Chemical formula: C₂₇H₃₇N₃O₇S Molecular mass: 547.664 g/mol PubChem compound: 213039
Darunavir interacts in the following cases:
A safe and effective dose of sildenafil for the treatment of pulmonary arterial hypertension coadministered with boosted darunavir has not been established. There is an increased potential for sildenafilassociated adverse events (including visual disturbances, hypotension, prolonged erection and syncope). Therefore, co-administration of boosted darunavir and sildenafil when used for the treatment of pulmonary arterial hypertension is contraindicated.
Co-administration of tadalafil for the treatment of pulmonary arterial hypertension with boosted darunavir is not recommended.
Concomitant use of sildenafil or tadalafil for the treatment of pulmonary arterial hypertension and boosted darunavir may increase plasma concentrations of sildenafil or tadalafil (CYP3A inhibition).
Concomitant use of boosted darunavir and corticosteroids (all routes of administration) that are metabolised by CYP3A may increase the risk of development of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression.
Co-administration with CYP3Ametabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects.
Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone should be considered, particularly for long term use.
Interaction – Geometric mean change (%):
Fluticasone: in a clinical study where ritonavir 100 mg capsules twice daily were co-administered with 50 μg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82-89%). Greater effects may be expected when fluticasone is inhaled. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone. The effects of high fluticasone systemic exposure on ritonavir plasma levels are unknown.
Other corticosteroids: interaction not studied. Plasma concentrations of these medicinal products may be increased when co-administered with boosted darunavir, resulting in reduced serum cortisol concentrations.
Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of these compounds and consequently that of darunavir, leading to loss of therapeutic effect and possible development of resistance. CYP3A inducers that are contraindicated include rifampicin, St John’s wort and lopinavir.
Darunavir and cobicistat are metabolised by CYP3A, and co-administration with CYP3A inducers may therefore result in subtherapeutic plasma exposure to darunavir. Darunavir boosted with cobicistat is more sensitive to CYP3A induction than ritonavir-boosted darunavir: co-administration of darunavir/cobicistat with medicinal products that are strong inducers of CYP3A (e.g. St John’s wort, rifampicin, carbamazepine, phenobarbital, and phenytoin) is contraindicated. Co-administration of darunavir/cobicistat with weak to moderate CYP3A inducers (e.g. efavirenz, etravirine, nevirapine, boceprevir, fluticasone, and bosentan) is not recommended.
Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrations of darunavir and ritonavir. Co-administration with strong CYP3A4 inhibitors is not recommended and caution is warranted, these interactions are described in the interaction table below.
Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or transported by P-gp may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.
Darunavir co-administered with low dose ritonavir must not be combined with medicinal products that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index).
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily. Therefore, darunavir must only be used in combination with a pharmacokinetic enhancer.
A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to the presence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone, repaglinide) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration with substrates of these transporters can result in increased plasma concentrations of these compounds (e.g. dabigatran etexilate, digoxin, statins and bosentan).
Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, darunavir should be used with caution in these patients.
The recommended dose of emtricitabine/tenofovir alafenamide is 200/10 mg once daily when used with boosted darunavir.
Interaction – Geometric mean change (%):
Tenofovir alafenamide ↔
Tenofovir ↑
The combination of boosted darunavir and artemether/lumefantrine can be used without dose adjustments; however, due to the increase in lumefantrine exposure, the combination should be used with caution.
Interaction – Geometric mean change (%):
Artemether/Lumefantrine 80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours
artemether: AUC ↓ 16%, Cmin ↔, Cmax ↓ 18%
dihydroartemisinin: AUC ↓18%, Cmin ↔, Cmax ↓ 18%
lumefantrine: AUC ↑ 175%, Cmin ↑ 126%, Cmax ↑ 65%
darunavir: AUC ↔, Cmin ↓13%, Cmax ↔
The concomitant use with boosted darunavir may require to lower the dose of alfentanil and requires monitoring for risks of prolonged or delayed respiratory depression.
The metabolism of alfentanil is mediated via CYP3A, and may as such be inhibited by boosted darunavir.
Clinical monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with boosted darunavir.
