Danavir
UkraineTable of Contents
- INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DANA VIR (DANAVIR)
- Composition:
- Pharmacological Properties
- Clinical characteristics
- Studies were conducted with darunavir doses lower than recommended or with a different dosing regimen (see section "Posology and method of administration").
- Special precautions for use
- Method of Administration and Dosage
- Adverse Reactions
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DANA VIR (DANAVIR)
Composition:
active substance: darunavir;
1 tablet contains 600 mg of darunavir;
excipients: silicified microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II Orange 85F530007 (composition: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171), yellow FCF (E 110)).
Pharmaceutical form. Film-coated tablets.
Basic physicochemical properties: film-coated tablets, orange-colored, oval-shaped, biconvex, with imprint «J» on one side and «7» on the other.
Pharmacotherapeutic group. Antiviral agents for systemic use. Protease inhibitors. ATC code J05AE10.
Pharmacological Properties
Pharmacodynamics
Mechanism of action. Darunavir is an inhibitor of human immunodeficiency virus type 1 (HIV-1) protease dimerization and catalytic activity (KD 4.5 × 10–12 M). It selectively inhibits the cleavage of HIV Gag-Pol polyproteins in virus-infected cells and prevents the formation of mature infectious viral particles.
Antiviral activity in vitro
Darunavir is active against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, peripheral blood mononuclear cells, and human monocytes/macrophages, with mean EC50 values ranging from 1.2 to 8.5 nM (0.7–5.0 ng/mL). Darunavir demonstrates antiviral activity in vitro against a broad spectrum of primary isolates of HIV-1 group M (A, B, C, D, E, F, G) and group O, with EC50 values ranging from <0.1 to 4.3 nM. These EC50 values are substantially lower than 50% of the cellular cytotoxic concentration range (from 87 µM to >100 µM).
Resistance
In vitro selection of darunavir-resistant HIV-1 wild-type virus was a prolonged process (>3 years). Selected viruses were unable to grow in the presence of darunavir at concentrations exceeding 400 nM. Viruses selected under these conditions and showing reduced susceptibility to darunavir (range: 23- to 50-fold change) harbored 2 to 4 amino acid substitutions in the protease gene. The reduced susceptibility of new viruses in selection experiments could not be explained solely by the emergence of these protease mutations.
Clinical trials in antiretroviral-experienced patients showed that virological response to darunavir/low-dose ritonavir combination therapy decreased when three or more darunavir resistance-associated mutations (DRV-RAMs) (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V, and L89V) were present at baseline or developed during treatment.
Increased baseline fold change (FC) in darunavir EC50 was associated with reduced virological response. Upper and lower clinical cut-off values of 40 and 10 have been identified. Isolates with baseline FC ≤10 are considered sensitive, isolates with FC >10–40 have reduced susceptibility, and isolates with FC >40 are considered resistant.
Viruses isolated from patients who received darunavir/ritonavir 600/100 mg twice daily and experienced virological failure due to rebound viremia remained largely susceptible to tipranavir after treatment, despite being initially susceptible to tipranavir before treatment.
The lowest incidence of HIV resistance development was observed in antiretroviral-naïve patients who were newly treated with darunavir in combination with other antiretroviral agents.
Cross-resistance
The fold change in darunavir EC50 was less than 10 in 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and/or tipranavir, indicating that viruses resistant to most protease inhibitors remain sensitive to darunavir.
Pharmacokinetics
The pharmacokinetic properties of darunavir administered in combination with ritonavir were studied in healthy adult volunteers and in HIV-1-infected patients. Plasma concentrations of darunavir were higher in HIV-1-infected patients than in healthy volunteers. This difference can be explained by higher levels of alpha-1-acid glycoprotein (AAG) in HIV-1-infected patients, resulting in increased binding of darunavir to plasma AAG and thus higher total plasma concentrations of darunavir. Darunavir is primarily metabolized by CYP3A enzymes. Ritonavir inhibits hepatic CYP3A enzymes and thereby significantly increases darunavir plasma concentrations.
Absorption
After oral administration, darunavir is rapidly absorbed in the gastrointestinal tract. Maximum plasma concentration of darunavir, when co-administered with low-dose ritonavir, is reached within 2.5–4.0 hours. The absolute bioavailability of a single 600 mg dose of darunavir administered orally is approximately 37%, increasing to 82% when co-administered with ritonavir (100 mg twice daily). The overall pharmacokinetic effect of ritonavir results in an approximately 14-fold increase in darunavir plasma concentration after a single 600 mg oral dose of darunavir co-administered with ritonavir (100 mg twice daily).
When administered under fasting conditions, the relative bioavailability of darunavir with low-dose ritonavir was 30% lower than when administered with food. Therefore, Danavir tablets should be taken with ritonavir and with food. The type of food does not affect darunavir plasma concentrations.
Distribution
Approximately 95% of darunavir is bound to plasma proteins, primarily to alpha-1-acid glycoprotein.
After intravenous administration, the volume of distribution of darunavir was 88.1 ± 59.01 (mean ± standard deviation (SD)) and increased to 131 ± 49.91 (mean ± SD) when administered with ritonavir 100 mg twice daily.
Metabolism
In vitro studies using human liver microsomes have shown that darunavir undergoes predominantly oxidative metabolism. Darunavir is extensively metabolized in the liver by the cytochrome P450 system, almost exclusively by the CYP3A4 enzyme. A study in healthy volunteers receiving 14C-darunavir showed that the majority of radioactivity in plasma after a single 400 mg dose of darunavir and 100 mg ritonavir was due to unchanged darunavir. At least three oxidative metabolites of darunavir have been identified in humans; the activity of all metabolites against wild-type HIV was at least 10-fold lower than that of darunavir itself.
Elimination. After a single dose of 400 mg 14C-darunavir and 100 mg ritonavir, approximately 79.5% and 13.9% of radioactivity was recovered in feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of radioactivity in feces and urine, respectively. The terminal half-life of darunavir is approximately 15 hours when administered in combination with ritonavir. The clearance of darunavir after intravenous administration of 150 mg was 32.8 L/h (without ritonavir) and 5.9 L/h when low-dose ritonavir is co-administered.
Special patient populations
Children
Pharmacokinetics of darunavir in combination with ritonavir twice daily in treatment-experienced patients aged 6 to 17 years and weighing at least 20 kg showed that darunavir/ritonavir plasma concentrations at weight-based dosing were similar to those in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section "Dosage and administration").
Pharmacokinetics of darunavir in combination with ritonavir twice daily in treatment-experienced patients aged 3 to 6 years and weighing 15 to 20 kg showed that darunavir/ritonavir plasma concentrations at weight-based dosing were similar to those in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section "Dosage and administration").
Pharmacokinetics of darunavir in combination with ritonavir once daily in antiretroviral treatment-naïve patients aged 12 to 18 years and weighing at least 40 kg showed that darunavir/ritonavir plasma concentrations after administration of 800/100 mg once daily were similar to those in adults receiving darunavir/ritonavir 800/100 mg once daily. Therefore, the same dosing regimen of 800 mg once daily is recommended for children aged 12 to 18 years weighing at least 40 kg who are antiretroviral treatment-naïve, in the absence of HIV-1 darunavir resistance-associated mutations (DRV-RAMs)1 and with HIV-1 RNA plasma levels <100,000 copies/mL and CD4+ ≥100 cells×106/L (see section "Dosage and administration").
1 (DRV-RAMs): V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, and L89V.
Pharmacokinetics of darunavir in combination with ritonavir once daily in treatment-experienced patients aged 3 to 6 years and weighing 14 to 20 kg showed that darunavir/ritonavir plasma concentrations at weight-based dosing were similar to those in adults receiving darunavir/ritonavir 800/100 mg once daily. Pharmacokinetic modeling of darunavir distribution in patients aged 3 to 18 years confirmed similarity to that observed in clinical studies and enabled dosing recommendations for children weighing at least 15 kg who are either antiretroviral treatment-naïve or treatment-experienced, in the absence of HIV-1 darunavir resistance-associated mutations (DRV-RAMs)1 and with HIV-1 RNA plasma levels <100,000 copies/mL and CD4+ ≥100 cells×106/L (see section "Dosage and administration").
1 (DRV-RAMs): V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, and L89V.
Elderly patients
Population pharmacokinetic analysis demonstrated no significant differences in darunavir pharmacokinetic parameters among HIV-infected patients aged 18–75 years (including 12 HIV-infected patients aged ≥65 years). However, only limited data are available for patients aged 65 years and older.
Gender
Population pharmacokinetic analysis revealed slightly higher (16.8%) darunavir concentrations in HIV-infected women compared to HIV-infected men. This difference is not considered clinically significant.
Patients with renal impairment
Studies using 14C-darunavir in combination with ritonavir showed that approximately 7.7% of the administered dose was excreted unchanged in urine. Darunavir pharmacokinetics have not been studied in patients with renal impairment; however, population pharmacokinetic analysis showed no significant differences in darunavir pharmacokinetics in patients with moderate renal impairment (creatinine clearance 30–60 mL/min, n = 20) (see sections "Special warnings and precautions for use" and "Dosage and administration").
