INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DANA VIR (DANAVIR)

Composition:

active substance: darunavir;

1 tablet contains 400 mg of darunavir;

excipients: silicified microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II Orange 85F530007 (composition: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171), Yellow FCF (E 110)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets of orange color, oval-shaped, with beveled edges, biconvex, marked with "H" on one side and "189" on the other.

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 virions.

In vitro antiviral activity

Darunavir demonstrates activity against laboratory strains and clinical isolates of HIV-1, as well as laboratory strains of HIV-2, in acutely infected T-cell lines, human 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 exhibits in vitro antiviral activity against a broad spectrum of primary isolates of HIV-1 group M (A, B, C, D, E, F, G) and group O, with EC50 values ranging from <0.1 to 4.3 nM. These EC50 values are substantially lower than the 50% range of cellular cytotoxic concentrations (87 µM to >100 µM).

Resistance

In vitro selection of darunavir-resistant viruses from wild-type HIV-1 was a prolonged process (>3 years). Selected viruses were unable to grow in the presence of darunavir at concentrations exceeding 400 nM. Viruses selected under these conditions and showing reduced susceptibility to darunavir (range: 23- to 50-fold change) harbored 2 to 4 amino acid substitutions in the protease gene. The reduced susceptibility of newly emerging viruses in selection experiments could not be fully explained by the emergence of these protease mutations alone.

Clinical trials in treatment-experienced patients demonstrated that virological response to darunavir/low-dose ritonavir combination therapy decreased when three or more darunavir resistance-associated mutations (DRV-RAMs) (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V, and L89V) were present at baseline or developed during treatment.

Increased baseline fold change (FC) in darunavir EC50 was associated with reduced virological response. Clinical cutoff values have been identified at 10 and 40. Isolates with baseline FC ≤10 are considered sensitive, isolates with FC >10–40 have reduced sensitivity, and isolates with FC >40 are considered resistant.

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

The lowest frequency of HIV resistance development was observed in antiretroviral therapy-naïve patients receiving darunavir for the first time in combination with other antiretroviral agents.

Low rates of HIV-1 resistance development were observed in treatment-naïve patients initiating darunavir/cobicistat once daily in combination with other antiretroviral drugs, as well as in treatment-experienced patients without darunavir-resistant mutations receiving darunavir/cobicistat.

Cross-resistance

The fold change in darunavir EC50 was less than 10 in 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and/or tipranavir, indicating that viruses resistant to most protease inhibitors remain sensitive to darunavir.

Pharmacokinetics

The pharmacokinetic properties of darunavir administered in combination with cobicistat or ritonavir have been studied in healthy adult volunteers and in HIV-1-infected patients. Darunavir plasma concentrations were higher in HIV-1-infected patients than in healthy volunteers. This difference can be explained by higher levels of alpha-1-acid glycoprotein (AAG) in HIV-1-infected patients, resulting in greater binding of darunavir to plasma AAG and thus increased total darunavir plasma concentrations. Darunavir is primarily metabolized by CYP3A enzymes. Cobicistat and ritonavir inhibit hepatic CYP3A enzymes, thereby significantly increasing darunavir plasma concentrations. Information on cobicistat pharmacokinetics is provided in its medical instructions.

Absorption

After oral administration, darunavir is rapidly absorbed in the gastrointestinal tract. Maximum plasma concentration 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%, increasing to 82% when co-administered with ritonavir (100 mg twice daily). The overall pharmacokinetic effect of ritonavir results in an approximately 14-fold increase in darunavir plasma concentration after a single 600 mg oral dose of darunavir co-administered with ritonavir (100 mg twice daily).

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

Distribution

Approximately 95% of darunavir is bound to plasma proteins, primarily to alpha-1-acid glycoprotein.

Following 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 ritonavir 100 mg twice daily.

Metabolism

In vitro studies using human liver microsomes have shown that darunavir undergoes primarily oxidative metabolism. Darunavir is extensively metabolized in the liver by the cytochrome P450 system, almost exclusively by the CYP3A4 enzyme. A study in healthy volunteers receiving 14C-darunavir showed that the majority of radioactivity in plasma after a single 400 mg dose of darunavir and 100 mg ritonavir was attributable to unchanged darunavir. At least three oxidative metabolites of darunavir have been identified in humans; the antiviral activity of all metabolites against wild-type HIV was at least 10-fold lower than that of darunavir itself.

