INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo PREZISTA® (film-coated tablets)

SCHEDULING STATUS:
Schedule 4

PROPRIETARY NAME
(and dosage form):

PREZISTA® (film-coated tablets)

COMPOSITION:
Each film-coated tablet contains 300 mg of
Darunavir (corresponding to 325,23 mg of Darunavir Ethanolate).
The other ingredients are microcrystalline cellulose, colloidal anhydrous silica, crospovidone, magnesium stearate.
The film-coating contains poly(vinyl alcohol) –partially hydrolyzed, macrogol 3350, titanium dioxide, talc.

PHARMACOLOGICAL CLASSIFICATION:
A.20.2.8 Antiviral agents.

PHARMACOLOGICAL ACTION:
Pharmacodynamic properties
Mechanism of action
Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus infected cells, thereby preventing the formation of mature infectious virus particles. Darunavir tightly binds to the HIV-1 protease.
Antiviral activity in-vitro
Darunavir exhibited activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages in-vitro with median EC
50 values ranging from 1,2 to 8,5 nM (0,7 to 5,0 ng/mL). Darunavir demonstrated antiviral activity in-vitro against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from <0,1 to 4,3 nM. These EC50 values are well below the 50% cellular toxicity concentration range of 87 µM to >100 µM.
The EC
50 value of darunavir increases by a median factor of 5,4 in the presence of human serum. Darunavir showed synergistic antiviral activity when studied in combination with the protease inhibitors ritonavir, nelfinavir, or amprenavir and additive antiviral activity when studied in combination with the protease inhibitors indinavir, saquinavir, lopinavir, atazanavir, or tipranavir, the N(t)RTIs zidovudine, lamivudine, zalcitabine, didanosine, stavudine, abacavir, emtricitabine, or tenofovir, the NNRTIs nevirapine, delavirdine, or efavirenz and the fusion inhibitor enfuvirtide. No antagonism was observed between darunavir and any of those antiretrovirals.
Resistance in-vitro
In-vitro darunavir-resistant virus isolates from wild type HIV-1 were selected. Viruses showing decreased susceptibility to darunavir (range: 6 –21-fold) harboured 3 to 6 amino acid substitutions in the protease gene. Determinants of decreased susceptibility to darunavir in those viruses have not been identified. In-vitro selection of darunavir-resistant HIV-1 (range: 53 –641-fold change in EC
50 values) from 9 HIV-1 strains harbouring multiple PI resistance-associated mutations resulted in the overall emergence of 22 mutations in the protease, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V and I84V were present in more than 50% of the 9 darunavir-resistant isolates. A minimum of 8 of these darunavir in-vitro selected mutations, from which at least 2 were already present in the protease prior to selection, were required in the HIV-1 protease to render a virus resistant (fold change [FC] >10) to darunavir.
In 1113 clinical isolates resistant to at least one protease inhibitor and in 886 baseline isolates from the patients enrolled in the clinical trials only the subgroups with >10 PI resistance-associated mutations showed a median FC for darunavir >10.
Cross-resistance in-vitro
Cross-resistance has been observed among protease inhibitors. Darunavir has a <10-fold decreased susceptibility against 90% of 3309 clinical isolates resistant to at least one protease inhibitor.
Cross-resistance between darunavir and the nucleoside/nucleotide reverse transcriptase inhibitors, the non-nucleoside reverse transcriptase inhibitors or the fusion inhibitor, is unlikely because the viral targets for those inhibitors are different.
Pharmacokinetic properties
The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infected patients compared to healthy subjects may be explained by the higher concentrations of alpha-1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG and, therefore, higher plasma concentrations.
Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir considerably.
Absorption
Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of darunavir in the presence of low-dose ritonavir is generally achieved within 2,5 – 4,0 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg twice daily ritonavir.
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold 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 twice daily (see “Special Precautions”).
When administered without food, the relative bioavailability of darunavir in the presence of low-dose ritonavir is 30% lower as compared to intake with food. Therefore, darunavir tablets should be taken with ritonavir and with food. The type of food does not affect exposure to darunavir.
Distribution
Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma alpha-1-acid glycoprotein.
Metabolism
In-vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir/rtv dose was due to the parent drug. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild type HIV.
Elimination
After a 400/100 mg
14C-darunavir/rtv dose, approximately 79,5% and 13,9% of the administered dose of 14C-darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately 41,2% and 7,7% of the administered dose in faeces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir. The intravenous clearance of darunavir alone (150 mg) and in the presence of low-dose ritonavir was 32,8 L/h and 5,9 L/h, respectively.
Special populations
Paediatrics
There is no information on the pharmacokinetics of darunavir in combination with ritonavir in paediatric subjects.
Elderly
Population pharmacokinetic analysis in HIV-infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (n=12, age = 65) (see “Special Precautions”).
Gender
Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16,8%) in HIV infected females compared to males. This difference is not clinically relevant.
Renal impairment
Results from a mass balance study with
14C-darunavir/rtv showed that approximately 7,7% of the administered dose of darunavir is excreted in the urine as unchanged drug. Darunavir has not been studied in patients with renal impairment.
Hepatic impairment
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with darunavir co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the steady-state pharmacokinetic parameters of darunavir in subjects with mild (Child-Pugh Class A, n=8) hepatic impairment were comparable with those in healthy subjects. In moderate hepatic impairment (Child-Pugh Class B, n=8) the mean C
max was increased by 22%, the AUC by 20% and the Cmin by 27% after multiple doses. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see DOSAGE AND DIRECTIONS FOR USE and “Special Precautions”).