Patients with hepatic impairment
Darunavir is primarily metabolized and eliminated by the liver. In dose-ranging studies with darunavir co-administered with ritonavir (600/100 mg) twice daily, total plasma concentrations of darunavir in patients with mild (Child-Pugh class A, n = 8) and moderate (Child-Pugh class B, n = 8) hepatic impairment were similar to those in healthy volunteers. However, the concentration of unbound (free) darunavir was approximately 55% (class A) and 100% (class B) higher, respectively. The clinical significance of this increase is unknown; however, Danavir should be used with caution. The effect of severe hepatic impairment on darunavir pharmacokinetics has not been studied (see sections "Special warnings and precautions for use" and "Dosage and administration").
Pregnancy and postpartum period
Overall exposure to darunavir and ritonavir after administration of 600 mg/100 mg twice daily and 800 mg/100 mg once daily as part of antiretroviral therapy was generally lower during pregnancy compared to the postpartum period, although pharmacokinetic parameters of unbound darunavir decreased less during pregnancy than postpartum due to increased unbound fraction of darunavir during pregnancy.
In women receiving darunavir/ritonavir 600 mg/100 mg twice daily during the second trimester of pregnancy, mean within-subject values of Cmax, AUC12h, and Cmin for total darunavir were 28%, 26%, and 26% lower, respectively, compared to the postpartum period; during the third trimester, these values were 18%, 16%, and 2% lower or higher, respectively, compared to postpartum.
In women receiving darunavir/ritonavir 800 mg/100 mg once daily during the second trimester of pregnancy, mean within-subject values of Cmax, AUC24h, and Cmin for total darunavir were 33%, 31%, and 30% lower, respectively; during the third trimester, these values were 29%, 32%, and 50% lower, respectively, compared to the postpartum period.
Clinical characteristics
Indications
The drug Danavir in combination with low-dose ritonavir and other antiretroviral medicinal products is indicated for the treatment of patients infected with human immunodeficiency virus (HIV-1).
Danavir 600 mg is indicated:
- for the treatment of HIV-1 infection in adult patients who have previously received antiretroviral therapy, including those who have undergone intensive antiretroviral treatment;
- for the treatment of HIV-1 infection in children aged 12 years and older with body weight of at least 40 kg.
At the initiation of Danavir therapy in combination with low-dose ritonavir, the treatment history of each patient and resistance-associated mutations related to various antiretroviral agents should be considered. Genotypic and phenotypic testing results (if available) and the patient’s treatment history should guide the use of Danavir.
Contraindications
Hypersensitivity to darunavir or to any of the excipients of the medicinal product.
Severe hepatic impairment (Child-Pugh class C).
The combination of strong CYP3A inducers such as rifampicin with Danavir is contraindicated when used concomitantly with low-dose ritonavir*.
The combination of lopinavir/ritonavir is contraindicated for concomitant use with Danavir*.
Concomitant use with herbal products containing St. John’s wort (Hypericum perforatum)*.
Concomitant administration of darunavir with low-dose ritonavir and medicinal substances whose clearance is largely dependent on CYP3A4 enzyme activity, and whose increased plasma concentrations are associated with serious and/or life-threatening adverse reactions. These include:
- alfuzosin;
- amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine;
- astemizole, terfenadine;
- colchicine when administered to patients with renal and/or hepatic impairment*;
- medicinal products containing ergot alkaloids (dihydroergotamine, ergometrine, ergotamine, and methylergonovine);
- elbasvir/grazoprevir;
- cisapride;
- dapoxetine;
- domperidone;
- naloxegol;
- lurasidone, pimozide, quetiapine, sertindole*;
- triazolam, oral midazolam (caution regarding parenteral midazolam administration, see section "Interaction with other medicinal products and other forms of interaction");
- sildenafil used for the treatment of pulmonary arterial hypertension, avanafil;
- simvastatin, lovastatin, and lomitapide*;
- ticagrelor*.
*See section "Interaction with other medicinal products and other forms of interaction".
Interaction with other medicinal products and other forms of interaction
Interaction studies have been conducted only in adults.
Medicinal products that may be affected by darunavir boosted with ritonavir
Darunavir and ritonavir are inhibitors of CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concomitant administration of the darunavir/ritonavir combination with medicinal products that are primarily metabolized by CYP3A4 and/or CYP2D6 or transported by P-gp may lead to increased plasma concentrations of these agents, potentially resulting in enhanced or prolonged therapeutic effects and adverse reactions.
The combination of darunavir with low-dose ritonavir should not be used concomitantly with medicinal products whose clearance is highly dependent on CYP3A4 isoenzyme activity, and whose increased plasma concentrations may lead to serious and/or life-threatening adverse reactions (narrow therapeutic index) (see section "Contraindications").
The overall pharmacokinetic effect of ritonavir results in approximately a 14-fold increase in darunavir plasma concentration following a single 600 mg dose of darunavir co-administered with 100 mg ritonavir twice daily. Therefore, Danavir should be used only in combination with low-dose ritonavir as a pharmacokinetic enhancer (see sections "Pharmacokinetics" and "Special precautions for use").
Clinical studies with medicinal products metabolized by CYP2C9, CYP2C19, and CYP2D6 isoenzymes showed induction of CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity with the darunavir/ritonavir combination, which is characteristic of low-dose ritonavir use. Concomitant administration of darunavir and ritonavir with medicinal products primarily metabolized by CYP2D6 (such as flecainide, propafenone, metoprolol) may increase plasma concentrations of these agents, potentially enhancing or prolonging their therapeutic effects and adverse reactions. Concomitant use of darunavir and ritonavir with medicinal products primarily metabolized by CYP2C9 (e.g., warfarin) and CYP2C19 (e.g., methadone) may reduce systemic exposure to these agents, potentially diminishing or shortening their therapeutic effect.
Although the effect on CYP2C8 has been studied only in vitro, concomitant administration of darunavir and ritonavir with medicinal products primarily metabolized by CYP2C8 (such as paclitaxel, rosiglitazone, repaglinide) may reduce systemic exposure to these agents, potentially diminishing or shortening their therapeutic effect.
Ritonavir inhibits the transporter proteins P-gp, OATP1B1, and OATP1B3; therefore, concomitant use with substrates of these transporters may increase plasma concentrations of these substances (e.g., dabigatran etexilate, digoxin, statins, and bosentan; see interaction table below).
Medicinal products that affect plasma levels of darunavir/ritonavir
Darunavir and ritonavir are metabolized by CYP3A enzymes. Medicinal products that induce CYP3A activity (e.g., rifampicin, St. John’s wort extract, lopinavir) may increase the clearance of darunavir and ritonavir, leading to reduced plasma concentrations of both agents.
Concomitant administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A (e.g., indinavir, azole antifungals such as clotrimazole) may reduce the clearance of darunavir and ritonavir, leading to increased plasma concentrations of both agents. These interactions are detailed in the interaction table below.
Interaction table
Interactions between darunavir/ritonavir and other antiretroviral and non-antiretroviral medicinal products are listed in the table below (not determined – ND). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval (CI) of the geometric mean ratio: within (↔), below (↓), or above (↑) the 80–125% range.
Some interaction studies (marked in the table with #) were conducted with a lower dose of darunavir than recommended or with a different dosing regimen; therefore, the effects of concomitant administration may be underestimated, and clinical safety monitoring is advised.
The list of drug interaction examples provided below is not exhaustive. Therefore, the prescribing information for each medicinal product used concomitantly with darunavir should be consulted to obtain information on metabolism, interaction pathways, potential risks, and necessary management strategies.
| INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND DOSING RECOMMENDATIONS |
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| Medicinal products |
Interaction Change in geometric mean value (%) |
Recommendations for concomitant use |
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| ANTIRETROVIRAL AGENTS |
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| Integrase strand transfer inhibitors |
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| Dolutegravir |
dolutegravir AUC ↓ 22 % dolutegravir C24 h ↓ 38 % dolutegravir Cmax ↓ 11 % darunavir ↔* * Based on comparative data from cross-study and historical pharmacokinetic data. |
Darunavir with low-dose ritonavir and dolutegravir may be used without dose adjustment. |
|
| Raltegravir |
Some clinical studies have shown that raltegravir may lead to a minor decrease in darunavir plasma concentrations. |
The effect of raltegravir on darunavir plasma concentrations is not clinically significant. No dose adjustment is required when darunavir with low-dose ritonavir is used concomitantly with raltegravir. |
|
| Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) |
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| Didanosine 400 mg once daily |
didanosine AUC ↓ 9 % didanosine Cmin N/A didanosine Cmax ↓ 16 % darunavir AUC ↔ darunavir Cmin ↔ darunavir Cmax ↔ |
The combination of darunavir/ritonavir and didanosine may be used without dose adjustment. Didanosine should be administered on an empty stomach and therefore should be taken 1 hour before or 2 hours after darunavir/ritonavir with food. |
|
| Tenofovir disoproxil fumarate 300 mg once daily |
tenofovir AUC ↑ 22 % tenofovir Cmin ↑ 37 % tenofovir Cmax ↑ 24 % # darunavir AUC ↑ 21 % # darunavir Cmin ↑ 24 % # darunavir Cmax ↑ 16 % (↑ tenofovir due to MDR-1 transport effect in renal tubules) |
Renal function monitoring is recommended when darunavir with low-dose ritonavir is used concomitantly, especially in patients with systemic or renal disease and in patients receiving nephrotoxic agents. |
|
| Emtricitabine/ tenofovir alafenamide |
tenofovir alafenamide ↔ tenofovir ↑ |
The recommended dose of emtricitabine/tenofovir alafenamide is 200/10 mg once daily when used with darunavir and low-dose ritonavir. |
|
| Abacavir Emtricitabine Lamivudine Stavudine Zidovudine |
Not studied. Based on different elimination pathways of other protease inhibitors, zidovudine, emtricitabine, stavudine, lamivudine, which are primarily renally excreted, and abacavir, which is not metabolized by CYP450, no interaction is expected between these medicinal products and darunavir/ritonavir combination. |
Darunavir with low-dose ritonavir may be used with these NRTIs without dose adjustment. |
|
| Non-nucleos(t)ide reverse transcriptase inhibitors (NNRTIs) |
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| Efavirenz 600 mg once daily |
efavirenz AUC ↑ 21 % efavirenz Cmin ↑ 17 % efavirenz Cmax ↑ 15 % # darunavir AUC ↓ 13 % # darunavir Cmin ↓ 31 % # darunavir Cmax ↓ 15 % (↑ efavirenz due to CYP3A inhibition) (↓ darunavir due to CYP3A induction) |
When darunavir with low-dose ritonavir is used in combination with efavirenz, monitor for CNS toxicity related to increased efavirenz concentrations. Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in suboptimal darunavir Cmin. If concomitant use of these agents is necessary, the dosing regimen darunavir/ritonavir 600/100 mg twice daily should be used. |
|
| Etravirine 100 mg twice daily |
etravirine AUC ↓ 37 % etravirine Cmin ↓ 49 % etravirine Cmax ↓ 32 % darunavir AUC ↑ 15 % darunavir Cmin ↔ darunavir Cmax ↔ |
Darunavir with low-dose ritonavir may be used concomitantly with etravirine at a dose of 200 mg twice daily without dose adjustment. |
|
| Nevaripine 200 mg twice daily |
nevirapine AUC ↑ 27 % nevirapine Cmin ↑ 47 % nevirapine Cmax ↑ 18 % # darunavir: concentrations were consistent with previous data (↑ nevirapine due to CYP3A inhibition) |
Darunavir with low-dose ritonavir may be used with nevirapine without dose adjustment. |
|
| Rilpivirine 150 mg once daily |
rilpivirine AUC ↑ 130 % rilpivirine Cmin ↑ 178 % rilpivirine Cmax ↑ 79 % darunavir AUC ↔ darunavir Cmin ↓ 11 % darunavir Cmax ↔ |
Darunavir with low-dose ritonavir may be used concomitantly with rilpivirine without dose adjustment. |
|
| Protease inhibitors (PIs) – without additional low-dose ritonavir† |
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| Atazanavir 300 mg once daily |
atazanavir AUC ↔ atazanavir Cmin ↑ 52 % atazanavir Cmax ↓ 11 % # darunavir AUC ↔ # darunavir Cmin ↔ # darunavir Cmax ↔ Atazanavir: comparison of atazanavir/ritonavir 300/100 mg once daily and atazanavir 300 mg once daily in combination with darunavir/ritonavir 400/100 mg twice daily. Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily and darunavir/ritonavir 400/100 mg twice daily in combination with atazanavir 300 mg once daily. |
Darunavir with low-dose ritonavir may be used with atazanavir without dose adjustment. |
|
| Indinavir 800 mg twice daily |
indinavir AUC ↑ 23 % indinavir Cmin ↑ 125 % indinavir Cmax ↔ # darunavir Cmin ↑ 44 % # darunavir Cmax ↑ 11 % Indinavir: comparison of indinavir/ritonavir 800/100 mg twice daily with indinavir/darunavir/ritonavir 800/400/100 mg twice daily. Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily with darunavir/ritonavir 400/100 mg in combination with indinavir 800 mg twice daily. |
When darunavir/ritonavir is used concomitantly with indinavir, a reduction in indinavir dose from 800 mg twice daily to 600 mg twice daily should be considered in case of intolerance. |
|
| Tipranavir 1000 mg twice daily |
# darunavir AUC ↓ 26 % # darunavir Cmin ↓ 42 % # darunavir Cmax ↓ 17 % tipranavir AUC ↓ 6 % tipranavir Cmin ↓ 18 % tipranavir Cmax ↓ 6 % Tipranavir: comparison of tipranavir/ritonavir 1000/100 mg twice daily and tipranavir/darunavir/ritonavir 1000/400/100 mg twice daily. Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily and darunavir/ritonavir 400/100 mg in combination with tipranavir 1000 mg twice daily. |
Concomitant use of darunavir with low-dose ritonavir and tipranavir is not recommended. |
|
| Protease inhibitors (PIs) – with low-dose ritonavir1 |
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| Lopinavir/ritonavir 400/100 mg twice daily Lopinavir/ritonavir 533/133.3 mg twice daily |
lopinavir AUC ↑ 9 % lopinavir Cmin ↑ 23 % lopinavir Cmax ↓ 2 % darunavir AUC ↓ 38 % ‡ darunavir Cmin ↓ 51 % ‡ darunavir Cmax ↓ 21 % ‡ lopinavir AUC ↔ lopinavir Cmin ↑ 13 % lopinavir Cmax ↑ 11 % darunavir AUC ↓ 41 % darunavir Cmin ↓ 55 % darunavir Cmax ↓ 21 % ‡ Data based on non-standardized dose. |
Due to a 40 % decrease in darunavir AUC, appropriate doses of the combination have not been established. Therefore, concomitant use of darunavir/ritonavir and lopinavir/ritonavir combination is contraindicated. |
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| CCR5 ANTAGONISTS |
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| Maraviroc 150 mg twice daily |
maraviroc AUC ↑ 305 % maraviroc Cmin N/A maraviroc Cmax ↑ 129 % Concentrations of darunavir and ritonavir were consistent with previous data. |
The dose of maraviroc should be 150 mg twice daily when used concomitantly with darunavir and low-dose ritonavir. |
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| α-1 ADRENERGIC ANTAGONISTS |
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| Alfuzosin |
Based on theoretical considerations, darunavir is expected to increase plasma concentrations of alfuzosin (CYP3A inhibition). |
Concomitant use of darunavir/low-dose ritonavir and alfuzosin is contraindicated (see section "Contraindications"). |
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| ANESTHETICS |
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| Alfentanil |
Not studied. Alfentanil is metabolized by CYP3A enzymes; therefore, its metabolism may be inhibited when used concomitantly with darunavir/low-dose ritonavir. |
Concomitant use with darunavir/low-dose ritonavir may require a reduced dose of alfentanil and monitoring for risks of prolonged or delayed respiratory depression. |
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| ANTIANGINAL/ANTIARRHYTHMIC AGENTS |
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| Disopyramide Flecainide Lidocaine (systemic) Mexiletine Propafenone Amiodarone Bepiridil Dronedarone Ivabradine Quinidine Ranolazine |
Not studied. Darunavir may increase plasma concentrations of these antiarrhythmic agents (inhibition of CYP3A and/or CYP2D6). |
Use darunavir with low-dose ritonavir and antiarrhythmic agents with caution and, if possible, monitor therapeutic concentrations of these agents. Concomitant use of darunavir/low-dose ritonavir with amiodarone, bepiridil, dronedarone, ivabradine, quinidine, or ranolazine is contraindicated (see section "Contraindications"). |
|
| Digoxin 0.4 mg single dose |
digoxin AUC ↑ 61 % digoxin Cmin N/A digoxin Cmax ↑ 29 % (↑ digoxin due to possible P-gp inhibition) |
Digoxin has a narrow therapeutic range; therefore, the lowest possible digoxin dose should be initiated when used concomitantly with darunavir/ritonavir. Digoxin dose should be titrated to achieve the desired therapeutic effect while assessing the overall clinical condition. |
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| ANTIBIOTICS |
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| Clarithromycin 500 mg twice daily |