Elimination. After a single oral dose of 400 mg 14C-darunavir and 100 mg ritonavir, approximately 79.5% and 13.9% of radioactivity were recovered in feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of radioactivity in feces and urine, respectively. The terminal half-life of darunavir is approximately 15 hours when administered in combination with ritonavir. Darunavir clearance after intravenous administration of 150 mg was 32.8 L/h (without ritonavir) and 5.9 L/h with low-dose ritonavir.

Special patient populations

Children

Pharmacokinetics of darunavir in combination with ritonavir twice daily in patients aged 6 to 17 years and weighing at least 20 kg who had prior antiretroviral treatment showed that darunavir/ritonavir plasma concentrations at weight-based dosing were similar to those in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section "Dosage and administration").

Pharmacokinetics of darunavir in combination with ritonavir twice daily in patients aged 3 to 6 years and weighing 15 to 20 kg who had prior antiretroviral treatment showed that darunavir/ritonavir plasma concentrations at weight-based dosing were similar to those in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section "Dosage and administration").

Pharmacokinetics of darunavir in combination with ritonavir once daily in patients aged 12 to 18 years and weighing at least 40 kg who were antiretroviral therapy-naïve showed that darunavir/ritonavir plasma concentrations after administration of 800/100 mg once daily were similar to those in adults receiving darunavir/ritonavir 800/100 mg once daily. Therefore, the same dosing regimen of 800 mg once daily is recommended for children aged 12 to 18 years weighing over 40 kg who are antiretroviral therapy-naïve, in the absence of HIV-1 darunavir resistance-associated mutations (DRV-RAMs)1 and with plasma HIV-1 RNA <100,000 copies/mL and CD4+ ≥100 cells×106/L (see section "Dosage and administration").

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

Pharmacokinetics of darunavir in combination with ritonavir once daily in patients aged 3 to 6 years and weighing 14 to 20 kg who had prior antiretroviral treatment showed that darunavir/ritonavir plasma concentrations at weight-based dosing were similar to those in adults receiving darunavir/ritonavir 800/100 mg once daily. Population pharmacokinetic modeling of darunavir in patients aged 3 to 18 years confirmed comparable exposure to that observed in clinical studies and allowed dose recommendations to be established for children weighing at least 15 kg, whether antiretroviral therapy-naïve or experienced, in the absence of HIV-1 darunavir resistance-associated mutations (DRV-RAMs)1, with plasma HIV-1 RNA <100,000 copies/mL and CD4+ ≥100 cells×106/L (see section "Dosage and administration").

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

The pharmacokinetics of darunavir 800 mg with cobicistat 150 mg were studied in adolescents aged 12 to 18 years weighing at least 40 kg. Geometric mean exposure (AUCtau) in adolescents was similar for darunavir and 19% higher for cobicistat compared to adults receiving darunavir 800 mg with cobicistat 150 mg. The difference observed for cobicistat was not considered clinically significant.

Elderly patients

Population pharmacokinetic analysis demonstrated no significant differences in darunavir pharmacokinetic parameters in HIV-infected patients aged 18–75 years (including 12 HIV-infected patients aged ≥65 years). However, only limited data are available for patients aged 65 years and older.

Gender

Population pharmacokinetic analysis revealed slightly higher (16.8%) darunavir concentrations in HIV-infected women compared to HIV-infected men. This difference is not considered clinically significant.

Patients with renal impairment

Studies using 14C-darunavir in combination with ritonavir showed that approximately 7.7% of the administered dose was excreted unchanged in urine. Darunavir pharmacokinetics have not been studied in patients with renal impairment; however, population pharmacokinetic analysis showed no significant differences in darunavir pharmacokinetics in patients with moderate renal impairment (creatinine clearance 30–60 mL/min, n = 20) (see sections "Special warnings and precautions for use" and "Dosage and administration").

Patients with hepatic impairment

Darunavir is predominantly metabolized and eliminated by the liver. In dose-ranging studies with darunavir co-administered with ritonavir (600/100 mg) twice daily, total darunavir plasma concentrations in patients with mild (Child-Pugh class A, n = 8) and moderate (Child-Pugh class B, n = 8) hepatic impairment were similar to those in healthy volunteers. However, free darunavir concentrations were approximately 55% (class A) and 100% (class B) higher, respectively. The clinical significance of this increase is unknown; however, Danavir should be used with caution. The effect of severe hepatic impairment on darunavir pharmacokinetics has not been studied (see sections "Contraindications", "Special warnings and precautions for use", and "Dosage and administration").

