INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DARUNAVIR KRKA (Darunavir KRKA)

Composition:

Active substance: darunavir;

One film-coated tablet contains 600 mg of darunavir;

Excipients: microcrystalline cellulose; crospovidone, type A; hydroxypropylcellulose; colloidal anhydrous silicon dioxide; siliconized microcrystalline cellulose; magnesium stearate; film coating: film mixture (a mixture of polyvinyl alcohol, macrogol, titanium dioxide, talc); yellow iron oxide; red iron oxide.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: orange-brown, oval, biconvex, film-coated tablets with the engraving "S 2" on one side.

Pharmacotherapeutic group. Antiviral agents for systemic use. Protease inhibitors. ATC code J05A E10.

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 viral particles.

Antiviral activity in vitro

Darunavir is active against laboratory strains and clinical isolates of HIV-1, as well as laboratory strains of HIV-2 in acutely infected human T-cell lines, peripheral blood mononuclear cells, and 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 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 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 viruses was prolonged (>3 years). Selected viruses were unable to replicate in the presence of darunavir at concentrations exceeding 400 nM. Viruses selected under these conditions and showing reduced susceptibility to darunavir (range: 23–50-fold) harbored 2 to 4 amino acid substitutions in the protease gene. The reduced susceptibility to darunavir observed in viruses emerging during the selection process could not be fully explained by the presence of these protease mutations alone.

Antiretroviral therapy experience has shown that virological response to treatment with darunavir boosted by low-dose ritonavir decreases if, at baseline, three or more darunavir resistance-associated mutations (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V, and L89V) are present, or if such mutations develop during treatment.

Viruses isolated from patients who received darunavir/ritonavir 600/100 mg twice daily and experienced virological failure due to rebound viremia remained predominantly sensitive to tipranavir after treatment, despite being initially tipranavir-sensitive before treatment.

The lowest incidence of HIV resistance development was observed in treatment-naïve patients who were initiated on darunavir in combination with other antiretroviral agents.

Cross-resistance

Viruses resistant to most other protease inhibitors have been shown to remain sensitive to darunavir; no cross-resistance with other protease inhibitors has been observed.

Pharmacokinetics.

Darunavir exposure is higher in HIV-1-infected patients than in healthy volunteers. The increased darunavir exposure in HIV-1-infected patients compared to healthy volunteers can be explained by higher plasma concentrations of alpha-1-acid glycoprotein (AAG) in HIV-1-infected individuals, resulting in greater binding of darunavir to plasma AAG and thus increased plasma concentrations of darunavir.

Darunavir is primarily metabolized by CYP3A enzymes. Ritonavir inhibits CYP3A enzymes and thereby significantly increases darunavir plasma concentrations.

Absorption

After oral administration, darunavir is rapidly absorbed. The maximum plasma concentration (Cmax) 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 following oral administration is approximately 37%, increasing to 82% when co-administered with 100 mg ritonavir twice daily. The overall pharmacokinetic boosting effect of ritonavir results in approximately a 14-fold increase in systemic exposure to darunavir after a single 600 mg oral dose of darunavir co-administered with 100 mg ritonavir twice daily (see section "Clinical Use").

When administered under fasting conditions, the relative bioavailability of darunavir with low-dose ritonavir was 30% lower than when administered with food. Therefore, darunavir tablets should be taken with ritonavir and with food. The type of food does not affect darunavir exposure.

Distribution

Approximately 95% of darunavir is bound to plasma proteins, primarily to AAG.

After intravenous administration, the volume of distribution of darunavir was 88.1 ± 59.01 L (mean ± standard deviation (SD)), increasing to 131 ± 49.91 L (mean ± SD) when administered with 100 mg ritonavir twice daily.

Biotransformation

In vitro studies using human liver microsomes have shown that darunavir undergoes predominantly oxidative metabolism. Darunavir is extensively metabolized in the liver by the CYP system, almost exclusively by the CYP3A4 isoenzyme. After administration of 14C-darunavir, the majority of radioactivity in plasma following a single 400 mg dose of darunavir and 100 mg ritonavir was attributed to the parent drug. At least three oxidative metabolites of darunavir have been identified in humans; all metabolites showed at least 10-fold lower activity against wild-type HIV compared to darunavir itself.

Elimination

After a single 400/100 mg dose of 14C-darunavir co-administered with ritonavir, approximately 79.5% and 13.9% of the administered 14C-darunavir was recovered in feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal half-life of darunavir is approximately 15 hours when administered in combination with ritonavir.

Darunavir clearance after intravenous administration of darunavir alone (150 mg) was 32.8 L/hour, compared to 5.9 L/hour when co-administered with low-dose ritonavir.

Special patient populations

Children

Pharmacokinetics of darunavir in combination with ritonavir twice daily in children aged 6 to 17 years weighing ≥20 kg who had received prior antiretroviral therapy showed that administration of darunavir/ritonavir at body weight-adjusted doses resulted in exposure similar to that observed 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 children aged 3 to 6 years weighing 15–20 kg who had received prior antiretroviral therapy showed that administration of darunavir/ritonavir at body weight-adjusted doses resulted in exposure comparable to that 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 treatment-naïve children aged 12 to 18 years weighing ≥40 kg showed that administration of darunavir/ritonavir 800/100 mg once daily resulted in exposure similar to that in adults receiving darunavir/ritonavir 800/100 mg once daily. Therefore, the same once-daily regimen may be used for treating adolescents aged 12 to 18 years weighing >40 kg who have received prior antiretroviral therapy, provided they lack darunavir resistance-associated mutations (DRV-RAMs)*, have HIV-1 RNA plasma levels <100,000 copies/mL, and CD4+ ≥100 cells × 10⁶/L (see section "Dosage and Administration").

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, and L89V.

Pharmacokinetics of darunavir in combination with ritonavir once daily in children aged 3 to 6 years weighing 14 kg to <20 kg who had received prior antiretroviral therapy showed that administration of darunavir/ritonavir at body weight-adjusted doses resulted in exposure similar to that in adults receiving darunavir/ritonavir 800/100 mg once daily (see section "Dosage and Administration"). Additionally, once-daily dosing regimens of darunavir/ritonavir have been confirmed for children weighing ≥15 kg, whether treatment-naïve or previously treated, provided they lack darunavir resistance-associated mutations (DRV-RAMs)*, have HIV-1 RNA plasma levels <100,000 copies/mL, and CD4+ ≥100 cells × 10⁶/L (see section "Dosage and Administration").

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, and L89V.

Elderly patients

Population pharmacokinetic analysis in HIV-infected patients (n=12, age ≥65) showed that darunavir pharmacokinetics do not differ significantly across the age range of 18–75 years (see section "Clinical Use"). However, data in patients aged 65 years and older remain limited.

Gender

Slightly higher (16.8%) darunavir exposure was observed in HIV-infected women compared to men. This difference is not considered clinically significant.

Patients with renal impairment

Mass balance study results using 14C-darunavir in combination with ritonavir showed that approximately 7.7% of the administered darunavir dose was excreted unchanged in urine.

No significant differences in darunavir pharmacokinetics were observed in patients with moderate renal impairment (creatinine clearance 30–60 mL/min) (see sections "Clinical Use" and "Dosage and Administration").

