Daru-Rito

Darunavir, ritonavir.

A light-yellow film-coated, ovaloid, biconvex, beveled edge tablet debossed with "M" on one side of the tablet and "DRL" on the other side.
Each film-coated tablet contains Darunavir Ethanolate 433.648 mg equivalent to Darunavir 400 mg, Ritonavir (Form II) USP 50 mg.
Excipients/Inactive Ingredients: Tablet core: Microcrystalline Cellulose, Crospovidone, Copovidone, Colloidal Silicon Dioxide, Iron Oxide Yellow, Sodium Steryl Fumarate, Sorbitan Monolaurate, Sodium Chloride.
Tablet film-coat: Hypromellose, Titanium Dioxide, Macrogols, Talc, Hydroxypropyl Cellulose, Polysorbate 80, Colloidal Silicon Dioxide, Iron Oxide Yellow, Iron Oxide Red.

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitors. ATC code: Not yet assigned.
Namibia Pharmacological Classification: 20.2.8 - Antiviral agents.
Pharmacology: Pharmacodynamics: Mechanism of action: Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease (KD of 4.5 x 10-12M). It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus infected cells, thereby preventing the formation of mature infectious virus particles.
Antiviral activity in vitro: Darunavir exhibits 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 with median EC₅₀ values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/ml). Darunavir demonstrates 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.
Resistance: In vitro selection of darunavir-resistant virus from wild type HIV-1 was lengthy (>3 years). The selected viruses were unable to grow in the presence of darunavir concentrations above 400 nM. Viruses selected in these conditions and showing decreased susceptibility to darunavir (range: 23-50-fold) harboured 2 to 4 amino acid substitutions in the protease gene. The decreased susceptibility to darunavir of the emerging viruses in the selection experiment could not be explained by the emergence of these protease mutations.
The clinical trial data from ART-experienced patients (TITAN trial and the pooled analysis of the POWER 1, 2 and 3 and DUET 1 and 2 trials) showed that virologic response to Darunavir co-administered with low dose ritonavir was decreased when 3 or more darunavir RAMs (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V and L89V) were present at baseline or when these mutations developed during treatment.
Increasing baseline darunavir fold change in EC50 (FC) was associated with decreasing Virologic response. A lower and upper clinical cut-off of 10 and 40 were identified. Isolates with baseline FC ≤10 are susceptible; isolates with FC >10 to 40 have decreased susceptibility; isolates with FC >40 are resistant (see Clinical results as follows).
Viruses isolated from patients on Darunavir/ritonavir 600/100 mg twice daily experiencing Virologic failure by rebound that were susceptible to tipranavir at baseline remained susceptible to Tipranavir after treatment in the vast majority of cases.
The lowest rates of developing resistant HIV virus are observed in ART-naïve patients who are treated for the first time with darunavir in combination with other ART.
The table as follows shows the development of HIV-1 protease mutations and loss of susceptibility to PIs in virologic failures at endpoint in the ARTEMIS, ODIN and TITAN trials. (See Table 1.)

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Cross-resistance: Darunavir FC was less than 10 for 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to most PIs remain susceptible to darunavir.
In the virologic failures of the ARTEMIS trial no cross-resistance with other PIs was observed.
Clinical results: Efficacy of Darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in ART-naïve patients: The evidence of efficacy of Darunavir/ritonavir 800/100 mg once daily is based on the analyses of 192 week data from the randomised, controlled, open-label Phase III trial ARTEMIS in antiretroviral treatment-naïve HIV-1 infected patients comparing Darunavir/ritonavir 800/100 mg once daily with lopinavir/ritonavir 800/200 mg per day (given as a twice-daily or as a once-daily regimen). Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily and emtricitabine 200 mg once daily.
The table as follows shows the efficacy data of the 48 week and 96 week analyses from the ARTEMIS trial: See Table 2.