clarithromycin AUC ↑ 57 % clarithromycin Cmin ↑ 174 % clarithromycin Cmax ↑ 26 % # darunavir AUC ↓ 13 % # darunavir Cmin ↑ 1 % # darunavir Cmax ↓ 17 % Concentrations of the 14-OH-clarithromycin metabolite were not detected when combined with darunavir/ritonavir. (↑ clarithromycin due to CYP3A inhibition and possible P-gp inhibition) |
Use clarithromycin with caution when used concomitantly with darunavir/low-dose ritonavir. For patients with renal impairment, refer to the clarithromycin prescribing information for recommended dosing. |
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| ANTICOAGULANTS/ANTIPLATELETS |
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| Apixaban Rivaroxaban |
Not studied. Concomitant use of darunavir with these anticoagulants may increase their concentrations (inhibition of CYP3A and/or P-gp). |
Use of boosted darunavir with a direct oral anticoagulant (DOAC) metabolized by CYP3A4 and transported by P-gp is not recommended, as it may increase the risk of bleeding. |
|
| Dabigatran etexilate Edoxaban |
Dabigatran etexilate (150 mg): darunavir/ritonavir 800/100 mg single dose: dabigatran AUC ↑ 72 % dabigatran Cmax ↑ 64 % Darunavir/ritonavir 800/100 mg once daily: dabigatran AUC ↑ 18 % dabigatran Cmax ↑ 22 % |
Darunavir/ritonavir: consider clinical monitoring and/or dose reduction of DOAC when used concomitantly with darunavir/ritonavir, if DOAC is transported by P-gp but not metabolized by CYP3A4, including dabigatran etexilate and edoxaban. |
|
| Ticagrelor |
Based on theoretical considerations, concomitant use of boosted darunavir with ticagrelor may increase ticagrelor concentrations (inhibition of CYP3A and/or P-gp). |
Concomitant use of boosted darunavir with ticagrelor is contraindicated (see section "Contraindications"). |
|
| Clopidogrel |
Not studied. Concomitant use of clopidogrel with boosted darunavir is expected to reduce plasma concentrations of clopidogrel's active metabolite, potentially reducing its antiplatelet effect. |
Concomitant use of clopidogrel with boosted darunavir is not recommended. Alternative antiplatelet agents not affected by CYP inhibition or induction (e.g., prasugrel) should be used. |
|
| Warfarin |
Not studied. Warfarin concentrations may change due to concomitant use of darunavir and ritonavir. |
International normalized ratio (INR) monitoring is recommended when warfarin is used in combination with darunavir and low-dose ritonavir. |
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| ANTICONVULSANTS |
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| Phenobarbital Phenytoin |
Not studied. Phenobarbital and phenytoin are expected to reduce darunavir plasma concentrations (induction of CYP450 enzymes). |
Darunavir with low-dose ritonavir should not be used concomitantly with these agents. |
|
| Carbamazepine 200 mg twice daily |
carbamazepine AUC ↑ 45 % carbamazepine Cmin ↑ 54 % carbamazepine Cmax ↑ 43 % darunavir AUC ↔ darunavir Cmin ↓ 15 % darunavir Cmax ↔ |
Do not change the dose of darunavir/ritonavir. If combination with darunavir/ritonavir and carbamazepine is necessary, monitor patients for possible carbamazepine-related adverse reactions. Carbamazepine concentrations should be monitored and dose titrated for adequate effect. Based on study results, carbamazepine dose may be reduced by 25–50 % in the presence of darunavir/ritonavir. |
|
| Clonazepam |
Not studied. Concomitant use of boosted darunavir with clonazepam may increase clonazepam concentrations (CYP3A inhibition). |
Clinical monitoring is recommended when boosted darunavir is used concomitantly with clonazepam. |
|
| ANTIDEPRESSANTS |
|||
| Paroxetine 20 mg once daily Sertraline 50 mg once daily Amitriptyline Desipramine Imipramine Nortriptyline Trazodone |
paroxetine AUC ↓ 39 % paroxetine Cmin ↓ 37 % paroxetine Cmax ↓ 36 % # darunavir AUC ↔ # darunavir Cmin ↔ # darunavir Cmax ↔ sertraline AUC ↓ 49 % sertraline Cmin ↓ 49 % sertraline Cmax ↓ 44 % # darunavir AUC ↔ # darunavir Cmin ↓ 6 % # darunavir Cmax ↔ Concomitant use with darunavir/low-dose ritonavir may increase plasma concentrations of these antidepressants (inhibition of CYP2D6 and/or CYP3A). |
Dose titration of antidepressants is recommended when used concomitantly with darunavir/low-dose ritonavir based on clinical response. Monitor clinical response in patients receiving stable doses of antidepressants who initiate darunavir/ritonavir therapy. Clinical monitoring is recommended when darunavir/low-dose ritonavir is used concomitantly with these antidepressants; dose adjustment of antidepressants may be necessary. |
|
| ANTIEMETICS |
|||
| Domperidone |
Not studied. |
Concomitant use of domperidone with boosted darunavir is contraindicated. |
|
| ANTIFUNGALS |
|||
| Voriconazole |
Not studied. Ritonavir may reduce voriconazole plasma concentrations (induction of CYP450 enzymes). |
Voriconazole should not be used concomitantly with darunavir/ritonavir, except when benefit-risk assessment justifies its use. |
|
| Fluconazole Isavuconazole Itraconazole Posaconazole Clotrimazole |
Not studied. Darunavir may increase plasma concentrations of antifungal agents (P-gp inhibition), and posaconazole, isavuconazole, itraconazole, or fluconazole may increase darunavir concentrations (inhibition of CYP3A and/or P-gp). Not studied. Concomitant systemic use of clotrimazole and darunavir/ritonavir combination may increase darunavir plasma concentrations. darunavir AUC24h ↑ 33 % (based on population pharmacokinetic model). |
Caution and clinical monitoring are recommended. When used concomitantly, the daily dose of itraconazole should not exceed 200 mg. |
|
| GOUT TREATMENT AGENTS |
|||
| Colchicine |
Not studied. Concomitant use of colchicine and darunavir/ritonavir combination may increase colchicine effects (inhibition of CYP3A and/or P-gp). |
In patients with normal liver and kidney function, colchicine dose reduction or interruption is recommended if darunavir/low-dose ritonavir is required. Concomitant use of darunavir/ritonavir and colchicine is contraindicated in patients with impaired liver or kidney function (see sections "Contraindications" and "Special precautions"). |
|
| ANTIMALARIALS |
|||
| Artemether/ lumefantrine 80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours |
artemether AUC ↓ 16 % artemether Cmin ↔ artemether Cmax ↓ 18 % dihydroartemisinin AUC ↓ 18 % dihydroartemisinin Cmin ↔ dihydroartemisinin Cmax ↓ 18 % lumefantrine AUC ↑ 175 % lumefantrine Cmin ↑ 126 % lumefantrine Cmax ↑ 65 % darunavir AUC ↔ darunavir Cmin ↓ 13 % darunavir Cmax ↔ |
Use of darunavir with artemether/lumefantrine is possible without dose adjustment; however, due to increased lumefantrine effects, the combination should be used with caution. |
|
| ANTIMYCOBACTERIAL AGENTS |
|||
| Rifampicin Rifapentine |
Not studied. Rifapentine and rifampicin are potent CYP3A inducers and may lead to significant reduction in concentrations of other protease inhibitors and, consequently, virological failure and development of resistance (induction of CYP450 enzymes). Attempts to overcome reduced concentrations by increasing doses of other protease inhibitors with low-dose ritonavir have frequently resulted in hepatic reactions. |
Concomitant use of rifapentine and darunavir with low-dose ritonavir is not recommended. Concomitant use of darunavir/low-dose ritonavir with rifampicin is contraindicated (see section "Contraindications"). |
|
| Rifabutin 150 mg every other day |
rifabutin AUC** ↑ 55 % rifabutin Cmin** ↑ N/A rifabutin Cmax** ↔ darunavir AUC ↑ 53 % darunavir Cmin ↑ 68 % darunavir Cmax ↑ 39 % ** Sum of active fraction of rifabutin (parent drug + 25-O-desacetyl metabolite). Interaction studies showed comparable systemic concentrations of rifabutin when 300 mg rifabutin once daily alone was compared to 150 mg rifabutin once every two days in combination with darunavir/ritonavir (600/100 mg twice daily), with a 10-fold increase in daily concentration of the active metabolite 25-O-desacetylrifabutin. Additionally, AUC of the sum of active rifabutin components (unchanged active substance + 25-O-desacetyl metabolite) increased 1.6-fold, while Cmax remained comparable. No data available comparing with standard dose of 150 mg once daily (rifabutin is both an inducer and substrate of cytochrome CYP3A). Interaction studies observed increased systemic concentration of darunavir when darunavir/ritonavir combination was used concomitantly with rifabutin (150 mg every other day). |
A 75 % reduction in rifabutin dose from the usual 300 mg daily (to 150 mg rifabutin every other day) and increased monitoring for rifabutin-related adverse reactions are necessary for patients using the combination. If safety is insufficient, further extension of dosing interval for rifabutin and/or monitoring of rifabutin levels should be considered. Appropriate tuberculosis treatment in HIV-infected patients should be approached with caution. Based on safety data of darunavir/ritonavir combination, increased systemic distribution of darunavir in the presence of rifabutin does not require dose adjustment of darunavir/ritonavir. Based on pharmacokinetic modeling data, a 75 % dose reduction should also be applied to patients receiving rifabutin at doses other than 300 mg daily. |
|
| ANTINEOPLASTIC AGENTS |
|||
| Dasatinib Nilotinib Vinblastine Vincristine Everolimus |
Not studied. Darunavir may increase plasma concentrations of these agents (CYP3A inhibition). |
Plasma concentrations of these anticancer agents may increase when used concomitantly with darunavir/low-dose ritonavir, potentially increasing the frequency of adverse reactions associated with these agents. Use these anticancer agents with caution when used concomitantly with darunavir/low-dose ritonavir. Concomitant use of everolimus with darunavir/low-dose ritonavir is not recommended. |
