Generic Name
Darunavir (as ethanolate)

Drug Description
Each filmcoated tablet contains 300 mg of darunavir (as ethanolate).Excipient: Each tablet contains 1.375 mg sunset yellow FCF (E110).

Presentation
Filmcoated tablet.Orange oval shaped tablet, debossed with “300MG” on one side and “TMC114” on the other side.

Indications
PREZISTA, coadministered with 100 mg ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV1) infection in treatment-experienced adult patients, including those that have been highly pre-treated.In deciding to initiate treatment with PREZISTA coadministered with 100 mg ritonavir careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of PREZISTA.

Adult Dosage
Therapy should be initiated by a physician experienced in the management of HIV infection.PREZISTA must always be given orally with 100 mg ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of ritonavir must therefore be consulted prior to initiation of therapy with PREZISTA.Adults: The recommended dosage of PREZISTA is 600 mg twice daily (b.i.d.) taken with ritonavir 100 mg b.i.d. and with food. The type of food does not affect the exposure to darunavir.Children and adolescents: PREZISTA is not recommended for use in children and adolescents because there are no data on safety, efficacy and pharmacokinetics.Elderly: Limited information is available in this population.Hepatic impairment: Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with mild (ChildPugh Class A) or moderate (ChildPugh Class B) hepatic impairment, however, PREZISTA should be used with caution in these patients. No pharmacokinetic data are available in patients with severe hepatic impairment. Severe hepatic impairment could result in an increase of darunavir exposure and a worsening of its safety profile. Therefore, PREZISTA should not be used in patients with severe hepatic impairment (ChildPugh Class C).Renal impairment: No dose adjustment is required in patients with renal impairment.In case a dose of PREZISTA and/or ritonavir was missed within 6 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of PREZISTA and ritonavir with food as soon as possible. If this was noticed later than 6 hours of the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.This guidance is based on the 15 hour halflife of darunavir in the presence of ritonavir and the recommended dosing interval of approximately 12 hours.

Elderly Dosage
Patients should be advised that current antiretroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.PREZISTA should only be used in combination with 100 mg of ritonavir as a pharmacokinetic enhancer.Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect darunavir concentrations and is not recommended.Elderly: As limited information is available on the use of PREZISTA in patients aged 65 and over, caution should be exercised in the administration of PREZISTA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy.Darunavir binds predominantly to α1acid glycoprotein. This protein binding is concentration dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products highly bound to α1acid glycoprotein cannot be ruled out.Severe skin rash, which may be accompanied with fever and/or elevations of transaminases, has occurred in 0.5% of patients treated with PREZISTA. Erythema multiforme and Stevens-Johnson Syndrome have been rarely (< 0.1%) observed. Treatment with PREZISTA should be discontinued if such a condition develops.Darunavir contains a sulphonamide moiety. PREZISTA should be used with caution in patients with a known sulphonamide allergy.Patients with coexisting conditionsHepatic impairmentThe safety and efficacy of PREZISTA have not been established in patients with severe underlying liver disorders and PREZISTA is therefore contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, PREZISTA should be used with caution in patients with mild or moderate hepatic impairment.Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.Patients with preexisting liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.Renal impairmentNo special precautions or dose adjustments are required in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these patients.Haemophiliac patientsThere have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with 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/HyperglycaemiaNew onset diabetes mellitus, hyperglycaemia, or exacerbation of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including 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 disordersCombination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients. The longterm consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and 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.OsteonecrosisAlthough the etiology 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 longterm 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 reactivation syndromeIn HIV infected patients with severe immune deficiency at the time of institution 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 jiroveci (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 studies with PREZISTA coadministered with 100 mg ritonavir.Interactions with medicinal productsSeveral of the interaction studies have been performed at lower than recommended doses of darunavir. The effects on coadministered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated.PREZISTA tablets contain sunset yellow FCF (E110) which may cause an allergic reaction.