Patients with hepatic impairment

Darunavir is primarily metabolized and eliminated by the liver. When darunavir was co-administered with ritonavir (600/100 mg) twice daily, total darunavir plasma concentrations in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment were similar to those in healthy volunteers.

However, the concentration of unbound (free) darunavir was approximately 55% higher (Child-Pugh class A) and 100% higher (Child-Pugh class B), respectively. The clinical significance of this increase is unknown; therefore, darunavir should be used with caution in these patients. The effect of severe hepatic impairment on darunavir pharmacokinetics has not been studied (see sections "Contraindications", "Clinical Use", and "Dosage and Administration").

Pregnancy and postpartum

Overall exposure to darunavir/ritonavir following 600/100 mg twice daily or 800/100 mg once daily as part of antiretroviral therapy was generally lower during pregnancy compared to the postpartum period. However, pharmacokinetic parameters of unbound (i.e., active) darunavir were less reduced during pregnancy compared to the postpartum period due to an increased unbound fraction of darunavir during pregnancy.

Clinical characteristics.

Indications.

Darunavir KRKA in combination with a low dose of ritonavir and other antiretroviral medicinal products is indicated for the treatment of patients infected with human immunodeficiency virus (HIV-1) (see section "Dosage and administration").

Darunavir KRKA, film-coated tablets, 600 mg, is indicated to provide the required dosing regimen:

• for treatment of HIV-1 infection in adult patients who have previously received antiretroviral therapy, including those who have received intensive antiretroviral treatment;
• for treatment of HIV-1 infection in children aged 12 years and older with body weight of at least 40 kg.

Initiation of treatment with Darunavir KRKA in combination with a low dose of ritonavir should be done with caution, taking into account each patient's treatment history and resistance mutation patterns associated with various drugs. Treatment decisions should be guided by results of genotypic or phenotypic testing, if available, and the patient's treatment history when using Darunavir KRKA (see sections "Pharmacodynamics", "Special precautions for use", and "Dosage and administration").

Contraindications.

Hypersensitivity to darunavir or to any of the excipients of the medicinal product.

Severe hepatic impairment (Child-Pugh class C).

Combination with rifampicin when used concomitantly with a low dose of ritonavir*.

Concomitant use with the combination lopinavir/ritonavir*.

Concomitant use with herbal products containing St. John’s wort (Hypericum perforatum)*.

Concomitant administration of darunavir with a low dose of ritonavir and medicinal products whose clearance is predominantly determined by the activity of the CYP3A4 isoenzyme, and for which 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 adult patients.

Medicinal products that may be affected by darunavir boosted with ritonavir

Darunavir/ritonavir are inhibitors of CYP3A, CYP2D6, and P-glycoprotein (P-gp). Concomitant administration of darunavir/ritonavir with medicinal products that are primarily metabolized by CYP3A and/or CYP2D6 or transported by P-gp may result in increased plasma concentrations of such drugs, potentially leading to enhanced or prolonged therapeutic effects and adverse reactions.

Concomitant administration of darunavir/ritonavir with medicinal products that are actively metabolized by CYP3A may lead to reduced plasma concentrations of these active metabolites, potentially resulting in loss of therapeutic efficacy (see Table 1). The combination of darunavir with a low dose of ritonavir should not be used concomitantly with medicinal products whose clearance is largely dependent on CYP3A isoenzymes and for which increased systemic exposure may cause serious and/or life-threatening adverse reactions (narrow therapeutic index) (see section "Contraindications").

The overall pharmacokinetic boosting effect of ritonavir results in approximately a 14-fold increase in systemic exposure to darunavir after a single oral dose of 600 mg darunavir co-administered with 100 mg ritonavir twice daily. Therefore, darunavir should only be administered with a low dose of ritonavir as a pharmacokinetic enhancer (see section "Pharmacokinetics").

Clinical studies using medicinal products metabolized by cytochromes CYP2C9, CYP2C19, and CYP2D6 have shown induction of CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity with darunavir/ritonavir, which may be attributed to the use of low-dose ritonavir. Concomitant use of darunavir and ritonavir with medicinal products primarily metabolized by CYP2D6 (e.g., flecainide, propafenone, metoprolol) may lead to increased plasma concentrations of these drugs, potentially increasing or prolonging their therapeutic effects and adverse reactions. Concomitant use of darunavir and ritonavir with medicinal products primarily metabolized by CYP2C9 (e.g., warfarin) or CYP2C19 (e.g., methadone) may lead to reduced systemic exposure to these drugs, potentially reducing 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 (e.g., paclitaxel, rosiglitazone, repaglinide) may lead to reduced systemic exposure to these drugs, potentially reducing or shortening their therapeutic effect.

Ritonavir inhibits transporter proteins P-gp, OATP1B1, and OATP1B3; therefore, concomitant administration with substrates of these transporters may lead to increased plasma concentrations of such substances (e.g., dabigatran etexilate, digoxin, statins, and bosentan; see Table 1).

Medicinal products that affect exposure to darunavir/ritonavir

Darunavir and ritonavir are metabolized by CYP3A enzymes. Medicinal products that induce CYP3A are expected to increase the clearance of darunavir and ritonavir, leading to reduced plasma concentrations of these compounds and subsequently of darunavir, resulting in loss of therapeutic effect and potential development of resistance (see sections "Contraindications" and "Special precautions for use"). Contraindicated CYP3A inducers include rifampicin, herbal products containing St. John’s wort extract, and lopinavir.

Concomitant administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may reduce the clearance of darunavir and ritonavir and lead to increased plasma concentrations of darunavir and ritonavir. Concomitant use with strong CYP3A4 inhibitors (e.g., indinavir, azole antifungals, particularly clotrimazole) is not recommended; these interactions are described in Table 1.

Table of interactions

Interactions of darunavir/ritonavir with antiretroviral and non-antiretroviral medicinal products are listed in Table 1. 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 (not determined – ND).

Some interaction studies (marked in the table with "#") were conducted using a lower dose of darunavir than recommended or using a different dosing regimen (see section "Dosage and administration"). Therefore, the effects of concomitant administration of medicinal products may be underestimated, and clinical monitoring of safety is advised.

The list of examples of drug interactions provided below is not exhaustive. Therefore, the summary of product characteristics for each medicinal product used concomitantly with darunavir should be consulted to obtain information on metabolism, interaction pathways, potential risks, and necessary actions required when used concomitantly.