|
| ANTIPSYCHOTICS |
|||
| Quetiapine |
Not studied. Boosted darunavir is expected to increase plasma concentrations of these antipsychotics (CYP3A inhibition). |
Concomitant use of darunavir/low-dose ritonavir with quetiapine is contraindicated, as it may lead to increased quetiapine-related toxicity. Increased quetiapine concentration may lead to coma. |
|
| Perphenazine Risperidone Thioridazine Lurasidone Pimozide Sertindole |
Not studied. Darunavir may increase plasma concentrations of these antipsychotics (inhibition of CYP3A, CYP2D6 and/or P-gp). |
Dose reduction of these agents may be necessary when used concomitantly with darunavir and low-dose ritonavir. Concomitant use of darunavir/low-dose ritonavir with lurasidone, pimozide or sertindole is contraindicated (see section "Contraindications"). |
|
| BETA-BLOCKERS |
|||
| Carvedilol Metoprolol Timolol |
Not studied. Darunavir may increase plasma concentrations of these beta-blockers (CYP2D6 inhibition). |
Clinical monitoring is recommended when these agents are used concomitantly with darunavir and low-dose ritonavir. Consider reducing the dose of the beta-blocker. |
|
| CALCIUM CHANNEL BLOCKERS |
|||
| Amlodipine Diltiazem Felodipine Nicardipine Nifedipine Verapamil |
Not studied. Darunavir with low-dose ritonavir is expected to increase concentrations of calcium channel antagonists (inhibition of CYP3A and/or CYP2D6). |
Clinical monitoring for therapeutic and adverse effects is recommended when these agents are used concomitantly with darunavir and low-dose ritonavir. |
|
| CORTICOSTEROIDS |
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| Corticosteroids primarily metabolized by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone) |
Fluticasone: in clinical studies, when 100 mg ritonavir capsules twice daily and 50 mcg intranasal fluticasone propionate (4 times daily) were used concomitantly for 7 days in healthy volunteers, fluticasone propionate plasma concentrations significantly increased, while endogenous cortisol levels decreased by up to 86 % (90 % CI 82–89 %). A greater effect may be expected with inhaled fluticasone. Systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, have been reported in patients receiving ritonavir and inhaled or intranasal fluticasone propionate. The effect of high systemic fluticasone concentrations on ritonavir plasma levels is unknown. Other corticosteroids: interaction not studied. Plasma concentrations of these agents may increase when used concomitantly with darunavir/low-dose ritonavir, potentially leading to reduced serum cortisol levels. |
Concomitant use of darunavir/low-dose ritonavir and corticosteroids metabolized by CYP3A (e.g., fluticasone propionate or other inhaled or intranasal corticosteroids) may increase the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression. Concomitant use of darunavir/low-dose ritonavir and corticosteroids metabolized by CYP3A is not recommended unless the expected benefit outweighs the potential risk; in such cases, monitoring for systemic corticosteroid effects is recommended. Consider using alternative corticosteroids less dependent on CYP3A metabolism, especially for long-term use, such as intranasal or inhaled beclomethasone. |
|
| Dexamethasone (systemic use) |
Not studied. Dexamethasone may reduce darunavir plasma concentrations (CYP3A induction). |
Use darunavir/ritonavir combination with dexamethasone for systemic use with caution. |
|
| ENDOTHELIN RECEPTOR ANTAGONISTS |
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| Bosentan |
Not studied. Concomitant use of bosentan with darunavir/ritonavir may increase bosentan plasma levels. Bosentan is expected to reduce plasma concentrations of darunavir and/or its pharmacoenhancer (CYP3A induction). |
Monitor for bosentan tolerability when used concomitantly with darunavir/ritonavir combination. |
|
| DIRECT-ACTING ANTIVIRALS (HEPATITIS C VIRUS (HCV)) |
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| NS3-4A inhibitors |
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| Elbasvir/ grazoprevir |
Darunavir/low-dose ritonavir may increase grazoprevir concentrations (inhibition of CYP3A and OATP1B). |
Concomitant use of darunavir/low-dose ritonavir and elbasvir/grazoprevir is contraindicated (see section "Contraindications"). |
|
| Glecaprevir/pibrentasvir |
Theoretically, boosted darunavir may increase effects of glecaprevir and pibrentasvir (inhibition of P-gp, BCRP and/or OATP1B1/3). |
Concomitant use of boosted darunavir with glecaprevir/pibrentasvir is not recommended. |
|
| HERBAL PRODUCTS |
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| St. John's wort (Hypericum perforatum) |
Not studied. St. John's wort is expected to reduce darunavir and ritonavir plasma concentrations (induction of cytochrome CYP450 enzymes). |
Darunavir with low-dose ritonavir should not be used concomitantly with medicinal products containing St. John's wort (Hypericum perforatum) (see section "Contraindications"). If a patient is already taking St. John's wort, its use should be discontinued and, if possible, viral load should be monitored. Darunavir (and ritonavir distribution) plasma concentrations may increase upon discontinuation of St. John's wort. The inductive effect may last at least 2 weeks after stopping St. John's wort. |
|
| HMG-COA REDUCTASE INHIBITORS |
|||
| Lovastatin Simvastatin |
Not studied. Lovastatin and simvastatin may have markedly increased plasma concentrations when used concomitantly with darunavir/ritonavir (CYP3A inhibition). |
Increased concentrations of lovastatin and simvastatin may cause myopathy, including rhabdomyolysis. Therefore, concomitant use of darunavir/ritonavir combination with lovastatin and simvastatin is contraindicated (see section "Contraindications"). |
|
| Atorvastatin 10 mg once daily |
atorvastatin AUC ↑ 3–4 fold atorvastatin Cmin ↑ ≈ 5.5–10 fold atorvastatin Cmax ↑ ≈ 2 fold # darunavir/ritonavir |
If atorvastatin and darunavir/ritonavir use is necessary, a starting dose of atorvastatin 10 mg once daily is recommended. Gradual dose escalation of atorvastatin should be based on clinical response. |
|
| Pravastatin 40 mg single dose |
pravastatin AUC ↑ 81 % ¶ pravastatin Cmin N/A pravastatin Cmax ↑ 63 % ¶ Five-fold increase observed in a limited subgroup of patients. |
If concomitant use of pravastatin and darunavir/ritonavir is necessary, the lowest possible starting dose of pravastatin is recommended, with gradual dose escalation to achieve desired clinical effect, with concurrent safety monitoring. |
|
| Rosuvastatin 10 mg once daily |
rosuvastatin AUC ↑ 48 % ║ rosuvastatin Cmax ↑ 144 % ║ ║ According to published data on darunavir/ritonavir. |
If concomitant use of rosuvastatin and darunavir/ritonavir is necessary, the lowest possible starting dose of rosuvastatin is recommended, with gradual dose escalation to achieve desired clinical effect, with concurrent safety monitoring. |
|
| OTHER LIPID-LOWERING AGENTS |
|||
| Lomitapide |
Not studied. Theoretically, boosted darunavir may increase lomitapide effects when used concomitantly (CYP3A inhibition). |
Concomitant use is contraindicated (see section "Contraindications"). |
|
| H2 RECEPTOR ANTAGONISTS |
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| Ranitidine 150 mg twice daily |
# darunavir AUC ↔ # darunavir Cmin ↔ # darunavir Cmax ↔ |
Darunavir/ritonavir may be used concomitantly with H2 receptor antagonists without dose adjustment. |
|
| IMMUNOSUPPRESSANTS |
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| Cyclosporine Sirolimus Tacrolimus Everolimus |
Not studied. Concentrations of these immunosuppressants will increase when used concomitantly with darunavir/ritonavir combination (CYP3A inhibition). |
Therapeutic effect monitoring of immunosuppressants is recommended when used concomitantly. Concomitant use of everolimus and darunavir with low-dose ritonavir is not recommended. |
|
| INHALED BETA-AGONISTS |
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| Salmeterol |
Not studied. Concomitant use of salmeterol with darunavir/ritonavir combination may increase salmeterol plasma concentrations. |
Concomitant use of darunavir/ritonavir and salmeterol is not recommended, as it may lead to adverse cardiovascular reactions, including QT prolongation, palpitations, and sinus tachycardia. |
|
| NARCOTIC ANALGESICS/OPIOID DEPENDENCE TREATMENT |
|||
| Methadone individual dose ranging from 55 to 150 mg once daily |
R(–) methadone AUC ↓ 16 % R(–) methadone Cmin ↓ 15 % R(–) methadone Cmax ↓ 24 % |
No need to reduce methadone dose at initiation of therapy with concomitant darunavir/ritonavir. However, dose increase of methadone may be necessary during prolonged concomitant use due to ritonavir-induced metabolism induction. Therefore, clinical monitoring is recommended, as maintenance therapy may require dose adjustments for some patients. |
|
| Buprenorphine/ naloxone 8/2 mg – 16/4 mg once daily |
buprenorphine AUC ↓ 11 % buprenorphine Cmin ↔ buprenorphine Cmax ↓ 8 % norbuprenorphine AUC ↑ 46 % norbuprenorphine Cmin ↑ 71 % norbuprenorphine Cmax ↑ 36 % naloxone AUC ↔ naloxone Cmin N/A naloxone Cmax ↔ |
The clinical significance of increased pharmacokinetic parameters of norbuprenorphine has not been established. Dose adjustment is not required when used concomitantly with darunavir/ritonavir, but clinical monitoring for signs of opioid intoxication is recommended. |
|