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Non-inferiority in virologic response to the Darunavir/ritonavir treatment, defined as the percentage of patients with plasma HIV-1 RNA level <50 copies/ml, was demonstrated (at the pre-defined 12% non-inferiority margin) for both Intent-To-Treat (ITT) and On Protocol (OP) populations in the 48 week analysis. These results were confirmed in the analyses of data at 96 weeks of treatment in the ARTEMIS trial. These results were sustained up to 192 weeks of treatment in the ARTEMIS trial.
Efficacy of Darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in ART-experienced patients: ODIN is a Phase III, randomised, open-label trial comparing Darunavir/ritonavir 800/100 mg once daily versus Darunavir/ritonavir 600/100 mg twice daily in ART-experienced HIV-1 infected patients with screening genotype resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V) and a screening HIV-1 RNA >1,000 copies/ml. Efficacy analysis is based on 48 weeks of treatment (see table as follows). Both arms used an optimised background regimen (OBR) of ≥2 NRTIs. (See Table 3.)

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At 48 weeks, virologic response, defined as the percentage of patients with plasma HIV-1 RNA level <50 copies/ml, with Darunavir/ritonavir 800/100 mg once daily treatment was demonstrated to be non-inferior (at the pre-defined 12% non-inferiority margin) compared to Darunavir/ritonavir 600/100 mg twice daily for both ITT and OP populations.
Darunavir/ritonavir 800/100 mg once daily in ART-experienced patients should not be used in patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA ≥100,000 copies/ml or CD4+ cell count <100 cells x 10⁶/l (see Dosage & Administration and Precautions). Limited data is available in patients with HIV-1 clades other than B.
Paediatric patients: ART-naïve paediatric patients from the age of 12 years to <18 years, and weighing at least 40 kg: DIONE is an open-label, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of Darunavir with low dose ritonavir in 12 ART-naïve HIV-1 infected paediatric patients aged 12 to less than 18 years and weighing at least 40 kg. These patients received Darunavir/ritonavir 800/100 mg once daily in combination with other antiretroviral agents. Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1.0 log10 versus baseline. (See Table 4.)

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Pregnancy and postpartum: Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was evaluated in a clinical trial of 34 pregnant women (17 in each arm) during the second and third trimesters, and postpartum. Virologic response was preserved throughout the study period in both arms. No mother to child transmission occurred in the infants born to the 29 subjects who stayed on the antiretroviral treatment through delivery. There were no new clinically relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1 infected adults (see Dosage & Administration, Precautions and Pharmacokinetics as follows).
Pharmacokinetics: Darunavir: 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 α₁-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG and, therefore, higher plasma concentrations.
Darunavir is primarily metabolised by CYP3A. Ritonavir inhibit 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 Precautions).
When administered without food, the relative bioavailability of darunavir in the presence of low dose ritonavir is 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 α₁-acid glycoprotein.
Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 l (Mean ± SD) and increased to 131 ± 49.9 l (Mean ± SD) in the presence of 100 mg twice-daily ritonavir.
Biotransformation: 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 with ritonavir dose was due to the parent active substance. 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 with ritonavir 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: Paediatric population: The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 74 treatment-experienced paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that the administered weight-based doses of Darunavir/ritonavir resulted in darunavir exposure comparable to that in adults receiving Darunavir/ritonavir 600/100 mg twice daily (see Dosage & Administration).
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 14 treatment-experienced paediatric patients, aged 3 to <6 years and weighing at least 15 kg to <20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving Darunavir/ritonavir 600/100 mg twice daily (see Dosage & Administration).
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naïve paediatric patients, aged 12 to <18 years and weighing at least 40 kg, showed that Darunavir/ritonavir 800/100 mg once daily results in darunavir exposure that was comparable to that achieved in adults receiving Darunavir/ritonavir 800/100 mg once daily. Therefore the same once daily dosage may be used in treatment-experienced adolescents aged 12 to <18 years and weighing at least 40 kg without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA <100,000 copies/ml and CD4+ cell count ≥100 cells x 10⁶/l (see Dosage & Administration).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V.
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment-experienced paediatric patients, aged 3 to <6 years and weighing at least 14 kg to <20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving Darunavir/ritonavir 800/100 mg once daily (see Dosage & Administration). In addition, pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages of 3 to <18 years confirmed the darunavir exposures as observed in the clinical studies and allowed the identification of weight-based Darunavir/ritonavir once daily dosing regimens for paediatric patients weighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patients without DRV-RAMs* and who have plasma HIV-1 RNA <100,000 copies/ml and CD4+ cell count ≥100 cells x 10^6/l (see Dosage & Administration).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V.
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 Precautions). However, only limited data were available in patients above the age of 65 year.
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 with ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine unchanged.
Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20) (see Dosage & Administration and Precautions).
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 total plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects. However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown therefore, Darunavir should be used with caution. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see Dosage & Administration, Contraindications and Precautions).
Pregnancy and postpartum: The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum. (See Tables 5 and 6.)