INDICATIONS:
PREZISTA, in combination with 100 mg ritonavir (PREZISTA/rtv) and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor.
This indication is based on week-24 analyses from 2 controlled clinical trials in treatment-experienced, HIV-1 infected patients, where PREZISTA/rtv showed a significantly greater reduction of plasma HIV RNA levels and greater increase in CD4
+ cell counts when compared to a protease inhibitor (PI) regimen of choice, each given in combination with other antiretrovirals. (Additional data is available from open label studies (see “Pharmacodynamic Properties”) ).
There is no information on the use of PREZISTA/rtv in HIV infected paediatric patients and in antiretroviral treatment naïve adult patients. Treatment history, and when available, genotypic or phenotypic testing, should guide the use of PREZISTA/rtv.

CONTRA-INDICATIONS:
Hypersensitivity to darunavir or to any of the excipients.
The presence of a contra-indication to ritonavir.
Darunavir and ritonavir are both inhibitors of the cytochrome P450 3A4 (CYP3A4) isoform. PREZISTA/rtv should not be co-administered with medicinal products that are highly dependent on CYP3A4 for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These medicinal products are included in the table below:
Medicines that are contra-indicated with PREZISTA/rtv
Medicine Class: Drug Name Clinical Comment
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. PREZISTA/rtv should not be used in combination with phenobarbital, phenytoin, or carbamazepine as co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Antihistamines:
astemizole,
terfenadine
CONTRA-INDICATED due to potential for serious and/or life-threatening reactions such as cardiac dysrhythmia.
Antimycobacterial:
rifampicin
Rifampicin is a potent inducer of CYP450 metabolism. PREZISTA/rtv should not be used in combination with rifampicin, as this may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. (see INTERACTIONS).
Ergot Derivatives:
dihydroergotamine,
ergonovine,
ergotamine,
methylergonovine
CONTRA-INDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Gastrointestinal Motility
Agent:
Cisapride
CONTRA-INDICATED due to potential for serious and/or life-threatening reactions such as cardiac dysrhythmia.
Herbal Products:
St. John’s wort
(Hypericum perforatum)
PREZISTA/rtv should not be used concomitantly with products containing St. John’s wort (Hypericum perforatum) because co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. (see INTERACTIONS).
HMG-CoA Reductase Inhibitors:
lovastatin,
simvastatin
Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic:
pimozide
CONTRA-INDICATED due to the potential for serious and/or life-threatening reactions such as cardiac dysrhythmia.
Sedative/Hypnotics:
midazolam,
triazolam
CONTRA-INDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
Antifungals:
Ketoconazole, itraconazole and voriconazole
CONTRA-INDICATED because concomitant systemic use of ketoconazole, itraconazole or voriconazole and PREZISTA/rtv may increase plasma concentrations of darunavir. Simultaneously, plasma concentrations of ketoconazole or itraconazole may be increased by PREZISTA/rtv, while the plasma concentrations of voriconazole may be decreased in the presence of PREZISTA/rtv (see CONTRA-INDICATIONS).
Buprenorphine/naloxone: The results of an interaction trial with PREZISTA/rtv and buprenorphine/naloxone demonstrated that buprenorphine exposure was not affected when administered with PREZISTA/rtv. Exposure of the active metabolite, norbuprenorphine, increased by 46%. No dose adjustment for buprenorphine was required. Careful clinical monitoring is recommended if PREZISTA/rtv and buprenorphine are co-administered (see INTERACTIONS).