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.Patients with severe (ChildPugh Class C) hepatic impairment.Combination of rifampicin with PREZISTA with concomitant low dose ritonavir is contraindicated.The combination product lopinavir/ritonavir should not be used with PREZISTA because coadministration causes large decreases in darunavir concentrations, which may in turn significantly decrease the darunavir therapeutic effect.Herbal preparations containing St John's wort (Hypericum perforatum) must not be used while taking PREZISTA due to the risk of decreased plasma concentrations and reduced clinical effects of darunavir.Coadministration of PREZISTA with 100 mg ritonavir, with active substances that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or lifethreatening events is contraindicated. These active substances include e.g. antiarrhythmics (amiodarone, bepridil, quinidine, systemic lidocaine), antihistamines (astemizole, terfenadine), ergot derivatives (e.g. dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility agents (cisapride), neuroleptics (pimozide, sertindole), sedatives/hypnotics (triazolam, midazolam administered orally (for caution on parenterally administered midazolam) and HMGCoA reductase inhibitors (simvastatin and lovastatin)

Special Precautions
Patients should be advised that current antiretroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.PREZISTA should only be used in combination with 100 mg of ritonavir as a pharmacokinetic enhancer.Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect darunavir concentrations and is not recommended.Elderly: As limited information is available on the use of PREZISTA in patients aged 65 and over, caution should be exercised in the administration of PREZISTA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy.Darunavir binds predominantly to α1acid glycoprotein. This protein binding is concentration dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products highly bound to α1acid glycoprotein cannot be ruled out.Severe skin rash, which may be accompanied with fever and/or elevations of transaminases, has occurred in 0.5% of patients treated with PREZISTA. Erythema multiforme and StevensJohnson Syndrome have been rarely (< 0.1%) observed. Treatment with PREZISTA should be discontinued if such a condition develops.Darunavir contains a sulphonamide moiety. PREZISTA should be used with caution in patients with a known sulphonamide allergy.Patients with coexisting conditionsHepatic impairmentThe safety and efficacy of PREZISTA have not been established in patients with severe underlying liver disorders and PREZISTA is therefore contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, PREZISTA should be used with caution in patients with mild or moderate hepatic impairment.Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.Patients with preexisting liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.Renal impairmentNo special precautions or dose adjustments are required in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these patients.Haemophiliac patientsThere have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with 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/HyperglycaemiaNew onset diabetes mellitus, hyperglycaemia, or exacerbation of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including 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 disordersCombination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients. The longterm consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and 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.OsteonecrosisAlthough the etiology 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 longterm 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 reactivation syndromeIn HIV infected patients with severe immune deficiency at the time of institution 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 jiroveci (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 studies with PREZISTA coadministered with 100 mg ritonavir.Interactions with medicinal productsSeveral of the interaction studies have been performed at lower than recommended doses of darunavir. The effects on coadministered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated. For full information on interactions with other medicinal products.PREZISTA tablets contain sunset yellow FCF (E110) which may cause an allergic reaction.