Pregnancy and postpartum period

Overall exposure to darunavir and ritonavir after administration of 600 mg/100 mg twice daily or 800 mg/100 mg once daily as part of antiretroviral therapy was generally lower during pregnancy compared to the postpartum period, although pharmacokinetic parameters of unbound darunavir decreased less during pregnancy than postpartum due to increased unbound darunavir fraction during pregnancy.

In women receiving darunavir/ritonavir 600 mg/100 mg twice daily during the second trimester of pregnancy, mean intrasubject values of Cmax, AUC12h, and Cmin for total darunavir were 28%, 26%, and 26% lower, respectively, compared to the postpartum period; during the third trimester, these values were 18%, 16%, and 2% lower, respectively, compared to postpartum.

In women receiving darunavir/ritonavir 800 mg/100 mg twice daily during the second trimester of pregnancy, mean intrasubject values of Cmax, AUC24h, and Cmin for total darunavir were 33%, 31%, and 30% lower, respectively; during the third trimester, they were 29%, 32%, and 50% lower, respectively, compared to the postpartum period.

Darunavir/cobicistat 800/150 mg once daily during pregnancy results in low darunavir exposure. In women receiving darunavir/cobicistat during the second trimester of pregnancy, mean intra-individual values of Cmax, AUC24h, and Cmin for darunavir were 49%, 56%, and 92% lower, respectively, compared to the postpartum period; during the third trimester, total Cmax, AUC24h, and Cmin values for darunavir were 37%, 50%, and 89% lower, respectively, compared to the postpartum period. The unbound fraction was also substantially reduced, including approximately 90% reduction in Cmin levels. The primary reason for these low exposures is the marked reduction in cobicistat exposure due to pregnancy-related enzyme induction.

Cobicistat exposure was lower during pregnancy, potentially leading to suboptimal boosting of darunavir. During the second trimester, Cmax, AUC24h, and Cmin of cobicistat were 50%, 63%, and 83% lower, respectively, compared to the postpartum period. During the third trimester, Cmax, AUC24h, and Cmin of cobicistat were 27%, 49%, and 83% lower, respectively, compared to the postpartum period.

Clinical characteristics

Indications

Davavir in combination with low-dose ritonavir and other antiretroviral medicinal products is indicated for the treatment of patients infected with human immunodeficiency virus (HIV-1).

Davavir in combination with cobicistat and other antiretroviral medicinal products is indicated for the treatment of adult patients infected with human immunodeficiency virus (HIV-1).

Davavir 400 mg is indicated 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;
• who have previously received antiretroviral therapy and who do not have HIV-1 resistance-associated mutations to darunavir (DRV-RAMs), with plasma HIV-1 RNA levels <100,000 copies/mL and CD4+ cell count ≥100 cells×10⁶/L. Genotypic testing results should be considered when deciding to initiate treatment with Davavir in this patient group.

Contraindications

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

Severe hepatic impairment (Child-Pugh class C).

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

• For darunavir boosted with ritonavir or cobicistat:
  • combination lopinavir/ritonavir#;
  • strong inducers of CYP3A4 – 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 compared to 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 to the concomitant medicinal product. 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 the section "Interaction with other medicinal products and other types of interactions");
• sildenafil used for the treatment of pulmonary arterial hypertension, avanafil;
• simvastatin, lovastatin, and lomitapide#;
• ticagrelor#.

Interaction with other medicinal products and other types of interactions

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 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 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 activity are expected to increase the clearance of darunavir and ritonavir, leading to reduced plasma concentrations, loss of therapeutic effect, and development of resistance (see sections "Contraindications" and "Special precautions for use"). Contraindicated CYP3A inducers include rifampicin, herbal products containing St. John’s wort, 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 the table below).

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 lead to 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/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/cobicistat with weak and moderate CYP3A inducers (e.g., efavirenz, etravirine, nevirapine, fluticasone, bosentan) is not recommended (see table below).

The same recommendations apply regarding concomitant use with strong CYP3A4 inhibitors, regardless of whether darunavir is boosted with ritonavir or cobicistat (see section above).

Medicinal products affected by darunavir boosted with ritonavir

Darunavir and ritonavir are inhibitors of CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concomitant use of the darunavir/ritonavir combination with medicinal products that are primarily metabolized by CYP3A4 and/or CYP2D6 or transported by P-gp may lead to increased plasma concentrations of such products, which in turn may cause 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 CYP3A4 isoenzymes and whose increased plasma concentrations 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 below).