WARNINGS:
PREZISTA should not be used in patients with severe hepatic impairment (see WARNINGS and “Special Precautions”).
General
PREZISTA must be co-administered with ritonavir and food to exert its therapeutic effect (see DOSAGE AND DIRECTIONS FOR USE). Failure to correctly administer PREZISTA with ritonavir and food will result in reduced plasma concentrations of darunavir that will be insufficient to achieve the desired antiviral effect.
Please refer to ritonavir prescribing information for additional information on precautionary measures.
Skin rash
During the clinical development program, severe skin rash, including erythema multiforme and Stevens-Johnson Syndrome, has been reported. In some cases, fever and elevations of transaminases have also been reported. In clinical trials (n=924), rash (all grades, regardless of causality) occurred in 7% of subjects treated with PREZISTA; the discontinuation rate due to rash was 0,3%. Rashes were generally mild-to-moderate, self-limited maculopapular skin eruptions. Treatment with PREZISTA should be discontinued if severe rash develops.
Sulpha allergy
Darunavir contains a sulphonamide moiety. PREZISTA should be used with caution in patients with a known sulphonamide allergy.
Drug interactions
PREZISTA and ritonavir are both inhibitors of CYP3A. Co-administration of PREZISTA/rtv with drugs primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see CONTRA-INDICATIONS and INTERACTIONS).
Diabetes mellitus/Hyperglycaemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycaemia have been reported during post-marketing surveillance in HIV-infected patients receiving PREZISTA. Some patients required either initiation or dose adjustments of insulin or oral hypoglycaemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PREZISTA, hyperglycaemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PREZISTA and these events have not been established.
Oestrogen-based contraceptives
Plasma concentrations of ethinylestradiol are decreased by induction of its metabolism by ritonavir and alternative methods of non-hormonal contraception are recommended. (see INTERACTIONS and “Special Precautions”).
The phosphodiesterase type 5 (PDE5) inhibitors sildenafil, vardenafil and tadalafil are highly dependent on CYP3A4 for their metabolism. If concomitant use of PREZISTA/rtv with sildenafil, vardenafil, or tadalafil is indicated, reduced doses of the PDE5 inhibitors are recommended (see INTERACTIONS).