Interactions
Darunavir and ritonavir are both inhibitors of the CYP3A4 isoform. Coadministration of darunavir and ritonavir and medicinal products primarily metabolised by CYP3A4 may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.PREZISTA coadministered with 100 mg ritonavir must not be combined with medicinal products that are highly dependent on CYP3A4 for clearance and for which increased systemic exposure is associated with serious and/or lifethreatening events (narrow therapeutic index). These medicinal products include amiodarone, bepridil, quinidine, systemic lidocaine, astemizole, terfenadine, midazolam administered orally, triazolam, cisapride, pimozide, sertindole, simvastatin, lovastatin and the ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine).The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg b.i.d. Therefore, PREZISTA must only be used in combination with 100 mg of ritonavir as a pharmacokinetic enhancer.A clinical study utilising a cocktail of drugs that are metabolised by cytochromes CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity in the presence of PREZISTA/rtv, which may be attributed to the presence of low dose ritonavir. Coadministration of darunavir and ritonavir and medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions. Coadministration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.Although the effect on CYP2C8 has only been studied in vitro, coadministration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone, repaglinide) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.Medicinal products that affect darunavir/ritonavir exposureDarunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir (e.g. rifampicin, St John's wort, lopinavir). Coadministration of darunavir and ritonavir and other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (e.g. indinavir, systemic azoles like ketoconazole and clotrimazole). These interactions are described in the interaction tables below.Interaction tableInteractions between darunavir/ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors and other nonantiretroviral medicinal products are listed in the tables below (increase is indicated as “↑”, decrease as “”, no change as “↔”, not determined as “ND”, twice daily as “b.i.d.”, once daily as “q.d.” and once every other day as “q.o.d.”).Several of the interaction studies (indicated by # in the table below) have been performed at lower than recommended doses of darunavir or with a different dosing regimen. The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated.Interactions – Darunavir/ritonavir with Protease InhibitorsThe efficacy and safety of the use of PREZISTA with 100 mg ritonavir and any other PI (e.g. (fos)amprenavir, nelfinavir and tipranavir) has not been established in HIV patients. Generally, dual therapy with protease inhibitors is not recommended. Co-administered Medicinal ProductDose of Co-administered Medicinal Product (mg)Dose of darunavir/ritonavir (mg)Medicinal Product AssessedAUCCminLopinavir/ritonavir400/100 b.i.d.533/133.3 b.i.d.1,200/100 b.i.d.1,200 b.i.d.LopinavirDarunavirLopinavirDarunavir↔ 38%*↔ 41%↔ 51%*↔ 55%* based upon not dose normalised valuesDue to a decrease in the exposure (AUC) of darunavir by 40%, appropriate doses of the combination have not been established. Hence, concomitant use of PREZISTA coadministered with 100 mg ritonavir and the combination product lopinavir/ritonavir is contraindicated.Saquinavir1,000 b.i.d.400/100 b.i.d.#Darunavir 26% 42%The study with boosted saquinavir showed no significant effect of darunavir on saquinavir. It is not recommended to combine PREZISTA coadministered with 100 mg ritonavir with saquinavir.Indinavir800 b.i.d.400/100 b.i.d. #IndinavirDarunavir↑ 23%↑ 24%↑ 125%↑ 44%When used in combination with PREZISTA coadministered with 100 mg ritonavir, dose adjustment of indinavir from 800 mg b.i.d. to 600 mg b.i.d. may be warranted in case of intolerance.Atazanavir300 q.d.400/100 b.i.d. #AtazanavirDarunavir↔↔↔↔Darunavir/ritonavir did not significantly affect atazanavir exposure, however 90% CI for Cmin were 99 – 234%. Atazanavir can be used with PREZISTA