Table 1

Interaction with other medicinal products and dosage recommendations

Medicinal product by treatment area	Interaction Change in mean geometric value (%)		Recommendations for concomitant use
ANTIRETROVIRAL AGENTS FOR HIV TREATMENT
Integrase strand transfer inhibitors
Dolutegravir	dolutegravir AUC ↓ 22 % dolutegravir C24 h ↓ 38 % dolutegravir Cmax ↓ 11 % darunavir ↔* * Based on comparative cross-study and historical pharmacokinetic data		Darunavir with low-dose ritonavir and dolutegravir can be used without dose adjustment.
Raltegravir	Some clinical studies have shown that raltegravir may lead to a minor decrease in darunavir plasma concentrations.		So far, the effect of raltegravir on darunavir plasma concentrations is not clinically significant. Darunavir with low-dose ritonavir and raltegravir can be used without dose adjustment.
Nucleoside reverse transcriptase inhibitors (NRTIs)
Didanosine 400 mg once daily	didanosine AUC ↓ 9 % didanosine Cmin ND didanosine Cmax ↓ 16 % darunavir AUC ↔ darunavir Cmin ↔ darunavir Cmax ↔		Darunavir with low-dose ritonavir and didanosine can be used without dose adjustment. Didanosine should be administered on an empty stomach: taken 1 hour before or 2 hours after taking darunavir with low-dose ritonavir with food.
Tenofovir disoproxil 245 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 transporter effect in renal tubules)		When co-administering darunavir with low-dose ritonavir in combination with tenofovir disoproxil, monitoring of kidney function is recommended, especially in patients with systemic or renal disease or in patients taking 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. Since elimination pathways differ for other NRTIs — zidovudine, emtricitabine, stavudine, lamivudine, which are predominantly renally excreted, and abacavir, which is not metabolized by CYP450 — no interaction with darunavir with low-dose ritonavir is expected.		Darunavir with low-dose ritonavir can be used with these NRTIs without dose adjustment.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
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 using darunavir with low-dose ritonavir in combination with efavirenz, monitoring for CNS toxicity related to increased efavirenz concentrations is recommended. Efavirenz in combination with darunavir/ritonavir at a dose of 800/100 mg once daily may result in subtherapeutic darunavir Cmin. If efavirenz must be used in combination with darunavir/ritonavir, a dosage of darunavir/ritonavir 600/100 mg twice daily should be prescribed (see section "Special precautions").
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 can 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 Cmax ↑ 47 % nevirapine Cmax ↑ 18 % #darunavir: concentration converged with previous data (↑ nevirapine due to CYP3A inhibition)		Darunavir with low-dose ritonavir can 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 and rilpivirine can be used without dose adjustment.
HIV protease inhibitors (PIs) – without additional low-dose ritonavir†
Atazanavir 300 mg once daily	atazanavir AUC ↔ atazanavir Cmin ↑ 52 % atazanavir Cmax ↓ 11 % #darunavir AUC ↔ #darunavir Cmin ↔ #darunavir Cmax ↔ Atazanavir: comparison atazanavir/ritonavir 300/100 mg once daily vs atazanavir 300 mg once daily in combination with darunavir/ritonavir 400/100 mg twice daily. Darunavir: comparison darunavir/ritonavir 400/100 mg twice daily vs darunavir/ritonavir 400/100 mg twice daily in combination with atazanavir 300 mg once daily.		Darunavir with low-dose ritonavir can be used with atazanavir without dose adjustment.
Indinavir 800 mg twice daily	indinavir AUC ↑ 23 % indinavir Cmin ↑ 125 % indinavir Cmax ↔ #darunavir AUC ↑ 24 % #darunavir Cmin ↑ 44 % #darunavir Cmax ↑ 11 % Indinavir: comparison indinavir/ritonavir 800/100 mg twice daily vs indinavir/darunavir/ritonavir 800/400/100 mg twice daily. Darunavir: comparison darunavir/ritonavir 400/100 mg twice daily vs darunavir/ritonavir 400/100 mg twice daily in combination with indinavir 800 mg twice daily.		When used in combination with darunavir with low-dose ritonavir, a reduction in indinavir dose from 800 mg twice daily to 600 mg twice daily may be necessary in case of intolerance.
Saquinavir 1000 mg twice daily	#darunavir AUC ↓ 26 % #darunavir Cmin ↓ 42 % #darunavir Cmax ↓ 17 % saquinavir AUC ↓ 6 % saquinavir Cmin ↓ 18 % saquinavir Cmax ↓ 6 % Saquinavir: comparison saquinavir/ritonavir 1000/100 mg twice daily vs saquinavir/darunavir/ritonavir 1000/400/100 mg twice daily. Darunavir: comparison darunavir/ritonavir 400/100 mg twice daily vs darunavir/ritonavir 400/100 mg in combination with saquinavir 1000 mg twice daily.		Concomitant use of darunavir with low-dose ritonavir and saquinavir is not recommended.
HIV PIs – with concomitant use of low-dose ritonavir †
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 % reduction in darunavir exposure (AUC), appropriate doses of the combination are not established. Therefore, concomitant use of darunavir with low-dose ritonavir and lopinavir/ritonavir combination is contraindicated (see section "Contraindications").
CCR5 ANTAGONIST
Maraviroc 150 mg twice daily	maraviroc AUC ↑ 305 % maraviroc Cmin ND maraviroc Cmax ↑ 129 % concentrations of darunavir and ritonavir matched previous data		The dose of maraviroc should be 150 mg twice daily when used concomitantly with darunavir with low-dose ritonavir.
α1-ADRENERGIC ANTAGONIST
Alfuzosin	Based on theoretical considerations, darunavir is expected to increase plasma concentrations of alfuzosin (CYP3A inhibition).		Concomitant use of darunavir with low-dose ritonavir and alfuzosin is contraindicated (see section "Contraindications").
ANESTHETIC
Alfentanil	Not studied. Alfentanil metabolism occurs via CYP3A enzymes, which may be inhibited by darunavir with low-dose ritonavir.		Concomitant use with darunavir with low-dose ritonavir may require a reduced alfentanil dose and monitoring for risk of prolonged or delayed respiratory depression.
ANTIANGINAL/ANTIARRHYTHMIC AGENTS
Disopyramide Flecainide Lidocaine (systemic) Mexiletine Propafenone Amiodarone Bepridil Dronedarone Ivabradine Quinidine Ranolazine	Not studied. Darunavir with low-dose ritonavir is expected to increase plasma concentrations of these antiarrhythmics (CYP3A and/or CYP2D6 inhibition).		Use of darunavir with low-dose ritonavir with antiarrhythmics is recommended with caution and, if possible, therapeutic drug monitoring of these agents. Concomitant use of darunavir with low-dose ritonavir with amiodarone, bepridil, dronedarone, ivabradine, quinidine or ranolazine is contraindicated (see section "Contraindications").
Digoxin 0.4 mg single dose	digoxin AUC ↑ 61 % digoxin Cmin ND digoxin Cmax ↑ 29 % (↑ digoxin due to possible P-gp inhibition)		Digoxin has a narrow therapeutic range; therefore, the lowest possible digoxin dose is recommended at the start of therapy when used concomitantly with darunavir/ritonavir combination. Digoxin dose should be titrated to achieve desired therapeutic effect while assessing overall clinical status.
ANTIBIOTICS
Clarithromycin 500 mg twice daily	clarithromycin AUC ↑ 57 % clarithromycin Cmin ↑ 174 % clarithromycin Cmax ↑ 26 % #darunavir AUC ↓ 13 % #darunavir Cmin ↑ 1 % #darunavir Cmax ↓ 17 % Concentration of 14-OH-clarithromycin was not detected when used in combination with darunavir/ritonavir (↑ clarithromycin due to CYP3A inhibition and possible P-gp inhibition).		Use of clarithromycin concomitantly with darunavir with low-dose ritonavir is recommended with caution. For patients with renal impairment, refer to clarithromycin prescribing information for recommended dosing.
ANTICOAGULANTS/ANTIPLATELETS
Apixaban Rivaroxaban	Not studied. Concomitant use of boosted darunavir with these anticoagulants may increase their concentrations (CYP3A and/or P-gp inhibition).		Use of boosted darunavir with a direct oral anticoagulant (DOAC) metabolized by CYP3A4 and transported by P-gp is not recommended, as it may lead to increased bleeding risk.
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/cobicistat 800 mg/150 mg single dose: dabigatran AUC ↑ 164 % dabigatran Cmax ↑ 164 % darunavir/cobicistat 800 mg/150 mg once daily: dabigatran AUC ↑ 88 % dabigatran Cmax ↑ 99 %		darunavir/ritonavir: Clinical monitoring and/or DOAC dose reduction should be considered when used concomitantly with darunavir/ritonavir, if the DOAC is transported by P-gp but not metabolized by CYP3A4, including dabigatran etexilate and edoxaban. darunavir/cobicistat: Clinical monitoring and dose reduction are required when used concomitantly with darunavir/cobicistat, if the 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 concentration (CYP3A and/or P-gp inhibition).		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 antiplatelets not affected by CYP inhibition or induction (e.g., prasugrel) should be used.
Warfarin	Not studied. Warfarin concentrations may change with concomitant use of darunavir with low-dose ritonavir.		INR monitoring is recommended when using warfarin in combination with darunavir with low-dose ritonavir.
