Rezolsta

/ J-C Health Care Ltd

ART-naïve patients
The recommended dose regimen is one film-coated tablet once daily taken with food. Patients should be instructed to take the drug within 30 minutes after completion of a meal.
ART-experienced patients One film-coated 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.
* 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 this medical product is not appropriate and another antiretroviral regimen should be used.
See prescribing information for full details.

Treatment of human immunodeficiency virus (HIV 1) infection in treatment-naïve and treatment-experienced adults with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) in combination with other antiretroviral agents.

* Hypersensitivity to the active substances or to any of the excipients
* Patients with severe (Child-Pugh Class C) hepatic impairment.
* Co-administration with strong CYP3A inducers

* Co-administration with medicinal products:
Alfuzosin, amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine, astemizole, terfenadine, colchicine (when used in patients with renal and/or hepatic impairment), rifampicin, ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine), cisapride, dapoxetine, domperidone, naloxegol, lurasidone, pimozide, quetiapine, sertindole, elbasvir/grazoprevir, triazolam, midazolam administered orally, sildenafil, when used for the treatment of pulmonary arterial hypertension, avanafil, simvastatin, lovastatin and lomitapide, ticagrelor.

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.
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. 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. Darunavir given with low dose ritonavir may be considered as an alternative.
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. Drug  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.
Sulphonamide allergy: Darunavir contains a sulphonamide moiety.
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.
Appropriate laboratory testing should be conducted prior to initiating therapy with the drug and patients should be monitored during 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.
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.
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).
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. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. 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.
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.
Paediatric population: Rezolsta is not indicated in children and adolescents below 18 years. The drug should not be used in paediatric patients below 3 years of age.
See prescribing information for full details.

Very common: Headache, diarrhoea, nausea, rash (including macular, maculopapular, papular, erythematous, pruritic rash, generalised
rash, and allergic dermatitis).
Common: Hypersensitivity, anorexia, hypercholesterolaemia,
hypertriglyceridaemia, abnormal dreams, vomiting, abdominal pain, abdominal distension, dyspepsia, flatulence, hepatic enzyme increased, pruritus, myalgia, fatigue, asthenia, increased blood creatinine.
See prescribing information for full details

This medicinal product contains darunavir and cobicistat.
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. 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. This medicinal product 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 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.
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). Co-administration with 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). REZOLSTA should not be used concurrently with products or regimens containing ritonavir or cobicistat. This medicinal product should not be used in combination with the individual components of this medicinal product (darunavir or cobicistat). This medicinal product should not be used in combination with another antiretroviral that requires pharmacoenhancement since dosing recommendations for such combination have not been established.
See prescribing information for full details.

Pregnancy: There are no adequate and well controlled trials with darunavir, or cobicistat, in pregnant women. Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure, 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 should be switched to an alternative regimen.
Breast‑feeding: It is not known whether darunavir or cobicistat are excreted in human milk. Because of the potential for adverse reactions in breast‑fed infants, women should be instructed not to breast‑feed if they are receiving the medication. In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast‑feed.

Human experience of acute overdose with 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. 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.

Do not store above 30°C.