coadministered with 100 mg ritonavir.Interactions - Darunavir/ritonavir with Antiretroviral Agents other than Protease Inhibitors Co-administered Medicinal ProductDose of Co-administered Medicinal Product (mg)Dose of darunavir/ritonavir (mg)Medicinal Product AssessedAUCCminEfavirenz600 q.d.300/100 b.i.d. #EfavirenzDarunavir↑ 21% 13%↑ 17% 31%Efavirenz decreases the plasma concentrations of darunavir as a result of CYP3A4 induction. Darunavir/ritonavir increases the plasma concentrations of efavirenz as a result of CYP3A4 inhibition. Clinical monitoring for central nervous system toxicity associated with increased exposure to efavirenz may be indicated when PREZISTA coadministered with 100 mg ritonavir is given in combination with efavirenz.Etravirine100 b.i.d.*600/100 b.i.d.EtravirineDarunavir 37%↔ 49%↔* dose used in druginteraction study. For recommended dose see paragraph below.There was a 37% decrease in etravirine exposure in the presence of darunavir/ritonavir and no relevant change in exposure to darunavir. Therefore, PREZISTA coadministered with low dose ritonavir can be co-administered with etravirine 200 mg b.i.d. without dose adjustments.Nevirapine200 b.i.d.400/100 b.i.d. #NevirapineDarunavir↑ 27%↔↑ 47%↔Darunavir/ritonavir increases the plasma concentrations of nevirapine as a result of CYP3A4 inhibition. Since this difference is not considered to be clinically relevant, the combination of PREZISTA coadministered with 100 mg ritonavir and nevirapine can be used without dose adjustments.Tenofovir300 q.d.300/100 b.i.d. #TenofovirDarunavir↑ 22%↔↑ 37%↔Ritonavir effect on MDR1 transport in renal tubuli has been a proposed mechanism for increased plasma concentrations of tenofovir. Monitoring of renal function may be indicated when PREZISTA coadministered with 100 mg ritonavir is given in combination with tenofovir, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.ZidovudineZalcitabineEmtricitabineStavudineLamivudineAbacavirBased on the different elimination pathways of the other NRTIs zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine, that are primarily renally excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and PREZISTA coadministered with 100 mg ritonavir.Didanosine400 q.d.600/100 b.i.d.DidanosineDarunavir↔↔NA↔Didanosine was administered on an empty stomach 2 hours prior to administration of darunavir/ritonavir.Systemic exposure to darunavir coadministered with low dose ritonavir, with or without didanosine was comparable. The combination of PREZISTA coadministered with 100 mg ritonavir and didanosine can be used without dose adjustments.Maraviroc150 b.i.d.600/100 b.i.d.MaravirocDarunavir↑ 305%↔NDNDThe maraviroc dose should be 150 mg twice daily when coadministered with PREZISTA with low dose ritonavir. Darunavir/ritonavir concentrations were consistent with historical data.Interactions – Darunavir/ritonavir with Nonantiretroviral coadministered Medicinal Products Coadministered Medicinal ProductDose of Coadministered Medicinal Product (mg)Dose of darunavir/ritonavir (mg)Medicinal Product AssessedAUCCminAntiarrhythmicsDigoxin0.4 mg single dose600/100 b.i.d.Digoxin↑ 60%NDDarunavir/ritonavir increases the plasma concentrations of digoxin. Inhibition of Pgp may be a likely explanation. Given that digoxin has as a narrow therapeutic index, it is recommended that the lowest possible dose of digoxin should initially be prescribed in case digoxin is given to patients on darunavir/ritonavir therapy. The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.AntibioticsClarithromycin500 b.i.d.400/100 b.i.d. #ClarithromycinDarunavir↑ 57%↔↑ 174%↔Darunavir/ritonavir increases the plasma concentrations of clarithromycin as a result of CYP3A4 inhibition and possible Pgp inhibition. Concentrations of the metabolite 14OHclarithromycin were not detectable. Caution is warranted and clinical monitoring is recommended. For patients with renal impairment, a dose reduction of clarithromycin should be considered.AnticoagulantWarfarinWarfarin concentrations may be affected when coadministered with darunavir with ritonavir. The international normalised ratio (INR) should be monitored when