The overall pharmacokinetic effect of ritonavir results in approximately a 14-fold increase in darunavir plasma concentration after a single 600 mg dose of darunavir in combination with 100 mg ritonavir twice daily. Therefore, Davavir should be used only in combination with a pharmacokinetic booster (see sections "Pharmacokinetics" and "Special 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 the darunavir/ritonavir combination, which may be characteristic when ritonavir doses are low. Concomitant use of darunavir and ritonavir with medicinal products primarily metabolized by CYP2D6 (such as flecainide, propafenone, metoprolol) may lead to increased plasma concentrations of these medicinal products, potentially increasing or prolonging their therapeutic effect 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 lead to reduced systemic exposure to these medicinal products, potentially reducing 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 (such as paclitaxel, rosiglitazone, repaglinide) may lead to reduced systemic exposure to these medicinal products, potentially reducing or shortening their therapeutic effect.

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

Medicinal products affected by darunavir boosted with cobicistat

Recommendations regarding the effect of darunavir on other medicinal products when used with ritonavir may also apply to darunavir in combination with cobicistat for substrates of CYP3A4, CYP2D6, P-gp, OATP1B1, and OATP1B3 (see contraindications and recommendations above). Cobicistat at a dose of 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 other properties of cobicistat, see the instructions for medical use of this medicinal product.

Interaction table

Interaction studies were conducted only in adults.

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

The interaction profile of darunavir depends on the pharmacokinetic booster (cobicistat or ritonavir) used concomitantly; therefore, darunavir may have different contraindications and recommendations for use with other medicinal products. Interaction studies listed in the table were not conducted with darunavir boosted with cobicistat. Unless otherwise specified, the same dosing recommendations may apply. For detailed information, refer to the instructions for medical use of cobicistat.

Interactions of darunavir/ritonavir with other antiretroviral and non-antiretroviral medicinal products are indicated in the table below (not determined – ND). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval (CI) of the geometric mean ratio: within (↔), below (↓), or above (↑) the range of 80–125%. If recommendations differ for ritonavir and cobicistat, the booster is specified. If recommendations for concomitant use are the same, the term "boosted Davavir" is used.

The list of examples of interactions between medicinal products provided below is not exhaustive; therefore, refer to the instructions for medical use of each medicinal product used concomitantly with darunavir to obtain information on metabolism, interaction pathways, potential risks, and necessary specific actions when used concomitantly.

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., (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.

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.

DANAVIR must always be administered in combination with cobicistat or a low dose of ritonavir as pharmacokinetic enhancers, and also in combination with other antiretroviral agents (see section "Pharmacokinetics"). Prior to initiating therapy with DANAVIR, the prescribing information for cobicistat and ritonavir should be reviewed.

Increasing the ritonavir dose above that recommended in the 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 α1-acid glycoprotein. This protein binding is concentration-dependent with saturation characteristics. Therefore, displacement by drugs with higher affinity for binding to α1-acid glycoprotein cannot be excluded (see section "Interaction with other medicinal products and other forms of interaction").

Previously antiretroviral-treated patients – once-daily dosing regimen

The medicinal product DANAVIR in combination with cobicistat or low-dose ritonavir once daily must not be used in patients with one or more darunavir resistance-associated mutations (DRV-RAMs), or with HIV-1 RNA ≥100,000 copies/mL, or 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 subtypes other than subtype B (see section "Pharmacological properties. Pharmacokinetics").

Children

DANAVIR is not recommended for use in children under 3 years of age or weighing less than 15 kg. DANAVIR 400 mg tablets must not be administered to children under 12 years of age or weighing less than 40 kg.

Pregnancy

DANAVIR may be used during pregnancy only if the expected benefit outweighs the potential risk. Caution should be exercised when administering DANAVIR to pregnant women in combination with other medicinal products that may reduce darunavir concentrations (see sections "Pharmacokinetics" and "Dosage and administration").

Treatment with darunavir/cobicistat 800/150 mg once daily during the second and third trimesters of pregnancy has been shown to result in low darunavir exposure, with approximately a 90% reduction in Cmin levels (see section "Pharmacokinetics"). Cobicistat levels are also reduced and may not provide sufficient boosting. Markedly reduced darunavir exposure may lead to virological failure and an increased risk of mother-to-child transmission of HIV. Therefore, darunavir/cobicistat therapy should not be initiated during pregnancy, and women who become pregnant while on darunavir/cobicistat therapy should be switched to an alternative regimen (see sections "Special precautions for use" and "Adverse reactions").