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In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of pregnancy, mean intra-individual values for total darunavir C_max, AUC_12h and C_min were 28%, 24% and 17% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir C_max, AUC_12h and C_min values were 19%, 17% lower and 2% higher, respectively, as compared with postpartum.
In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of pregnancy, mean intra-individual values for total darunavir C_max, AUC_12h and C_min were 34%, 34% and 32% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir C_max, AUC_12h and C_min values were 31%, 35% and 50% lower, respectively, as compared with postpartum.
Ritonavir: Absorption: There is no parenteral formulation of ritonavir, therefore the extent of absorption and absolute bioavailability have not been determined. In healthy subjects (n=44) under fed conditions, using a single dose of two Ritonavir Tablets 100 mg, the following results were obtained (arithmetic mean +/- SD): T_max (h) 5.2+/-1.7, C_max (ng/ml) 3089 +/- 1105, AUC_0-t (ng.h/ml) 22019 +/- 7915, AUC_0-inf (ng.h/ml) 22816 +/- 7993.
Effects of food on oral absorption: Food slightly decreases the bioavailability of the Ritonavir. Administration of a single 100 mg dose of Ritonavir with a moderate fat meal (857 kcal, 31% calories from fat) or a high fat meal (907 kcal, 52% calories from fat) was associated with a mean decrease of 20-23% in ritonavir AUC and C_max.
Distribution: The apparent volume of distribution (V_B/F) of ritonavir is approximately 20-40 l after a single 600 mg dose. The protein binding of ritonavir in human plasma is approximately 98-99% and is constant over the concentration range of 1.0-100 μg/ml. Ritonavir binds to both human alpha 1-acid glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities.
Tissue distribution studies with ¹⁴C-labelled ritonavir in rats showed the liver, adrenals, pancreas, kidneys and thyroid to have the highest concentrations of ritonavir. Tissue to plasma ratios of approximately 1 measured in rat lymph nodes suggests that ritonavir distributes into lymphatic tissues. Ritonavir penetrates minimally into the brain.
Metabolism: Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily by the CYP3A isozyme family and to a lesser extent by the CYP2D6 isoform. Animal studies as well as in vitro experiments with human hepatic microsomes indicated that ritonavir primarily underwent oxidative metabolism. Four ritonavir metabolites have been identified in man. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent compound. However, the AUC of the M-2 metabolite was approximately 3% of the AUC of parent compound.
Low doses of Ritonavir have shown profound effects on the pharmacokinetics of other protease inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence the pharmacokinetics of Ritonavir (see Interactions).
Elimination: Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir. In these studies renal elimination was not found to be a major route of elimination of ritonavir. This was consistent with the observations in animal studies.
Toxicology: Preclinical safety data: Darunavir: Animal toxicology studies have been conducted at exposures up to clinical exposure levels with darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.
In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment with darunavir. In rodents the target organs identified were the haematopoietic system, the blood coagulation system, liver and thyroid. A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated partial thromboplastin time.
Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and thyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a small increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the pancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicity findings or target organs were identified up to exposures equivalent to clinical exposure at the recommended dose.
In a study conducted in rats, the number of corpora lutea and implantations were decreased in the presence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavir treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The exposure levels were lower than those with the recommended clinical dose in humans. In a pre- and postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening of eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pups that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation. These effects may be secondary to pup exposure to the active substance via the milk and/or maternal toxicity. No post weaning functions were affected with darunavir alone or in combination with ritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed with convulsions in some animals. Exposure in plasma, liver and brain was considerably higher than in adult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, the exposure was comparable to that in adult rats. The increased exposure was likely at least partly due to immaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalities were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats.
Due to uncertainties regarding the rate of development of the human blood brain barrier and liver enzymes, Darunavir with low dose ritonavir should not be used in paediatric patients below 3 years of age.
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1,000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences of hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. The observed hepatocellular and thyroid tumours in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses.
After 2 years administration of darunavir at exposures at or below the human exposure, kidney changes were observed in mice (nephrosis) and rats (chronic progressive nephropathy).
Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.
Ritonavir: Repeated dose toxicity studies in animals identified major target organs as the liver, retina, thyroid gland and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and were accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigment epithelium (RPE) and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have not been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary to phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced ocular changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir. Clinical investigation in humans has revealed no clinically significant alteration in thyroid function tests. Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted in rats and are felt to be attributable to species-specific spontaneous disease. Furthermore, no clinically significant renal abnormalities were noted in clinical trials.
Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a maternally toxic dosage. Developmental toxicity in rabbits (embryolethality, decreased litter size and decreased foetal weights) occurred at a maternally toxic dosage.
Ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.
Long term carcinogenicity studies of ritonavir in mice and rats revealed tumourigenic potential specific for these species, but are regarded as of no relevance for humans.