warfarin is combined with PREZISTA coadministered with 100 mg ritonavir.AnticonvulsantsPhenobarbitalPhenytoinPhenobarbital and phenytoin are inducers of CYP450 enzymes. PREZISTA coadministered with 100 mg ritonavir should not be used in combination with these medicines, as coadministration may cause significant decreases in darunavir plasma concentrations.Carbamazepine200 b.i.d.600/100 b.i.d.CarbamazepineDarunavir↑ 45%↔↑ 54%↔Exposure to darunavir, coadministered with ritonavir, was unaffected by carbamazepine. Ritonavir exposure (AUC12h) was decreased by 49%. For carbamazepine, AUC12h was increased by 45%. No dose adjustment for PREZISTA/rtv is recommended. If there is a need to combine PREZISTA/rtv and carbamazepine, patients should be monitored for potential carbamazepinerelated adverse events. Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response. Based upon the findings, the carbamazepine dose may need to be reduced by 25% to 50% in the presence of PREZISTA/rtv.AntifungalsVoriconazoleThe combined use of voriconazole with darunavir coadministered with 100 mg ritonavir has not been studied. Voriconazole is metabolised by cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4. Ritonavir, which can induce some of these isoenzymes, may decrease voriconazole plasma concentrations. Voriconazole should not be coadministered with PREZISTA with 100 mg ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.Ketoconazole200 b.i.d.400/100 b.i.d. #KetoconazoleDarunavir↑ 212%↑ 42%↑ 868%↑ 73%Ketoconazole is a potent inhibitor as well as substrate of CYP3A4. Caution is warranted and clinical monitoring is recommended. When coadministration is required the daily dose of ketoconazole should not exceed 200 mg.ItraconazoleItraconazole, like ketoconazole, is a potent inhibitor as well as substrate of CYP3A4. Concomitant systemic use of itraconazole and darunavir coadministered with 100 mg ritonavir may increase plasma concentrations of darunavir. Simultaneously, plasma concentrations of itraconazole may be increased by darunavir coadministered with 100 mg ritonavir. Caution is warranted and clinical monitoring is recommended. When coadministration is required the daily dose of itraconazole should not exceed 200 mg.ClotrimazoleConcomitant systemic use of clotrimazole and darunavir coadministered with 100 mg ritonavir may increase plasma concentrations of darunavir. This was confirmed using a population pharmacokinetic model. The increase in the median darunavir AUC24h value for the patients taking clotrimazole from the overall median was 33% . Caution is warranted and clinical monitoring is recommended, when coadministration of clotrimazole is required.Calcium channel blockersFelodipineNifedipineNicardipineDarunavir and ritonavir inhibit CYP3A4 and as a result can be expected to increase the plasma concentrations of calcium channel antagonists, which are CYP3A4 substrates. Clinical monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with PREZISTA with 100 mg ritonavir.HMG CoA Reductase InhibitorsLovastatinSimvastatinLovastatin and simvastatin, which are highly dependent on CYP3A4 metabolism are expected to have markedly increased plasma concentrations when coadministered with darunavir coadministered with 100 mg ritonavir. This may cause myopathy, including rhabdomyolysis. Concomitant use of PREZISTA coadministered with 100 mg ritonavir with lovastatin and simvastatin is therefore contraindicated.Atorvastatin10 q.d.300/100 b.i.d. #AtorvastatinDarunavir3 - 4 times ↑ND3 - 4 times ↑NDThe results of this interaction trial show that atorvastatin (10 mg q.d.) in combination with darunavir/ritonavir (300/100 mg b.i.d.) provides an exposure to atorvastatin, which is only 15% lower than that obtained with (40 mg q.d.) atorvastatin alone. When administration of atorvastatin and PREZISTA coadministered with 100 mg ritonavir is desired, it is recommended to start with an atorvastatin dose of 10 mg q.d. A gradual dose increase of atorvastatin may be tailored to the clinical response.Pravastatin40 mg single dose600/100 b.i.d.Pravastatin0 – 5 times ↑NDDarunavir/ritonavir did not increase exposure to a single dose of pravastatin in most subjects but up to 5fold in a limited subset of subjects. When administration of pravastatin and PREZISTA coadministered with 100 mg ritonavir is required, it is recommended to start with the lowest possible dose of pravastatin and titrate it up to the desired clinical effect while monitoring for safety.Hormonal contraceptiveEthinylestradiolNorethindrone35 μg/1 mg q.d.600/100 b.i.d.EthinylestradiolNorethindrone 44% 14% 62% 30%Alternative or additional contraceptive measures are recommended when oestrogenbased contraceptives are coadministered with PREZISTA and 100 mg ritonavir. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.ImmunosupressantsCyclosporineTacrolimusSirolimusExposure to cyclosporine, tacrolimus, or sirolimus will be increased when coadministered with PREZISTA coadministered with 100 mg ritonavir. Therapeutic drug monitoring of the immunosuppressive agent must be done when coadministration occurs.H2receptor antagonists and proton pump inhibitorsRanitidine150 b.i.d.400/100 b.i.d. #Darunavir↔↔Based on these results, PREZISTA coadministered with 100 mg ritonavir can be coadministered with H2receptor antagonists without dose adjustments.Omeprazole20 q.d.400/100 b.i.d. #Darunavir↔↔Based on these results, PREZISTA coadministered with 100 mg ritonavir can be coadministered with proton pump inhibitors without dose adjustments.OpiodsMethadone55 - 150 q.d.600/100 b.i.d.(dosed for 7 days)Rmethadone 16% 15%Based on pharmacokinetic and clinical findings, no adjustment of methadone dosage is required when initiating coadministration with PREZISTA/ritonavir. However, increased methadone dose may be necessary when concomitantly administered for a longer period of time due to induction of metabolism by ritonavir. Therefore, clinical monitoring is recommended, as maintenance therapy may need to be adjusted in some patients.PDE5 inhibitorsSildenafilVardenafilTadalafilIn an interaction study a comparable systemic exposure to sildenafil was observed for a single intake of 100 mg sildenafil alone and a single intake of 25 mg sildenafil coadministered with darunavir/ritonavir (400/100 mg b.i.d.). Concomitant use of PDE5 inhibitors with PREZISTA coadministered with 100 mg ritonavir should be done with caution. If concomitant use of PREZISTA coadministered with 100 mg ritonavir 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 dose in 72 hours or tadalafil at a single dose not exceeding 10 mg dose in 72 hours is recommended.RifamycinesRifampicinRifampicin is a strong CYP3A4 inducer and has been shown to cause profound decreases in concentrations of other protease inhibitors, which can result in virological failure and resistance development. During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with ritonavir, a high frequency of liver reactions was seen. The combination of rifampicin and PREZISTA with concomitant low dose ritonavir is contraindicated.Rifabutin150 q.o.d.600/100 b.i.d.Rifabutin*Darunavir 1.6 times ↑↑ 53%ND↑ 68%* sum of active moieties of rifabutin (parent drug + 25O desacetyl metabolite)A dosage reduction of rifabutin by 75% of the usual dose of 300 mg/day [i.e. rifabutin 150 mg q.o.d. (once every other day)] and increased monitoring for rifabutin related adverse events is warranted in patients receiving the combination. In case of safety issues, a further increase of the dosing interval for rifabutin and/or moni

Adverse Reactions
The adverse drug reactions are derived from Phase IIb and Phase III trials, in which a total of 1,968 treatmentexperienced patients initiated therapy with the recommended dose of PREZISTA 600 mg with ritonavir 100 mg twice daily.Median exposure to PREZISTA/ritonavir in this group was 37.3 weeks. Thirty percent of these patients experienced at least one adverse drug reaction of at least grade 2 severity. The most frequent ( 2%) of those were diarrhoea (3.9%), hypertriglyceridaemia (3.8%), rash (2.8%), nausea (2.6%), hypercholesterolaemia (2.5%) and headache (2.0%).2.6% of the patients discontinued treatment due to adverse reactions.Adverse reactions are listed by system organ class (SOC) and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as