4.1. Therapeutic indications

REZOLSTA is indicated, in combination with other antiretroviral medicinal products, for the treatment of human immunodeficiency virus‑1 (HIV‑1) infection in adults and paediatric patients (aged 6 years and older, weighing at least 25 kg).

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

4.2. Posology and method of administration

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

Posology

Adults and paediatric patients weighing at least 40 kg

ART‑naïve patients

The recommended dose regimen is one 800 mg darunavir/150 mg cobicistat tablet once daily taken with food.

ART‑experienced patients

One 800 mg darunavir/150 mg cobicistat tablet once daily taken with food may be used in patients with prior exposure to antiretroviral medicinal products, but without darunavir resistance associated mutations (DRV‑RAMs)* and who have plasma HIV‑1 RNA < 100,000 copies/mL and CD4+ cell count ≥ 100 cells x 106/L (see section 4.1).

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

Paediatric patients aged 6 years and older weighing at least 25 kg to less than 40 kg

ART‑naïve paediatric patients

The recommended dose regimen is one 675 mg darunavir/150 mg cobicistat tablet once daily taken with food.

ART‑experienced paediatric patients

One 675 mg darunavir/150 mg cobicistat tablet once daily taken with food may be used in patients with prior exposure to antiretroviral medicinal products, but without DRV-RAMs* and who have plasma HIV‑1 RNA < 100,000 copies/mL and CD4+ cell count ≥ 100 cells x 106/L (see section 4.1).

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

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

Advice on missed doses

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

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

Special populations

Elderly

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

Hepatic impairment

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

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

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

Renal impairment

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

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

For more information consult the cobicistat Summary of Product Characteristics.

Paediatric population

The safety and efficacy of darunavir in combination with cobicistat in paediatric patients aged 3 to < 6 years, or weighing < 25 kg, have not been established. No data are available yet. Darunavir in combination with cobicistat should not be used in paediatric patients below 3 years of age because of safety concerns related to toxicity and mortality observed in juvenile rats dosed with darunavir up to days 23 to 26 of age (see section 5.3).

Pregnancy and postpartum

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure (see sections 4.4 and 5.2). Therefore, this combination should not be initiated during pregnancy, and women who become pregnant during therapy with REZOLSTA should be switched to an alternative regimen (see sections 4.4 and 4.6). Darunavir/ritonavir may be considered as an alternative.

Method of administration

Oral use

To ensure administration of the entire dose of both darunavir and cobicistat, the tablet should be swallowed whole.

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

Adults and paediatric patients weighing at least 40 kg

For patients unable to swallow the 800 mg/150 mg tablet whole, the tablet may be split into two pieces using a tablet‑cutter. Each piece should be consumed immediately after splitting to ensure the entire dose is administered.

Paediatric patients aged 6 years and older weighing at least 25 kg to less than 40 kg

For patients unable to swallow the 675 mg/150 mg tablet whole, the scored tablet may be split by hand into two pieces. Each piece should be consumed immediately after splitting to ensure the entire dose is administered.

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, bepridil, dronedarone, ivabradine, quinidine, ranolazine

- astemizole, terfenadine

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

- rifampicin

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

- cisapride

- dapoxetine

- domperidone

- naloxegol

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

- elbasvir/grazoprevir

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

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

- simvastatin, lovastatin and lomitapide (see section 4.5)

- ticagrelor.

4.4. Special warnings and precautions for use

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

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

ART‑experienced patients

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

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

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, this combination should not be initiated during pregnancy, and women who become pregnant during therapy with REZOLSTA should be switched to an alternative regimen (see sections 4.2 and 4.6). Darunavir given with low dose ritonavir may be considered as an alternative.