| Fentanyl Oxycodone Tramadol |
Theoretically, boosted darunavir may increase plasma concentrations of these analgesics (inhibition of CYP2D6 and/or CYP3A). |
Clinical monitoring is recommended when boosted darunavir is used concomitantly with these analgesics. |
|
| ESTROGEN-CONTAINING CONTRACEPTIVES |
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| Drospirenone Ethinylestradiol (3 mg/0.02 mg once daily) Ethinylestradiol Norethindrone 35 mcg/1 mg once daily |
Not studied with darunavir/ritonavir. ethinylestradiol AUC ↓ 44 % β ethinylestradiol Cmin ↓ 62 % β ethinylestradiol Cmax ↓ 32 % β norethindrone AUC ↓ 14 % β norethindrone Cmin ↓ 30 % β norethindrone Cmax ↔ β β with darunavir/ritonavir |
Clinical monitoring is recommended when darunavir is used with drospirenone-containing contraceptives due to risk of hyperkalemia. Alternative or additional contraceptive measures are recommended when using estrogen-containing contraceptives concomitantly with darunavir/ritonavir. Patients receiving estrogens as hormone replacement therapy should be under clinical monitoring for signs of estrogen deficiency. |
|
| OPIOID RECEPTOR ANTAGONISTS |
|||
| Naloxegol |
Not studied. |
Concomitant use of boosted darunavir and naloxegol is contraindicated. |
|
| PHOSPHODIESTERASE-5 INHIBITORS |
|||
| For erectile dysfunction Avanafil Sildenafil Tadalafil Vardenafil |
In interaction studies,# comparable sildenafil concentrations were observed with 100 mg sildenafil alone and 25 mg sildenafil with darunavir/ritonavir combination. |
Use of avanafil with darunavir and low-dose ritonavir is contraindicated (see section "Contraindications"). Concomitant use of other phosphodiesterase-5 inhibitors with darunavir/ritonavir should be used with caution. If concomitant use of darunavir/ritonavir with sildenafil, vardenafil or tadalafil is indicated, the recommended single dose is no more than 25 mg sildenafil every 48 hours, 2.5 mg vardenafil every 72 hours or 10 mg tadalafil every 72 hours. |
|
| For pulmonary arterial hypertension Sildenafil Tadalafil |
Not studied. Concomitant use of sildenafil or tadalafil for pulmonary arterial hypertension with darunavir/low-dose ritonavir may increase plasma levels of sildenafil or tadalafil (CYP3A inhibition). |
Safe and effective dose of sildenafil for pulmonary arterial hypertension with concomitant darunavir/ritonavir has not been established. There is an increased risk of sildenafil-related adverse reactions (including visual disturbances, arterial hypotension, prolonged erection and syncope). Therefore, concomitant use of sildenafil for pulmonary arterial hypertension with darunavir/ritonavir is contraindicated (see section "Contraindications"). Concomitant use of tadalafil for pulmonary arterial hypertension with darunavir/ritonavir is not recommended. |
|
| PROTON PUMP INHIBITORS |
|||
| Omeprazole 20 mg once daily |
# darunavir AUC ↔ # darunavir Cmin ↔ # darunavir Cmax ↔ |
Darunavir/ritonavir may be used concomitantly with proton pump inhibitors without dose adjustment. |
|
| SEDATIVES/HYPNOTICS |
|||
| Buspirone Clorazepate Diazepam Estazolam Flurazepam Midazolam (parenteral) Zolpidem Midazolam (oral) Triazolam |
Not studied. Sedatives/hypnotics are primarily metabolized by CYP3A. Concomitant use with darunavir/ritonavir may significantly increase concentrations of these agents. If parenteral midazolam is administered concomitantly with darunavir and low-dose ritonavir, it may lead to a significant increase in plasma concentration of this benzodiazepine. Data from concomitant use of parenteral midazolam with other protease inhibitors indicate a possible 3–4-fold increase in midazolam plasma levels. |
Clinical monitoring is recommended when darunavir is used concomitantly with these agents; consider using lower doses of sedatives/hypnotics. If parenteral midazolam is administered concomitantly with darunavir and low-dose ritonavir, it should be done in an intensive care unit (ICU) or similar setting ensuring close clinical monitoring and appropriate medical treatment in case of respiratory depression and/or prolonged sedation. Dose adjustment of midazolam should be considered, especially if more than one dose of midazolam is administered. Use of darunavir with low-dose ritonavir with triazolam or oral midazolam is contraindicated (see section "Contraindications"). |
|
| PREMATURE EJACULATION TREATMENT AGENTS |
|||
| Dapoxetine |
Not studied. |
Concomitant use of boosted darunavir with dapoxetine is contraindicated. |
|
| UROLOGICAL AGENTS |
|||
| Fesoterodine Solifenacin |
Not studied. |
Use with caution. Monitor for adverse reactions of fesoterodine or solifenacin; dose reduction of fesoterodine or solifenacin may be necessary. |
|
Studies were conducted with darunavir doses lower than recommended or with a different dosing regimen (see section "Posology and method of administration").
† The safety and efficacy of darunavir/100 mg ritonavir with any other protease inhibitors (e.g., (fos)amprenavir, nelfinavir, and tipranavir) in HIV-infected patients have not been established. According to current treatment guidelines, dual therapy with protease inhibitors is not recommended.
Special precautions for use
Regular assessment of virological response is recommended. If a decrease or loss of virological response occurs, resistance testing should be performed.
The medicinal product Danavir must be used only in combination with low-dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products (see section "Pharmacokinetics"). Therefore, the prescribing information for ritonavir should be consulted prior to initiating therapy.
Increasing the dose of ritonavir above that recommended in the section "Dosage and administration" results in only a minor increase in darunavir concentrations. Changing the dose of ritonavir is not recommended.
Darunavir is predominantly bound to α1-acid glycoprotein. This protein binding is concentration-dependent with saturable characteristics. Therefore, displacement by other medicinal products with higher affinity for binding to α1-acid glycoprotein cannot be excluded (see section "Interaction with other medicinal products and other forms of interaction").
Previously treated patients – once-daily dosing regimen
The medicinal product Danavir in combination with cobicistat or low-dose ritonavir once daily must not be used in patients with one or more darunavir resistance-associated mutations (DRV-RAMs) or with HIV-1 RNA ≥ 100,000 copies/ml or CD4+ count < 100 cells×10⁶/l (see section "Dosage and administration"). Combinations with an optimized background regimen (OBR) other than ≥ 2 NRTIs have not been studied in this patient population. Limited data are available in patients infected with HIV-1 non-group M subtypes other than group B (see section "Pharmacological properties. Pharmacodynamics").
Children
Danavir is not recommended for use in children under 3 years of age or with body weight less than 15 kg. Danavir 600 mg tablets should not be used in children with body weight less than 40 kg.
Pregnancy
The medicinal product Danavir may be used during pregnancy only if the expected benefit outweighs the potential risk. Caution should be exercised when administering Danavir to pregnant women in combination with other medicinal products that may reduce darunavir concentrations (see sections "Pharmacokinetics" and "Interaction with other medicinal products and other forms of interaction").
Elderly patients
Information on the use of Danavir in patients aged 65 years and older is limited; therefore, caution should be exercised when administering this medicinal product to such patients, as they more frequently have hepatic dysfunction and are more likely to have concomitant diseases or receive concomitant therapy (see sections "Pharmacokinetics" and "Interaction with other medicinal products and other forms of interaction").
Severe skin reactions
During clinical trials (N = 3063), severe cases of rash accompanied by fever and/or elevated liver transaminases were reported in 0.4% of patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson syndrome were observed rarely (< 0.1%). Cases of toxic epidermal necrolysis and acute generalized exanthematous pustulosis (< 0.01%) have been reported during the post-marketing period. If severe skin reactions develop, Danavir/ritonavir should be discontinued immediately. Such reactions may include, but are not limited to: severe rash or rash accompanied by fever, malaise, fatigue, muscle pain, joint pain, blistering, mucosal lesions in the oral cavity, conjunctivitis, hepatitis, and/or eosinophilia.
In previously treated patients, rash occurred more frequently with darunavir + raltegravir regimens compared to darunavir without raltegravir or raltegravir without darunavir (see section "Adverse reactions").
Darunavir contains a sulfonamide group. Danavir should be used with caution in patients with known hypersensitivity to sulfonamides.
Hepatotoxicity
Cases of drug-induced hepatitis (acute hepatitis, cytolytic hepatitis) have been reported during darunavir treatment. During clinical trials, hepatitis was observed in 0.5% of patients receiving combination antiretroviral therapy with darunavir/ritonavir. Patients with pre-existing hepatic dysfunction, including chronic hepatitis B and C, have an increased risk of hepatic reactions, including severe and potentially life-threatening adverse reactions. In case of concomitant antiviral therapy for hepatitis B and C, appropriate information should be obtained from the prescribing information for these medicinal products.
