INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DARUNAVIR KRKA (DARUNAVIR KRKA)

Composition:

Active substance: darunavir;

One film-coated tablet contains 400 mg or 800 mg of darunavir;

Excipients: microcrystalline cellulose; crospovidone, type A; hydroxypropylcellulose; colloidal anhydrous silicon dioxide; siliconized microcrystalline cellulose; magnesium stearate; film coating: film mixture (polyvinyl alcohol, macrogol, titanium dioxide, talc); iron oxide yellow (only for 400 mg tablets); iron oxide red.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

400 mg: yellowish-brown, oval, biconvex, film-coated tablets with "S 1" engraved on one side;

800 mg: brownish-red, oval, biconvex, film-coated tablets with "S 3" engraved on one side.

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 virions.

In vitro antiviral activity

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 in vitro antiviral activity 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% cellular cytotoxic concentrations (ranging from 87 µM to >100 µM).

Resistance

In vitro selection of darunavir-resistant viruses from wild-type HIV-1 was prolonged (> 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: 23–50-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 explained solely by the emergence of these protease mutations.

Antiretroviral therapy experience has shown that virological response to treatment with darunavir in combination with low-dose ritonavir decreases if, at baseline, there are 3 or more darunavir resistance-associated mutations (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V, and L89V), or if these mutations develop during treatment.

The lowest frequency of HIV resistance development was observed in patients who had not previously received antiretroviral therapy and were newly treated with darunavir in combination with other antiretroviral agents.

Cross-resistance

Viruses resistant to most other protease inhibitors have been shown to remain sensitive to darunavir; cross-resistance with other protease inhibitors has not been observed.

Pharmacokinetics.

The pharmacokinetic properties of darunavir administered in combination with cobicistat or ritonavir have been studied in healthy adult volunteers and in HIV-1-infected patients. Darunavir exposure was 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 levels of alpha-1 acid glycoprotein (AAG) in HIV-1-infected patients, resulting in greater plasma protein binding of darunavir and thus increased total plasma concentrations.

Darunavir is primarily metabolized by CYP3A enzymes. Cobicistat and ritonavir inhibit CYP3A enzymes and thereby significantly increase darunavir plasma concentrations. Information on the pharmacokinetics of cobicistat is provided in its medical instruction leaflet.

Absorption

After oral administration, darunavir is rapidly absorbed. The maximum plasma concentration (C_max) of darunavir in the presence of 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% and increases 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 oral dose of 600 mg darunavir in combination with 100 mg ritonavir twice daily (see section «Use in specific populations»).

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

Distribution

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

After intravenous administration, the volume of distribution of darunavir was 88.1 ± 59.01 L (mean ± standard deviation (SD)) and increased to 131 ± 49.91 L (mean ± SD) in the presence of 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. A study in which healthy volunteers received 14C-darunavir showed that the majority of radioactivity in plasma after a single 400 mg dose of darunavir with 100 mg ritonavir was attributable to the parent drug. At least three oxidized 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 400/100 mg 14C-darunavir with ritonavir, approximately 79.5% and 13.9% of the administered 14C-darunavir were 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.

The clearance of darunavir after intravenous administration of darunavir alone (150 mg) was 32.8 L/hour and 5.9 L/hour with low-dose ritonavir.

Special patient populations

Children

The pharmacokinetics of darunavir in combination with ritonavir twice daily in children aged 6 to 17 years with body weight ≥ 20 kg who had previously received antiretroviral treatment showed that administration of weight-based darunavir/ritonavir doses resulted in exposure similar to that observed in adults receiving the darunavir/ritonavir combination at a dose of 600/100 mg twice daily (see section «Dosage and administration»).

The pharmacokinetics of darunavir in combination with ritonavir twice daily in children aged 3 to 6 years with body weight 15–20 kg who had previously received antiretroviral treatment showed that administration of weight-based darunavir/ritonavir doses resulted in exposure similar to that observed in adults receiving the darunavir/ritonavir combination at a dose of 600/100 mg twice daily (see section «Dosage and administration»).

The pharmacokinetics of darunavir in combination with ritonavir once daily in adolescents aged 12 to 18 years with body weight ≥ 40 kg who had not previously received antiretroviral treatment showed that administration of darunavir/ritonavir at a dose of 800/100 mg once daily resulted in exposure similar to that observed in adults receiving the darunavir/ritonavir combination at a dose of 800/100 mg once daily. Therefore, the same once-daily dosing regimen can be used for the treatment of adolescents aged 12 to 18 years with body weight > 40 kg who have previously received antiretroviral treatment and who do not have darunavir resistance-associated mutations (DRV-RAMs)*, and with 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.

The pharmacokinetics of darunavir in combination with ritonavir once daily in children aged 3 to 6 years with body weight from 14 kg to < 20 kg who had previously received antiretroviral treatment showed that administration of weight-based darunavir/ritonavir doses resulted in exposure similar to that observed in adults receiving the darunavir/ritonavir combination at a dose of 800/100 mg once daily (see section «Dosage and administration»). Additionally, once-daily dosing regimens of darunavir/ritonavir have been confirmed for children with body weight ≥ 15 kg who have either not previously received antiretroviral therapy or have previously received antiretroviral therapy, with no darunavir resistance-associated mutations (DRV-RAMs)*, 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 years) showed that the pharmacokinetics of darunavir do not differ significantly across the age range (18–75 years) (see section «Use in specific populations»). However, data in patients aged 65 years and older are limited.

Gender

A 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 dose of darunavir 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 «Use in specific populations» and «Dosage and administration»).

Patients with hepatic impairment

Darunavir is metabolized and eliminated primarily by the liver. When darunavir was co-administered with ritonavir (600/100 mg) twice daily, total plasma concentrations of darunavir 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 free (unbound) 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. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see sections «Contraindications», «Use in specific populations», and «Dosage and administration»).

Pregnancy and postpartum period

Overall exposure to darunavir/ritonavir after administration at doses of 600/100 mg twice daily and 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 relative to the postpartum period.

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).

Darunavir KRKA, 400 mg and 800 mg tablets, is indicated to provide the required dosing regimen for the treatment of HIV-1 infection in adult patients and children aged 12 years and older with body weight of at least 40 kg:

• who have not previously received antiretroviral therapy (see section "Dosage and administration");

• who have previously received antiretroviral therapy and who do not have HIV-1 resistance-associated mutations to darunavir (DRV-RAMs), with plasma HIV RNA levels < 100,000 copies/mL and CD4+ cell count ≥ 100 cells × 10⁶/L; genotypic testing should guide the decision to initiate darunavir in this patient group (see sections "Pharmacodynamics", "Contraindications", "Special warnings and precautions for use", and "Dosage and administration").