Elderly

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

Severe skin reactions

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

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

Sulphonamide allergy

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

Hepatotoxicity

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

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

Patients with coexisting conditions

Hepatic impairment

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

Renal impairment

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

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

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

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

Haemophiliac patients

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

Weight and metabolic parameters

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

Osteonecrosis

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

Immune reconstitution inflammatory syndrome (IRIS)

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

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

Interactions with medicinal products

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

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

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

Excipients

REZOLSTA 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

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

Medicinal products that may be affected by darunavir/cobicistat

Darunavir is an inhibitor of CYP3A, a weak inhibitor of CYP2D6 and an inhibitor of P‑gp. Cobicistat is a mechanism based inhibitor of CYP3A, and a weak CYP2D6 inhibitor. Cobicistat inhibits the transporters p‑glycoprotein (P‑gp), BCRP, MATE1, OATP1B1 and OATP1B3. Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Cobicistat is not expected to induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, UGT1A1, or P‑gp (MDR1). Co‑administration of darunavir/cobicistat and medicinal products primarily metabolised by CYP3A 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).

REZOLSTA 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 REZOLSTA with 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.

Medicinal products that affect darunavir/cobicistat exposure

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

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

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

Interaction table

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

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

The below list of examples of drug-drug interactions in Table 1 is not comprehensive and therefore the label of each drug that is co-administered with REZOLSTA should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co‑administration.

Table 1: INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

Medicinal product examples by therapeutic area

Interaction

Recommendations concerning co‑administration

HIV ANTIRETROVIRALS

Integrase strand transfer inhibitors

Dolutegravir

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

REZOLSTA and dolutegravir can be used without dose adjustments.

Raltegravir

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

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

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

Didanosine

400 mg once daily

No mechanistic interaction expected based on theoretical consideration.

REZOLSTA and didanosine can be used without dose adjustments.

When didanosine is co‑administered with REZOLSTA, didanosine should be administered on an empty stomach 1 hour before or 2 hours after REZOLSTA (which is administered with food).

Tenofovir disoproxil *

*study was done with tenofovir disoproxil fumarate

Based on theoretical considerations REZOLSTA is expected to increase tenofovir plasma concentrations.

(P‑glycoprotein inhibition)

REZOLSTA and tenofovir disoproxil can be used without dose adjustments.

Monitoring of renal function may be indicated when REZOLSTA is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.

Emtricitabine/tenofovir alafenamide

Tenofovir alafenamide ↔

Tenofovir ↑

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

Abacavir

Emtricitabine

Lamivudine

Stavudine

Zidovudine

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

REZOLSTA can be used with these NRTIs without dose adjustment.

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

Efavirenz

Based on theoretical considerations efavirenz is expected to decrease darunavir and/or cobicistat plasma concentrations.

(CYP3A induction)

Co‑administration of REZOLSTA and efavirenz is not recommended.

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

Etravirine

Based on theoretical considerations etravirine is expected to decrease darunavir and/or cobicistat plasma concentrations.

(CYP3A induction)

Co‑administration of REZOLSTA and etravirine is not recommended.

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

Nevirapine

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

(CYP3A inhibition)

Co‑administration of REZOLSTA and nevirapine is not recommended.

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

Rilpivirine

Based on theoretical considerations REZOLSTA is expected to increase rilpivirine plasma concentrations.

(CYP3A inhibition)

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

CCR5 ANTAGONIST

Maraviroc

150 mg twice daily

Based on theoretical considerations REZOLSTA is expected to increase maraviroc plasma concentrations.

(CYP3A inhibition)

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

α1-ADRENORECEPTOR ANTAGONIST

Alfuzosin

Based on theoretical considerations REZOLSTA is expected to increase alfuzosin plasma concentrations.

(CYP3A inhibition)

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

ANAESTHETIC

Alfentanil

Based on theoretical considerations REZOLSTA is expected to increase alfentanil plasma concentrations.

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

ANTACIDS

Aluminium/magnesium hydroxide

Calcium carbonate

No mechanistic interaction expected based on theoretical consideration.

REZOLSTA and antacids can be used concomitantly without dose adjustment.

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide

Flecainide

Lidocaine (systemic)

Mexiletine

Propafenone

Amiodarone

Bepridil

Dronedarone

Ivabradine

Quinidine

Ranolazine

Based on theoretical considerations REZOLSTA is expected to increase these antiarrhythmic plasma concentrations.

