REZOLSTA 800 mg/150 mg film-coated tablets
Each film-coated tablet contains 800 mg of darunavir (as ethanolate) and 150 mg of cobicistat.
For the full list of excipients, see section 6.1.
Film-coated tablet.
Pink oval shaped tablet of 23 mm x 11.5 mm, debossed with “800” on one side and “TG” on the other side.
REZOLSTA, is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged 18 years or older.
Genotypic testing should guide the use of REZOLSTA (see sections 4.2, 4.3, 4.4 and 5.1).
Therapy should be initiated by a healthcare provider experienced in the management of HIV infection.
Posology
After therapy with REZOLSTA has been initiated, patients should not alter the dosage or discontinue therapy without the instruction of their healthcare provider.
ART-naïve patients
The recommended dose regimen is one film-coated tablet of REZOLSTA once daily taken with food.
ART-experienced patients
One film-coated tablet of REZOLSTA 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.
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 agents 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 of REZOLSTA 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.
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 agent (e.g. emtricitabine, lamivudine, tenofovir disoproxil fumarate, 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 REZOLSTA in paediatric patients aged 3 to 17 years has not been established (see sections 4.4 and 5.3). No data are available. REZOLSTA should not be used in paediatric patients below 3 years of age because of safety concerns (see sections 4.4 and 5.3).
Method of administration
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 4.4, 4.5 and 5.2).
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Patients with severe (Child-Pugh Class C) hepatic impairment.
Co-administration with the following medicinal products is contraindicated due to the potential for loss of therapeutic effect (see section 4.5):
- carbamazepine, phenobarbital, phenytoin (anticonvulsants)
- rifampicin (antimycobacterial)
- St John's wort, (Hypericum perforatum) (herbal product).
Co-administration with the following medicinal products is contraindicated due to the potential for serious and/or life-threatening adverse reactions (see section 4.5):
- alfuzosin (alpha 1-adrenoreceptor antagonist)
- amiodarone, bepridil, dronedarone, quinidine, ranolazine, systemic lidocaine (antiarrhythmics/antianginals)
- astemizole, terfenadine (antihistamines)
- colchicine, when used in patients with renal and/or hepatic impairment (antigout) (see section 4.5)
- rifampicin (antimycobacterial)
- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
- cisapride (gastrointestinal motility agent)
- pimozide, quetiapine, sertindole (antipsychotics/neuroleptics) (see section 4.5)
- triazolam, midazolam administered orally (sedatives/hypnotics) (for caution on parenterally administered midazolam, see section 4.5)
- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil (PDE-5 inhibitors)
- simvastatin and lovastatin (HMG-CoA reductase inhibitors) (see section 4.5)
- ticagrelor (platelet aggregation inhibitor).
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Regular assessment of virological response is advised. In the setting of lack or loss of virological response, resistance testing should be performed.
Darunavir 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).
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 REZOLSTA 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 REZOLSTA, interruption or discontinuation of treatment should be considered promptly.
Patients with coexisting conditions
Hepatic impairment
The safety and efficacy of REZOLSTA, darunavir, 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 fumarate 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 fumarate and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil fumarate 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.
Diabetes mellitus/hyperglycaemia
New onset diabetes mellitus, hyperglycaemia, or exacerbation of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including HIV PIs. In some of these patients the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycaemia.
Fat redistribution and metabolic disorders
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and HIV PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include eva luation for physical signs of fat redistribution. Consideration should be given to measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
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 eva luated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical trials with darunavir co-administered with low dose ritonavir.
Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).
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.
Paediatric population
REZOLSTA is not recommended for use in paediatric patients (3 to 17 years of age). REZOLSTA should not be used in paediatric patients below 3 years of age (see sections 4.2 and 5.3).
No drug interaction trials have been performed using REZOLSTA. As REZOLSTA contains darunavir and cobicistat, interactions that have been identified with darunavir (in combination with low dose ritonavir) and with cobicistat determine the interactions that may occur with REZOLSTA. Interaction trials with 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. Co-administration of cobicistat with medicinal products that are substrates of these transporters can result in increased plasma concentrations of the co-administered medicinal products. Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Cobicistat is not expected to induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, UGT1A1, or P-gp (MDR1). Co-administration of darunavir/cobicistat and medicinal products primarily metabolised by CYP3A may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.
REZOLSTA must therefore not be combined with medicinal products that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) (see section 4.3).
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. systemic azoles like ketoconazole and 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 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.
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INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
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Medicinal products by therapeutic areas
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Interaction
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Recommendations concerning co-administration
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HIV ANTIRETROVIRALS
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Integrase strand transfer inhibitors
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Dolutegravir
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Based on theoretical considerations dolutegravir is not expected to affect the pharmacokinetics of REZOLSTA.
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REZOLSTA and dolutegravir can be used without dose adjustments.
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Raltegravir
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Some clinical trials suggest raltegravir may cause a modest decrease in darunavir plasma concentrations.