Contraindications.

Hypersensitivity to darunavir or to any of the excipients.

Severe hepatic impairment (Child-Pugh class C).

Concomitant use with any of the following medicinal products due to the potential for decreased concentrations of darunavir, ritonavir, and cobicistat, and loss of therapeutic effect*, &.

For darunavir boosted with ritonavir or cobicistat:

• combination lopinavir/ritonavir&;
• strong CYP3A4 inducers – rifampicin and herbal products containing St John's wort (Hypericum perforatum); concomitant use is expected to reduce concentrations of darunavir, ritonavir, and cobicistat, which may lead to loss of therapeutic effect and development of resistance*, &.

For darunavir boosted with cobicistat (in addition to ritonavir):

• darunavir boosted with cobicistat is more sensitive to CYP3A enzyme induction than darunavir boosted with ritonavir. Concomitant use with strong CYP3A inducers is contraindicated, as this may reduce exposure to cobicistat and darunavir and lead to loss of therapeutic effect. Strong CYP3A inducers include, for example, carbamazepine, phenobarbital, and phenytoin*, &.

Darunavir boosted with ritonavir or cobicistat inhibits the elimination of active substances whose clearance is largely determined by CYP3A isoenzyme activity, leading to increased exposure of the concomitant drug. Therefore, concomitant use with medicinal products whose increased plasma concentrations are associated with serious and/or life-threatening adverse reactions is contraindicated (for darunavir boosted with ritonavir or cobicistat). 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 is provided in 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 "Special warnings and precautions for use".

& See section "Interaction with other medicinal products and other forms of interaction".

Interaction with other medicinal products and other forms of interaction.

The interaction profile of darunavir may differ depending on whether ritonavir or cobicistat is used. Therefore, recommendations for concomitant use of darunavir with other medicinal products differ depending on whether darunavir is boosted with ritonavir or cobicistat (see sections "Contraindications" and "Special warnings and precautions for use"). Caution should also be exercised during the period following the switch of the pharmacokinetic booster from ritonavir to cobicistat (see section "Special warnings and precautions for use").

Medicinal products affecting darunavir plasma levels (ritonavir as pharmacokinetic booster)

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

Concomitant use 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 such as clotrimazole) is not recommended; these interactions are described in Table 1.

Medicinal products affecting darunavir plasma levels (cobicistat as pharmacokinetic booster)

Darunavir and cobicistat are metabolized by CYP3A isoenzymes; therefore, concomitant use with CYP3A inducers may result in subtherapeutic plasma concentrations of darunavir. Darunavir boosted with cobicistat is more sensitive to CYP3A enzyme induction compared to darunavir boosted with ritonavir: concomitant use of darunavir and cobicistat with strong CYP3A inducers (e.g., herbal products containing St John's wort (Hypericum perforatum), rifampicin, carbamazepine, phenobarbital, phenytoin) is contraindicated (see section "Contraindications").

Concomitant use of darunavir boosted with cobicistat with weak and moderate CYP3A inducers (e.g., efavirenz, etravirine, nevirapine, fluticasone, bosentan) is not recommended (see Table 1).

Recommendations for concomitant use with strong CYP3A4 inhibitors are the same regardless of whether darunavir is boosted with ritonavir or cobicistat (see section above).

Medicinal products that may be affected by darunavir boosted with ritonavir

Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6, and P-glycoprotein (P-gp). Concomitant use of the darunavir/ritonavir combination with medicinal products primarily metabolized by CYP3A and/or CYP2D6 or transported by P-gp may increase plasma concentrations of such drugs, potentially leading to 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 largely determined by CYP3A isoenzymes and whose increased systemic exposure may cause serious and/or life-threatening adverse reactions (narrow therapeutic index) (see section "Contraindications").

Concomitant use of boosted darunavir with medicinal products that are actively metabolized by CYP3A may lead to reduced plasma concentrations of these active metabolites, potentially resulting in loss of their therapeutic effect (see Table 1). 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 in combination with 100 mg ritonavir twice daily. Therefore, darunavir should only be taken with a pharmacokinetic booster (see sections "Pharmacokinetics" and "Special warnings and precautions for use").

Clinical studies using medicinal products metabolized by CYP2C9, CYP2C19, and CYP2D6 cytochromes showed increased activity of CYP2C9 and CYP2C19 and inhibition of CYP2D6 activity with darunavir/ritonavir combination, which may be explained by 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 increase plasma concentrations of these drugs, 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 drugs, potentially diminishing or shortening their therapeutic effect.

Although the effect on CYP2C8 has been studied only in vitro, concomitant use of darunavir and ritonavir with medicinal products primarily metabolized by CYP2C8 (e.g., paclitaxel, rosiglitazone, repaglinide) may reduce systemic exposure to these drugs, 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, bosentan; see Table 1).

Medicinal products that may be affected by darunavir boosted with cobicistat

Recommendations regarding the effect of ritonavir-boosted darunavir on other medicinal products with respect to CYP3A4, CYP2D6, P-glycoprotein, OATP1B1, and OATP1B3 substrates are similar to those for darunavir boosted with cobicistat (see sections above). Cobicistat 150 mg, when used concomitantly with 800 mg darunavir once daily, enhances the pharmacokinetic parameters of darunavir similarly to ritonavir (see section "Pharmacokinetics").

Unlike ritonavir, cobicistat does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or UGT1A1. For detailed information, refer to the cobicistat product information.

Interaction table

Interaction studies have been conducted only in adults.

Some interaction studies (marked with "#" in the table) 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 use of medicinal products may be underestimated; clinical safety monitoring is indicated.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as the pharmacokinetic booster. Therefore, darunavir may have different recommendations for use with concomitant medications depending on whether it is boosted with ritonavir or cobicistat. Interaction studies listed in Table 1 were not conducted with darunavir boosted with cobicistat.

Unless otherwise specified, the same recommendations may apply. For detailed information, refer to the cobicistat product information.

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: within (↔), below (↓), or above (↑) the 80–125% range (not determined – ND).

In Table 1, a specific booster is indicated if recommendations differ.

If recommendations are the same as for concomitant use of darunavir with low-dose ritonavir or cobicistat, the term "boosted darunavir" is used.