(CYP3A and/or CYP2D6 inhibition)

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

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

Digoxin

Based on theoretical considerations REZOLSTA is expected to increase digoxin plasma concentrations.

(P‑glycoprotein inhibition)

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

ANTIBIOTIC

Clarithromycin

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

(CYP3A inhibition)

Concentrations of clarithromycin may be increased upon co‑administration with REZOLSTA.

(CYP3A inhibition)

Caution should be exercised when clarithromycin is combined with REZOLSTA.

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

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR

Apixaban

Rivaroxaban

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

(CYP3A and/or P‑glycoprotein inhibition)

Co‑administration of REZOLSTA and 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 REZOLSTA with ticagrelor may increase concentrations of ticagrelor.

(CYP3A and/or P‑glycoprotein inhibition).

Based on theoretical considerations co‑administration of REZOLSTA 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 REZOLSTA.

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

Co‑administration of REZOLSTA 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 REZOLSTA may alter warfarin plasma concentrations.

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

ANTICONVULSANTS

Carbamazepine

Phenobarbital

Phenytoin

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

(CYP3A induction)

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

Clonazepam

Based on theoretical considerations REZOLSTA is expected to increase concentrations of clonazepam.

(inhibition of CYP3A)

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

ANTI‑DEPRESSANTS

Herbal supplements

St John's Wort

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

(CYP3A induction)

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

Paroxetine

Sertraline

Amitriptyline

Desipramine

Imipramine

Nortriptyline

Trazodone

Based on theoretical considerations REZOLSTA is expected to increase these anti‑depressant plasma concentrations.

(CYP2D6 and/or CYP3A inhibition)

Prior data with ritonavir‑boosted darunavir however showed a decrease in these anti‑depressant plasma concentrations (unknown mechanism); the latter may be specific to ritonavir.

Based on theoretical considerations REZOLSTA is expected to increase these anti‑depressant plasma concentrations.

(CYP2D6 and/or CYP3A inhibition)

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

ANTI‑DIABETICS

Metformin

Based on theoretical considerations REZOLSTA is expected to increase metformin plasma concentrations.

(MATE1 inhibition)

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

ANTIEMETICS

Domperidone

Not studied.

Co-administration of domperidone with REZOLSTA is contraindicated.

ANTIFUNGALS

Clotrimazole

Fluconazole

Itraconazole

Isavuconazole

Posaconazole

Voriconazole

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

(CYP3A inhibition and/or P‑gp inhibition)

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

Caution is warranted and clinical monitoring is recommended.

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

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

ANTIGOUT MEDICINES

Colchicine

Based on theoretical considerations REZOLSTA is expected to increase colchicine plasma concentrations.

(CYP3A and/or P‑glycoprotein inhibition)

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

The combination of colchicine and REZOLSTA is contraindicated in patients with renal or hepatic impairment (see section 4.3).

ANTIMALARIALS

Artemether/Lumefantrine

Based on theoretical considerations REZOLSTA is expected to increase lumefantrine plasma concentrations.

(CYP3A inhibition)

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

ANTIMYCOBACTERIALS

Rifampicin

Based on theoretical considerations rifampin is expected to decrease darunavir and/or cobicistat plasma concentrations.

(CYP3A induction)

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

Rifabutin

Rifapentine

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

(CYP3A induction)

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

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

ANTI‑NEOPLASTICS

Dasatinib

Nilotinib

Vinblastine

Vincristine

Everolimus

Irinotecan

Based on theoretical considerations REZOLSTA is expected to increase these anti‑neoplastic plasma concentrations.

(CYP3A inhibition)

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

Caution should be exercised when combining one of these anti‑neoplastic agents with REZOLSTA.

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

ANTIPSYCHOTICS/NEUROLEPTICS

Perphenazine

Risperidone

Thioridazine

Lurasidone

Pimozide

Sertindole

Quetiapine

Based on theoretical considerations REZOLSTA is expected to increase these neuroleptic plasma concentrations.