very common ( 1/10), common ( 1/100 to < 1/10) and uncommon ( 1/1,000 to < 1/100).SOC Frequency categoryAdverse reaction* All gradesAdverse reaction** Grade 24Infections and infestationsUncommonHerpes simplexBlood and lymphatic system disordersUncommonThrombocytopenia, neutropenia, anaemia, increased eosinophil count, leukopeniaThrombocytopenia, neutropenia, anaemiaImmune system disordersUncommonImmune reconstitution syndromeImmune reconstitution syndromeEndocrine disordersUncommonHypothyroidism, increased blood thyroid stimulating hormoneMetabolism and nutrition disordersCommonLipodystrophy (including lipohypertrophy, lipodystrophy, lipoatrophy), hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemiaHypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemiaUncommondiabetes mellitus, gout, anorexia, decreased appetite, decreased weight, increased weight, hyperglycaemia, insulin resistance, decreased high density lipoprotein, increased appetite, polydipsia, increased blood lactate dehydrogenaseDiabetes mellitus, lipodystrophy (including lipohypertrophy, lipodystrophy, lipoatrophy), gout, anorexia, decreased appetite, decreased weight, increased weight, hyperglycaemia, insulin resistancePsychiatric disordersCommonInsomniaUncommonDepression, confusional state, disorientation, anxiety, altered mood, sleep disorder, abnormal dreams, nightmare, decreased libido, restlessnessDepression, confusional state, disorientation, anxiety, altered mood, insomnia, sleep disorder, abnormal dreamsNervous system disordersCommonHeadache, peripheral neuropathy, dizzinessHeadacheUncommonSyncope, convulsion, lethargy, paraesthesia, hypoaesthesia, ageusia, dysgeusia, disturbance in attention, memory impairment, somnolence, sleep phase rhythm disturbancePeripheral neuropathy, dizziness, lethargy, paraesthesia, hypoaesthesia, somnolenceEye disordersUncommonVisual disturbance, conjunctival hyperaemia, dry eyeConjunctival hyperaemiaEar and labyrinth disordersuncommonVertigoVertigoCardiac disordersUncommonAcute myocardial infarction, myocardial infarction, angina pectoris, prolonged electrocardiogram QT, sinus bradycardia, tachycardia, palpitationsAcute myocardial infarction, myocardial infarction, angina pectoris, prolonged electrocardiogram QTVascular disordersUncommonHypertension, flushingHypertensionRespiratory, thoracic and mediastinal disordersUncommonDyspnoea, cough, epistaxis, rhinorrhoea, throat irritationDyspnoea, coughGastrointestinal disordersVery commonDiarrhoeaCommonVomiting, nausea, abdominal pain, increased blood amylase, dyspepsia, abdominal distension, flatulenceVomiting, diarrhoea, nausea, abdominal pain, increased blood amylaseUncommonpancreatitis, gastritis, gastrooesophageal reflux disease, aphthous stomatitis, stomatitis, retching, haematemesis, dry mouth, abdominal discomfort, constipation, increased lipase, eructation, oral dysaesthesia, cheilitis, dry lip, coated tonguePancreatitis, gastritis, gastrooesophageal reflux disease, aphthous stomatitis, retching, dry mouth, abdominal distension, abdominal discomfort, flatulence, dyspepsia, constipation, increased lipaseHepatobiliary disordersCommonIncreased alanine aminotransferase, increased aspartate aminotransferaseIncreased alanine aminotransferaseUncommonHepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased transaminase, increased blood bilirubin, increased blood alkaline phosphatase, increased gammaglutamyltransferaseHepatitis, cytolytic hepatitis, hepatic steatosis, increased transaminase, increased aspartate aminotransferase, increased blood alkaline phosphatase, increased gammaglutamyltransferaseSkin and subcutaneous tissue disordersCommonRash (including macular, maculopapular, papular, erythematous and pruritic rash), pruritusRash (including macular, maculopapular, papular, erythematous and pruritic rash)UncommonGeneralised rash, allergic dermatitis, face oedema, urticaria, dermatitis, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, seborrhoeic dermatitis, skin lesion, xeroderma, dry skin, nail pigmentationGeneralised rash, allergic dermatitis, urticaria, pruritus, hyperhidrosis, night