Darunavir/Ritonavir Tablets 400 mg/50 mg is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.
Darunavir/Ritonavir Tablets 400 mg/50 mg may be used to provide suitable dose regimens for the treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are: antiretroviral therapy (ART)-naïve (see Dosage & Administration); ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1 RNA <100,000 copies/ml and CD4+ cell count ≥100 cells x 10⁶/l. In deciding to initiate treatment with Darunavir in such ART-experienced patients, genotypic testing should guide the use of Darunavir (see Dosage & Administration, Contraindications, Precautions and Pharmacology: Pharmacodynamics under Actions).

Therapy should be initiated by a health care provider experienced in the management of HIV infection. After therapy with Darunavir/Ritonavir Tablets 400 mg/50 mg has been initiated, patients should be advised not to alter the dosage, dose form or discontinue therapy without discussing with their health care provider.
Posology: ART-naïve adult patients: The recommended dose regimen is Darunavir 800 mg once daily with ritonavir 100 mg once daily taken with food. Darunavir/Ritonavir Tablets 400 mg/50 mg can be used to construct the once daily Darunavir/Ritonavir 800/100 mg regimen.
ART-experienced adult patients: The recommended dose regimens are as follows: In ART-experienced patients with no darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA <100,000 copies/ml and CD4+ cell count ≥100 cells x 10⁶/l (see Indications/Uses) a regimen of 800 mg once daily with ritonavir 100 mg once daily taken with food may be used. Darunavir/Ritonavir Tablets 400/50 mg tablets can be used to construct the once daily Darunavir/Ritonavir 800/100 mg regimen.
In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen is Darunavir 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V.
ART-naïve paediatric patients (3 to 17 years of age and weighing at least 40 kg): The recommended dose regimen is Darunavir 800 mg once daily with ritonavir 100 mg once daily taken food.
ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg): The recommended dose regimens are as follows: In ART-experienced patients without DRV-RAMs* and who have plasma HIV-1 RNA <100,000 copies/ml and CD4+ cell count ≥100 cells x 10⁶/l (see Indications/Uses) a regimen of Darunavir 800 mg once daily with ritonavir 100 mg once daily taken with food may be used. Darunavir/Ritonavir Tablets 400/50 mg tablets can be used to construct the once daily Darunavir/Ritonavir 800/100 mg regimen.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V.
Advice on missed doses: If a once daily dose of Darunavir/Ritonavir is missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of Darunavir/Ritonavir with food as soon as possible. If this is noticed later than 12 hours after 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 half-life of darunavir in the presence of ritonavir and the recommended dosing interval of approximately 24 hours.
Special populations: Elderly: Limited information is available in this population, and therefore, Darunavir/Ritonavir should be used with caution in this age group (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: Darunavir: Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, Darunavir 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, Darunavir/Ritonavir Tablets 400/50 mg must not be used in patients with severe hepatic impairment (Child-Pugh Class C) (see Contraindications, Precautions and Pharmacology: Pharmacokinetics under Actions).
Ritonavir: Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver disease (see Contraindications). In the absence of pharmacokinetic studies in patients with stable severe hepatic impairment (Child Pugh Grade C) without decompensation, caution should be exercised when Ritonavir is used as a pharmacokinetic enhancer as increased levels of the co-administered PI may occur.
Renal impairment: No dose adjustment is required for darunavir/ritonavir in patients with renal impairment (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Paediatric population: Darunavir/Ritonavir should not be used in paediatric patients below 3 years of age or less than 15 kg body weight (see Precautions and Pharmacology: Toxicology: Preclinical safety data under Actions).
ART-naïve paediatric patients (less than 3 years of age or less than 15 kg body weight): No recommendations on posology can be made in this population.
ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg): Darunavir exposures in treatment-naïve adolescents 12 to 17 years weighing at least 40 kg receiving Darunavir/ritonavir 800/100 mg once daily have been determined and were found to be within the therapeutic range as has been established in adults receiving Darunavir/ritonavir 800/100 mg once daily. As a consequence, since Darunavir/ritonavir 800/100 mg once daily has also been registered for use in treatment-experienced adults without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA <100,000 copies/ml and CD4+ cell count ≥100 cells x 10⁶/l, the same indication of Darunavir 800 mg once daily applies to treatment-experienced children 3 to 17 years weighing at least 40 kg.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V.
Darunavir should not be used in children less than 15 kg body weight as the dose for this population has not been established in a sufficient number of patients. Darunavir should not be used in children below 3 years of age because of safety concerns.
Pregnancy and postpartum: No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. Darunavir/Ritonavir Tablets 400/50 mg should be used during pregnancy only if the potential benefit justifies the potential risk (see Precautions, Use in Pregnancy & Lactation and Pharmacology: Pharmacokinetics under Actions).
Method of administration: Patients should be instructed to take Darunavir/Ritonavir Tablets 400/50 mg within 30 minutes after completion of a meal. The type of food does not affect the exposure to darunavir (see Precautions, Interactions and Pharmacology: Pharmacokinetics under Actions).