The list of examples of drug interactions provided below is not exhaustive; therefore, refer to the product information of each medicinal product used concomitantly with darunavir 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 indication	Interaction Change in mean geometric value (%)	Recommendations for concomitant use
ANTIRETROVIRAL AGENTS FOR HIV TREATMENT
Integrase strand transfer inhibitors
Dolutegravir	dolutegravir AUC ↓ 22 % dolutegravir C24h ↓ 38 % dolutegravir Cmax ↓ 11 % darunavir ↔* * Based on comparative data from cross-study and historical pharmacokinetic data	Boosted darunavir and dolutegravir can be used without dose adjustment.
Raltegravir	Some clinical studies have shown that raltegravir may lead to a slight decrease in plasma concentrations of darunavir.	So far, the effect of raltegravir on plasma concentrations of darunavir is not clinically significant. Boosted darunavir and raltegravir can be used without dose adjustment.
Nucleoside reverse transcriptase inhibitors (NRTIs)
Didanosine 400 mg once daily	didanosine AUC ↓ 9 % didanosine Cmin NB didanosine Cmax ↓ 16 % darunavir AUC ↔ darunavir Cmin ↔ darunavir Cmax ↔	Boosted darunavir and didanosine can be used without dose adjustment. Didanosine should be taken on an empty stomach and therefore must be taken 1 hour before or 2 hours after taking boosted darunavir 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 using boosted darunavir in combination with tenofovir disoproxil, monitoring of kidney function is recommended, especially in patients with systemic or kidney disease or in patients taking nephrotoxic agents. When used concomitantly with a specific pharmacokinetic booster, darunavir reduces creatinine clearance. See section "Special precautions" if necessary to use creatinine clearance value for dose adjustment of tenofovir disoproxil.
Emtricitabine/tenofovir alafenamide	tenofovir alafenamide ↔ tenofovir ↑	The recommended dose of emtricitabine/tenofovir alafenamide is 200/10 mg once daily when used with boosted darunavir.
Abacavir Emtricitabine Lamivudine Stavudine Zidovudine	Not studied. Since elimination pathways differ among other NRTIs – zidovudine, emtricitabine, stavudine, lamivudine, which are primarily excreted by the kidneys, and abacavir, which is not metabolized by CYP450, no interaction between these drugs and boosted darunavir is expected.	Boosted darunavir can be used with these NRTIs without dose adjustment. When used concomitantly with cobicistat, darunavir reduces creatinine clearance. See section "Special precautions" if necessary to use creatinine clearance value for dose adjustment of emtricitabine or lamivudine.
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 darunavir with low-dose ritonavir is used in combination with efavirenz, monitoring for CNS toxicity related to increased efavirenz concentrations is recommended. Efaverenz in combination with darunavir/ritonavir at a dose of 800/100 mg once daily may result in insufficient darunavir Cmin. If efavirenz must be used in combination with darunavir/ritonavir, a dosage of darunavir/ritonavir of 600/100 mg twice daily should be prescribed (see section "Special precautions"). Concomitant use with darunavir and cobicistat is not recommended (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. Concomitant use with darunavir and cobicistat is not recommended (see section "Special precautions").
Nevaripine 200 mg twice daily	nevaripine AUC ↑ 27 % nevaripine Cmax ↑ 47 % nevaripine Cmax ↑ 18 % #darunavir: concentrations consistent with previous data (↑ nevaripine due to CYP3A inhibition).	Darunavir with low-dose ritonavir can be used with nevaripine without dose adjustment. Concomitant use with darunavir and cobicistat is not recommended (see section "Special precautions").
Rilpivirine 150 mg once daily	rilpivirine AUC ↑ 130 % rilpivirine Cmin ↑ 178 % rilpivirine Cmax ↑ 79 % darunavir AUC ↔ darunavir Cmin ↓ 11 % darunavir Cmax ↔	Boosted darunavir and rilpivirine can be used without dose adjustment.
HIV protease inhibitors (PIs) – without additional use of 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. The combination of darunavir with cobicistat cannot be used concomitantly with other antiretroviral agents requiring pharmacokinetic boosting by concomitant use with a CYP3A4 inhibitor (see section "Interaction with other medicinal products and other types of interactions").
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 in combination with indinavir 800 mg twice daily.	When used in combination with darunavir with low-dose ritonavir, a dose reduction of indinavir from 800 mg twice daily to 600 mg twice daily may be necessary in case of intolerance. The combination of darunavir with cobicistat cannot be used concomitantly with other antiretroviral agents requiring pharmacokinetic boosting by concomitant use with a CYP3A4 inhibitor.
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. The combination of darunavir with cobicistat cannot be used concomitantly with other antiretroviral agents requiring pharmacokinetic boosting by concomitant use with a CYP3A4 inhibitor.
HIV protease inhibitors (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 have not been established. Therefore, concomitant use of boosted darunavir and lopinavir/ritonavir combination is contraindicated (see section "Contraindications").
CCR5 ANTAGONIST
Maraviroc 150 mg twice daily	maraviroc AUC ↑ 305 % maraviroc Cmin NB maraviroc Cmax ↑ 129 % concentrations of darunavir and ritonavir consistent with previous data	Maraviroc dose should be 150 mg twice daily when used concomitantly with boosted darunavir.
α1-ADRENERGIC ANTAGONIST
Alfuzosin	Based on theoretical considerations, darunavir is expected to increase plasma concentrations of alfuzosin (CYP3A inhibition).	Concomitant use of boosted darunavir and alfuzosin is contraindicated (see section "Contraindications").
ANESTHETIC
Alfentanil	Not studied. Alfentanil metabolism occurs via CYP3A enzymes, so it may be inhibited by boosted darunavir.	Concomitant use with boosted darunavir may require a reduced dose of alfentanil and requires monitoring for risk of prolonged or delayed respiratory depression.
ANTIANGINAL/ANTIARRHYTHMIC AGENTS
Disopyramide Flecainide Lidocaine (systemic) Mexiletine Propafenone Amiodarone Bepiridil Dronedarone Ivabradine Quinidine Ranolazine	Not studied. Boosted darunavir is expected to increase plasma concentrations of these antiarrhythmic agents (CYP3A and/or CYP2D6 inhibition).	Use of boosted darunavir with antiarrhythmic agents is recommended with caution and, if possible, therapeutic concentrations of these agents should be monitored. Concomitant use of boosted darunavir with amiodarone, bepridil, dronedarone, ivabradine, quinidine or ranolazine is contraindicated (see section "Contraindications").
Digoxin 0.4 mg single dose	digoxin AUC ↑ 61 % digoxin Cmin NB digoxin Cmax ↑ 29 % (↑ digoxin due to possible P-gp inhibition).	Digoxin has a narrow therapeutic range, so the lowest possible digoxin dose should be prescribed at the start of therapy when used concomitantly with boosted darunavir. Digoxin dose should be titrated to achieve desired therapeutic effect with assessment of overall clinical condition of the patient.
ANTIBIOTIC
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 14-OH-clarithromycin were not detected when used in combination with darunavir/ritonavir (↑ clarithromycin due to CYP3A inhibition and possible P-gp inhibition).	Use of clarithromycin concomitantly with boosted darunavir is recommended with caution. For patients with impaired renal function, see clarithromycin prescribing information for recommended dose.
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 direct oral anticoagulants (DOACs) metabolized by CYP3A4 and transported by P-gp is not recommended, as this may lead to increased 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/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: 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. Darunavir/cobicistat: Clinical monitoring and dose reduction are required when used concomitantly with darunavir/cobicistat, 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 (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 decrease plasma concentrations of clopidogrel's active metabolite, which may reduce clopidogrel's antiplatelet effect.	Concomitant use of clopidogrel with boosted darunavir is not recommended. Other antiplatelets not affected by CYP inhibition or induction (e.g., prasugrel) should be used.