Boosted darunavir can be expected to increase the plasma concentrations of calcium channel blockers (CYP3A and/or CYP2D6 inhibition).
Darunavir co-administered with low dose ritonavir and atazanavir can be used without dose adjustments.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4.
Interaction – Geometric mean change (%):
atazanavir: AUC ↔, Cmin ↑52%, Cmax ↓11%
#darunavir AUC: ↔, Cmin ↔, Cmax ↔
Atazanavir: comparison of 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 of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg twice daily in combination with atazanavir 300 mg once daily.
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen.
When administration of atorvastatin and boosted darunavir is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily. A gradual dose increase of atorvastatin may be tailored to the clinical response.
Interaction – Geometric mean change (%):
Atorvastatin 10 mg once daily
atorvastatin: AUC ↑ 3-4 fold, Cmin ↑ ≈5.5-10 fold, Cmax ↑ ≈2 fold
#darunavir/ritonavir
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen.
atorvastatin: AUC ↑ 290%Ω, Cmax ↑ 319%Ω, Cmin NDΩ
Ω: with darunavir/cobicistat 800/150 mg
It is not recommended to co-administer boosted darunavir and boceprevir.
boceprevir AUC: ↓32%
boceprevir Cmin: ↓35%
boceprevir Cmax: ↓25%
darunavir AUC: ↓44%
darunavir Cmin: ↓59%
darunavir Cmax: ↓36%
When administered concomitantly with darunavir and low dose ritonavir, the patient’s tolerability of bosentan should be monitored.
Co administration of darunavir co-administered with cobicistat and bosentan is not recommended.
Concomitant use of bosentan and boosted darunavir may increase plasma concentrations of bosentan.
Bosentan is expected to decrease plasma concentrations of darunavir and/or its pharmacoenhancer (CYP3A induction).
The clinical relevance of the increase in norbuprenorphine pharmacokinetic parameters has not been established. Dose adjustment for buprenorphine may not be necessary when co-administered with boosted darunavir but a careful clinical monitoring for signs of opiate toxicity is recommended.
Interaction – Geometric mean change (%):
Buprenorphine/naloxone 8/2 mg – 16/4 mg once daily
buprenorphine: AUC ↓ 11%, Cmin ↔, Cmax ↓ 8%
norbuprenorphine: AUC ↑ 46%, Cmin ↑ 71%, Cmax ↑ 36%
naloxone: AUC ↔, Cmin ND, Cmax ↔
Clinical monitoring is recommended when co-administering boosted darunavir with these sedatives/hypnotics and a lower dose of the sedatives/hypnotics should be considered.
Sedative/hypnotics are extensively metabolised by CYP3A. Coadministration with boosted darunavir may cause a large increase in the concentration of these medicines.
If parenteral midazolam is coadministered with boosted darunavir, it should be done in an intensive care unit (ICU) or similar setting, which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.
If parenteral midazolam is co-administered with boosted darunavir it may cause a large increase in the concentration of this benzodiazepine. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.
No dose adjustment for darunavir/ritonavir is recommended. If there is a need to combine darunavir/ritonavir and carbamazepine, patients should be monitored for potential carbamazepine-related adverse events. Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response. Based upon the findings, the carbamazepine dose may need to be reduced by 25% to 50% in the presence of darunavir/ritonavir.
The use of carbamazepine with darunavir co-administered with cobicistat is contraindicated.
carbamazepine: AUC ↑ 45%, Cmin ↑ 54%, Cmax ↑ 43%
darunavir: AUC ↔, Cmin ↓ 15%, Cmax ↔
Clinical monitoring is recommended when co-administering boosted darunavir with β-blockers. A lower dose of the β-blocker should be considered.
Boosted darunavir is expected to increase these β-blocker plasma concentrations (CYP2D6 inhibition).
Therapeutic drug monitoring of the immunosuppressive agent must be done when co-administration occurs.
Exposure to these immunosuppressants will be increased when co-administered with boosted darunavir (CYP3A inhibition).
Caution should be exercised when clarithromycin is combined with boosted darunavir.