INTERACTIONS:
Darunavir and ritonavir are both inhibitors of the CYP3A4 isoform. Co-administration of PREZISTA and ritonavir and medicinal products primarily metabolized by CYP3A4 may result in increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect and adverse events. PREZISTA/rtv should not be co-administered with medicinal products that are highly dependent on CYP3A4 for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These medicinal products include astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide and the ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine) (see CONTRA-INDICATIONS).
Rifampicin is a potent inducer of CYP450 metabolism. PREZISTA/rtv should not be used in combination with rifampicin, as co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA (see “Special Precautions”).
PREZISTA/rtv should not be used concomitantly with products containing St. John’s Wort (Hypericum perforatum) because co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA (see “Special Precautions”).
Antiretroviral medicinal products
Nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs)
Didanosine
PREZISTA/rtv (600/100 mg twice daily) did not significantly affect didanosine exposure. The combination of PREZISTA co-administered with 100 mg ritonavir and didanosine can be used without dose adjustments. As it is recommended that didanosine be administered on an empty stomach, didanosine should be administered 1 hour before or 2 hours after PREZISTA/rtv (which are administered with food).
Tenofovir
The results of an interaction trial with tenofovir (tenofovir disoproxil fumarate 300 mg once daily demonstrated that the systemic exposure of tenofovir was increased by 22% when co-administered with PREZISTA/rtv (300/100 mg twice daily). This finding is not considered to be clinically relevant. Tenofovir did not have a significant influence on darunavir exposure. No dose adjustments of PREZISTA, ritonavir, or tenofovir disoproxil fumarate are required when these medicines are co-administered.
Other NRTIs
Based on the different elimination pathways of the other NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally excreted, no drug interactions are expected for these medicinal compounds and PREZISTA/rtv.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz
An interaction trial between PREZISTA/rtv (300/100 mg twice daily) and efavirenz (600 mg once daily) has been performed. In the presence of efavirenz, a decrease of 13% for darunavir exposure and a decrease of darunavir C
min by 31% were observed. Exposure to efavirenz was increased by 21% when administered in combination with PREZISTA/rtv. The combination of PREZISTA/rtv and efavirenz should be used with caution.
Nevirapine
The results of an interaction trial with PREZISTA/rtv (400/100 mg twice daily) and nevirapine (200 mg twice daily) demonstrated that darunavir exposure was not affected when administered concomitantly with nevirapine. Exposure to nevirapine increased by 27% (compared to historical controls) when administered in combination with PREZISTA/rtv. Since this difference is not considered to be clinically relevant, the combination of PREZISTA/rtv and nevirapine can be used without dose adjustments.
Protease inhibitors (PIs)
Ritonavir
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg PREZISTA was given orally in combination with ritonavir at 100 mg twice daily. Therefore, PREZISTA should only be used in combination with 100 mg of ritonavir as a pharmacokinetic enhancer (see “Special Precautions”and “Pharmacokinetic Properties”).
Lopinavir/ritonavir
Results of interaction trials with PREZISTA with or without ritonavir and lopinavir/ritonavir (1200 mg darunavir twice daily with or without 100 mg ritonavir twice daily and lopinavir/ritonavir 400/100 mg twice daily or 533/133,3 mg twice daily) demonstrated a decrease in the exposure (AUC) of darunavir by 40%. The appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer PREZISTA/rtv with lopinavir/ritonavir.
Saquinavir
In an interaction study between PREZISTA (400 mg twice daily), saquinavir (1000 mg twice daily) and ritonavir (100 mg twice daily), darunavir exposure was decreased by 26% in the presence of saquinavir/rtv; saquinavir exposure was not affected by the presence of PREZISTA/rtv. It is not recommended to combine saquinavir and PREZISTA, (with or without low-dose ritonavir).
Atazanavir
An interaction trial between PREZISTA/rtv (400/100 mg twice daily) and atazanavir (300 mg once daily) and ritonavir 100 mg once daily demonstrated that systemic exposure to darunavir and atazanavir was not significantly affected when co-administered. Atazanavir can be co-administered with PREZISTA/rtv.
Indinavir
In an interaction study between PREZISTA/rtv (400/100 mg twice daily) and indinavir (800 mg twice daily), darunavir exposure was increased by 24% in the presence of indinavir/rtv; indinavir exposure was increased by 23% in the presence of PREZISTA/rtv. The appropriate dose of indinavir in combination with PREZISTA/rtv has not been established.
Other medicinal products
Antidysrhythmics (bepridil, systemic lidocaine, quinidine and amiodarone)
Exposure to bepridil, lidocaine, quinidine and amiodarone may be increased when co-administered with PREZISTA/rtv. Caution is warranted and therapeutic drug monitoring of antidysrhythmics, if available, is recommended, when co-administered with PREZISTA/rtv.
Digoxin
An interaction trial with PREZISTA/rtv (600/100 mg twice daily) and a single dose of digoxin (0,4 mg) showed an increase of digoxin AUC
last of 77% (ratio of Least Square Means (LSM) was 1,77 with a 90% CI of 0,90 to 3,50). It is recommended that the lowest dose of digoxin should initially be prescribed and digoxin dose should be titrated to obtain the desired clinical effect when co-administered with PREZISTA/rtv. Serum digoxin concentrations should be monitored to assist in the titration.
Anticoagulants
Warfarin concentrations may be affected (decreased) when co-administered with PREZISTA/rtv. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/rtv. Anticonvulsants (phenobarbital, phenytoin and carbamazepine)
Phenobarbital, phenytoin and carbamazepine are inducers of CYP450 enzymes. PREZISTA/rtv should not be used in combination with these medicines, as co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA (see “Special Precautions”).
Calcium channel blockers
The exposure to calcium channel blockers (e.g. felodipine, nifedipine, nicardipine) may increase when PREZISTA/rtv are used concomitantly. Caution is warranted and careful clinical monitoring is recommended.