Warfarin	Not studied. Warfarin concentrations may change when used concomitantly with boosted darunavir.	Monitoring of international normalized ratio is recommended when warfarin is used in combination with boosted darunavir.
ANTICONVULSANTS
Phenobarbital Phenytoin	Not studied. Phenobarbital and phenytoin are expected to decrease plasma concentrations of darunavir and its pharmacokinetic booster (CYP450 enzyme induction).	Darunavir with low-dose ritonavir should not be used concomitantly with these agents. Concomitant use of these agents with darunavir/cobicistat is contraindicated (see section "Contraindications").
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 concentrations 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. Concomitant use of carbamazepine with darunavir and cobicistat is contraindicated (see section "Contraindications").
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 Amtriptyline 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 ↔ In contrast to these data, use of darunavir/cobicistat combination may increase plasma concentrations of these antidepressants (CYP2D6 and/or CYP3A inhibition). Concomitant use of boosted darunavir with these antidepressants may increase antidepressant concentrations (CYP2D6 and/or CYP3A inhibition).	When using boosted darunavir concomitantly with antidepressants, dose titration of antidepressants is recommended based on clinical assessment of antidepressant response. Monitor antidepressant response in patients receiving stable doses of antidepressants who start treatment with boosted darunavir. Clinical monitoring is recommended when using boosted darunavir concomitantly with these antidepressants; dose adjustment of antidepressants may be necessary.
ANTIDIABETIC AGENTS
Metformin	Not studied. Based on theoretical data, darunavir in combination with cobicistat is expected to increase plasma concentrations of metformin (MATE1 inhibition).	Close monitoring of patient status and dose adjustment of metformin is recommended when darunavir is used with cobicistat (does not apply if darunavir is used with ritonavir).
ANTIEMETICS
Domperidone	Not studied.	Concomitant use of domperidone with boosted darunavir is contraindicated.
ANTIFUNGAL AGENTS
Voriconazole	Not studied. Ritonavir may decrease plasma concentrations of voriconazole (CYP450 enzyme induction). Plasma concentrations of voriconazole may increase or decrease when used concomitantly with darunavir in combination with cobicistat (CYP450 enzyme inhibition).	Voriconazole should not be used with boosted darunavir, except in cases where benefit-risk assessment justifies use of voriconazole.
Fluconazole Isavuconazole Itraconazole Posaconazole Clotrimazole	Not studied. Boosted darunavir may increase plasma concentrations of antifungal agents, and posaconazole, isavuconazole, itraconazole or fluconazole may increase darunavir concentrations (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.
ANTIGOUT AGENTS
Colchicine	Not studied. Concomitant use of colchicine and boosted darunavir may increase colchicine exposure (CYP3A and/or P-gp inhibition).	For patients with normal liver or kidney function, colchicine dose should be reduced or treatment interrupted if use of boosted darunavir is necessary. Concomitant use of boosted darunavir with colchicine in patients with impaired liver or kidney function is contraindicated (see sections "Contraindications" and "Special precautions").
ANTIMALARIAL AGENTS
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 boosted darunavir and artemether/lumefantrine is possible without dose adjustment, but due to increased lumefantrine exposure, 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 and, as a result, virological failure and development of resistance (CYP450 enzyme induction). During attempts to overcome reduced exposure by increasing doses of other protease inhibitors with low-dose ritonavir when using rifampicin, hepatic reactions were very frequently observed.	Concomitant use of boosted darunavir and rifapentine is not recommended. Concomitant use of rifampicin with boosted darunavir is contraindicated (see section "Contraindications").
Rifabutin 150 mg every other day	rifabutin AUC** ↑ 55 % rifabutin Cmin ** ↑ NB 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 exposures of rifabutin when 300 mg rifabutin once daily alone and 150 mg every other day in combination with darunavir/ritonavir (600/100 mg twice daily) were used, with a 10-fold increase in daily exposure of active metabolite 25-O-desacetylrifabutin. In addition, AUC of sum of active rifabutin substances (unchanged parent substance + 25-O-desacetyl metabolite) increased 1.6-fold, while Cmax remained comparable. Comparison data 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/ritonavir combination was used concomitantly with rifabutin (150 mg every other day).	Dose reduction of rifabutin by 75 % from usual dose of 300 mg daily (to 150 mg rifabutin every other day) and increased monitoring for rifabutin-related adverse reactions are required for patients using darunavir/ritonavir combination. If safety is insufficient, further increase in dosing interval of rifabutin and/or monitoring of rifabutin levels should be considered. Consider official guidelines for appropriate treatment of tuberculosis in HIV-infected patients. Based on safety data of darunavir/ritonavir, increased exposure of darunavir when using rifabutin does not require dose adjustment of darunavir/ritonavir. Based on pharmacokinetic modeling data, 75 % dose reduction should also be applied to patients receiving rifabutin doses other than 300 mg daily. Concomitant use of darunavir and cobicistat with rifabutin is not recommended.
ANTINEOPLASTIC AGENTS
Dasatinib Nilotinib Vinblastine Vincristine Everolimus Irinotecan	Not studied. Boosted darunavir is expected to increase plasma concentrations of these anticancer agents (CYP3A inhibition).	Concentrations of these agents may increase when used concomitantly with boosted darunavir, potentially increasing frequency of adverse reactions associated with these drugs. Use of these anticancer agents concomitantly with boosted darunavir should be done with caution. Concomitant use of everolimus or irinotecan with boosted darunavir is not recommended.
ANTIPSYCHOTICS/NEUROLEPTICS
Quetiapine	Not studied. Boosted darunavir is expected to increase plasma concentrations of these antipsychotics (CYP3A inhibition).	Concomitant use of boosted darunavir with quetiapine is contraindicated, as it may cause increased quetiapine-dependent toxicity. Increased quetiapine concentration may lead to coma (see section "Contraindications").
Perphenazine Risperidone Thioridazine Lurasidone Pimozide Sertindole	Not studied. Boosted darunavir is expected to increase plasma concentrations of these antipsychotics (CYP3A, CYP2D6 and/or P-gp inhibition).	Dose reduction of these agents may be necessary when used concomitantly with boosted darunavir. Concomitant use of boosted darunavir with lurasidone, pimozide or sertindole is contraindicated (see section "Contraindications").
BETA-BLOCKERS
Carvedilol Metoprolol Timolol	Not studied. Boosted darunavir is expected to increase plasma concentrations of these beta-blockers (CYP2D6 inhibition).	Clinical monitoring is recommended when boosted darunavir is used concomitantly with beta-blockers. Consideration should be given to reducing beta-blocker dose.
CALCIUM CHANNEL BLOCKERS
Amlodipine Diltiazem Felodipine Nicardipine Nifedipine Verapamil	Not studied. Boosted darunavir may increase plasma concentrations of calcium channel blockers (CYP3A and/or CYP2D6 inhibition).	Clinical monitoring for therapeutic and adverse effects is recommended when these agents are used concomitantly with boosted darunavir.
CORTICOSTEROIDS
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 (four times daily) were used concomitantly for 7 days in healthy volunteers, plasma concentrations of fluticasone propionate significantly increased, while endogenous cortisol levels decreased to approximately 86 % (90 % CI 82–89 %). Greater effect may be expected with inhaled route of fluticasone administration. Systemic effects of corticosteroids, including Cushing's syndrome and adrenal suppression, have been reported in patients receiving ritonavir and inhaled or intranasal fluticasone. The effect of high systemic exposure to fluticasone on plasma concentrations of ritonavir is unknown. Other corticosteroids: interaction not studied. Plasma concentrations of these agents may increase when used concomitantly with darunavir with low-dose ritonavir, leading to decreased 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 in cases where potential benefit outweighs risk, and patients should be monitored for systemic corticosteroid effects. Consider use of alternative corticosteroids less dependent on CYP3A metabolism, such as beclomethasone, especially for long-term use.