Darunavir: Human experience of acute overdose with Darunavir co-administered with low dose ritonavir is limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
There is no specific antidote for overdose with Darunavir. Treatment of overdose with Darunavir 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.
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.
Ritonavir: Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took Ritonavir 1500 mg/day for two days and reported paraesthesia, which resolved after the dose was decreased. A case of renal failure with eosinophilia has been reported.
The signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnoea and tremors.
There is no specific antidote for overdose with Ritonavir. Treatment of overdose with Ritonavir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Due to the solubility characteristics and possibility of transintestinal elimination, it is proposed that management of overdose could entail gastric lavage and administration of activated charcoal. Since Ritonavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the medicine.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Use in patients with severe (Child-Pugh Class C) hepatic impairment.
Concomitant treatment with any of the following medicinal products is contraindicated given the expected decrease in plasma concentrations of darunavir and ritonavir and the potential for loss of therapeutic effect (see Precautions and Interactions).
Applicable to darunavir boosted with ritonavir: The combination product lopinavir/ritonavir (see Interactions).
The strong CYP3A inducers rifampicin and herbal preparations containing St John's wort (Hypericum perforatum). Co-administration is expected to reduce plasma concentrations of darunavir and ritonavir which could lead to loss of therapeutic effect and possible development of resistance (see Precautions and Interactions).
Darunavir boosted with ritonavir inhibits the elimination of active substances that are highly dependent on CYP3A for clearance, which results in increased exposure to the co-administered medicinal product. Therefore, concomitant treatment with such medicinal products for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated (applies to Darunavir boosted with ritonavir). These active substances include e.g.: alfuzosin (alpha 1-adrenoreceptor antagonist); amiodarone, bepridil, dronedarone, quinidine, ranolazine, systemic lidocaine (antiarrhythmics/antianginals); astemizole, terfenadine (antihistamines); colchicine when used in patients with renal and/or hepatic impairment (antigout) (see Interactions); ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine); cisapride (gastrointestinal motility agents); pimozide, quetiapine, sertindole (antipsychotics/neuroleptics) (see Interactions); triazolam, midazolam administered orally (sedatives/hypnotics) (for caution on parenterally administered midazolam, see Interactions); sildenafil-when used for the treatment of pulmonary arterial hypertension, avanafil (PDE-5 inhibitors); simvastatin and lovastatin (HMG-CoA reductase inhibitors) (see Interactions); ticagrelor (antiplatelets) (see Interactions).

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Regular assessment of virological response is advised. In the setting of lack or loss of virological response, resistance testing should be performed.
Patients receiving antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection.
Darunavir binds predominantly to α₁-acid glycoprotein. This protein binding is concentration-dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products highly bound to α₁-acid glycoprotein cannot be ruled out (see Interactions).
ART-experienced patients-once daily dosing: Darunavir used in combination with low dose ritonavir once daily in ART-experienced patients should not be used in patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA ≥100,000 copies/ml or CD4+ cell count <100 cells x 10⁶/l (see Dosage & Administration). Combinations with optimised background regimen (OBRs) other than ≥2 NRTIs have not been studied in this population. Limited data are available in patients with HIV-1 clades other than B (see Pharmacology: Pharmacodynamics under Actions).