Clarithromycin
An interaction trial between PREZISTA/rtv (400/100 mg twice daily) and clarithromycin (500 mg twice daily) showed an increase in exposure to clarithromycin by 57%, while exposure to darunavir was not affected. For patients with renal impairment, a dose reduction of clarithromycin should be considered.
No dose adjustment of darunavir or clarithromycin is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered:
•        For subjects with CL
cr of 30 –60 mL/min, the dose of clarithromycin should be reduced by 50%.
•        For subjects with CL
cr of <30 mL/min, the dose of clarithromycin should be reduced by 75%.
Dexamethasone
Systemic dexamethasone induces CYP3A4 and thereby may decrease darunavir exposure. This may result in loss of therapeutic effect. Therefore this combination should be used with caution.
Fluticasone propionate
Concomitant use of inhaled fluticasone propionate and PREZISTA/rtv may increase plasma concentrations of fluticasone propionate. Alternatives should be considered, particularly for long term use.
HMG-CoA reductase inhibitors
HMG-CoA reductase inhibitors, such as lovastatin and simvastatin, which are highly dependent on CYP3A4 metabolism, are expected to have markedly increased plasma concentrations when co-administered with PREZISTA/rtv. Increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis. Concomitant use of PREZISTA/rtv with lovastatin and simvastatin is therefore not recommended.
The results of an interaction trial with atorvastatin show that atorvastatin (10 mg once daily) in combination with PREZISTA/rtv (300/100 mg twice daily) provides an exposure to atorvastatin, which is only 15% lower than that obtained with atorvastatin (40 mg once daily) alone. When administration of atorvastatin and PREZISTA/rtv is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily A gradual dose increase of atorvastatin may be tailored to the clinical response. PREZISTA/rtv (600/100 mg twice daily) increased exposure to a single dose of pravastatin (40 mg) by approximately 80%. However in a subset of subjects the pravastatin exposure was increased 5-fold. Until more information is available regarding this interaction and the underlying mechanism, it is not recommended to co-administer pravastatin with PREZISTA/rtv (see “Special Precautions”).
H
2-Receptor antagonists and proton pump inhibitors
Co-administration of omeprazole (20 mg once daily) or ranitidine (150 mg twice daily) and PREZISTA/rtv (400/100 mg twice daily) did not affect the exposure to darunavir. Based on these results, PREZISTA/rtv can be co-administered with H
2-receptor antagonists and proton pump inhibitors without dose adjustments.
Immunosuppressants (cyclosporin, tacrolimus, sirolimus)
Exposure to cyclosporine, tacrolimus, or sirolimus may be increased when co-administered with PREZISTA/rtv.
Therapeutic drug monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/rtv.
Ketoconazole, itraconazole and voriconazole
Ketoconazole, itraconazole and voriconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of ketoconazole, itraconazole or voriconazole and PREZISTA/rtv may increase plasma concentrations of darunavir. Simultaneously, plasma concentrations of ketoconazole or itraconazole may be increased by PREZISTA/rtv. The concomitant administration of ketoconazole (200 mg twice daily) with PREZISTA/rtv (400/100 mg twice daily) increased exposure of ketoconazole and darunavir by 212% and 42%, respectively. Concomitant use of ketoconazole, itraconazole and voriconazole with PREZISTA is contra-indicated (see CONTRA-INDICATIONS).
Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving PREZISTA/rtv (see CONTRA-INDICATIONS).
Methadone
An interaction trial investigating the effect of PREZISTA/rtv (600/100 mg twice daily) on a stable methadone maintenance therapy showed an AUC decrease of 16% for R-methadone. Based on pharmacokinetic and clinical findings, no adjustment of methadone dosage is required when initiating co-administration of PREZISTA/rtv. However, clinical monitoring is recommended as maintenance therapy may need to be adjusted in some patients (see “Special precautions”).
Buprenorphine/naloxone
The results of an interaction trial with PREZISTA/rtv and buprenorphine/naloxone demonstrated that buprenorphine exposure was not affected when administered with PREZISTA/rtv. Exposure of the active metabolite, norbuprenorphine, increased by 46%. No dose adjustment for buprenorphine was required. Careful clinical monitoring is recommended if PREZISTA/rtv and buprenorphine are co-administered (see CONTRA-INDICATIONS).
Oestrogen-based contraceptives
The results of an interaction trial between PREZISTA/rtv (600/100 mg twice daily) and ethinylestradiol 35 mcg and norethindrone 1 mg demonstrated that at steady-state systemic exposures to ethinylestradiol and norethindrone are decreased by 44% and 14%, respectively. Therefore, alternative methods of non-hormonal contraception should be used. (see “Special Precautions”).
PDE-5 inhibitors
In an interaction trial 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 co-administered with PREZISTA/rtv (400/100 mg twice daily).
Concomitant use of PDE-5 inhibitors with PREZISTA/rtv should be done with caution. If concomitant use of PREZISTA/rtv 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 (see “Special Precautions”).
Rifabutin
Rifabutin is an inducer and substrate of CYP450 enzymes. Concomitant use of rifabutin and PREZISTA/rtv is expected to increase rifabutin exposure and decrease darunavir exposure. When indicated, it is recommended to administer rifabutin at a dosage of 150 mg once every other day when combined with PREZISTA/rtv.
Selective Serotonin Reuptake Inhibitors (SSRIs)
In an interaction trial between paroxetine (20 mg once daily) or sertraline (50 mg once daily) and PREZISTA/rtv (400/100 mg twice daily), the exposure to darunavir was not affected by the presence of sertraline or paroxetine.
Exposure to sertraline and paroxetine, was decreased by 49% and 39%, respectively, in the presence of PREZISTA/rtv. If SSRIs are co-administered with PREZISTA/rtv, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/rtv should be monitored for antidepressant response.
Antidepressants (Trazodone)
Concomitant use of trazodone and PREZISTA/rtv may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A inhibitor such as PREZISTA/rtv, the combination should be used with caution and a lower dose of trazodone should be considered.