Darunavir co-administered with low-dose ritonavir may be considered as an alternative.

Elderly patients

Information on the use of DANAVIR in patients aged 65 years and older is limited; therefore, caution should be exercised when administering this medicinal product to such patients, as they are more likely to have hepatic dysfunction and are more likely to have comorbid conditions or receive concomitant medications (see sections "Pharmacokinetics" and "Dosage and administration").

Severe skin reactions

During clinical trials of darunavir/ritonavir, severe skin reactions, including fever and/or elevated liver transaminases, were observed in 0.4% of patients. DRESS syndrome and Stevens-Johnson syndrome were reported rarely (< 0.1%). Cases of toxic epidermal necrolysis and acute generalized exanthematous pustulosis have been reported during the post-marketing period (< 0.01%). If severe skin reactions occur, DANAVIR should be discontinued immediately. These reactions may include, but are not limited to: severe rash or rash accompanied by fever, malaise, fatigue, muscle or joint pain, blistering, mucosal lesions in the oral cavity, conjunctivitis, hepatitis, and/or eosinophilia.

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

Darunavir contains a sulfonamide moiety. DANAVIR should be used with caution in patients with known hypersensitivity to sulfonamides.

Hepatotoxicity

Cases of drug-induced hepatitis (acute hepatitis, cytolytic hepatitis) have been reported during darunavir treatment. In clinical trial programs, hepatitis was observed in 0.5% of patients receiving combination antiretroviral therapy with darunavir/ritonavir. Patients with pre-existing hepatic impairment, including chronic hepatitis B and C, have an increased risk of hepatic reactions, including severe and potentially life-threatening adverse reactions. When concomitant antiviral therapy for hepatitis B and C is administered, appropriate information should be obtained from the prescribing information for those medicinal products.

Prior to initiating treatment with DANAVIR boosted with cobicistat or low-dose ritonavir, appropriate laboratory tests should be performed and patients should be monitored throughout therapy. Monitoring of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels is recommended in patients with chronic hepatitis, cirrhosis, or those with elevated transaminase levels prior to treatment initiation, especially during the first months of therapy with DANAVIR boosted with cobicistat or low-dose ritonavir.

If new or worsening hepatic dysfunction occurs (including clinically significant elevations in liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, hepatic tenderness, or hepatomegaly) in patients receiving DANAVIR with cobicistat or low-dose ritonavir, consideration should be given to interrupting or discontinuing therapy.

Patients with comorbidities

Patients with hepatic disease

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

Patients with renal disease

There are no specific warnings or need for dose adjustment in patients with renal impairment. Darunavir and ritonavir are highly protein-bound in plasma; therefore, hemodialysis or peritoneal dialysis does not significantly contribute to the elimination of these drugs. There are no specific warnings or need for dose adjustment in patients with renal impairment (see sections "Pharmacokinetics" and "Dosage and administration"). The use of cobicistat in patients on dialysis has not been studied; therefore, no dosing recommendations for darunavir/cobicistat can be provided for this patient population (see section "Dosage and administration").

Cobicistat reduces creatinine clearance by inhibiting tubular secretion of creatinine. This should be taken into account when prescribing darunavir in combination with cobicistat to patients whose creatinine clearance values are used to adjust doses of other medicinal products (see section "Dosage and administration" and the prescribing information for cobicistat).

Currently, 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 hemophilia

There are reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia A and B during treatment with protease inhibitors. Some of these patients were receiving factor VIII. In more than half of the reported cases, protease inhibitor treatment was continued uninterrupted or resumed after a temporary interruption. A causal relationship between protease inhibitor therapy and increased bleeding in hemophilia patients has been suggested, although the mechanism remains unclear. Hemophilia patients should be informed about the possibility of increased bleeding.

Body weight and metabolic parameters

During antiretroviral therapy, increases in body weight and levels of blood lipids and glucose may occur. These changes may be partly related to disease control and lifestyle. In some cases, elevated lipid levels have been linked to treatment, while sufficient evidence linking weight gain to treatment has not been established. Guidelines for HIV management should be followed regarding monitoring of blood lipid and glucose levels. Lipid abnormalities should be managed according to clinical practice.