Dexamethasone (for systemic use)	Not studied. Dexamethasone may decrease plasma concentrations of darunavir (CYP3A induction).	Systemic dexamethasone should be used with caution when used concomitantly with boosted darunavir.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan	Not studied. Concomitant systemic use of bosentan and boosted darunavir may increase plasma concentrations of bosentan. Bosentan is expected to decrease plasma concentrations of darunavir and/or its pharmacokinetic booster (CYP3A induction).	When used concomitantly with darunavir with low-dose ritonavir, monitor patient tolerance to bosentan. Concomitant use of darunavir and another pharmacokinetic booster with bosentan is not recommended.
DIRECT-ACTING ANTIVIRALS (HEPATITIS C VIRUS (HCV))
NS3-4A inhibitors
Elbasvir/grazoprevir	Darunavir with low-dose ritonavir may increase exposure to grazoprevir (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).	It is not recommended to use boosted darunavir concomitantly with glecaprevir/pibrentasvir.
HERBAL PRODUCTS
St. John's wort (Hypericum perforatum)	Not studied. St. John's wort is expected to decrease plasma concentrations of darunavir and/or its pharmacokinetic booster (CYP450 induction).	Boosted darunavir should not be used concomitantly with 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, if possible, viral levels should be checked. Exposure to darunavir (and ritonavir) may increase after discontinuation of St. John's wort. Induction effect may last at least 2 weeks after discontinuation of 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 boosted darunavir (CYP3A inhibition).	Increased concentrations of lovastatin and simvastatin may cause myopathy, including rhabdomyolysis. Therefore, concomitant use of boosted darunavir with 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 atorvastatin AUC ↑ 290 % Ω atorvastatin Cmax ↑ 319 % Ω atorvastatin Cmin ND Ω Ω with darunavir/cobicistat 800/150 mg	If atorvastatin and boosted darunavir are indicated, initial atorvastatin dose should be 10 mg once daily. Gradual increase in atorvastatin dose should be based on clinical response.
Pravastatin 40 mg, single dose	pravastatin AUC ↑ 81 %¶ pravastatin Cmin NB pravastatin Cmax ↑ 63 % ¶ in a limited subgroup of patients, a 5-fold increase was observed	If use of pravastatin and boosted darunavir is necessary, the lowest possible initial dose of pravastatin is recommended, with titration to achieve desired clinical effect, while considering safety of use.
Rosuvastatin 10 mg once daily	rosuvastatin AUC ↑ 48 %║ rosuvastatin Cmax ↑ 144 %║ ║ according to published data with darunavir/ritonavir rosuvastatin AUC ↑ 93 %§ rosuvastatin Cmax ↑ 277 %§ rosuvastatin Cmin ND§ § with darunavir/cobicistat 800/150 mg	If use of rosuvastatin and boosted darunavir is necessary, the lowest possible initial dose of rosuvastatin is recommended, with titration to achieve desired clinical effect, while considering safety of use.
OTHER HYPO-LIPIDEMIC AGENTS
Lomitapide	Not studied. Theoretically, boosted darunavir may increase effects of lomitapide 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 ↔	Boosted darunavir 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 boosted darunavir (CYP3A inhibition).	Monitoring for therapeutic effects of immunosuppressants is recommended when used concomitantly. Concomitant use of everolimus with boosted darunavir is not recommended.
INHALATIONAL BETA-AGONISTS
Salbutamol	Not studied. Concomitant use of salbutamol and boosted darunavir may increase plasma concentrations of salbutamol.	Concomitant use of salbutamol and boosted darunavir is not recommended. This combination may increase risk of cardiovascular adverse reactions, including QT prolongation, palpitations, sinus tachycardia with use of salbutamol.
NARCOTIC ANALGESICS/TREATMENT OF OPIOID DEPENDENCE
Methadone individual dose – from 55 to 150 mg once daily	R(-) methadone AUC ↓ 16 % R(-) methadone Cmin ↓ 15 % R(-) methadone Cmax ↓ 24 % Darunavir/cobicistat, conversely, may increase plasma concentrations of methadone (see cobicistat prescribing information).	There is no need to reduce methadone dose at the start of therapy with concomitant use of boosted darunavir. However, dose increase of methadone may be necessary with long-term concomitant use. 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 NB naloxone Cmax ↔	Clinical significance of increased pharmacokinetic parameters of norbuprenorphine has not been established. Dose adjustment of buprenorphine is not required when used concomitantly with boosted darunavir, but careful clinical monitoring for symptoms of opioid intoxication 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 boosted darunavir is used concomitantly with these analgesics.
ESTROGEN-CONTAINING CONTRACEPTIVES
Drospirenone Ethinylestradiol (3 mg/0.02 mg once daily) Ethinylestradiol Norethindrone 35 mcg/1 mg once daily	drospirenone AUC ↑ 58 %€ drospirenone Cmin ND € drospirenone Cmax ↑ 15 %€ ethinylestradiol AUC ↓ 30 %€ ethinylestradiol Cmin ND€ ethinylestradiol Cmax ↓ 14 %€ € with darunavir/cobicistat 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	When using darunavir with a drug containing drospirenone, clinical monitoring is recommended due to risk of hyperkalemia. Alternative or additional contraceptive measures are recommended when estrogen-containing contraceptives are used concomitantly with boosted darunavir. 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 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 both with single 100 mg dose of sildenafil alone and with concomitant use of single 25 mg dose of sildenafil in combination with darunavir and low-dose ritonavir.	Concomitant use of avanafil with boosted darunavir is contraindicated (see section "Contraindications"). Concomitant use of other phosphodiesterase-5 inhibitors with boosted darunavir for treatment of erectile dysfunction should be done with caution. If concomitant use of boosted darunavir 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 treatment of pulmonary arterial hypertension Sildenafil Tadalafil	Not studied. Concomitant use of sildenafil or tadalafil for treatment of pulmonary arterial hypertension with boosted darunavir may increase plasma concentrations of sildenafil or tadalafil (CYP3A inhibition).	Safe and effective dose of sildenafil for treatment of pulmonary arterial hypertension with concomitant use of boosted darunavir 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 boosted darunavir and sildenafil for treatment of pulmonary arterial hypertension is contraindicated (see section "Contraindications"). Concomitant use of tadalafil for treatment of pulmonary arterial hypertension with boosted darunavir is not recommended.
PROTON PUMP INHIBITORS
Omeprazole 20 mg once daily	#darunavir AUC ↔ #darunavir Cmin ↔ #darunavir Cmax ↔	Boosted darunavir 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 primarily metabolized by CYP3A. Concomitant use with boosted darunavir may significantly increase concentrations of these agents. Concomitant use of parenteral midazolam with boosted darunavir may significantly increase concentration of this benzodiazepine. Data on concomitant use of parenteral midazolam with other protease inhibitors indicate possible 3–4-fold increase in midazolam plasma concentrations.	When using boosted darunavir concomitantly with these sedatives/hypnotics, clinical monitoring of patients is recommended; dose reduction of sedatives/hypnotics may be necessary. If parenteral midazolam is used with boosted darunavir, it should be done in an intensive care unit or similar setting to ensure close clinical monitoring and provision of appropriate medical care in case of respiratory depression and/or prolonged sedation. Possibility of midazolam dose adjustment should be considered, especially if more than a single dose is administered. Use of boosted darunavir with triazolam or oral midazolam is contraindicated (see section "Contraindications").
AGENTS FOR TREATMENT OF PREMATURE EJACULATION
Dapoxetine	Not studied.	Concomitant use of dapoxetine with boosted darunavir is contraindicated.
UROLOGICAL AGENTS
Fesoterodine Solifenacin	Not studied.	Should be used with caution. Monitor for adverse reactions of fesoterodine or solifenacin; dose reduction of fesoterodine or solifenacin may be needed.