Severe skin reactions: During the darunavir/ritonavir clinical development program (N=3,063), severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson Syndrome has been rarely (<0.1%) reported, and during post-marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported. Darunavir should be discontinued immediately if signs or symptoms of severe skin reactions develop. These can include, but are not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
Rash occurred more commonly in treatment-experienced patients receiving regimens containing Darunavir/ritonavir + raltegravir compared to patients receiving Darunavir/ritonavir without raltegravir or raltegravir without Darunavir (see Adverse Reactions).
Darunavir contains a sulphonamide moiety. Darunavir should be used with caution in patients with a known sulphonamide allergy.
Hepatotoxicity: Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with Darunavir. During the darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy with Darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.
Appropriate laboratory testing should be conducted prior to initiating therapy with Darunavir used in combination with low dose ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of Darunavir used in combination with low dose ritonavir treatment.
If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients using Darunavir used in combination with low dose ritonavir, interruption or discontinuation of treatment should be considered promptly.
Patients with coexisting conditions: Hepatic impairment: The safety and efficacy of Darunavir have not been established in patients with severe underlying liver disorders and Darunavir is therefore contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, Darunavir should be used with caution in patients with mild or moderate hepatic impairment (see Dosage & Administration, Contraindications and Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No special precautions or dose adjustments for darunavir/ritonavir 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 (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
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.
Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Immune reconstitution inflammatory syndrome: In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with Darunavir co-administered with low dose ritonavir.
Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see Adverse Reactions).
Interactions with medicinal products: Pharmacokinetic enhancer and concomitant medications: Concomitant use of darunavir/ritonavir with lopinavir/ritonavir, rifampicin and herbal products containing St John's wort, Hypericum perforatum, is contraindicated (see Interactions).
Unlike ritonavir, cobicistat does not have inducing effects on enzymes or transport proteins (see Interactions). If switching the pharmacoenhancer from ritonavir to cobicistat, caution is required during the first two weeks of treatment with darunavir/cobicistat, particularly if doses of any concomitantly administered medicinal products have been titrated or adjusted during use of ritonavir as a pharmacoenhancer. A dose reduction of the co-administered drug may be needed in these cases.
Efavirenz in combination with Darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir C_min. If efavirenz is to be used in combination with Darunavir/ritonavir, the Darunavir/ritonavir 600/100 mg twice daily regimen should be used.
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-glycoprotein (P-gp; see Contraindications and Interactions).
Effects on ability to drive and use machines: Darunavir in combination with ritonavir has no or negligible influence on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing Darunavir co-administered with low dose ritonavir and should be borne in mind when considering a patient's ability to drive or operate machinery (see Adverse Reactions).
Use in Pregnancy: Darunavir should be used during pregnancy only if the potential benefit justifies the potential risk. Caution should be used in pregnant women with concomitant medications which may further decrease darunavir exposure (see Interactions and Pharmacology: Pharmacokinetics under Actions).
Use in Children: Darunavir is not recommended for use in paediatric patients below 3 years of age or less than 15 kg body weight (see Dosage & Administration and Pharmacology: Toxicology: Preclinical safety data under Actions).
Use in the Elderly: As limited information is available on the use of Darunavir in patients aged 65 and over, caution should be exercised in the administration of Darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).