sweats, alopeciaMusculoskeletal and connective tissue disordersUncommonMyalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, arthritis, arthralgia, joint stiffness, pain in extremity, osteoporosis, increased blood creatine phosphokinaseMyalgia, arthralgia, pain in extremity, osteoporosis, increased blood creatine phosphokinaseRenal and urinary disordersUncommonAcute renal failure, renal failure, nephrolithiasis, increased blood creatinine, decreased creatinine renal clearance, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuriaAcute renal failure, renal failure, nephrolithiasis, increased blood creatinine, decreased creatinine renal clearance, proteinuria, bilirubinuriaReproductive system and breast disordersUncommonErectile dysfunction, gynaecomastiaErectile dysfunction, gynaecomastiaGeneral disorders and administration site conditionsCommonAsthenia, fatigueFatigueUncommonPyrexia, chest pain, peripheral oedema, malaise, chills, abnormal feeling, feeling hot, irritability, pain, xerosisPyrexia, chest pain, asthenia, peripheral oedema, malaise* Adverse events, considered at least possibly related by the investigator to PREZISTA coadministered with low dose ritonavir, occurring in more than 1 patient.** Adverse events, at least grade 2 in severity and considered at least possibly related by the investigator to PREZISTA coadministered with low dose ritonavir, occurring in more than 1 patient.In clinical trials (n=1,968), rash (all grades, at least possibly related) occurred in 5.6% of patients treated with PREZISTA. Rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. Grade 24 rash was reported in 2.9% of patients. The discontinuation rate due to rash in patients using PREZISTA coadministered with 100 mg ritonavir was 0.5%.Severe cases of skin rash, including erythema multiforme and StevensJohnson Syndrome (both rare) have been reported in ongoing clinical trials with PREZISTA coadministered with 100 mg ritonavir.The safety assessment in antiretroviral treatmentnaïve adult patients (n=343) is based on all safety data from the Phase III trial ARTEMIS comparing PREZISTA/rtv 800/100 mg q.d. versus lopinavir/ritonavir 800/200 mg per day. Median exposure in the PREZISTA/ritonavir group was 56.3 weeks.0.6% of the patients discontinued treatment due to adverse drug reactions.In these treatment naïvepatients, the following adverse drug reactions were identified:ADRs of at least moderate intensity and reported in more than one patientCommon: hypertriglyceridaemia, hypercholesterolaemia, headache, diarrhoea, nausea, increased alanine aminotransferase.Uncommon: hyperlipidaemia, vomiting, abdominal pain, increased aspartate aminotransferase, rash (including maculopapular rash), allergic dermatitis, pruritus.ADRs of all severity grades and reported in more than one patientVery common: diarrhoea, nausea.Common: hypertriglyceridaemia, hypercholesterolaemia, anorexia, insomnia, headache, dizziness, dysgeusia, vomiting, abdominal pain, abdominal discomfort, abdominal distension, flatulence, increased alanine aminotransferase, rash (including maculopapular, papular rash), alopecia, dry skin, pruritus, fatigue.Uncommon: upper respiratory tract infection, diabetes mellitus, hyperlipidaemia, abnormal dreams, hypoaesthesia, disturbance in attention, somnolence, dyspepsia, eructation, increased aspartate aminotransferase, allergic dermatitis, urticaria, dermatitis, night sweats, myalgia, muscle spasms, asthenia.Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intraabdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).Combination antiretroviral therapy has also been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of 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 longterm exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors.Patients co-infected with hepatitis B and/or hepatitis C virusAmong 1,968 treatmentexperienced patients receiving PREZISTA coadministered with ritonavir 600/100 mg b.i.d., 236 patients were coinfected with hepatitis B or C. Coinfected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis.

Manufacturer
Janssen-Cilag

Drug Availability
POM

Updated
31 July 2009