolimus

Based on theoretical considerations DRV/COBI is expected to increase these immunosuppressant plasma concentrations.

(CYP3A inhibition)

Co-administration of ciclosporin is expected to increase plasma concentrations of tenofovir alafenamide.

(P-gp inhibition)

Concentration 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 dose is expected when initiating co-administration with Symtuza. Clinical monitoring is recommended, as maintenance therapy may need to be adjusted in some patients.

Fentanyl

Oxycodone

Tramadol

Based on theoretical considerations DRV/COBI may increase plasma concentrations of these analgesics.

(CYP2D6 and/or CYP3A inhibition)

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

OESTROGEN-BASED CONTRACEPTIVES

Drospirenone Ethinylestradiol (3 mg/0.02 mg once daily)

Ethinylestradiol

Norethindrone

drospirenone AUC ↑ 58%

drospirenone Cmax ↑ 15%

drospirenone Cmin ND

ethinylestradiol AUC ↓ 30%

ethinylestradiol Cmax ↓ 14%

ethinylestradiol Cmin ND

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

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

When Symtuza is co-administered with a drospirenone-containing product, clinical monitoring is recommended due to the potential for hyperkalaemia.

OPIOID ANTAGONIST

Naloxegol

Not studied.

Co-administration of Symtuza and naloxegol is contraindicated.

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

For the treatment of erectile dysfunction

Sildenafil

Tadalafil

Vardenafil

Avanafil

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

(CYP3A inhibition)

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

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

For the treatment of pulmonary arterial hypertension

Sildenafil

Tadalafil

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

(CYP3A inhibition)

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

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

PROTON PUMP INHIBITORS

Dexlansoprazole

Esomeprazole

Lansoprazole

Omeprazole

Pantoprazole

Rabeprazole

Based on theoretical considerations, no mechanistic interaction is expected.

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

SEDATIVES/HYPNOTICS

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Midazolam (parenteral)

Zolpidem

Midazolam (oral)

Triazolam

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

(CYP3A inhibition)

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

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

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

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

TREATMENT FOR PREMATURE EJACULATION

Dapoxetine

Not studied.

Co-administration of Symtuza with dapoxetine is contraindicated.

UROLOGICAL MEDICINAL PRODUCTS

Fesoterodine

Solifenacin

Not studied.

Use with caution. Monitor for fesoterodine or solifenacin adverse reactions, dose reduction of fesoterodine or solifenacin may be necessary.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of Symtuza in pregnant women. A moderate amount of data on pregnant women (between 300-1 000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of darunavir, cobicistat or tenofovir alafenamide. A large amount of data on pregnant women (more than 1 000 exposed outcomes) indicate no malformative nor foetal/neonatal toxicity associated with emtricitabine.

Animal studies do not indicate direct or indirect harmful effects of darunavir or emtricitabine with respect to reproductive toxicity (see section 5.3). Animal studies do not indicate direct harmful effects of cobicistat or tenofovir alafenamide with respect to reproductive toxicity (see section 5.3).

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

Breast-feeding

Emtricitabine is excreted in human milk. It is unknown 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. Studies in rats have demonstrated that darunavir is excreted in milk and at high levels (1 000 mg/kg/day) resulted in toxicity of the offspring.

Because of the potential for adverse reactions in breast fed infants, women should be instructed not to breast feed if they are receiving Symtuza.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast feed.

Fertility

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

4.7. Effects on ability to drive and use machines

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

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

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

Tabulated list of adverse reactions

Adverse reactions are listed by system organ class (SOC) and frequency category in Table 2. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000) and not known (frequency cannot be estimated from the available data)

Table 2

MedDRA system organ class

Frequency category

Adverse reaction

Blood and lymphatic system disorders

common

anaemia

Immune system disorders

common

(drug) hypersensitivity

uncommon

immune reconstitution inflammatory syndrome

Metabolism and nutrition disorders

common

diabetes mellitus, anorexia, hypercholesterolaemia, low density lipoprotein increased, hypertriglyceridaemia, hyperlipidaemia, dyslipidaemia

uncommon

hyperglycaemia

Psychiatric disorders

common

abnormal dreams

Nervous system disorders

very common

headache

common

dizziness

Gastrointestinal disorders

very common

diarrhoea

common

vomiting, nausea, abdominal pain, abdominal distension, dyspepsia, flatulence

uncommon

pancreatitis acute, pancreatic enzymes increased

Hepatobiliary disorders

common

hepatic enzyme increased

uncommon

acute hepatitisa, cytolytic hepatitisa

Skin and subcutaneous tissue disorders

very common

rash (including macular, maculopapular, papular, erythematous, pruritic rash, generalised rash, and allergic dermatitis)

common

pruritus, urticaria

uncommon

angioedema

rare

drug reaction with eosinophilia and systemic symptomsa, Stevens-Johnson syndromea

not known

toxic epidermal necrolysisa, acute generalised exanthematous pustulosisa

Musculoskeletal and connective tissue disorders

common

arthralgia, myalgia

uncommon

osteonecrosis

Renal and urinary disorders

rare

crystal nephropathya§

Reproductive system and breast disorders

uncommon

gynaecomastiaa

General disorders and administration site conditions

common

asthenia, fatigue

Investigations

Common

increased blood creatinine

a Additional adverse drug reactions only seen with darunavir/ritonavir in other trials or post-marketing experience

§ Adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics (Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determined using the "Rule of 3".

Description of selected adverse reactions

Rash

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

Metabolic parameters

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

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

Table 3

Lipid parameter

Baseline median

Median increase from baseline at

Week 48

D/C/F/TAF

Week 48

D/C + F/TDF

Week 96*

D/C/F/TAF

Total cholesterol (mmol/L)

4.22

0.74

0.27

0.88

LDL cholesterol (mmol/L)

2.49

0.45

0.13

0.56

HDL cholesterol (mmol/L)

1.08

0.12

0.04

0.13

Triglycerides (mmol/L)

1.09

0.28

0.16

0.33

p < 0.001 for all 4 lipid parameters when comparing D/C/F/TAF versus D/C + F/TDF at Week 48

* No comparator data available beyond Week 48

Musculoskeletal abnormalities

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

Osteonecrosis

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

Immune reconstitution inflammatory syndrome

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

Bleeding in haemophiliac patients

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

Decrease estimated creatinine clearance

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

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

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 trial 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 trial (GS-US-292-1249). Based on this limited experience, the safety profile of emtricitabine/tenofovir alafenamide in patients with HIV/HBV co-infection appears to be similar to that in patients with HIV-1 monoinfection (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Human experience of acute overdose with Symtuza is limited.

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8).

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

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