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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.
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HIV Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
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Didanosine
400 mg once daily
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No mechanistic interaction expected based on theoretical consideration.
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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).
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Tenofovir disoproxil fumarate
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Based on theoretical considerations REZOLSTA is expected to increase tenofovir plasma concentrations.
(P-glycoprotein inhibition)
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REZOLSTA and tenofovir disoproxil fumarate can be used without dose adjustments.
Monitoring of renal function may be indicated when REZOLSTA is given in combination with tenofovir disoproxil fumarate, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.
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Abacavir
Emtricitabine
Lamivudine
Stavudine
Zidovudine
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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.
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REZOLSTA can be used with these NRTIs without dose adjustment.
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HIV Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
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Efavirenz
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Based on theoretical considerations efavirenz is expected to decrease darunavir and/or cobicistat plasma concentrations.
(CYP3A induction)
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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.
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Etravirine
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Based on theoretical considerations etravirine is expected to decrease darunavir and/or cobicistat plasma concentrations.
(CYP3A induction)
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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.
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Nevirapine
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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)
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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.
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Rilpivirine
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Based on theoretical considerations REZOLSTA is expected to increase rilpivirine plasma concentrations.
(CYP3A inhibition)
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Co-administration of REZOLSTA and rilpivirine can be used without dose adjustments, as the expected increase in rilpivirine concentrations is not considered clinically relevant.
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CCR5 ANTAGONIST
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Maraviroc
150 mg twice daily
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Based on theoretical considerations REZOLSTA is expected to increase maraviroc plasma concentrations.
(CYP3A inhibition)
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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.
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ANAESTHETIC
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Alfentanil
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Based on theoretical considerations REZOLSTA is expected to increase alfentanil plasma concentrations.
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The concomitant use with REZOLSTA may require to lower the dose of alfentanil and requires monitoring for risks of prolonged or delayed respiratory depression.
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ANTACIDS
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Aluminium/magnesium hydroxide
Calcium carbonate
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No mechanistic interaction expected based on theoretical consideration.
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REZOLSTA and antacids can be used concomitantly without dose adjustment.
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ANTIANGINA/ANTIARRHYTHMIC
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Disopyramide
Flecainide
Mexiletine
Propafenone
Amiodarone
Bepridil
Dronedarone
Lidocaine (systemic)
Quinidine
Ranolazine
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Based on theoretical considerations REZOLSTA is expected to increase these antiarrhythmic plasma concentrations.
(CYP3A inhibition)
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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, lidocaine (systemic), quinidine, or ranolazine and REZOLSTA is contraindicated (see section 4.3).
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Digoxin
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Based on theoretical considerations REZOLSTA is expected to increase digoxin plasma concentrations.
(P-glycoprotein inhibition)
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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.
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ANTIBIOTIC
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Clarithromycin
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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)
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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.
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ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
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Apixaban
Dabigatran etexilate
Rivaroxaban
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Based on theoretical considerations co-administration of REZOLSTA with these anticoagulants may increase concentrations of the anticoagulant.
(CYP3A and/or P-glycoprotein inhibition)
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Co-administration of REZOLSTA and these anticoagulants is not recommended.
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Ticagrelor
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Based on theoretical considerations co-administration of REZOLSTA with ticagrelor may increase concentrations of the anticoagulant.
(CYP3A and/or P-glycoprotein inhibition).
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Concomitant administration of REZOLSTA with ticagrelor is contraindicated.
Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended (see section 4.3).
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Warfarin
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Based on theoretical considerations REZOLSTA may alter warfarin plasma concentrations.
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It is recommended that the international normalised ratio (INR) be monitored when warfarin is co-administered with REZOLSTA.
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ANTICONVULSANTS
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Carbamazepine
Phenobarbital
Phenytoin
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Based on theoretical considerations these anticonvulsants are expected to decrease darunavir and/or cobicistat plasma concentrations.
(CYP3A induction).
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Co-administration of REZOLSTA and these anticonvulsants is contraindicated (see section 4.3).
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ANTI-DEPRESSANTS
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Herbal supplements
St John's wort
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Based on theoretical considerations St John's wort is expected to decrease darunavir and/or cobicistat plasma concentrations.
(CYP3A induction)
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Co-administration of St John's wort and REZOLSTA is contraindicated (see section 4.3).
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Paroxetine
Sertraline
Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone
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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)
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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.
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ANTI-DIABETICS
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Metformin
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Based on theoretical considerations REZOLSTA is expected to increase metformin plasma concentrations.
(MATE1 inhibition)
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Careful patient monitoring and dose adjustment of metformin is recommended in patients who are taking REZOLSTA.
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ANTIFUNGALS
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Clotrimazole
Fluconazole
Itraconazole
Ketoconazole
Posaconazole
Voriconazole
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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)
Concentrations of voriconazole may increase or decrease when co-administered with REZOLSTA.
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Caution is warranted and clinical monitoring is recommended.