ANTICONVULSANTS
Phenobarbital Phenytoin	Not studied. Phenobarbital and phenytoin are expected to reduce plasma concentrations of darunavir and its pharmacokinetic booster (CYP450 enzyme induction).		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 ↔		Dose adjustment of darunavir/ritonavir is not recommended. If combination of darunavir/ritonavir with carbamazepine is necessary, patients should be monitored for possible carbamazepine-related adverse reactions. Carbamazepine concentration should be monitored and dose titrated to achieve adequate response. Based on study results, carbamazepine dose may be reduced by 25–50 % when used with darunavir/ritonavir.
Clonazepam	Not studied. Concomitant use of boosted darunavir with clonazepam may increase clonazepam concentration (CYP3A inhibition).		Clinical monitoring is recommended when using boosted darunavir 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/ritonavir (low dose) may increase plasma concentrations of these antidepressants (CYP2D6 and/or CYP3A inhibition).		When using darunavir with low-dose ritonavir with antidepressants, dose titration of antidepressants is recommended based on clinical assessment of antidepressant response. Antidepressant response should be monitored in patients receiving stable doses of antidepressants who start treatment with darunavir with low-dose ritonavir. Clinical monitoring is recommended when using darunavir with low-dose ritonavir with these antidepressants; dose adjustment of antidepressants may be necessary.
ANTIEMETICS
Domperidone	Not studied.		Concomitant use of domperidone with boosted darunavir is contraindicated.
ANTIFUNGAL AGENTS
Voriconazole	Not studied. Ritonavir may reduce voriconazole plasma concentrations (CYP450 enzyme induction).		Voriconazole should not be used with darunavir with low-dose ritonavir, except when benefit-risk assessment justifies its use.
Fluconazole Isavuconazole Itraconazole Posaconazole Clotrimazole	Not studied. Darunavir may increase plasma concentrations of antifungals, and posaconazole, isavuconazole, itraconazole or fluconazole may increase darunavir concentration (CYP3A and/or P-gp inhibition). Not studied. Concomitant systemic use of clotrimazole and boosted darunavir may increase plasma concentrations of darunavir and/or clotrimazole. Darunavir AUC24h ↑ 33 % (based on population pharmacokinetic model).		Caution and clinical monitoring are recommended. When used concomitantly, daily dose of itraconazole should not exceed 200 mg.
GOUT TREATMENT AGENTS
Colchicine	Not studied. Concomitant use of colchicine and darunavir with low-dose ritonavir may increase colchicine exposure (CYP3A and/or P-gp inhibition).		In patients with normal liver or kidney function, colchicine dose should be reduced or a treatment break considered if darunavir with low-dose ritonavir is required. Concomitant use of darunavir with colchicine is contraindicated in patients with impaired kidney or liver 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, but due to increased lumefantrine exposure, this combination should be used with caution.
ANTIMYCOBACTERIAL AGENTS
Rifampicin Rifapentine	Not studied. Rifampicin and rifapentine are potent CYP3A inducers and may lead to significant reduction in concentrations of other protease inhibitors, resulting in virological failure and resistance development (CYP450 enzyme induction). Attempts to overcome reduced exposure by increasing doses of other protease inhibitors with low-dose ritonavir when using rifampicin have frequently resulted in liver reactions.		Concomitant use of darunavir with low-dose ritonavir and rifapentine is not recommended. Concomitant use of rifampicin with darunavir with low-dose ritonavir is contraindicated (see section "Contraindications").
Rifabutin 150 mg every other day	rifabutin AUC** ↑ 55 % rifabutin Cmin** ↑ ND rifabutin Cmax** ↔ darunavir AUC ↑ 53 % darunavir Cmin ↑ 68 % darunavir Cmax ↑ 39 % ** sum of active fraction of rifabutin (parent drug + metabolite 25-O-desacetyl) Interaction studies showed comparable systemic exposures of rifabutin when 300 mg rifabutin once daily alone vs 150 mg every other day in combination with darunavir/ritonavir (600/100 mg twice daily) was used, with a 10-fold increase in daily exposure of active metabolite 25-O-desacetylrifabutin. Additionally, AUC of sum of active rifabutin substances (unchanged parent compound + metabolite 25-O-desacetyl) increased 1.6-fold, while Cmax remained comparable. Data comparing with standard dose of 150 mg once daily are lacking. (rifabutin is an inducer and substrate of CYP3A enzymes). Interaction studies observed increased systemic exposure of darunavir when darunavir/100 mg ritonavir was used concomitantly with rifabutin (150 mg every other day).		Dose reduction of rifabutin by 75 % from usual 300 mg daily dose (to 150 mg rifabutin every other day) and increased monitoring for rifabutin-related adverse reactions are required for patients using darunavir with ritonavir combination. If safety issues arise, further extension of rifabutin dosing interval and/or monitoring of rifabutin levels should be considered. Official guidelines for appropriate tuberculosis treatment in HIV-infected patients should be considered. Based on safety data of darunavir/ritonavir, increased darunavir exposure with rifabutin does not require dose adjustment of darunavir/ritonavir. Based on pharmacokinetic modeling data, dose reduction by 75 % is also recommended for patients receiving rifabutin at doses other than 300 mg daily.
ANTINEOPLASTIC AGENTS
Dasatinib Nilotinib Vinblastine Vincristine Everolimus Irinotecan	Not studied. Darunavir is expected to increase plasma concentrations of these anticancer agents (CYP3A inhibition).		Concentrations of these drugs may increase when used concomitantly with darunavir with low-dose ritonavir, potentially increasing frequency of adverse reactions associated with these drugs. These anticancer agents should be prescribed with caution when used concomitantly with darunavir with low-dose ritonavir. Concomitant use of everolimus or irinotecan with darunavir with low-dose ritonavir is not recommended.
ANTIPSYCHOTICS/NEUROLEPTICS
Quetiapine	Not studied. Boosted darunavir is expected to increase plasma concentrations of these antipsychotics (CYP3A inhibition).		Concomitant use of darunavir with low-dose ritonavir and quetiapine is contraindicated, as it may cause increased quetiapine-dependent toxicity. Increased quetiapine concentration may lead to coma.
Perphenazine Risperidone Thioridazine Lurasidone Pimozide Sertindole	Not studied. Darunavir is expected to increase plasma concentrations of these antipsychotics (CYP3A, CYP2D6 and/or P-gp inhibition).		Dose reduction of these drugs may be necessary when used concomitantly with darunavir with low-dose ritonavir. Concomitant use of darunavir with low-dose ritonavir and pimozide or sertindole is contraindicated (see section "Contraindications").
BETA-BLOCKERS
Carvedilol Metoprolol Timolol	Not studied. Darunavir is expected to increase plasma concentrations of these beta-blockers (CYP2D6 inhibition).		Clinical monitoring is recommended when using darunavir with beta-blockers. Dose reduction of beta-blocker should be considered.
CALCIUM CHANNEL BLOCKERS
Amlodipine Diltiazem Felodipine Nicardipine Nifedipine Verapamil	Not studied. Darunavir with low-dose ritonavir is expected to increase plasma concentrations of calcium channel blockers (CYP3A and/or CYP2D6 inhibition).		Clinical monitoring for therapeutic and adverse effects is recommended when using these drugs concomitantly with darunavir with low-dose ritonavir.
CORTICOSTEROIDS
Corticosteroids predominantly 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 (four times daily) were used for 7 days in healthy volunteers, plasma concentrations of fluticasone propionate significantly increased, while endogenous cortisol levels decreased by approximately 86 % (90 % CI 82–89 %). A greater effect may be expected with inhaled fluticasone. Systemic effects of corticosteroids, including Cushing's syndrome and adrenal suppression, have been reported in patients receiving ritonavir and inhaled or intranasal fluticasone. The impact of high systemic fluticasone exposure on plasma ritonavir concentrations is unknown. Other corticosteroids: interaction not studied. Plasma concentrations of these drugs may increase when used concomitantly with darunavir with low-dose ritonavir, leading to reduced serum cortisol concentrations.		Concomitant use of darunavir with low-dose ritonavir and corticosteroids (any route of administration) metabolized by CYP3A may increase risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression. Concomitant use with corticosteroids metabolized by CYP3A is not recommended, except when potential benefit outweighs risk, and patients should be monitored for systemic corticosteroid effects. Alternative corticosteroids less dependent on CYP3A metabolism, such as beclomethasone, especially for long-term use, should be considered.