Osteonecrosis

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

Immune reconstitution inflammatory syndrome

In HIV-infected patients with severe immunodeficiency at the initiation of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic infections may occur, leading to serious clinical complications or worsening of symptoms. Such reactions are typically observed within the first weeks or months of cART. Examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jirovecii pneumonia (previously known as Pneumocystis carinii pneumonia). The severity of any inflammatory condition should be assessed and appropriate therapy initiated. Reactivation of herpes simplex and herpes zoster has also been observed in clinical trials during concomitant use of darunavir/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 several months after initiation of antiretroviral therapy.

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 booster and concomitant medicinal products

Darunavir has different interaction profiles depending on whether cobicistat or ritonavir is used as the pharmacokinetic booster.

• Darunavir boosted with cobicistat is more sensitive to CYP3A enzyme induction: concomitant use of darunavir/cobicistat with CYP3A inducers is contraindicated (see section "Contraindications"), and concomitant use with weak/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 enzyme or transporter protein induction properties (see section "Interaction with other medicinal products and other forms of interaction"). When switching from ritonavir to cobicistat as the pharmacokinetic booster, caution should be exercised during the first two weeks of darunavir/cobicistat therapy, especially if doses of any concomitant medicinal product were adjusted during ritonavir use. In such cases, dose reduction of the concomitant drug may be necessary.

Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in suboptimal darunavir Cmin levels. If efavirenz must be used in combination with darunavir/ritonavir, a dosage regimen of darunavir/ritonavir 600/100 mg twice daily is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Life-threatening interactions have been reported in patients receiving colchicine concomitantly with strong inhibitors of CYP3A and P-gp (see section "Interaction with other medicinal products and other forms of interaction").

DANAVIR 400 mg tablets contain the colorant Yellow West FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy

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

Adequate and well-controlled studies on pregnancy outcomes with darunavir use in pregnant women have not been conducted. Animal studies did not reveal any direct adverse effects on pregnancy, embryonal/fetal development, parturition, or postnatal development.

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

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure (see section "Pharmacokinetics"), which may be associated with an increased risk of treatment failure and higher risk of mother-to-child HIV transmission. Therefore, darunavir/cobicistat therapy should not be initiated during pregnancy, and women who become pregnant while on darunavir/cobicistat therapy should be switched to an alternative regimen (see sections "Special precautions for use" and "Dosage and administration").

Prospective pregnancy data obtained from the Antiretroviral Pregnancy Registry are insufficient to adequately assess the risk of congenital malformations or spontaneous abortion. Available limited data do not show a statistically significant difference in the overall risk of major congenital malformations with darunavir use compared to the background rate of major congenital malformations.

Breastfeeding

It is unknown whether darunavir is excreted in human breast milk. Animal studies in rats showed that the drug was excreted in milk and caused toxicity in offspring at high doses (1000 mg/kg/day).

Given the potential for adverse reactions in breastfed infants, women should be advised not to breastfeed if they are receiving DANAVIR. To prevent HIV transmission to infants, breastfeeding is not recommended for women living with HIV.

Fertility

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

Ability to drive and use machines

Treatment with DANAVIR in combination with cobicistat or low-dose 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 considered when assessing a patient's ability to drive or operate complex machinery (see section "Adverse reactions").

Method of Administration and Dosage

Treatment should be initiated by a physician experienced in the management of HIV infection. After initiation of therapy with Danavir, patients should be advised not to change the dose or discontinue treatment without consulting their physician.

The interaction profile of darunavir depends on the pharmacokinetic booster (cobicistat or ritonavir) used concomitantly; therefore, darunavir may have different contraindications and recommendations for use with other medicinal products (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction", and "Special warnings and precautions for use").

Danavir must always be administered with cobicistat or low-dose ritonavir as agents that enhance its pharmacokinetic properties, and in combination with other antiretroviral agents. Prior to initiating therapy with Danavir, the prescribing information for cobicistat or ritonavir should be consulted. Cobicistat is not recommended for twice-daily regimens or for use in children under 12 years of age and weighing less than 40 kg.

Adult patients who have not previously received antiretroviral therapy

The recommended dose of Danavir is 800 mg once daily in combination with 150 mg cobicistat or 100 mg ritonavir; the combination should be taken with food. Danavir 400 mg tablets may be used to achieve the appropriate dosing regimen.

