Prescribing information For Healthcare Professionals Only

ACTIVE INGREDIENT(S):

Darunavir (as ethanolate) and cobicistat

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

INDICATION(S):

In combination with other antiretroviral medicinal products for treatment of adults and adolescents, aged 12 years and older, weighing at least 40kg with human immunodeficiency virus-1 (HIV-1) infection. Genotypic testing should guide use of REZOLSTA®.

DOSAGE & ADMINISTRATION:

Adults and adolescents: Therapy should be initiated by healthcare provider experienced in HIV management. Swallow tablets whole within 30 minutes after a meal or split the whole tablet into two if unable to swallow.
ART-naïve patients and ART‑experienced patients with no darunavir resistance associated mutations (DRV-RAMs) and plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/L; one REZOLSTA® tablet once daily.
All other ART-experienced patients or if HIV-1 genotype testing not available, REZOLSTA® is not appropriate. If dose > 12 hours late, do not take missed dose, resume usual dosing schedule. If patient vomits < 4 hour after taking tablet, take another dose with food as soon as possible; if > 4 hour, take next dose at regularly scheduled time. 

Children >3 years old and <11 years old or weighing < 40 kg: No data available; not recommended. Children <3 years old: Should not use REZOLSTA.
Elderly: Limited data; use with caution in patients > 65 years.
Renal impairment: Do not initiate therapy if creatinine clearance ≤ 70 ml/min if co-administered agent (e.g. emtricitabine, lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate) or adefovir dipivoxil) requires dose adjustment due to creatinine clearance. Limited data but no special precautions/dose adjustments with renal impairment.
Hepatic impairment: Use with caution but no dose adjustment with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. See Contraindications.

CONTRAINDICATIONS:

Hypersensitivity to active substance/excipients.
Severe hepatic impairment (Child-Pugh Class C).
Co-administration with carbamazepine, phenobarbital, phenytoin, rifampicin, lopinavir/ritonavir, St John’s Wort, alfuzosin, amiodarone, bepridil, dronedarone, quinidine, ivabradine, ranolazine, astemizole, terfenadine, colchicine (when renal and/or hepatic impairment present), ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine), dapoxetine, domperidone, naloxegol, cisapride, lurasidone, pimozide, quetiapine, sertindole, elbasvir/grazoprevir, triazolam, oral midazolam, sildenafil (for pulmonary arterial hypertension), avanafil, simvastatin, lovastatin, lomitapide, ticagrelor.

SPECIAL WARNINGS & PRECAUTIONS:

Regular assessment of virological response advised; perform resistance testing if lack/loss of response. Do not use REZOLSTA® in ART-experienced patients with one or more DRV-RAMs. Advise patients to take precautions to avoid transmission. Pregnancy: Darunavir and cobicistat levels decreased when REZOLSTA administered during pregnancy. May result in virological failure and increased risk of mother to child HIV transmission (see 'Pregnancy' below).
Severe skin reactions: Discontinue REZOLSTA® immediately if signs/symptoms of severe skin reactions (Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalised exanthematous pustulosis (reported with darunavir/ritonavir).
Patients with known sulphonamide allergy: Caution; contains sulphonamide moiety.
Hepatotoxicity: Test liver function prior to starting REZOLSTA®, monitor during treatment (drug-induced hepatitis reported with darunavir/ritonavir). More frequent AST/ALT monitoring in patients with underlying chronic hepatitis, cirrhosis or pre-treatment elevations of transaminases, especially during first several months of REZOLSTA® treatment. Prompt interruption/discontinuation of treatment if liver disease worsens.
Renal impairment: Cobicistat decreases estimated creatinine clearance.

Haemophiliac patients: Possibility of increased bleeding.
Immune reconstitution inflammatory syndrome (IRIS): Inflammatory response to asymptomatic or residual opportunistic pathogens may arise in patients with severe immune deficiency at start of combination antiretroviral therapy (CART). Autoimmune disorders reported.