Darunavir: Pregnancy: As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.
There are no adequate and well controlled studies on pregnancy outcome with darunavir in pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Darunavir co-administered with low dose ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk.
Breast-feeding: It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted in toxicity. Because of both the potential for HIV transmission and the potential for adverse reactions in breast-fed infants, mothers should be instructed not to breast-feed under any circumstances if they are receiving Darunavir.
Fertility: No human data on the effect of darunavir on fertility are available. There was no effect on mating or fertility with darunavir treatment in rats (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Ritonavir: A limited number (>800) of pregnant women were exposed to Ritonavir during pregnancy; a very limited number (<300) were exposed during the first trimester. These data largely refer to exposures where Ritonavir was used in combination therapy and not at therapeutic Ritonavir doses but at lower doses as a pharmacokinetic enhancer for other PIs. These limited data indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems. Animal data have shown reproductive toxicity. The use of Ritonavir tablets may be considered in pregnancy only when the benefits outweigh the risk to the foetus.
Ritonavir adversely interacts with oral contraceptives (OCs). Therefore, an alternative, effective and safe method of contraception should be used during treatment.
Breast-Feeding: Current recommendations on HIV and breastfeeding (e.g. those from the WHO) should be consulted before advising patients on this matter. Preferred options may vary depending on the local circumstances.
It is not known whether this medicine is excreted in human milk. Milk excretion has not been measured in the animal studies, however a study in rats showed some effects on offspring development during lactation which are compatible with excretion of ritonavir in milk in that species.

Summary of the safety profile: During the clinical development program (N=2,613 treatment-experienced subjects who initiated therapy with Darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent adverse reactions reported in clinical trials and as spontaneous reports are diarrhoea, nausea, rash, headache and vomiting. The most frequent serious reactions are acute renal failure, myocardial infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis and pyrexia.
In the 96 week analysis, the safety profile of Darunavir/ritonavir 800/100 mg once daily in treatment-naïve subjects was similar to that seen with Darunavir/ritonavir 600/100 mg twice daily in treatment-experienced subjects except for nausea which was observed more frequently in treatment-naïve subjects. This was driven by mild intensity nausea. No new safety findings were identified in the 192 week analysis of the treatment-naïve subjects in which the mean treatment duration of Darunavir/ritonavir 800/100 mg once daily was 162.5 weeks.
Tabulated list of adverse reactions: Adverse reactions are listed by system organ class (SOC) and frequency category. Within each frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and not known (frequency cannot be estimated from the available data).
Adverse reactions observed with darunavir/ritonavir in clinical trials and post-marketing: See Table 7.