For patients with renal impairment the Summary of Product Characteristics for clarithromycin should be consulted for the recommended dose.
clarithromycin: AUC ↑ 57%, Cmin ↑ 174%, Cmax ↑ 26%
#darunavir: AUC ↓ 13%, Cmin ↑ 1%, Cmax ↓ 17%
14-OH-clarithromycin concentrations were not detectable when combined with darunavir/ritonavir.
(↑ clarithromycin from CYP3A inhibition and possible P-gp inhibition)
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen.
Clinical monitoring is recommended when co-administering boosted darunavir and clonazepam.
Co-administration of boosted darunavir with clonazepam may increase concentrations of clonazepam. (CYP3A 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)
A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with boosted darunavir is required.
Concomitant use of colchicine and boosted darunavir may increase the exposure to colchicine (CYP3A and/or P-gp inhibition).
Darunavir/ritonavir: Clinical monitoring and/or dose reduction of the DOAC should be considered when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with darunavir/rtv.
Darunavir/cobicistat: Clinical monitoring and dose reduction is required when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with darunavir/cobi.
Interaction – Geometric mean change (%):
dabigatran etexilate (150 mg)
darunavir/ritonavir 800/100 mg single dose: dabigatran AUC ↑ 72%, Cmax ↑ 64%
darunavir/ritonavir 800/100 mg once daily: dabigatran AUC ↑ 18%, Cmax ↑ 22%
darunavir/cobicistat 800/150 mg single dose: dabigatran AUC ↑ 164%, Cmax ↑ 164%
darunavir/cobicistat 800/150 mg once daily: dabigatran AUC ↑ 88%, Cmax ↑ 99%
Concentrations of these medicinal products may be increased when co- administered with boosted darunavir resulting in the potential for increased adverse events usually associated with these agents.
Caution should be exercised when combining one of these antineoplastic agents with boosted darunavir.
Boosted darunavir is expected to increase these antineoplastic plasma concentrations (CYP3A inhibition).
Systemic dexamethasone should be used with caution when combined with boosted darunavir.
Not studied. Dexamethasone may decrease plasma concentrations of darunavir (CYP3A induction).
Boosted darunavir and didanosine can be used without dose adjustments. Didanosine is to be administered on an empty stomach, thus it should be administered 1 hour before or 2 hours after boosted darunavir given with food.
Interaction – Geometric mean change (%):
didanosine: AUC ↓9%, Cmin ND, Cmax ↓16%
darunavir: AUC ↔, Cmin ↔, Cmax ↔
Given that digoxin has a narrow therapeutic index, it is recommended that the lowest possible dose of digoxin should initially be prescribed in case digoxin is given to patients on boosted darunavir therapy. The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.
Interaction – Geometric mean change (%): digoxin AUC ↑ 61%, Cmin ND, Cmax ↑ 29% (↑ digoxin from probable inhibition of P-gp)
Caution is warranted and therapeutic concentration monitoring, if available, is recommended for these antiarrhythmics when co-administered with boosted darunavir.
Not studied. Boosted darunavir is expected to increase these antiarrhythmic plasma concentrations. (CYP3A and/or CYP2D6 inhibition)
Boosted darunavir and dolutegravir can be used without dose adjustment.
dolutegravir AUC: ↓22%
dolutegravir C24h: ↓38%
dolutegravir Cmax: ↓11%
darunavir ↔*
* Using cross-study comparisons to historical pharmacokinetic data.
When darunavir is coadministered with a drospirenone-containing product, clinical monitoring is recommended due to the potential for hyperkalaemia.
Alternative or additional contraceptive measures are recommended when oestrogen-based contraceptives are co-administered with boosted darunavir. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.
Interaction – Geometric mean change (%):
Drospirenone – Ethinylestradiol (3 mg/0.02 mg once daily)
drospirenone: AUC ↑ 58%€, Cmin ND€, Cmax ↑ 15%€
ethinylestradiol: AUC ↓ 30%€, Cmin ND€, Cmax ↓ 14%€
€ with darunavir/cobicistat
Ethinylestradiol – Norethindrone 35 μg/1 mg once daily
ethinylestradiol: AUC ↓ 44%β, Cmin ↓ 62%β, Cmax ↓ 32%β
norethindrone: AUC ↓ 14%β, Cmin ↓ 30%β, Cmax ↔β
β with darunavir/ritonavir
Clinical monitoring for central nervous system toxicity associated with increased exposure to efavirenz may be indicated when darunavir co-administered with low dose ritonavir is given in combination with efavirenz.
Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used.
Co-administration with darunavir co-administered with cobicistat is not recommended.
Interaction – Geometric mean change (%):
efavirenz AUC ↑ 21%, Cmin ↑ 17%, Cmax ↑ 15% (↑ efavirenz from CYP3A inhibition)
#darunavir AUC ↓ 13%, Cmin ↓ 31%, Cmax ↓ 15% (↓ darunavir from CYP3A induction)
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen.
Darunavir co-administered with low dose ritonavir and etravirine 200 mg twice daily can be used without dose adjustments.
Co-administration with darunavir co-administered with cobicistat is not recommended.
Interaction – Geometric mean change (%):
etravirine: AUC ↓37%, Cmin ↓49%, Cmax ↓32%
darunavir: AUC ↑15%, Cmin ↔, Cmax ↔
Clinical monitoring is recommended when co-administering boosted darunavir with these analgesics.
Based on theoretical considerations boosted darunavir may increase plasma concentrations of these analgesics (CYP2D6 and/or CYP3A inhibition).
Use with caution. Monitor for fesoterodine or solifenacin adverse reactions, dose reduction of fesoterodine or solifenacin may be necessary.
Caution is warranted and clinical monitoring is recommended.
When co-administration is required the daily dose of itraconazole should not exceed 200 mg.
Boosted darunavir may increase antifungal plasma concentrations and posaconazole, isavuconazole, itraconazole or fluconazole may increase darunavir concentrations (CYP3A and/or P-gp inhibition).
In a clinical study where ritonavir 100 mg capsules twice daily were co-administered with 50 μg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82-89%). Greater effects may be expected when fluticasone is inhaled. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone. The effects of high fluticasone systemic exposure on ritonavir plasma levels are unknown.
When used in combination with darunavir co-administered with low dose ritonavir, dose adjustment of indinavir from 800 mg twice daily to 600 mg twice daily may be warranted in case of intolerance.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4.
Interaction – Geometric mean change (%):
indinavir: AUC ↑ 23%, Cmin ↑ 125%, Cmax ↔
#darunavir: AUC ↑ 24%, Cmin ↑ 44%, Cmax ↑ 11%
Indinavir: comparison of indinavir/ritonavir 800/100 mg twice daily vs. indinavir/darunavir/ritonavir 800/400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with indinavir 800 mg twice daily.
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen.
The maraviroc dose should be 150 mg twice daily when co-administered with boosted darunavir.
Interaction – Geometric mean change (%): maraviroc AUC ↑ 305%, Cmin ND, Cmax ↑129%
Darunavir, ritonavir concentrations were consistent with historical data.
Careful patient monitoring and dose adjustment of metformin is recommended in patients who are taking darunavir co-administered with cobicistat (not applicable for darunavir co-administered with ritonavir).
Based on theoretical considerations darunavir co-administered with cobicistat is expected to increase metformin plasma concentrations (MATE1 inhibition).
No adjustment of methadone dosage is required when initiating co-administration with boosted darunavir. However, adjustment of the methadone dose may be necessary when concomitantly administered for a longer period of time. Therefore, clinical monitoring is recommended, as maintenance therapy may need to be adjusted in some patients.
Interaction – Geometric mean change (%):
Methadone individual dose ranging from 55 mg to 150 mg once daily
R(-) methadone AUC: ↓16%
R(-) methadone Cmin: ↓15%
R(-) methadone Cmax: ↓24%
Darunavir/cobicistat may, in contrast, increase methadone plasma concentrations.
Darunavir co-administered with low dose ritonavir and nevirapine can be used without dose adjustments.
Co-administration with darunavir co-administered with cobicistat is not recommended.
Interaction – Geometric mean change (%):
nevirapine: AUC ↑27%, Cmin ↑47%, Cmax ↑18% (↑ nevirapine from CYP3A inhibition)
#darunavir: concentrations were consistent with historical data
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen.
If antidepressants are co-administered with boosted darunavir, the recommended approach is a dose titration of the antidepressant based on a clinical assessment of antidepressant response.