Other: Increase in weight, levels of blood lipids and glucose may occur, may partly be linked to disease control and lifestyle. Monitor blood lipids and glucose; refer to HIV treatment guidelines; manage as appropriate. Patients with advanced HIV disease and/or long-term exposure to CART may develop osteonecrosis; seek medical advice. Do not use REZOLSTA® in combination with another antiretroviral requiring pharmaco-enhancement, with ritonavir or cobicistat. If switching from ritonavir to cobicistat, caution required during first two weeks of treatment with REZOLSTA®, particularly if there was dose titration/adjustment of concomitant medicinal products.

SIDE EFFECTS:

Very common: headache, diarrhoea, nausea, rash (including macular, maculopapular, papular, erythematous, pruritic rash, generalised, allergic dermatitis).
Common: drug hypersensitivity, anorexia, hypercholesterolaemia, hypertriglyceridaemia, abnormal dreams, vomiting, abdominal pain, abdominal distension, dyspepsia, flatulence, hepatic enzyme increased, pruritus, myalgia, fatigue, asthenia, increased blood creatinine.
Other side effects: IRIS, pancreatitis acute, hepatitis*, cytolytic hepatitis*, SJS*, DRESS*,TEN*, acute generalised exanthematous pustulosis*, osteonecrosis*, crystal nephropathy.

*adverse drug reactions noted with darunavir/ritonavir treatment could be expected with darunavir/cobicistat.

Refer to SmPC for other side effects.

PREGNANCY:

REZOLSTA should not be initiated during pregnancy. Switch to alternative regimen (e.g. darunavir/ low dose ritonavir) if REZOLSTA therapy started before pregnancy.

LACTATION:

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

INTERACTIONS:

Refer to the SmPC for full details before initiating therapy.
Do not use: voriconazole (unless positive benefit risk ratio).
Not recommended: rifabutin, rifapentine, efavirenz, etravirine, nevirapine, bosentan, irinotecan, apixaban, rivaroxaban, everolimus; budesonide, CYP3A-metabolised corticosteroids unless positive benefit risk ratio; then monitor for systemic effects (e.g. betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone; consider less CYP3A metabolised alternatives such as beclomethasone for intranasal or inhalational use), glecaprevir/pibrentasvir, salmeterol, tadalafil (for pulmonary arterial hypertension).
Use with caution: systemic dexamethasone, clarithromycin, artemether/lumefantrine, dasatinib, nilotinib, vinblastine, vincristine; sildenafil, vardenafil, tadalafil (erectile dysfunction).
Therapeutic drug monitoring advised: disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone, ciclosporin, sirolimus, tacrolimus.
Clinical monitoring recommended &/or dose adjustment: dabigatran etexilate, edoxaban, tenofovir disoproxil (monitor renal function), alfentanil, digoxin, warfarin (monitor INR), fesoterodine, solifenacin, clonazepam, paroxetine, sertraline, amitriptyline, desipramine, imipramine, nortriptyline, trazodone, metformin, clotrimazole, fluconazole, itraconazole, isavuconazole, posaconazole, colchicine (patients with normal renal/hepatic function), perphenazine, risperidone, thioridazine, carvedilol, metoprolol, timolol, amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil, prednisone, atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, methadone, buprenorphine/naloxone, fentanyl, oxycodone, tramadol, buspirone, clorazepate, diazepam, estazolam, flurazepam, parenteral midazolam, zolpidem, hormone replacement therapy (with oestrogen), drospirenone-containing products.
Recommended dose: emtricitabine/tenofovir alafenamide 200/10 mg once daily, maraviroc, 150 mg twice daily.
No dosing recommendations: oral contraceptives alternative or additional contraceptive measures required.

Refer to SmPC for full details of interactions.

LEGAL CATEGORY: POM

MARKETING AUTHORISATION HOLDER: 
Great Britain: Janssen-Cilag Ltd, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK.
Northern Ireland: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.

FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK.

Prescribing information last revised: December 2023