PREGNANCY AND LACTATION:
Pregnancy
Safety and efficacy have not been demonstrated. In animal studies the exposure was lower than in human exposure, and no conclusions were possible.
Lactation
It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk. Because of the potential for serious adverse events in nursing infants, mothers should be instructed not to breastfeed if they are receiving PREZISTA.
Fertility
There was no effect on mating or fertility with PREZISTA treatment in rats.

DOSAGE AND DIRECTIONS FOR USE:
PREZISTA must always be given with 100 mg ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products. The prescribing information of ritonavir including the contra-indications and warnings must therefore be consulted prior to initiation of therapy with PREZISTA/rtv.
Adults:
The recommended dosage of PREZISTA is 600 mg twice daily taken with ritonavir 100 mg twice daily and with food.
The type of food does not affect the exposure to darunavir. Ritonavir (100 mg twice daily) is used as a pharmacokinetic enhancer of darunavir (see INTERACTIONS and “Pharmacokinetics Properties”). A further increase in the dose of PREZISTA or ritonavir has been shown to not result in any clinically relevant increase in antiviral activity.
Children (less than 12 years of age) and adolescents (12 to 17 years of age):
The safety and efficacy of PREZISTA/rtv in these populations is not known.
Hepatic impairment:
No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no data regarding the use of PREZISTA/rtv when co-administered to patients with severe hepatic impairment; therefore, specific dosage recommendations cannot be made. PREZISTA/rtv should not be used in patients with severe hepatic impairment as safety and efficacy have not been demonstrated (see “WARNINGS”and “Special Precautions”)
Renal impairment:
No dose adjustment is required in patients with renal impairment (see “Special Precautions”and “Pharmacokinetic Properties”).

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Adverse drug reactions identified in the safety assessment
The safety assessment is based on all safety data from the Phase llb Clinical trials reported with the recommended dose PREZISTA/rtv 600/100 mg twice daily in the 458 patients who immediately started treatment with the recommended dose (de novo patients).
In Clinical trials, the most frequent (= 10%) ADRs were diarrhoea, headache, abdominal pain, nausea and fatigue.
The most frequent grade 3 or 4 ADRs were increased hepatic and pancreatic enzymes, hypertriglyceridaemia, diarrhoea, hypercholesterolaemia, headache, abdominal pain and vomiting. All other grade 3 or 4 ADRs were reported in less than 1% of the patients.
2.1 percent of the patients discontinued treatment due to ADRs.
Adverse Reactions to PREZISTA/rtv 600/100 mg twice daily all grades in antiretroviral treatment-experienced HIV-1 infected adult patients in the pooled Phase IIb Clinical trials are mentioned in the table below*:
*excluding laboratory abnormalities reported as ADRs
Within each System Organ Class, the ADRs are ranked under CIOMS headings of frequency, using the following convention: Very common (= 1/10); common (= 1/100, <1/10); uncommon (= 1/1 000, <1/100); rare (= 1/10 000, <1/1 000); very rare (= 1/10 000), including isolated reports.
                        Pooled analysis
Phase II b Clinical trials (PREZISTA/rtv 600/100 mg twice daily + OBR#, = n=467)
System Organ Class &
Frequency category
Adverse Drug Reaction
Immune system disorders
uncommon
       
Immune reconstitution syndrome
Metabolism and Nutrition disorders
common
       
Diabetes mellitus, Anorexia
Psychiatric disorders
uncommon
       
Abnormal dreams
Nervous system disorders
very common
       
Headache
Gastrointestinal disorders
very common
       
Diarrhoea, Nausea, Abdominal pain
common Vomiting, Dyspepsia, Abdominal distension, Flatulence
uncommon Acute pancreatitis
Hepatobiliary disorder
uncommon
       
Hepatitis acute
Skin and subcutaneous tissue disorders
common
       
Lipodystrophy (lipohypertrophy, lipodystrophy and lipoatrophy), Rash, Pruritus
Musculoskeletal and connective tissue disorders
common
       
Myalgia
Reproductive system and breast disorders
common
       
Gynaecomastia
General disorders and administration site conditions
very common
common
       
Fatigue
Asthenia
# Optimised Background Regimen

Laboratory abnormalities, considered ADRs, in antiretroviral treatment-experienced HIV-1 infected adult patients in the
pooled Phase IIb Clinical trials are shown in the table below:

Pooled analysis
Phase IIb Clinical trials
Laboratory parameter
Preferred Term
Limit PREZISTA/rtv 600/100 mg twice daily + OBR#
n=467
ALT  
Grade 2 >2,5 to = 5,0 x ULN 6,1%
Grade 3 >5,0 to = 10,0 x ULN 2,4%
Grade 4 >10,0 x ULN 0,9%
AST  
Grade 2 >2,5 to = 5,0 x ULN 6,9%
Grade 3 >5,0 to = 10,0 x ULN 3,0%
Grade 4 >10,0 x ULN 0,6%
ALP  
Grade 2 >2,5 to = 5,0 x ULN 3,9%
Grade 3 >5,0 to = 10,0 x ULN 0,9%
Grade 4 >10,0 x ULN 0%
Triglycerides  
Grade 2 5,65 –8,47 mmol/L 9,3%
Grade 3 8,48 –13,56 mmol/L 8,2%
Grade 4 >13,56 mmol/L 3,9%
Total cholesterol*  
Grade 2 6,22 –7,77 mmol/L 17,7%
Grade 3 >7,77 mmol/L 7,1%
LDL cholesterol*  
Grade 2 4,14 –4,92 mmol/L 13,2%
Grade 3 >4,92 mmol/L 9,1%
Elevated glucose levels  
Grade 2 6,99 –13,87 mmol/L 15,4%
Grade 3 13,93 –27,75 mmol/L 1,7%
Grade 4 >27,75 mmol/L 0,2%
Pancreatic lipase  
Grade 2 >1,5 to = 3,0 x ULN 5,2%
Grade 3 >3,0 to = 5,0 x ULN 2,6%
Grade 4 >5,0 x ULN 0,9%
Pancreatic amylase  
Grade 2 >1,5 to = 2,0 x ULN 7,4%
Grade 3 >2,0 to = 5,0 x ULN 7,8%
Grade 4 >5,0 x ULN 1,1%
# Optimised Background Regimen
* Grade 4 data not applicable in Division of AIDS grading scale