Dexamethasone (for systemic use)	Not studied. Dexamethasone may reduce darunavir plasma concentrations (CYP3A induction).		Systemic dexamethasine should be used with caution when used systemically with boosted darunavir.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan	Not studied. Concomitant systemic use of bosentan and darunavir with low-dose ritonavir may increase plasma concentrations of bosentan.		When used concomitantly with darunavir with low-dose ritonavir, patient tolerance to bosentan should be monitored.
DIRECT-ACTING ANTIVIRALS (HEPATITIS C VIRUS (HCV))
NS3-4A inhibitors
Elbasvir/grazoprevir	Darunavir with low-dose ritonavir may increase grazoprevir exposure (CYP3A and OATP1B inhibition).		Concomitant use of darunavir with low-dose ritonavir and elbasvir/grazoprevir is contraindicated (see section "Contraindications").
Glecaprevir/pibrentasvir	Based on theoretical considerations, boosted darunavir may increase effects of glecaprevir and pibrentasvir (P-gp, BCRP and/or OATP1B1/3 inhibition).		Concomitant use of boosted darunavir with glecaprevir/pibrentasvir is not recommended.
HERBAL PRODUCTS
St. John's wort (Hypericum perforatum)	Not studied. St. John's wort is expected to reduce plasma concentrations of darunavir and ritonavir (CYP450 induction).		Darunavir with low-dose ritonavir should not be used concomitantly with medicinal products containing St. John's wort (see section "Contraindications"). If a patient is already taking St. John's wort, its use should be discontinued and viral load should be checked if possible. Darunavir (and ritonavir) exposure may increase after discontinuation of St. John's wort. Induction effect may last at least 2 weeks after stopping St. John's wort.
HMG COA REDUCTASE INHIBITORS
Lovastatin Simvastatin	Not studied. Lovastatin and simvastatin are expected to have significantly higher plasma concentrations when used concomitantly with darunavir with low-dose ritonavir (CYP3A inhibition).		Increased concentrations of lovastatin and simvastatin may cause myopathy, including rhabdomyolysis. Therefore, concomitant use of darunavir with low-dose ritonavir and lovastatin and simvastatin is contraindicated (see section "Contraindications").
Atorvastatin 10 mg once daily	atorvastatin AUC ↑ 3–4 times atorvastatin Cmin ↑ ≈ 5.5–10 times atorvastatin Cmax ↑ ≈ 2 times #darunavir/ritonavir		If atorvastatin and darunavir with low-dose ritonavir are recommended, initial atorvastatin dose should be 10 mg once daily. Gradual dose increase of atorvastatin should be based on clinical response.
Pravastatin 40 mg, single dose	pravastatin AUC ↑ 81 %¶ pravastatin Cmin ND pravastatin Cmax ↑ 63 % ¶ in a limited subgroup of patients, 5-fold increase was observed		If pravastatin and darunavir with low-dose ritonavir are required, it is recommended to use the lowest possible initial pravastatin dose and titrate to achieve desired clinical effect, while considering safety.
Rosuvastatin 10 mg once daily	rosuvastatin AUC ↑ 48 %║ rosuvastatin Cmax ↑ 144 %║ ║ according to published data on darunavir/ritonavir		If rosuvastatin and darunavir with low-dose ritonavir are required, it is recommended to use the lowest possible initial rosuvastatin dose and titrate to achieve desired clinical effect, while considering safety.
OTHER LIPID-LOWERING AGENTS
Lomitapide	Not studied. Theoretically, boosted darunavir may increase lomitapide effect when used concomitantly (CYP3A inhibition).		Concomitant use is contraindicated (see section "Contraindications").
H2 RECEPTOR ANTAGONISTS
Ranitidine 150 mg twice daily	#darunavir AUC ↔ #darunavir Cmin ↔ #darunavir Cmax ↔		Darunavir with low-dose ritonavir can be used concomitantly with H2 receptor antagonists without dose adjustment.
IMMUNOSUPPRESSANTS
Cyclosporine Sirolimus Tacrolimus Everolimus	Not studied. Exposure to these immunosuppressants will increase when used concomitantly with darunavir with low-dose ritonavir (CYP3A inhibition).		Monitoring of immunosuppressant therapeutic effects is recommended when used concomitantly. Concomitant use of everolimus with darunavir with low-dose ritonavir is not recommended.
INHALED BETA-AGONISTS
Salmeterol	Not studied. Concomitant use of salmeterol and darunavir with low-dose ritonavir may increase plasma concentrations of salmeterol.		Concomitant use of salmeterol and darunavir with low-dose ritonavir is not recommended. This combination may increase risk of cardiovascular adverse reactions, including QT prolongation, palpitations, sinus tachycardia with salmeterol use.
NARCOTIC ANALGESICS/OPIONOID DEPENDENCE TREATMENT
Methadone individual dose 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 use of darunavir/ritonavir. However, methadone dose increase may be necessary with long-term concomitant use due to ritonavir metabolism induction. Therefore, clinical monitoring is recommended, as maintenance therapy may require dose adjustments for some patients.
Buprenorphine/naloxone 8 mg/2 mg – 16 mg/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 ND naloxone Cmax ↔		Clinical significance of increased norbuprenorphine pharmacokinetic parameters has not been established. When used concomitantly with darunavir/ritonavir, buprenorphine dose adjustment may not be necessary, but careful clinical monitoring for opioid intoxication symptoms is recommended.
Fentanyl Oxycodone Tramadol	Theoretically, boosted darunavir may increase plasma concentrations of these analgesics (CYP2D6 and/or CYP3A inhibition).		Clinical monitoring is recommended when using boosted darunavir with these analgesics.
ESTROGEN-CONTAINING CONTRACEPTIVES
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 using darunavir with drospirenone-containing products due to hyperkalemia risk. Alternative or additional contraceptive measures are recommended when estrogen-containing contraceptives are used concomitantly with darunavir with low-dose ritonavir. Patients receiving estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.
OPIOID RECEPTOR ANTAGONISTS
Naloxegol	Not studied.		Concomitant use of naloxegol with boosted darunavir is contraindicated.
PHOSPHODIESTERASE-5 INHIBITORS (PDE-5)
For erectile dysfunction Avanafil Sildenafil Tadalafil Vardenafil	In an interaction study# comparable systemic exposure of sildenafil was observed with single 100 mg sildenafil alone and with single 25 mg sildenafil dose co-administered with darunavir and low-dose ritonavir.		Concomitant use of avanafil with darunavir with low-dose ritonavir is contraindicated (see section "Contraindications"). Concomitant use of other PDE-5 inhibitors with darunavir with low-dose ritonavir for erectile dysfunction should be used with caution. If concomitant use of darunavir with low-dose ritonavir with sildenafil, vardenafil or tadalafil is indicated, recommended single dose of sildenafil should not exceed 25 mg every 48 hours, vardenafil 2.5 mg every 72 hours, tadalafil 10 mg every 72 hours.
For pulmonary arterial hypertension Sildenafil Tadalafil	Not studied. Concomitant use of sildenafil or tadalafil for pulmonary arterial hypertension with darunavir with low-dose ritonavir may increase plasma concentrations of sildenafil or tadalafil (CYP3A inhibition).		Safe and effective dose of sildenafil for pulmonary arterial hypertension with concomitant use of darunavir with low-dose 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 darunavir with low-dose ritonavir and sildenafil for pulmonary arterial hypertension is contraindicated (see section "Contraindications"). Concomitant use of tadalafil for pulmonary arterial hypertension with darunavir with low-dose ritonavir is not recommended.
PROTON PUMP INHIBITORS
Omeprazole 20 mg once daily	#darunavir AUC ↔ #darunavir Cmin ↔ #darunavir Cmax ↔		Darunavir with low-dose ritonavir can 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 extensively metabolized by CYP3A. Concomitant use with darunavir/ritonavir may significantly increase concentrations of these drugs. Concomitant use of parenteral midazolam with darunavir with low-dose ritonavir may significantly increase plasma concentration of this benzodiazepine. Data on concomitant use of parenteral midazolam with other protease inhibitors suggest a 3–4 fold increase in midazolam plasma concentration.		When using darunavir with these sedatives/hypnotics, clinical monitoring is recommended; dose adjustment of sedatives/hypnotics may be necessary. If parenteral midazolam is used with darunavir with low-dose ritonavir, it should be administered in an intensive care unit or similar setting to ensure close clinical monitoring and appropriate medical support in case of respiratory depression and/or prolonged sedation. Dose adjustment of midazolam should be considered, especially if more than a single dose is administered. Use of darunavir with low-dose ritonavir with triazolam or oral midazolam is contraindicated (see section "Contraindications").
AGENTS FOR PREMATURE EJACULATION TREATMENT
Dapoxetine		Not studied.		Concomitant use of dapoxetine with boosted darunavir 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 required.