Adult patients who have previously received antiretroviral therapy

• For patients without HIV-1 mutations associated with resistance to darunavir (DRV-RAMs)1, with plasma HIV-1 RNA levels <100,000 copies/mL and CD4+ cell count ≥ 100 cells×10⁶/L (see section "Indications"), a dosing regimen of 800 mg once daily in combination with 150 mg cobicistat or 100 mg ritonavir once daily with food may be used.
• For all other patients, or when genotypic testing is not feasible, the recommended dosing regimen is 600 mg twice daily in combination with 100 mg ritonavir twice daily with food.

1 (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 and weighing at least 40 kg)

The recommended dose of Danavir is 800 mg once daily in combination with 100 mg ritonavir; the combination should be taken with food; or 800 mg once daily with 150 mg cobicistat once daily with food (in adolescent patients aged 12 years and older). Danavir 400 mg tablets may be used to achieve the appropriate dosing regimen. The dose of cobicistat for use with Danavir in children under 12 years of age has not been established.

Children who have previously received antiretroviral therapy (aged 12 to 17 years and weighing at least 40 kg)

The dose of cobicistat for use with Danavir in children under 12 years of age has not been established.

• For patients without HIV-1 mutations associated with resistance to darunavir (DRV-RAMs)1, with plasma HIV-1 RNA levels <100,000 copies/mL and CD4+ cell count ≥ 100 cells×10⁶/L (see section "Indications"), a dosing regimen of 800 mg once daily in combination with 100 mg ritonavir once daily with food may be used; or 800 mg once daily with 150 mg cobicistat once daily with food (in adolescent patients aged 12 years and older). Danavir 400 mg tablets may be used to achieve the appropriate dosing regimen. The dose of cobicistat for use with Danavir in children under 12 years of age has not been established.
• For all other patients, or when genotypic testing is not feasible, the recommended dosing regimen is described in the prescribing information for Danavir 600 mg tablets.

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

Missed dose recommendations

If a once-daily dose of Danavir and/or cobicistat or ritonavir is missed within 12 hours of the usual dosing time, the prescribed dose of Danavir and cobicistat or 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; continue with the next scheduled dose.

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

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

Elderly patients

Limited data are available for this patient group; therefore, Danavir should be used with caution in elderly patients (see sections "Pharmacokinetics" and "Special warnings and precautions for use").

Patients with hepatic impairment

Darunavir is metabolized in the liver. Dose adjustment is not required in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment; however, Danavir 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 exposure to darunavir and a worsened safety profile. Therefore, Danavir 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

Dose adjustment of darunavir/ritonavir is not required in patients with renal impairment. The use of cobicistat in patients on dialysis has not been studied; therefore, no dosage recommendations can be made for this patient group.

Cobicistat inhibits tubular secretion of creatinine and may cause a small increase in serum creatinine levels and minor changes in creatinine clearance. Therefore, creatinine clearance as a marker of renal function may be unreliable. Cobicistat should not be used as a pharmacokinetic booster for darunavir in patients with creatinine clearance <70 mL/min if concomitantly administered drugs (e.g., emtricitabine, lamivudine, tenofovir disoproxil fumarate, or adefovir dipivoxil) require dose adjustment based on creatinine clearance.

For additional information on cobicistat, refer to the prescribing information for this medicinal product.

Pregnancy and postpartum period

Dose adjustment of darunavir/ritonavir during pregnancy and the postpartum period is not required. Danavir may be used during pregnancy only if the potential benefit outweighs the potential risk (see sections "Pharmacokinetics", "Special warnings and precautions for use", and "Use in pregnancy and breastfeeding").

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure (see sections "Pharmacokinetics" and "Special warnings and precautions for use"). Therefore, initiation of darunavir/cobicistat therapy during pregnancy is not recommended, and women who become pregnant while on darunavir/cobicistat should be switched to an alternative regimen (see sections "Special warnings and precautions for use" and "Adverse reactions"). Darunavir/ritonavir may be considered as an alternative.

Method of administration

Danavir with cobicistat or low-dose ritonavir should be taken within 30 minutes after a meal. The type of food does not affect darunavir exposure.

Children

Applicable to children aged 12 years and older weighing at least 40 kg.

Overdose

Information on acute overdose with darunavir in combination with cobicistat or 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 as darunavir tablets in combination with ritonavir, without observing adverse symptomatic effects.