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

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

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

β‑BLOCKERS

Carvedilol

Metoprolol

Timolol

Based on theoretical considerations REZOLSTA is expected to increase these beta blocker plasma concentrations.

(CYP3A inhibition)

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

CALCIUM CHANNEL BLOCKERS

Amlodipine

Diltiazem

Felodipine

Nicardipine

Nifedipine

Verapamil

Based on theoretical considerations REZOLSTA is expected to increase these calcium channel blocker plasma concentrations.

(CYP3A and/or CYP2D6 inhibition)

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

CORTICOSTEROIDS

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

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

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

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

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

Dexamethasone (systemic)

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

(CYP3A induction)

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

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan

Based on theoretical considerations bosentan is expected to decrease darunavir and/or cobicistat plasma concentrations.

(CYP3A induction)

REZOLSTA is expected to increase bosentan plasma concentrations.

(CYP3A inhibition)

Co‑administration of REZOLSTA and bosentan is not recommended.

HEPATITIS C VIRUS (HCV) DIRECT‑ACTING ANTIVIRALS

NS3‑4A inhibitors

Elbasvir/grazoprevir

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

(OATP1B and CYP3A inhibition)

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

Glecaprevir/pibrentasvir

Based on theoretical considerations REZOLSTA may increase the exposure to glecaprevir and pibrentasvir.

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

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

HMG CO‑A REDUCTASE INHIBITORS

Atorvastatin

Fluvastatin

Pitavastatin

Pravastatin

Rosuvastatin

Lovastatin

Simvastatin

Atorvastatin (10 mg once daily):

atorvastatin AUC ↑ 290%

atorvastatin Cmax ↑ 319%

atorvastatin Cmin ND

Rosuvastatin (10 mg once daily):

rosuvastatin AUC ↑ 93%

rosuvastatin Cmax ↑ 277%

rosuvastatin Cmin ND

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

(CYP3A inhibition and/or transport)

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

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

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

OTHER LIPID MODIFYING AGENTS

Lomitapide

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

(CYP3A inhibition)

Co-administration is contraindicated (see section 4.3)

H2‑RECEPTOR ANTAGONISTS

Cimetidine

Famotidine

Nizatidine

Ranitidine

Based on theoretical considerations, no mechanistic interaction is expected.

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

IMMUNOSUPPRESSANTS

Ciclosporin

Sirolimus

Tacrolimus

Everolimus

Based on theoretical considerations REZOLSTA is expected to increase these immunosuppressant plasma concentrations.

(CYP3A inhibition)

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

Concomitant use of everolimus and REZOLSTA is not recommended.

INHALED BETA AGONISTS

Salmeterol

Based on theoretical considerations REZOLSTA is expected to increase salmeterol plasma concentrations.

(CYP3A inhibition)

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

NARCOTIC ANALGESICS/TREATMENT OF OPIOID DEPENDENCE

Buprenorphine/naloxone

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

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

Methadone

Based on theoretical considerations REZOLSTA may increase methadone plasma concentrations.

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

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

Fentanyl

Oxycodone

Tramadol

Based on theoretical considerations REZOLSTA may increase plasma concentrations of these analgesics.

(CYP2D6 and/or CYP3A inhibition)

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

OESTROGEN‑BASED CONTRACEPTIVES

Drospirenone (3 mg once daily)

Ethinylestradiol (0.02 mg once daily)

Norethindrone

drospirenone AUC ↑ 58%

drospirenone Cmax ↑ 15%

drospirenone Cmin ND

ethinylestradiol AUC ↓ 30%

ethinylestradiol Cmax ↓ 14%

ethinylestradiol Cmin ND

Based on theoretical considerations REZOLSTA may alter norethindrone plasma concentrations.

(CYP3A inhibition, UGT/SULT induction)

Alternative or additional contraceptive measures are recommended when oestrogen based contraceptives are co administered with REZOLSTA. Patients using oestrogens as

hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.

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

OPIOID ANTAGONIST

Naloxegol

Not studied.