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Description of selected adverse reactions: Rash: In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in Precautions.
During the clinical development program of raltegravir in treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing Darunavir/ritonavir + raltegravir compared to those containing Darunavir/ritonavir without raltegravir or raltegravir without Darunavir/ritonavir. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see Precautions).
Lipodystrophy: 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) (see Precautions).
Metabolic abnormalities: Combination antiretroviral therapy has also been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see Precautions).
Musculoskeletal abnormalities: 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 long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see Precautions).
Immune reconstitution inflammatory syndrome: In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see Precautions).
Bleeding in haemophiliac patients: There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors (see Precautions).
Paediatric population: The safety assessment in paediatric patients is based on the 48-week analysis of safety data from three Phase II trials. The following patient populations were evaluated (see Pharmacology: Pharmacodynamics under Actions): 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at least 20 kg who received Darunavir tablets with low dose ritonavir twice daily in combination with other antiretroviral agents.
21 ART-experienced HIV-1 infected paediatric patients aged from 3 to <6 years and weighing 10 kg to <20 kg (16 participants from 15 kg to <20 kg) who received Darunavir oral suspension with low dose ritonavir twice daily in combination with other antiretroviral agents.
12 ART-naïve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 40 kg who received Darunavir tablets with low dose ritonavir once daily in combination with other antiretroviral agents (see Pharmacology: Pharmacodynamics under Actions).
Other special populations: Patients co-infected with hepatitis B and/or hepatitis C virus: Among 1,968 treatment-experienced patients receiving Darunavir co-administered with ritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis (see Precautions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer): Darunavir 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 these compounds and consequently that of darunavir, leading to loss of therapeutic effect and possible development of resistance (see Contraindications and Precautions). CYP3A inducers that are contraindicated include rifampicin, St John's wort and lopinavir.
Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrations of darunavir and ritonavir. Co-administration with strong CYP3A4 inhibitors is not recommended and caution is warranted, these interactions are described in the interaction table as follows (e.g. indinavir, systemic azoles like ketoconazole and clotrimazole).
Medicinal products that may be affected by darunavir boosted with ritonavir: Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or transported by P-gp may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.
Darunavir co-administered with low dose ritonavir must not be combined with medicinal products that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) (see Contraindications).
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. Cobicistat 150 mg given with darunavir 800 mg once daily enhances darunavir pharmacokinetic parameters in a comparable way to ritonavir (see Pharmacology: Pharmacokinetics under Actions). Therefore, darunavir must only be used in combination with a pharmacokinetic enhancer (see Pharmacology: Pharmacokinetics under Actions).
A clinical study utilising a cocktail of medicinal products 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 darunavir/ritonavir, which may be attributed to the presence of low dose ritonavir. Co-administration of darunavir and ritonavir with 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. Co-administration 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, co-administration 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.
Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration with substrates of these transporters can result in increased plasma concentrations of these compounds (e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table as follows).
Interaction table: Interaction studies have only been performed in adults.
Several of the interaction studies (indicated by # in the table as follows) have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see Posology under Dosage & Administration). The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated.
Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products are listed in the table as follows (not determined as "ND"). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range.
In the table as follows the specific pharmacokinetic enhancer is specified when recommendations differ. When the recommendation is the same for Darunavir when co-administered with a low dose ritonavir or cobicistat, the term "boosted Darunavir" is used. (See Table 8.)

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Incompatibilities: Not applicable.
Special precautions for disposal: No special requirements.

Do not store above 30°C. Store in the original container.
Shelf life: 24 months.

Antivirals

J05AE - Protease inhibitors ; Used in the systemic treatment of viral infections.

S