There is no specific antidote for overdose with Danavir. In case of overdose, general supportive measures should be implemented, with monitoring of vital signs and close observation of the patient's clinical status. Since darunavir is highly protein-bound, dialysis is unlikely to be beneficial for significant removal of the active substance.

Adverse Reactions

The most commonly reported adverse reactions in clinical trials and spontaneous reports were diarrhea, nausea, rash, headache, and vomiting. The most frequently reported serious reactions were acute renal failure, myocardial infarction, immune reconstitution syndrome, thrombocytopenia, osteonecrosis, diarrhea, hepatitis, and pyrexia.

The study established that the safety profile of darunavir/ritonavir at a dose of 800 mg/100 mg once daily in treatment-naïve subjects was similar to the safety profile of the combination at a dose of 600 mg/100 mg twice daily in treatment-experienced subjects, except for the incidence of moderate-intensity nausea, which was more frequently observed in treatment-naïve subjects. No additional safety data on the darunavir/ritonavir combination at a dose of 800 mg/100 mg once daily in treatment-naïve subjects were identified in the study.

During the study with darunavir/cobicistat, the most commonly reported adverse reactions were diarrhea, nausea, and rash. Serious adverse reactions included diabetes mellitus, hypersensitivity (to the medicinal product), immune reconstitution inflammatory syndrome, rash, and vomiting.

The adverse reactions listed below are grouped by organ systems and frequency. Within each frequency category, adverse reactions are listed in order of decreasing severity. Frequency is defined as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), and not known (frequency cannot be determined from available data).

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

§ Adverse reaction identified during the post-marketing period.

Adverse reactions observed in patients receiving darunavir/cobicistat

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

§ Adverse reaction identified during the post-marketing period.

Description of selected adverse reactions

Skin rash

During clinical trials, rashes observed were mild to moderate in severity, most commonly occurred during the first four weeks of treatment, and resolved upon discontinuation of treatment. For severe skin reactions, see section "Special precautions". In a study of darunavir 800 mg once daily in combination with cobicistat 150 mg and other antiretroviral agents, 2.2% of patients discontinued treatment due to rash.

During the clinical development program of raltegravir in treatment-experienced patients, rashes (regardless of cause) occurred more frequently with darunavir/ritonavir + raltegravir regimens compared to darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir. The incidence of drug-related rash was similar across regimens. The incidence rate of rash adjusted for exposure (all causes) was 10.9, 4.2, and 3.8 per 100 patient-years (PY), respectively; for drug-related rashes, the rates were 2.4, 1.1, and 2.3 per 100 PY, respectively. Rashes observed in clinical trials were mild to moderate and did not lead to discontinuation of therapy (see section "Special precautions").

Metabolic parameters

During antiretroviral therapy, increases in blood lipid and glucose levels may occur (see section "Special precautions").

Disorders of muscle and connective tissue

Cases of increased creatine kinase levels, myalgia, myositis, and rarely rhabdomyolysis have been reported with protease inhibitors, particularly when used in combination with nucleoside reverse transcriptase inhibitors.

Cases of osteonecrosis have been observed, particularly in patients with well-recognized risk factors, advanced HIV disease, or long-term combined antiretroviral therapy. The frequency of these cases is unknown (see section "Special precautions").

Immune reconstitution inflammatory syndrome

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

Bleeding in patients with haemophilia

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

Children

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

The safety of darunavir with cobicistat in pediatric patients was evaluated in adolescents aged 12 to less than 18 years with body weight at least 40 kg. Safety analysis from this adolescent study did not reveal any new safety concerns compared to the known safety profile of darunavir and cobicistat in adults.

Other patient categories

Patients with chronic hepatitis B and C

Among patients receiving darunavir with ritonavir 600/100 mg twice daily, some were co-infected with hepatitis B and/or C. In patients with chronic hepatitis, elevations in liver transaminases occurred more frequently than in patients without chronic viral hepatitis (see section "Special precautions").

Post-marketing experience

The following adverse reactions have been identified during post-marketing use of darunavir. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Redistribution of body fat has been reported.

Rhabdomyolysis has been rarely reported (associated with concomitant use of HMG-CoA reductase inhibitors and darunavir/ritonavir).

Additionally, rare cases of toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and drug-induced eosinophilia with systemic symptoms (DIHS) have been reported.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 60 tablets in a container; 1 container in a carton.

Prescription status. Prescription only.

Manufacturer

Hetero Labs Limited.

Manufacturer's address and location of its operations

Unit III, Formulation Plot No 22 – 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.