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 protease inhibitor therapy 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 reduction or loss of virological response occurs, resistance testing should be performed.

Darunavir must always be taken orally with cobicistat or low-dose ritonavir as a pharmacokinetic enhancer, and in combination with other antiretroviral agents (see section "Pharmacokinetics"). Therefore, depending on the circumstances, it may be necessary to review the prescribing information for cobicistat or ritonavir prior to initiating darunavir therapy.

Increasing the dose of ritonavir above the recommended dose in section "Dosage and administration" results in only a minor increase in darunavir concentrations. Dose adjustments of cobicistat or ritonavir are not recommended.

Darunavir is predominantly bound to AAG (alpha-1-acid glycoprotein). This protein binding is saturable and concentration-dependent. Therefore, displacement by other drugs 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 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 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 for patients infected with HIV-1 non-B subtypes (see section "Pharmacodynamics").

Children

Darunavir should not be used in children under 12 years of age with body weight < 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 darunavir 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

Since information on the use of darunavir in patients aged 65 years and older is limited, darunavir should be used with caution in such patients due to the higher likelihood of impaired liver function, concomitant diseases, or concomitant medications (see sections "Pharmacokinetics" and "Interaction with other medicinal products and other forms of interaction").

Severe skin reactions

During the darunavir/ritonavir clinical trial program (N = 3063), severe skin reactions associated with fever and/or elevated liver transaminases were observed in 0.4% of patients. DRESS syndrome (drug reaction 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 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, blistering, oral mucosal lesions, conjunctivitis, hepatitis, and/or eosinophilia.

In patients previously treated with antiretroviral therapy, rash occurred more frequently with darunavir/ritonavir + raltegravir regimens compared to darunavir/ritonavir without raltegravir or raltegravir without darunavir (see section "Adverse reactions").

Darunavir contains a sulfonamide moiety. 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.

During the darunavir/ritonavir clinical trial program (N = 3063), hepatitis was reported in 0.5% of patients receiving darunavir/ritonavir combination antiretroviral therapy (cART). Patients with pre-existing liver dysfunction, including active chronic hepatitis B or C, have an 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 consulted (see prescribing information for these medicinal products).

Appropriate laboratory tests should be performed before initiating darunavir therapy in combination with cobicistat or low-dose 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, particularly during the first months of therapy with darunavir and cobicistat or low-dose ritonavir.

If new or worsening liver function 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 with cobicistat or low-dose ritonavir, consideration should be given to interrupting or discontinuing therapy.

Patients with concomitant diseases

Patients with hepatic impairment

The safety and efficacy of darunavir have not been established in patients with severe hepatic disorders; therefore, the drug is contraindicated in patients with severe hepatic impairment. Due to increased plasma concentrations of free darunavir, darunavir should be used with caution in patients with mild to moderate hepatic impairment (see sections "Pharmacokinetics", "Contraindications", and "Dosage and administration").

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 does not significantly contribute to their elimination. Therefore, no specific warnings or dose adjustments are required for these patients (see sections "Pharmacokinetics" and "Dosage and administration"). The use of cobicistat in dialysis patients has not been studied; therefore, there are no dosage recommendations for darunavir/cobicistat in this patient population (see section "Dosage and administration").

Cobicistat reduces estimated creatinine clearance by inhibiting tubular secretion of creatinine. This should be considered when prescribing darunavir with cobicistat to patients whose estimated creatinine clearance is used to adjust dosing of other medicinal products (see section "Dosage and administration" and the prescribing information for cobicistat).