Studies were conducted with darunavir doses lower than recommended or with a different dosing regimen (see section "Dosage and administration").

† The efficacy and safety of darunavir and 100 mg ritonavir with any other HIV protease inhibitors (e.g., with (fos)amprenavir and tipranavir) in HIV-infected patients have not been established. According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.

‡ The study was conducted with tenofovir disoproxil fumarate 300 mg once daily.

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.

Darunavir must always be administered orally with low-dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products (see section "Pharmacodynamics"). Therefore, the prescribing information for ritonavir should be consulted before initiating therapy.

Increasing the dose of ritonavir above the recommended dose results in only a modest increase in darunavir concentrations. Altering the dose of ritonavir is not recommended.

Darunavir is primarily bound to AAG (alpha-1-acid glycoprotein). This protein binding shows concentration-dependent saturation. Therefore, displacement by other medicinal products with higher affinity for binding to AAG cannot be excluded (see section "Interaction with other medicinal products and other forms of interaction").

Patients previously treated with antiretroviral therapy (once-daily dosing regimen)

Darunavir in combination with cobicistat or low-dose ritonavir, or another pharmacokinetic booster administered once daily, must not be used in patients previously treated with antiretroviral therapy who have one or more darunavir resistance-associated mutations (DRV-RAMs), or with HIV-1 RNA levels ≥100,000 copies/mL, or with 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 for patients infected with HIV-1 non-B genetic subtypes (see section "Pharmacodynamics").

Children

Darunavir is not recommended for use in children under 12 years of age and weighing < 40 kg (see section "Dosage and administration").

Pregnancy

Darunavir/ritonavir may be used during pregnancy only if the expected benefit outweighs the potential risk. Caution should be exercised when administering the medicinal product to pregnant women concurrently receiving other medicinal products that may reduce darunavir concentrations (see sections "Pharmacokinetics" and "Interaction with other medicinal products and other forms of interaction").

Elderly patients

Since information on the use of darunavir in patients aged 65 years and older is limited, darunavir should be prescribed with caution in these patients, as they are more likely to have impaired hepatic function, comorbid conditions, or receive concomitant medications (see sections "Pharmacokinetics" and "Interaction with other medicinal products and other forms of interaction").

Severe skin reactions

During clinical trials of darunavir/ritonavir (N = 3063), severe skin reactions associated with fever and/or elevated liver transaminases were reported in 0.4% of patients. DRESS syndrome (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 have been reported during the post-marketing period. If signs or symptoms of severe skin reactions develop, darunavir/ritonavir should be discontinued immediately. These may include (but are not limited to) severe rash or rash accompanied by fever, malaise, fatigue, muscle or joint pain, blisters, mucosal lesions in the oral cavity, conjunctivitis, hepatitis, and/or eosinophilia.

Skin rash occurred more frequently in previously antiretroviral-treated patients receiving darunavir/ritonavir in combination with raltegravir compared to darunavir/ritonavir without raltegravir or raltegravir without darunavir (see section "Adverse reactions").

Darunavir contains a sulfonamide group. Darunavir 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.