When co-administration is required, the daily dose of itraconazole or ketoconazole 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.
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ANTIGOUT MEDICINES
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Colchicine
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Based on theoretical considerations REZOLSTA is expected to increase colchicine plasma concentrations.
(CYP3A and/or P-glycoprotein inhibition)
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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).
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ANTIMALARIALS
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Artemether/Lumefantrine
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Based on theoretical considerations REZOLSTA is expected to increase lumefantrine plasma concentrations.
(CYP3A inhibition)
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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.
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ANTIMYCOBACTERIALS
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Rifampicin
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Based on theoretical considerations rifampin is expected to decrease darunavir and/or cobicistat plasma concentrations.
(CYP3A induction)
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The combination of rifampicin and REZOLSTA is contraindicated (see section 4.3).
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Rifabutin
Rifapentine
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Based on theoretical considerations these antimycobacterials are expected to decrease darunavir and/or cobicistat plasma concentrations.
(CYP3A induction)
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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.
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ANTI-NEOPLASTICS
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Dasatinib
Nilotinib
Vinblastine
Vincristine
Everolimus
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Based on theoretical considerations REZOLSTA is expected to increase these anti-neoplastic plasma concentrations.
(CYP3A inhibition)
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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 and REZOLSTA is not recommended.
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ANTIPSYCHOTICS/NEUROLEPTICS
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Perphenazine
Risperidone
Thioridazine
Pimozide
Sertindole
Quetiapine
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Based on theoretical considerations REZOLSTA is expected to increase these neuroleptic plasma concentrations.
(CYP2D6 inhibition)
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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 pimozide, quetiapine or sertindole and REZOLSTA is contraindicated (see section 4.3).
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β-BLOCKERS
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Carvedilol
Metoprolol
Timolol
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Based on theoretical considerations REZOLSTA is expected to increase these beta blocker plasma concentrations.
(CYP3A inhibition)
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Clinical monitoring is recommended when co-administering REZOLSTA with beta-blockers and a lower dose of the beta-blocker should be considered.
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CALCIUM CHANNEL BLOCKERS
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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.
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CORTICOSTEROIDS
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Budesonide
Fluticasone
Prednisone
|
Based on theoretical considerations REZOLSTA is expected to increase these corticosteroid plasma concentrations.
(CYP3A inhibition)
|
Co-administration of REZOLSTA and budesonide or fluticasone is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid side effects.
Concomitant use of REZOLSTA may increase the risk for development of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression. Clinical monitoring is recommended when co-administering REZOLSTA with corticosteroids.
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Dexamethasone (systemic)
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Based on theoretical considerations (systemic) dexamethasone is expected to decrease darunavir and/or cobicistat plasma concentrations.
(CYP3A induction)
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Systemic dexamethasone should be used with caution when combined with REZOLSTA.
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ENDOTHELIN RECEPTOR ANTAGONISTS
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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.
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HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
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NS3-4A inhibitors
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Boceprevir
Telaprevir
|
Based on theoretical considerations these antivirals may decrease darunavir and/or cobicistat plasma concentrations. REZOLSTA may decrease these antiviral plasma concentrations.
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It is not recommended to co-administer REZOLSTA with boceprevir or telaprevir.
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Simeprevir
|
Based on theoretical considerations REZOLSTA is expected to increase simeprevir plasma concentrations. Simeprevir may increase darunavir and/or cobicistat plasma concentrations.
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It is not recommended to co-administer REZOLSTA with simeprevir.
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HMG CO-A REDUCTASE INHIBITORS
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Atorvastatin
Fluvastatin
Pitavastatin
Pravastatin
Rosuvastatin
Lovastatin
Simvastatin
|
Based on theoretical considerations REZOLSTA is expected to increase these HMG Co-A reductase inhibitor plasma concentrations.
(CYP3A inhibition and/or transport)
|
Concomitant use of a HMG CoA reductase inhibitor and 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).
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H2-RECEPTOR ANTAGONISTS
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|
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.
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IMMUNOSUPPRESSANTS
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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.
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INHALED BETA AGONISTS
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|
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.
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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.
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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.
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Fentanyl
Oxycodone
Tramadol
|
Based on theoretical considerations REZOLSTA may increase analgesic plasma concentrations.
(CYP2D6 and/or CYP3A inhibition)
|
Clinical monitoring is recommended when co-administering REZOLSTA with these analgesics.
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OESTROGEN-BASED CONTRACEPTIVES
|
|
Ethinyl estradiol
Norethindrone
|
Based on theoretical considerations REZOLSTA may alter ethinyl estradiol and/or norethindrone plasma concentrations.
(CYP3A inhibition, UGT/SULT induction)
|
No dosing recommendations can be made on the use of
REZOLSTA with oral contraceptives. Alternative forms of contraception should be considered.
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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).
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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.
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PROTON PUMP INHIBITORS
|
|
Dexlansoprazole
Esomeprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
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Based on theoretical considerations, no me |