There are insufficient data to determine whether concomitant use of tenofovir disoproxil fumarate and cobicistat is associated with an increased risk of renal adverse reactions compared to regimens containing tenofovir disoproxil fumarate without cobicistat.

Patients with haemophilia

There are reports of increased bleeding, including spontaneous skin bruising and haemarthrosis, in patients with haemophilia A and B during treatment with protease inhibitors. Some of these patients were also receiving factor VIII. In more than half of the reported cases, protease inhibitor treatment was continued without interruption or resumed after discontinuation. A causal relationship has been suggested, although the mechanism has not been established. Therefore, patients with haemophilia should be warned about the potential for increased bleeding.

Body weight and metabolic parameters

Weight gain and increases in blood lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly related to disease control and lifestyle. 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 HIV infection management should be followed regarding monitoring of lipid and glucose levels. Lipid abnormalities should be managed according to clinical practice.

Osteonecrosis

Although the aetiology of osteonecrosis is multifactorial (including corticosteroid use, alcohol abuse, severe immunosuppression, increased body mass index), cases of osteonecrosis have been reported more frequently in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy. Patients should be informed about the need for medical consultation if they experience joint pain, joint stiffness, or difficulty in movement.

Immune reconstitution inflammatory syndrome

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 usually observed within the first few weeks or months of cART initiation. Examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jiroveci (previously known as Pneumocystis carinii) pneumonia. The severity of any inflammatory condition should be assessed and appropriate therapy initiated. Additionally, in clinical trials, reactivation of herpes simplex and herpes zoster has 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 many months after initiation of antiretroviral therapy (see section "Adverse reactions").

Interaction with medicinal products

Several drug interaction studies have been conducted with darunavir at doses lower than recommended. Since the effect on concomitantly administered drugs may be underestimated, clinical monitoring for safety may be warranted. For complete information on drug interactions, see section "Interaction with other medicinal products and other forms of interaction".

Pharmacokinetic enhancer and concomitant medicinal products

Darunavir has different interaction profiles depending on whether it is boosted with ritonavir or cobicistat:

• Darunavir boosted with cobicistat is more sensitive to CYP3A enzyme induction; therefore, concomitant use of darunavir/cobicistat with strong CYP3A inducers is contraindicated (see section "Contraindications"), and concomitant use with weak or moderate CYP3A inducers is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of darunavir/ritonavir or darunavir/cobicistat with lopinavir/ritonavir, rifampicin, or herbal products containing St. John’s wort extract is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").
• Unlike ritonavir, cobicistat does not have properties of enzyme or transporter protein induction (see section "Interaction with other medicinal products and other forms of interaction"). When switching from ritonavir to cobicistat as a pharmacokinetic enhancer, caution should be exercised during the first two weeks of darunavir/cobicistat treatment, especially if doses of any concomitantly administered medicinal product were titrated or adjusted while using ritonavir as the pharmacokinetic enhancer. In such cases, dose reduction of the concomitant medicinal product may be necessary.

Efavirenz in combination with boosted darunavir may result in subtherapeutic darunavir Cmin levels. If efavirenz must be used in combination with darunavir, darunavir/ritonavir should be administered at a dosage of 600/100 mg twice daily (see prescribing information for Darunavir KRKA 600 mg tablets, film-coated).

Fatal and life-threatening interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-glycoprotein (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding.

Pregnancy

When making decisions about the use of antiretroviral agents for treating HIV infection in pregnant women 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 and adequate studies of darunavir use in pregnant women have not been conducted. Animal studies did not show direct harmful effects on pregnancy, embryonal/foetal development, parturition, or postnatal period.

The combination of darunavir with cobicistat or low-dose ritonavir may be prescribed to pregnant women only if the expected benefit to the mother outweighs the potential risk to the foetus.

Lactation

It is unknown whether darunavir is excreted in human breast milk. Animal studies have shown that darunavir is excreted in milk in large quantities (1000 mg/kg/day) and causes toxicity. Considering the risk of adverse reactions in infants, HIV-infected women receiving Darunavir KRKA should be advised not to breastfeed.

To prevent HIV transmission to infants, HIV-infected women are not recommended to breastfeed.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

Darunavir in combination with cobicistat or 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 cobicistat or low-dose ritonavir; therefore, this should be considered when assessing a patient's ability to drive or operate machinery (see section "Adverse reactions").

Method of Administration and Dosage

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

The interaction profile of darunavir depends on whether ritonavir is used as a pharmacokinetic enhancer. Therefore, darunavir may have different contraindications and recommendations for concomitant use with other medicinal products depending on whether the combination is boosted with ritonavir (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction", and "Special warnings and precautions for use").

Dosage

Darunavir Krka should always be administered orally with a low dose of ritonavir as a pharmacokinetic enhancer, and in combination with other antiretroviral agents. Thus, 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 and should not be used in patients unable to swallow whole tablets, such as young children. For treatment of such patients, the availability of more suitable dosage forms containing darunavir should be considered.

Adult patients who have not previously received antiretroviral therapy

The recommended dose of darunavir is 800 mg once daily in combination with 100 mg ritonavir once daily taken with food. Darunavir Krka, film-coated tablets of 400 mg and 800 mg, can be used to achieve the 800 mg once-daily dosing regimen.

Adult patients who have previously received antiretroviral therapy

Recommended dosing regimens:

• For patients who have previously received antiretroviral therapy and who do not have darunavir resistance-associated mutations (DRV-RAMs)*, with HIV-1 RNA levels < 100,000 copies/ml and CD4+ cell count ≥100 cells × 10^6/l (see section "Indications"), a dosing regimen of 800 mg once daily in combination with 100 mg ritonavir once daily taken with food may be used. Darunavir Krka, film-coated tablets of 400 mg and 800 mg, can be used to achieve the 800 mg once-daily dosing regimen.
• For all other patients who have previously received antiretroviral therapy, or when HIV-1 genotypic testing is not available, the recommended dosing regimen is 600 mg twice daily in combination with 100 mg ritonavir twice daily taken with food. Dosage recommendations are provided in the prescribing information for Darunavir Krka, film-coated tablets of 600 mg.

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

Children who have not previously received antiretroviral therapy (aged 12 to 17 years with body weight ≥ 40 kg)

The recommended dose of darunavir is 800 mg once daily in combination with 100 mg ritonavir once daily taken with food.