In clinical trials of darunavir/ritonavir (N = 3063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy (cART) with darunavir/ritonavir. Patients with pre-existing hepatic impairment, including active chronic hepatitis B or C, are at increased risk of developing liver disorders, including severe adverse reactions with potentially fatal outcomes. When concomitant antiviral therapy for hepatitis B or C is administered, appropriate information should be obtained from the prescribing information for those medicinal products.

Appropriate laboratory tests should be performed before initiating treatment with darunavir/ritonavir, and patients should be monitored throughout treatment.

Monitoring of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels is required in patients with chronic hepatitis, cirrhosis, or those with elevated transaminase levels prior to treatment initiation, especially during the first months of darunavir/ritonavir therapy.

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, liver tenderness, hepatomegaly) in patients receiving darunavir/ritonavir, interruption or discontinuation of therapy should be considered.

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, the medicinal product is contraindicated in patients with severe hepatic insufficiency. Due to increased plasma concentrations of free darunavir, darunavir 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 of darunavir/ritonavir in patients with renal impairment. Since darunavir and ritonavir are highly protein-bound, hemodialysis or peritoneal dialysis do not significantly contribute to their elimination from the body. Therefore, no specific warnings or dose adjustments are required for such patients.

Patients with hemophilia

There are reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia A and B receiving protease inhibitors. Some of these patients were receiving additional factor VIII. In more than half of the reported cases, treatment with protease inhibitors continued uninterrupted or was resumed after interruption. A causal relationship has been suggested, although the mechanism is not fully understood. Therefore, patients with hemophilia should be informed about the potential for increased bleeding.

Body weight and metabolic parameters

During antiretroviral therapy, increases in body weight and levels of blood lipids and glucose may occur. These changes may be partly related to improved disease control and lifestyle factors. In some cases, elevated lipid levels have been linked to treatment, but the relationship between weight gain and treatment is less well understood. Guidelines for the management of HIV infection should be followed regarding monitoring of blood lipid and glucose levels. Lipid abnormalities should be managed according to clinical practice.

Osteonecrosis

Although the etiology of osteonecrosis is multifactorial (including corticosteroid use, alcohol abuse, severe immunosuppression, increased body mass index), cases have been reported more frequently in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral 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 start of cART, an inflammatory response to asymptomatic or residual opportunistic infections may occur, leading to serious clinical complications or worsening of symptoms. Such reactions are typically observed within the first few weeks or months of cART initiation and may 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 and low-dose ritonavir.

Autoimmune disorders (e.g., Graves’ disease, autoimmune hepatitis) have also been reported in association with immune reconstitution; however, the onset of these conditions is more variable and may occur even several months after initiation of antiretroviral therapy (see section "Adverse reactions").

Interaction with medicinal products

Some interaction studies were conducted using lower doses of darunavir than recommended; therefore, the effects of concomitant administration may be underestimated. Clinical monitoring for safety is advised.

Efavirenz in combination with once-daily boosted darunavir may result in subtherapeutic darunavir trough concentrations (Cmin). If efavirenz must be used in combination with darunavir, darunavir/ritonavir should be administered at a dosage of 600/100 mg twice daily (see section "Interaction with other medicinal products and other forms of interaction"). Fatal and life-threatening interactions have been reported in patients receiving colchicine and strong inhibitors of CYP3A and P-gp (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding.

Pregnancy

When deciding on the use of antiretroviral agents for the treatment of HIV infection in pregnant women to reduce the risk of perinatal transmission, data from animal studies and clinical experience in pregnant women should be considered.

Well-controlled and adequate studies of darunavir use in pregnant women have not been conducted. Animal studies did not show direct harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

The combination of darunavir with low-dose ritonavir should be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Lactation

It is unknown whether darunavir is excreted in human breast milk. Animal studies have shown that darunavir is excreted in milk in high concentrations (1000 mg/kg/day) and causes toxicity in offspring. Considering the risk of adverse reactions in infants, women receiving darunavir CRKA should be instructed not to breastfeed. To prevent HIV transmission to infants, breastfeeding is not recommended for HIV-infected women.

Fertility

There are no data on the effect of darunavir on fertility in humans. In animal studies, no effects on mating or fertility were observed.

Ability to affect reaction rate when driving or operating machinery.

Darunavir in combination with ritonavir has no effect or 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 machinery (see section "Adverse reactions").

Method of administration and dosing.

Treatment should be prescribed by a physician experienced in the management of HIV infection. After initiation of darunavir therapy, patients should be advised that they must not change the dose, dosage form, or discontinue therapy without consulting their physician.

Dosing

Darunavir Krka medicinal product must always be taken orally with a low dose of ritonavir as a pharmacokinetic enhancer, and in combination with other antiretroviral agents. Therefore, depending on the circumstances, it may be necessary to review the prescribing information for ritonavir prior to initiating darunavir therapy.

This medicinal product is available only in tablet form; therefore, it should not be administered to patients unable to swallow whole tablets, such as young children. For treatment of such patients, availability of alternative dosage forms containing darunavir should be checked.

It is not possible to provide all dosing regimens of this medicinal product for children. The availability of other darunavir tablet strengths and dosage forms should be verified.

Adult patients previously treated with antiretroviral therapy

The recommended dose of darunavir is 600 mg twice daily in combination with 100 mg ritonavir twice daily, taken with food. Darunavir Krka, film-coated tablets, 600 mg, should be used for the 600 mg twice-daily dosing regimen.

Adult patients not previously treated with antiretroviral therapy

The recommended dosing regimen for patients who have not previously received antiretroviral therapy is provided in the prescribing information for Darunavir Krka medicinal product, film-coated tablets, 400 mg and 800 mg.

Children not previously treated with antiretroviral therapy (aged 12 to 17 years, body weight ≥ 40 kg)

Dosage of darunavir and ritonavir according to body weight for children is shown in Table 2.

Table 2

Dose of darunavir and ritonavir tablets recommended for children who have not previously received antiretroviral treatment (aged 12 to 17 years)
Body weight (kg)	Dose (once daily with food)
≥ 40 kg	800 mg darunavir/100 mg ritonavir once daily

Children previously treated with antiretroviral therapy (aged 12 to 17 years with body weight ≥ 40 kg)

The usual dose of darunavir is administered twice daily with ritonavir, taken with food.

A once-daily dosing regimen of darunavir with ritonavir taken with food may be used for treatment of patients who have previously received antiretroviral therapy and who do not have darunavir resistance-associated mutations (DRV-RAMs)*, have plasma HIV-1 RNA levels < 100,000 copies/mL, and have CD4+ cell counts ≥ 100 cells × 10⁶/L.

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, and L89V.

The body weight-based dose of darunavir and ritonavir for children is provided in Table 3.

The recommended dosing regimen of darunavir with low-dose ritonavir should not exceed the recommended adult dose (600 mg/100 mg twice daily or 800 mg/100 mg once daily).