Appropriate laboratory tests should be performed before initiating treatment with Danavir/ritonavir, and patients should be monitored during therapy with Danavir. Monitoring of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels is recommended in patients with chronic hepatitis, cirrhosis, or those with elevated transaminase levels prior to treatment initiation, especially during the first months of Danavir therapy combined with low-dose ritonavir.
If new or worsening hepatic abnormalities occur (including clinically significant elevations in liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, hepatic tenderness, hepatomegaly) in patients receiving Danavir/ritonavir combination therapy, consideration should be given to interrupting or discontinuing treatment.
Patients with concomitant diseases
Patients with hepatic impairment
The safety and efficacy of darunavir have not been established in patients with severe hepatic impairment; therefore, Danavir is contraindicated in patients with severe hepatic insufficiency. Due to increased plasma concentration of free darunavir fraction, Danavir should be used with caution in patients with mild to moderate hepatic impairment.
Patients with renal impairment
There are no specific warnings or need for dose adjustment in patients with renal impairment. Darunavir and ritonavir are highly bound to plasma proteins; therefore, hemodialysis or peritoneal dialysis play a negligible role in the elimination of these drugs from the body. Dose adjustment is not necessary in patients with renal impairment.
Patients with haemophilia
There are data on increased bleeding, including spontaneous skin haematomas and haemarthrosis, in patients with haemophilia A and B during treatment with protease inhibitors. Some of these patients were receiving factor VIII. In more than half of the reported cases, treatment with protease inhibitors was continued uninterrupted or resumed after a temporary interruption. An association between protease inhibitor therapy and increased bleeding in haemophilia patients has been suggested, although the mechanism of this association has not been established. Haemophilia patients should be informed about the possibility of increased bleeding.
Body weight and metabolic parameters
During antiretroviral therapy, increases in body weight and levels of lipids and glucose in blood may occur. These changes may be partly related to disease control and lifestyle. In some cases, elevated lipid levels have been linked to treatment, while sufficient evidence linking weight gain to treatment is lacking. Guidelines for HIV infection management should be followed regarding monitoring of blood lipid and glucose levels. Lipid metabolism disorders should be managed according to clinical practice.
Osteonecrosis
The aetiology is believed to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, increased body mass index); cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiviral therapy. Patients should be advised to seek medical consultation if they experience joint pain, stiffness, or difficulty in movement.
Immune Reconstitution Inflammatory Syndrome (IRIS)
In HIV-infected patients with severe immunodeficiency at the initiation of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic infections may occur, leading to serious clinical complications or worsening of symptoms. Such reactions are usually observed within the first weeks or months of cART. Examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jirovecii pneumonia (previously known as Pneumocystis carinii pneumonia). The severity of any inflammatory condition should be assessed and appropriate therapy initiated. In clinical trials, reactivation of herpes simplex and herpes zoster has also been observed during concomitant use of darunavir/low-dose ritonavir.
Development of autoimmune disorders (e.g., Graves' disease, autoimmune hepatitis) has also been reported in association with immune reconstitution; however, the onset of these disorders is more variable and may occur even several months after initiation of antiretroviral therapy (see section "Adverse reactions").
Interaction with medicinal products
Some drug interaction studies were conducted with lower doses of darunavir than recommended; therefore, the effects of concomitant use of medicinal products may be underestimated, and clinical monitoring of safety is warranted. For complete information on interactions with other medicinal products, see section "Interaction with other medicinal products and other forms of interaction".
Efavirenz in combination with boosted darunavir once daily may result in subtherapeutic darunavir Cmin levels. If efavirenz is required in combination with Danavir, a dosage of Danavir/ritonavir 600/100 mg twice daily should be prescribed (see section "Interaction with other medicinal products and other forms of interaction").
Life-threatening interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-gp (see section "Interaction with other medicinal products and other forms of interaction").
Danavir 600 mg tablets contain the colouring agent sunset yellow FCF (E 110), which may cause allergic reactions.
Use during pregnancy or breastfeeding
Pregnancy
When deciding on the use of antiretroviral agents for the treatment of HIV infection in pregnant women and to reduce the risk of HIV transmission to the newborn, data from animal studies and clinical experience in pregnant women should be considered.
Well-controlled studies on pregnancy outcomes with darunavir in pregnant women have not been conducted. Animal studies did not reveal any direct adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. The combination Danavir/low-dose ritonavir may be prescribed to pregnant women only if the expected benefit to the mother outweighs the potential risk to the fetus.
Prospective pregnancy data from the Antiretroviral Pregnancy Registry are insufficient to adequately assess the risk of congenital anomalies or miscarriage. Available limited data do not show a statistically significant difference in the overall risk of major congenital malformations with darunavir compared to the background rate of major congenital malformations.
Breastfeeding
It is unknown whether darunavir is excreted in human breast milk. Animal studies in rats showed that the drug passes into milk and at high doses (1000 mg/kg/day) caused toxicity in offspring.
Given the potential for adverse reactions in breastfed infants, women should be advised not to breastfeed while receiving Danavir. To prevent HIV transmission to infants, women living with HIV are not recommended to breastfeed.
Fertility
There are no data on the effect of darunavir on human fertility. In rat studies, no effects on mating or fertility were observed.
Ability to influence the speed of reactions when driving or operating machinery
Danavir/ritonavir combination therapy has no effect or only a negligible effect on the ability to drive or operate machinery. However, dizziness has been reported in some patients receiving treatment regimens containing darunavir with low-dose ritonavir; therefore, this should be taken into account when assessing a patient's ability to drive or operate complex machinery (see section "Adverse reactions").
Method of Administration and Dosage
Treatment should be initiated by a physician experienced in the management of HIV infection. After starting therapy with Darunavir, patients should be advised not to change the dose or discontinue treatment without consulting their physician.
Darunavir must always be administered with a low dose of ritonavir to enhance its pharmacokinetic profile, and in combination with other antiretroviral agents. Prior to initiating therapy with Darunavir, the prescribing information for ritonavir should be reviewed.
Adult patients who have previously received antiretroviral therapy
The recommended dose of Darunavir is 600 mg twice daily in combination with 100 mg ritonavir twice daily, taken with food. Darunavir 600 mg tablets may be used for the 600 mg twice-daily dosing regimen.
For patients without HIV-1 protease mutations associated with resistance to darunavir (DRV-RAMs)\textsuperscript{1}, with plasma HIV-1 RNA levels < 100,000 copies/mL and CD4+ cell count ≥ 100 cells/10\textsuperscript{6}/L (see section "Indications"), a once-daily regimen of 800 mg Darunavir in combination with either 150 mg cobicistat or 100 mg ritonavir once daily with food may be considered (see prescribing information for Darunavir 400 mg tablets).
\textsuperscript{1} (DRV-RAMs): V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, and L89V.
Adult patients who have not previously received antiretroviral therapy
For dosing recommendations in antiretroviral treatment-naïve patients, refer to the prescribing information for Darunavir 400 mg tablets.
Children previously treated with antiretroviral therapy (aged 12 years and older with body weight ≥ 40 kg)
The recommended dose of Darunavir with low-dose ritonavir in children depends on body weight and should not exceed the recommended adult dose (600/100 mg twice daily or 800/100 mg once daily). The adult dose may be used in children weighing ≥ 40 kg. For dosing recommendations in children weighing less than 40 kg, refer to the prescribing information for darunavir 75 mg or 150 mg tablets.
For patients aged 12 to 17 years with body weight ≥ 40 kg, who have previously received antiretroviral therapy and who lack HIV-1 mutations conferring resistance to darunavir (DRV-RAMs)\textsuperscript{1}, with plasma HIV-1 RNA levels < 100,000 copies/mL and CD4+ cell count ≥ 100 cells/10\textsuperscript{6}/L, a once-daily regimen of 800 mg Darunavir in combination with 100 mg ritonavir once daily with food may be considered (see prescribing information for Darunavir 400 mg tablets).
\textsuperscript{1} (DRV-RAMs): V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, and L89V.
In children previously treated with antiretroviral therapy, HIV genotypic testing is recommended. If genotypic testing is not available, a once-daily regimen is recommended for children who have not previously received protease inhibitors, and a twice-daily regimen is recommended for children previously treated with HIV protease inhibitors.
Children who have not previously received antiretroviral therapy (aged 12 to 17 years with body weight ≥ 40 kg)
For dosing recommendations, refer to the prescribing information for Darunavir 400 mg tablets.
Missed Dose Instructions
If a dose of Darunavir and/or ritonavir is missed within 6 hours of the usual dosing time, the prescribed dose of Darunavir and ritonavir should be taken with food as soon as possible. If more than 6 hours have passed since the usual dosing time, the missed dose should not be taken; patients should continue with the next scheduled dose.
These recommendations are based on the 15-hour half-life of darunavir when co-administered with ritonavir and the recommended dosing interval of approximately 12 hours.
If vomiting occurs within 4 hours after administration of the medication, the patient should take the next dose of Darunavir with ritonavir with food as soon as possible. If vomiting occurs more than 4 hours after administration, the patient does not need to take another dose of Darunavir with ritonavir until the next scheduled dose.
Elderly Patients
Limited data are available in this patient population; therefore, Darunavir should be used with caution in elderly patients (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").