Co‑administration of REZOLSTA and naloxegol is contraindicated.

PHOSPHODIESTERASE, TYPE 5 (PDE‑5) INHIBITORS

For the treatment of erectile dysfunction

Sildenafil

Tadalafil

Vardenafil

Avanafil

Based on theoretical considerations REZOLSTA is expected to increase these PDE‑5 inhibitor plasma concentrations.

(CYP3A inhibition)

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

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

For the treatment of pulmonary arterial hypertension

Sildenafil

Tadalafil

Based on theoretical considerations REZOLSTA is expected to increase these PDE‑5 inhibitor plasma concentrations.

(CYP3A inhibition)

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

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

PROTON PUMP INHIBITORS

Dexlansoprazole

Esomeprazole

Lansoprazole

Omeprazole

Pantoprazole

Rabeprazole

Based on theoretical considerations, no mechanistic interaction is expected.

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

SEDATIVES/HYPNOTICS

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Midazolam (parenteral)

Zolpidem

Midazolam (oral)

Triazolam

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

(CYP3A inhibition)

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

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

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

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

TREATMENT FOR PREMATURE EJACULATION

Dapoxetine

Not studied.

Co-administration of REZOLSTA with dapoxetine is contraindicated.

UROLOGICAL DRUGS

Fesoterodine

Solifenacin

Not studied.

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

4.6. Fertility, pregnancy and lactation

Pregnancy

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

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

Breast‑feeding

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

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

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

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

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

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

Tabulated list of adverse reactions

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

Table 2 Adverse reactions with darunavir/cobicistat in adult patients

MedDRA system organ class

Frequency category

Adverse reaction

Immune system disorders

Common

(drug) hypersensitivity

Uncommon

immune reconstitution inflammatory syndrome

Metabolism and nutrition disorders

Common

anorexia, hypercholesterolaemia, hypertriglyceridaemia

Uncommon

diabetes mellitus, dyslipidaemia, hyperglycaemia, hyperlipidaemia

Psychiatric disorders

Common

abnormal dreams

Nervous system disorders

Very common

headache

Gastrointestinal disorders

Very common

diarrhoea, nausea

Common

vomiting, abdominal pain, abdominal distension, dyspepsia, flatulence

Uncommon

pancreatitis acute, pancreatic enzymes increased

Hepatobiliary disorders

Common

hepatic enzyme increased

Uncommon

hepatitis*, cytolytic hepatitis*

Skin and subcutaneous tissue disorders

Very common

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

Common

pruritus

Uncommon

Stevens‑Johnson syndrome#, angioedema, urticaria

Rare

drug reaction with eosinophilia and systemic symptoms*

Not known

toxic epidermal necrolysis*, acute generalised exanthematous pustulosis*

Musculoskeletal and connective tissue disorders

Common

myalgia

Uncommon

osteonecrosis*

Renal and urinary disorders

Rare

crystal nephropathy*§

Reproductive system and breast disorders

Uncommon

gynaecomastia*

General disorders and administration site conditions

Common

fatigue, asthenia

Investigations

Common

increased blood creatinine

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

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

§ 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

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

Metabolic parameters

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

Musculoskeletal abnormalities

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

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

Immune reconstitution inflammatory syndrome

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

Bleeding in haemophiliac patients

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

Decrease estimated creatinine clearance

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

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

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

For more information consult the cobicistat Summary of Product Characteristics.

Paediatric population

The safety of darunavir in combination with cobicistat was evaluated through clinical study GS-US-216-0128 in virologically suppressed adolescents aged 12 to less than 18 years, weighing at least 40 kg (cohort 1; N = 7) and in children aged 6 to less than 12 years, weighing at least 25 kg (cohort 2; N = 8). Safety analyses of this study in a limited number of adolescent and paediatric subjects aged at least 6 years did not identify new safety concerns compared to the known safety profile in adult subjects.

Other special populations

Patients co‑infected with hepatitis B and/or hepatitis C virus

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the 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 REZOLSTA or darunavir in combination with cobicistat is limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.

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