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

Recommended dosing regimens:

• For patients who have previously received antiretroviral therapy and who do not have DRV-RAMs* with HIV-1 RNA levels < 100,000 copies/ml and CD4+ cell count ≥ 100 cells × 10^6/l (see section "Indications"), a dosing regimen of 800 mg once daily in combination with 100 mg ritonavir once daily taken with food may be used. Darunavir Krka, film-coated tablets of 400 mg and 800 mg, can be used to achieve the 800 mg once-daily dosing regimen. The dose of another pharmacokinetic enhancer for use with darunavir in children under 12 years of age has not been established.
• For all other patients who have previously received antiretroviral therapy, or when HIV-1 genotypic testing is not available, the recommended dosing regimen is described in the prescribing information for Darunavir Krka, film-coated tablets of 600 mg.
• *DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, and L89V.

Missed dose recommendations

If a patient misses a once-daily dose of darunavir and/or ritonavir within 12 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 12 hours have passed since the usual dosing time, the missed dose should not be taken; the patient should continue with the regular dosing schedule.

These recommendations are based on the elimination half-life of darunavir when administered with ritonavir or another pharmacokinetic enhancer and the recommended dosing interval of approximately 24 hours.

If vomiting occurs within 4 hours after administration of the medicinal product, the patient should take the next dose of Darunavir Krka with ritonavir with food as soon as possible. If vomiting occurs more than 4 hours after administration of the medicinal product, 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 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 not available. Severe hepatic impairment may lead to increased darunavir concentrations and a 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 warnings and precautions for use").

Patients with renal impairment

No dose adjustment of darunavir/ritonavir is required in patients with renal impairment (see sections "Pharmacokinetics" and "Special warnings and precautions for use").

Pregnancy and postpartum period

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

Method of administration

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

Children

Darunavir is not recommended for children under 12 years of age or with body weight < 40 kg (see section "Special warnings and precautions for use").

The recommended dosing regimen for children is described in the prescribing information for Darunavir Krka, film-coated tablets of 600 mg.

Overdose.

Information regarding experience with acute overdose of darunavir co-administered with cobicistat or low-dose ritonavir is limited. Healthy volunteers have received single doses of up to 3,200 mg darunavir as an oral solution and up to 1,600 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, general supportive measures should be employed, with monitoring of vital signs and close observation of the patient's clinical status.

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

Adverse Reactions

Summary of safety profile

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

List of adverse reactions (see Table 2)

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 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1,000); frequency not known (cannot be estimated from available data).

Table 2

Adverse reactions observed during clinical trials and post-marketing experience with darunavir/ritonavir

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, confusion, anxiety, sleep disorders, abnormal dreams, nightmares, decreased libido
rare	disorientation, emotional lability, restlessness
Nervous system disorders
common	headache, peripheral neuropathy, dizziness
uncommon	lethargy, paresthesia, hypoesthesia, dysgeusia, attention disturbances, memory impairment, somnolence
rare	syncope, convulsions, ageusia, sleep phase rhythm disturbances
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	increased ALT levels
uncommon	hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased transaminase levels, increased AST levels, increased blood bilirubin levels, increased alkaline phosphatase levels, increased gamma-glutamyl transferase levels
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	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, increased blood creatine phosphokinase levels
rare	musculoskeletal stiffness, arthritis, joint stiffness
Renal and urinary disorders
uncommon	acute renal failure, renal failure, nephrolithiasis, increased blood creatinine levels, proteinuria, bilirubinuria, dysuria, nocturia, polyuria
rare	decreased creatinine renal clearance
rare	crystalline nephropathy§
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, hot flushes, irritability, pain
rare	chills, abnormal sensations, xerosis

§ Adverse reaction identified during the post-marketing period.

Table 3

Adverse reactions observed in adult patients receiving darunavir/cobicistat

Organ system / frequency	Adverse reactions
Immune system disorders
common	hypersensitivity (to the medicinal product)
uncommon	immune reconstitution inflammatory syndrome
Metabolism and nutrition disorders
common	anorexia, diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia
Psychiatric disorders
common	abnormal dreams
Nervous system disorders
very common	headache
Gastrointestinal disorders
very common	diarrhea, nausea
common	vomiting, abdominal pain, bloating, dyspepsia, flatulence, increased pancreatic enzymes
uncommon	acute pancreatitis
Hepatobiliary disorders
common	elevated liver enzymes
uncommon	hepatitis*, cytolytic hepatitis*
Skin and subcutaneous tissue disorders
very common	rash (including macular, maculopapular, papular, erythematous, pruritic rash, generalized rash, and allergic dermatitis)
common	angioedema, pruritus, urticaria
rare	DRESS syndrome*, Stevens-Johnson syndrome*
frequency not known	toxic epidermal necrolysis*, acute generalized exanthematous pustulosis*
Musculoskeletal and connective tissue disorders
common	myalgia
uncommon	osteonecrosis*
Renal and urinary disorders
rare	crystalline nephropathy§
Reproductive system disorders
uncommon	gynecomastia*
General disorders
common	fatigue
uncommon	asthenia
Investigations
common	increased blood creatinine levels

* These adverse reactions were not observed during clinical trials of darunavir/cobicistat, but have been reported in trials with darunavir/ritonavir; these adverse reactions may also occur with darunavir/cobicistat.

§ Adverse reaction identified during the post-marketing period.

Description of selected adverse reactions

Rash

During clinical trials, rashes were mostly mild to moderate in severity, most commonly occurred within the first 4 weeks of treatment, and resolved while continuing treatment. In case of severe skin reactions, see warnings in section "Special warnings and precautions for use".

Metabolic parameters

Antiretroviral therapy may be associated with increased body weight and elevated levels of lipids and glucose in the blood (see section "Special warnings and precautions for use").

Musculoskeletal and connective tissue disorders

Elevated creatine phosphokinase levels, myalgia, myositis, and rarely rhabdomyolysis have been reported during treatment with protease inhibitors, particularly when used in combination with nucleoside reverse transcriptase inhibitors.

In particular, 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 combination antiretroviral therapy (cART). The frequency of such cases is unknown (see section "Special warnings and precautions for use").

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. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the onset of these disorders is more variable and may occur long after initiation of treatment (see section "Special warnings and precautions for use").

Bleeding in patients with hemophilia

Increased spontaneous bleeding has been observed in patients with hemophilia receiving antiretroviral protease inhibitors (see section "Special warnings and precautions for use").

Pediatric population

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

Other special patient populations

Patients with chronic hepatitis B or C

In such patients, elevations in liver transaminases occurred more frequently at the start and during treatment compared to patients without chronic viral hepatitis (see section "Special warnings and precautions for use").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, or their legal representatives should report any 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. After first opening of the bottle, the product may be used for up to 3 months.

Storage conditions.

Keep the bottle tightly closed to protect from moisture. Store out of reach of children.

Packaging.

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

800 mg: 30 tablets in a high-density polyethylene bottle with a polypropylene screw cap and child-resistant closure; 1 bottle per 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.