Table 3

Dosage of darunavir and ritonavir tablets recommended for children aged 12 to 17 years who have previously received antiretroviral treatment
Body weight (kg)	Dosage (once daily with food)	Dosage (twice daily with food)
≥ 40 kg	800 mg darunavir/100 mg ritonavir once daily	600 mg darunavir/100 mg ritonavir twice daily

For children who have previously received antiretroviral treatment, HIV genotypic testing is recommended. However, in the absence of the possibility of such testing, the recommended dosing regimen of darunavir/ritonavir is once daily for patients who have not previously been treated with protease inhibitors, and twice daily for patients who have previously received treatment with protease inhibitors.

Missed dose instructions

If a dose of darunavir and/or ritonavir is missed within 6 hours of the usual administration time, patients should be instructed to take the prescribed dose of darunavir and ritonavir 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, and the patient should resume the regular dosing schedule.

These instructions are based on the 15-hour elimination half-life of darunavir when co-administered with ritonavir and the recommended dosing interval of approximately 12 hours.

If a patient vomits within 4 hours after taking the medication, the next dose of Darunavir KRKA with ritonavir should be taken as soon as possible with food. If vomiting occurs more than 4 hours after taking the medication, the patient does not need to take another dose of Darunavir KRKA with ritonavir until the next scheduled dose.

Special patient populations

Elderly patients

Limited information is available for this patient group; therefore, darunavir should be used with caution (see sections "Pharmacokinetics" and "Special instructions").

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. There are no pharmacokinetic data available for patients with severe hepatic impairment. Severe hepatic impairment may lead to increased darunavir concentrations and worsening of its safety profile. Therefore, darunavir should not be used in patients with severe hepatic impairment (Child-Pugh class C) (see sections "Pharmacokinetics", "Contraindications", and "Special instructions").

Patients with renal impairment

Dosage adjustment of darunavir/ritonavir is not required in patients with renal impairment (see sections "Pharmacokinetics" and "Special instructions").

Pregnancy and postpartum period

Dose adjustment of darunavir/ritonavir is not required during pregnancy and the postpartum period. Darunavir/ritonavir should not be used during pregnancy except when the potential benefit outweighs the potential risk (see sections "Pharmacokinetics", "Special instructions", and "Use in pregnancy or breastfeeding").

Method of administration

The medicinal product Darunavir KRKA with low-dose ritonavir should be taken no later than 30 minutes after a meal. The type of food does not affect darunavir plasma concentrations (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Special instructions").

Children

Darunavir/ritonavir should not be used in children with body weight <40 kg, as dosing has not been established in a sufficient number of patients in this category (see section "Pharmacodynamics"). Darunavir/ritonavir should not be used in children under 12 years of age for safety reasons (see section "Special instructions").

The body weight-based dosage of Darunavir KRKA and ritonavir is provided in Table 3.

Overdose

Information regarding experience with acute overdose of darunavir co-administered 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 as tablets in combination with ritonavir, without observing adverse symptomatic effects.

There is no specific antidote for darunavir overdose. In case of overdose with darunavir, general supportive measures should be implemented, including monitoring of vital physiological parameters and observation of the patient's clinical status.

Since darunavir is highly protein-bound, dialysis is unlikely to be effective in removing a significant amount of the active substance.

Adverse reactions

The most common adverse reactions are diarrhea, nausea, rash, headache, and vomiting. The most frequent serious reactions are acute renal failure, myocardial infarction, immune reconstitution syndrome, thrombocytopenia, osteonecrosis, diarrhea, hepatitis, and pyrexia. Moderate nausea was observed more frequently in treatment-naive patients.

List of adverse reactions (see Table 4)

Adverse reactions are grouped by system organ class and frequency. Within each frequency category, reactions are listed in order of decreasing severity. Frequency is defined according to the following criteria: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100); rare (≥ 1/10,000 and < 1/1000); frequency not known (cannot be estimated from available data).

Table 4

Adverse reactions observed in clinical trials with darunavir/ritonavir and in the post-marketing period

System organ/ frequency	Adverse reaction
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 inflammatory syndrome, hypersensitivity (to the drug)
Endocrine disorders
uncommon	hypothyroidism, increased blood thyrotropin levels
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 levels
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, hypoesthesia, dysgeusia, attention disturbance, memory impairment, somnolence
rare	syncope, convulsions, ageusia, sleep phase rhythm disorder
Eye disorders
uncommon	conjunctival hyperemia, dry eyes
rare	vision disorders
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, 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, hematemesis, cheilitis, dry lips, coated tongue
Hepatobiliary disorders
common	elevated ALT levels
uncommon	hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, elevated transaminase levels, elevated AST levels, elevated blood bilirubin levels, elevated alkaline phosphatase levels, elevated gamma-glutamyl transferase levels
Skin and subcutaneous tissue disorders
common	rash (including macular, maculopapular, papular, erythematous, and pruritic rash), pruritus
uncommon	angioedema, generalized rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, nail pigmentation
rare	DRESS syndrome, Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrheic dermatitis, skin lesions, xeroderma
frequency 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, elevated blood creatine phosphokinase levels
rare	musculoskeletal stiffness, arthritis, joint stiffness
rare	crystalline nephropathy§
Renal and urinary disorders
uncommon	acute renal failure, renal failure, nephrolithiasis, elevated blood creatinine levels, proteinuria, bilirubinuria, dysuria, nocturia, polyuria
rare	decreased creatinine renal clearance
Reproductive system and breast disorders
uncommon	erectile dysfunction, gynecomastia
General disorders and administration site conditions
common	asthenia, fatigue
uncommon	pyrexia, chest pain, peripheral edema, malaise, feeling of warmth, irritability, pain
rare	chills, abnormal sensations, xerosis

§ Adverse reaction identified in the post-marketing period.

Description of selected adverse reactions

Rash

Rash occurred with mild to moderate severity (most frequently within the first four weeks of treatment) and resolved with continued treatment. In case of severe skin reactions, see warnings in section "Special precautions".

Metabolic parameters

Antiretroviral therapy may be associated with increased body weight as well as increased levels of lipids and glucose in blood (see section "Special precautions").

Disorders of muscle and connective tissue

Cases of elevated creatine phosphokinase, myalgia, myositis, and rarely rhabdomyolysis have been reported during protease inhibitor use, particularly in combination with nucleoside reverse transcriptase inhibitors.

Specifically, cases of osteonecrosis have been reported in patients with well-known risk factors, as well as in patients with advanced HIV infection and/or long-term exposure to CART. The frequency of such cases is unknown (see section "Special precautions").

Immune Reconstitution Inflammatory Syndrome

In HIV-infected patients with severe immunodeficiency at the initiation of CART, inflammatory reactions to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the onset of these conditions is more variable and may occur long after initiation of treatment (see section "Special precautions").

Bleeding in patients with hemophilia

Increased spontaneous bleeding has been observed in hemophiliac patients receiving antiretroviral protease inhibitors (see section "Special precautions").

Pediatric population

Overall, the safety profile in children was similar to that in adults.

Other special patient categories

Patients with chronic hepatitis B and C

In such patients, liver transaminase levels were more frequently elevated at the beginning and during treatment compared to patients without chronic viral hepatitis (see section "Special precautions").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

3 years. After first opening of the bottle, the product can be used for up to 3 months.

Storage conditions.

Keep the bottle tightly closed to protect from moisture. Store in a place inaccessible to children.

Packaging.

30 tablets in a high-density polyethylene bottle with a polypropylene screw cap and child-resistant closure; 2 bottles in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.