Patients with Hepatic Impairment
Darunavir is metabolized in the liver. Dose adjustment is not required 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. Pharmacokinetic data in patients with severe hepatic impairment are lacking. Severe hepatic impairment may lead to increased darunavir exposure and a worsened safety profile. Therefore, Darunavir is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use").
Patients with Renal Impairment
No dosage adjustment is required for patients with renal impairment.
Pregnancy and Postpartum Period
Dose adjustments of darunavir/ritonavir during pregnancy and the postpartum period are not required. Darunavir may be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see sections "Pharmacokinetics", "Special Warnings and Precautions for Use", and "Use in Pregnancy and Lactation").
Method of Administration
Darunavir with low-dose ritonavir should be taken with food or no later than 30 minutes after a meal. The type of food does not affect darunavir plasma concentrations.
Children
Applicable to children aged 12 years and older with body weight ≥ 40 kg.
Overdose
Information on acute overdose with darunavir in combination with low-dose ritonavir is limited. Healthy volunteers have received single doses of up to 3200 mg darunavir as an oral solution and up to 1600 mg darunavir tablets in combination with ritonavir, without observing significant adverse effects.
There is no specific antidote for darunavir overdose. In case of overdose, general supportive measures should be employed, including monitoring of vital signs and clinical status. Because darunavir is highly protein-bound, dialysis is unlikely to significantly enhance its elimination.
Adverse Reactions
The most commonly reported adverse reactions in clinical trials and spontaneous reports were diarrhea, nausea, rash, headache, and vomiting. The most common serious reactions include acute renal failure, myocardial infarction, immune reconstitution syndrome, thrombocytopenia, osteonecrosis, diarrhea, hepatitis, and pyrexia.
Moderate-intensity nausea was observed more frequently in treatment-naive patients.
The adverse reactions listed below are grouped by system organ class and frequency. Within each frequency class, adverse reactions are listed in order of decreasing severity. Frequency is defined as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), and not known (frequency cannot be estimated from available data).
Adverse reactions observed in clinical trials and during the post-marketing period
System organ class/frequency |
Adverse reactions |
| Infections and infestations |
|
| uncommon |
herpes |
| Blood and lymphatic system disorders |
|
| uncommon |
thrombocytopenia, neutropenia, anemia, leukopenia |
| rare |
increased eosinophil count |
| Immune system disorders |
|
| uncommon |
immune reconstitution syndrome, hypersensitivity (to the drug) |
| Endocrine disorders |
|
| uncommon |
hypothyroidism, increased blood thyrotropin level |
| Metabolism and nutrition disorders |
|
| common |
diabetes mellitus, hypertriglyceridemia, hypercholesterolemia, hyperlipidemia |
| uncommon |
gout, anorexia, decreased appetite, weight loss, weight gain, hyperglycemia, insulin resistance, decreased high-density lipoprotein levels, increased appetite, polydipsia, increased blood lactate dehydrogenase level |
| Psychiatric disorders |
|
| common |
insomnia |
| uncommon |
depression, disorientation, anxiety, sleep disorders, abnormal dreams, nightmares, decreased libido |
| rare |
confusion, emotional lability, restlessness |
| Nervous system disorders |
|
| common |
headache, peripheral neuropathy, dizziness |
| uncommon |
lethargy, paresthesia, hypesthesia, dysgeusia, attention disturbance, memory impairment, somnolence |
| rare |
syncope, convulsions, ageusia, sleep phase rhythm disorder |
| Eye disorders |
|
| uncommon |
conjunctival hyperemia, dry eyes |
| rare |
visual disturbances |
| Ear and labyrinth disorders |
|
| uncommon |
vertigo |
| Cardiac disorders |
|
| uncommon |
myocardial infarction, angina pectoris, QT interval prolongation, tachycardia |
| rare |
acute myocardial infarction, sinus bradycardia, palpitations |
| Vascular disorders |
|
| uncommon |
arterial hypertension, flushing |
| Respiratory, thoracic and mediastinal disorders |
|
| uncommon |
dyspnea, cough, epistaxis, throat irritation |
| rare |
rhinorrhea |
| Gastrointestinal disorders |
|
| very common |
diarrhea |
| common |
vomiting, nausea, abdominal pain, increased blood amylase level, dyspepsia, abdominal distension, flatulence |
| uncommon |
pancreatitis, gastritis, gastroesophageal reflux disease, aphthous stomatitis, vomiting urge, dry mouth, abdominal discomfort, constipation, increased lipase levels, belching, oral dysesthesia |
| rare |
stomatitis, vomiting blood, cheilitis, dry lips, coated tongue |
| Hepatobiliary disorders |
|
| common |
increased alanine aminotransferase level |
| uncommon |
hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased transaminase levels, increased aspartate aminotransferase level, increased blood bilirubin level, increased alkaline phosphatase level, increased gamma-glutamyltransferase level |
| Skin and subcutaneous tissue disorders |
|
| common |
rash (including macular, maculopapular, papular, erythematous and pruritic rashes), pruritus |
| uncommon |
angioedema, generalized rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, nail pigmentation |
| rare |
drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrheic dermatitis, skin lesions, xeroderma |
| not known |
toxic epidermal necrolysis, acute generalized exanthematous pustulosis |
| Musculoskeletal and connective tissue disorders |
|
| uncommon |
myalgia, osteonecrosis, muscle spasms, muscle weakness, arthralgia, limb pain, osteoporosis, increased blood creatine phosphokinase level |
| rare |
musculoskeletal stiffness, arthritis, joint stiffness |
| Renal and urinary disorders |
|
| uncommon |
acute renal failure, renal failure, nephrolithiasis, increased blood creatinine level, proteinuria, bilirubinuria, dysuria, nocturia, polyuria |
| rare |
decreased creatinine renal clearance, crystalline nephropathy§ |
| Reproductive system disorders |
|
| uncommon |
erectile dysfunction, gynecomastia |
| General disorders |
|
| common |
asthenia, fatigue |
| uncommon |
pyrexia, chest pain, peripheral edema, malaise, feeling of heat, irritability, pain |
| rare |
chills, abnormal sensations, xerosis |
§ Adverse reaction identified in the post-marketing period.
Description of some adverse reactions
Rash
Rashes observed during clinical trials were mild to moderate in severity, most commonly occurred within the first four weeks of treatment, and resolved upon discontinuation of therapy. For severe skin reactions, see section "Special warnings and precautions for use".
During the raltegravir clinical development program in treatment-experienced patients, rashes, regardless of cause, were observed more frequently in regimens containing darunavir + raltegravir compared to those containing darunavir without raltegravir or raltegravir without darunavir. Rash related to the study drug occurred at similar frequencies. The exposure-adjusted incidence rate (all causes) of rash was 10.9, 4.2, and 3.8 per 100 patient-years (PY), respectively; for drug-related rashes, the rates were 2.4, 1.1, and 2.3 per 100 PY, respectively. Rashes observed in clinical trials were mild to moderate in intensity and did not lead to discontinuation of therapy (see section "Special warnings and precautions for use").
Metabolic parameters
During antiretroviral therapy, increased levels of lipids and glucose in blood may occur (see section "Special warnings and precautions for use").
Musculoskeletal and connective tissue disorders
Cases of elevated creatine phosphokinase, myalgia, myositis, and rarely rhabdomyolysis have been reported with the use of protease inhibitors, particularly when used in combination with NRTIs.
Cases of osteonecrosis have been observed, particularly in patients with recognized risk factors, advanced HIV disease, or long-term combined antiretroviral therapy. The frequency of these cases is unknown (see section "Special warnings and precautions for use").
Immune reconstitution inflammatory syndrome
In HIV-infected patients with severe immunodeficiency at the start of combination antiretroviral therapy, inflammatory reactions to asymptomatic or opportunistic infections may occur. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the time to onset of these disorders is more variable and can occur long after initiation of treatment (see section "Special warnings and precautions for use").
Bleeding in patients with haemophilia
Increased spontaneous bleeding has been reported in haemophilia patients receiving antiretroviral protease inhibitors (see section "Special warnings and precautions for use").
Children
Overall, the safety profile in children was similar to that in adults.
Other patient categories
Patients with chronic hepatitis B and C
Among patients receiving darunavir with ritonavir at a dose of 600/100 mg twice daily, some patients were co-infected with hepatitis B and C. In patients with chronic hepatitis, elevations in liver transaminases occurred more frequently than in patients without chronic viral hepatitis (see section "Special warnings and precautions for use").
Post-marketing experience
The following adverse reactions have been identified during post-marketing use of darunavir. Because these reactions are reported voluntarily and the population size is not well defined, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Redistribution/accumulation of body fat has been reported.
Rare cases of rhabdomyolysis (associated with concomitant use of HMG-CoA reductase inhibitors and darunavir/ritonavir) have been reported.
In addition, rare cases of toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and drug-induced eosinophilia with systemic symptoms (DRESS) have been reported.
Reporting of adverse reactions
Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.
Packaging. 60 tablets in a container; 1 container in a carton.
Prescription status. Prescription only.
Manufacturer
Hetero Labs Limited.
Manufacturer's address and location of business activity
Unit III, Formulation Plot No 22 – 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.