Additional Adverse reactions in other clinical trials
System Organ Class &
Frequency category
Adverse Reaction
Skin and subcutaneous tissue disorders
rare
Stevens-Johnson Syndrome
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal 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.
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of protease inhibitors, particularly in combination with NRTIs.
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.
Patients co-infected with hepatitis B and/or hepatitis C virus
In patients co-infected with hepatitis B or C virus receiving PREZISTA/rtv, the incidence of adverse events and clinical chemistry abnormalities was not higher than in patients receiving PREZISTA/rtv who were not co-infected, except for increased hepatic enzymes. The pharmacokinetic exposure in co-infected patients was comparable to that in patients without co-infection. Standard clinical monitoring of patients with hepatitis co-infection is considered adequate.
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 and that they may continue to develop opportunistic infections and other complications associated with HIV disease. Appropriate precautions should continue to be employed.
Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using PREZISTA.
Patients should be advised to take PREZISTA and ritonavir with food every day as prescribed. The type of food does not affect exposure to PREZISTA. Patients should be instructed to swallow whole tablets with a drink such as water or milk. PREZISTA must always be used with 100 mg of ritonavir in combination with other antiretroviral drugs. Patients should not alter the dose of either PREZISTA or ritonavir, discontinue ritonavir, or discontinue therapy with PREZISTA without consulting their physician. If a patient misses a dose of PREZISTA or ritonavir by more than 6 hours, the patient should be told to wait and then take the next dose of PREZISTA and ritonavir at the regularly scheduled time. If the patient misses a dose of PREZISTA or ritonavir by less than 6 hours, the patient should be told to take PREZISTA and ritonavir immediately, and then take the next dose of PREZISTA and ritonavir at the regularly scheduled time. If a dose of PREZISTA or ritonavir is skipped, the patient should not double the next dose. Inform the patient that he or she should not take more or less than the prescribed dose of PREZISTA or ritonavir at any one time.
There are insufficient data at this time to recommend a dose in antiretroviral treatment naïve patients and in children.
Elderly: As limited information is available on the use of PREZISTA/rtv 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 (see “Pharmacokinetic Properties”).
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg PREZISTA was given orally in combination with ritonavir at 100 mg twice daily. Therefore, PREZISTA should only be used in combination with 100 mg of ritonavir as a pharmacokinetic enhancer (see “Pharmacokinetic Properties”). Increasing the dose of ritonavir did not significantly affect darunavir concentrations and is not recommended.
Darunavir contains a sulphonamide moiety. PREZISTA should be used with caution in patients with a known sulphonamide allergy.
During the clinical development program, severe skin rash, including erythema multiforme and Stevens-Johnson Syndrome, has been reported.
In some cases, fever and elevations of transaminases have also been reported. In clinical trials (n=924), rash (all grades, regardless of causality) occurred in 7% of subjects treated with PREZISTA; the discontinuation rate due to rash was 0,3%. Rashes were generally mild-to-moderate, self-limited maculopapular skin eruptions. Treatment with PREZISTA should be discontinued if severe rash develops.
Patients with coexisting conditions
Hepatic impairment
There are no data regarding the use of PREZISTA/rtv when co-administered to patients with severe hepatic impairment; therefore, PREZISTA should not be used (see WARNINGS). No dose adjustment is required in patients with mild or moderate hepatic impairment (see DOSAGE AND DIRECTIONS FOR USE and “Pharmacokinetic properties”).
Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk of liver function abnormalities including severe hepatic adverse events during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening of liver disease in such patients, interruption or discontinuation of treatment must be considered.
Renal impairment
Since the renal clearance of darunavir is limited, a decrease in total body clearance is not expected 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 (see DOSAGE AND DIRECTIONS FOR USE and “Pharmacokinetic Properties”).
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 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.
Hyperglycaemia
New onset diabetes mellitus, hyperglycaemia, or exacerbation of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including PREZISTA. 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 PIs and lipoatrophy and NRTIs has been hypothesized.
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 evaluation 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 “Side-effects”).
Immune reactivation syndrome
In 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 Pneumocystis jeroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Resistance/Cross-resistance
Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in PREZISTA/rtv treated patients, it is unknown what effect therapy with PREZISTA will have on the activity of subsequently administered protease inhibitors.
Interactions with medicinal products
Darunavir and ritonavir are both inhibitors of the CYP3A4 isoform. Co-administration of PREZISTA and ritonavir with medicinal products primarily metabolised by CYP3A4 may result in increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect and adverse events (see CONTRA-INDICATIONS and INTERACTIONS).
PREZISTA/rtv should not be used in combination with rifampicin, as this may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA (see CONTRA-INDICATIONS).
PREZISTA/rtv should not be used concomitantly with products containing St. John’s Wort (Hypericum perforatum) because co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA (see CONTRA-INDICATIONS).
The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A4 for their metabolism. Concomitant use of PREZISTA/rtv with simvastatin or lovastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis, as a consequence of increased plasma concentrations of simvastatin or lovastatin. PREZISTA/rtv increased exposure to pravastatin by approximately 80%, but only in a subset of subjects. The clinical relevance of this interaction is currently unknown. It is not recommended to co-administer pravastatin with PREZISTA/rtv. If treatment with an HMG-CoA reductase inhibitor is indicated, reduced starting doses of atorvastatin are recommended (see INTERACTIONS).
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/rtv. However, clinical monitoring is recommended as maintenance therapy may need to be adjusted in some patients (see INTERACTIONS).
Plasma concentrations of ethinylestradiol are decreased by induction of its metabolism by ritonavir and alternative methods of non-hormonal contraception are recommended (see INTERACTIONS).
The phosphodiesterase type 5 (PDE5) inhibitors sildenafil, vardenafil and tadalafil are highly dependent on CYP3A4 for their metabolism. If concomitant use of PREZISTA/rtv with sildenafil, vardenafil, or tadalafil is indicated, reduced doses of the PDE5 inhibitors are recommended (see INTERACTIONS).
For medicinal products that are highly dependent on the metabolism by CYP3A4 and that have a narrow therapeutic index, such as amiodarone, bepridil, (systemic) lidocaine and quinidine, plasma concentrations of such medicinal products could increase when combined with PREZISTA/rtv. This can lead to prolongation or increase of their therapeutic effect and adverse events (see INTERACTIONS).
Phenobarbital, phenytoin and carbamazepine are inducers of CYP450 enzymes. PREZISTA/rtv should not be used in combination with these medicines, as co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA (see INTERACTIONS).

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Human experience of acute overdose with PREZISTA/rtv is limited. Single doses up to 3200 mg of the oral solution of PREZISTA alone and up to 1600 mg of the tablet formulation of PREZISTA in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
There is no specific antidote for overdose with PREZISTA. Treatment of overdose with PREZISTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

IDENTIFICATION:
Film-coated tablet. White oval shaped tablet, debossed with 300 mg on one side and TMC114 on the other side.

PRESENTATION:
PREZISTA film-coated tablets are provided in white, high-density polyethylene (HDPE) plastic bottles containing 120 tablets fitted with yellow, polypropylene (PP) child resistant closures, lined with a silver aluminium induction seal.

STORAGE INSTRUCTIONS:
Store below 30ºC.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
41/20.2.8/0747

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE:
PHARMACARE LIMITED
Building 12
Healthcare Park
Woodlands Drive
Woodmead
2191

DATE OF PUBLICATION OF THE PACKAGE INSERT:
26 May 2009

575261
11/2009
BRITEPAK

New addition to this site: September 2010
Source: Pharmaceutical Industry

SAEPI HOME PAGE      TRADE NAME INDEX      GENERIC NAME INDEX      FEEDBACK
Information presented by Malahyde Information Systems © Copyright 1996-2010