In addition, patients on a stable dose of these antidepressants who start treatment with boosted darunavir should be monitored for antidepressant response.
Clinical monitoring is recommended when co-administering boosted darunavir with these antidepressants and a dose adjustment of the antidepressant may be needed.
Interaction – Geometric mean change (%):
Paroxetine 20 mg once daily
paroxetine: AUC ↓ 39%, Cmin ↓ 37%, Cmax ↓ 36%
#darunavir: AUC ↔, Cmin ↔, Cmax ↔
Sertraline 50 mg once daily
sertraline: AUC ↓ 49%, Cmin ↓ 49%, Cmax ↓ 44%
#darunavir: AUC ↔, Cmin ↓ 6%, Cmax ↔
In contrast to these data with darunavir/ritonavir, darunavir/cobicistat may increase these antidepressant plasma concentrations (CYP2D6 and/or CYP3A inhibition).
Amitriptyline, desipramine, imipramine, nortriptyline, trazodone
Concomitant use of boosted darunavir and these antidepressants may increase concentrations of the antidepressant. (CYP2D6 and/or CYP3A inhibition)
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen.
A dose decrease may be needed for these drugs when co-administered with boosted darunavir.
Not studied. Boosted darunavir is expected to increase these antipsychotic plasma concentrations (CYP3A, CYP2D6 and/or P-gp inhibition).
When administration of pravastatin and boosted darunavir is required, it is recommended to start with the lowest possible dose of pravastatin and titrate up to the desired clinical effect while monitoring for safety.
Interaction – Geometric mean change (%):
Pravastatin 40 mg single dose
pravastatin: AUC ↑ 81%¶, Cmin ND, Cmax ↑ 63%
¶: an up to five-fold increase was seen in a limited subset of subjects
At present the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically relevant. Boosted darunavir and raltegravir can be used without dose adjustments.
Some clinical studies suggest raltegravir may cause a modest decrease in darunavir plasma concentrations.
A dosage reduction of rifabutin by 75% of the usual dose of 300 mg/day (i.e. rifabutin 150 mg once every other day) and increased monitoring for rifabutin related adverse events is warranted in patients receiving the combination with darunavir co-administered with ritonavir. In case of safety issues, a further increase of the dosing interval for rifabutin and/or monitoring of rifabutin levels should be considered.
Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV infected patients.
Based upon the safety profile of darunavir/ritonavir, the increase in darunavir exposure in the presence of rifabutin does not warrant a dose adjustment for darunavir/ritonavir. Based on pharmacokinetic modeling, this dosage reduction of 75% is also applicable if patients receive rifabutin at doses other than 300 mg/day.
Co-administration of darunavir co-administered with cobicistat and rifabutin is not recommended.
The interaction trial showed a comparable daily systemic exposure for rifabutin between treatment at 300 mg once daily alone and 150 mg once every other day in combination with darunavir/ritonavir (600/100 mg twice daily) with an about 10-fold increase in the daily exposure to the active metabolite 25-O-desacetylrifabutin. Furthermore, AUC of the sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite) was increased 1.6-fold, while Cmax remained comparable. Data on comparison with a 150 mg once daily reference dose is lacking.
(Rifabutin is an inducer and substrate of CYP3A)
An increase of systemic exposure to darunavir was observed when darunavir co-administered with 100 mg ritonavir was co-administered with rifabutin (150 mg once every other day).
rifabutin: AUC** ↑ 55%, Cmin** ↑ ND, Cmax** ↔
darunavir: AUC ↑ 53%, Cmin ↑ 68%, Cmax ↑ 39%
** sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite)
When administration of rosuvastatin and boosted darunavir is required, it is recommended to start with the lowest possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for safety.
Interaction – Geometric mean change (%):
Rosuvastatin 10 mg once daily:
rosuvastatin: AUC ↑ 48%║, Cmax ↑ 144%║
║: based on published data with darunavir/ritonavir
rosuvastatin: AUC ↑ 93%§, Cmax ↑ 277%§, Cmin ND§
§: with darunavir/cobicistat 800/150 mg
It is not recommended to combine darunavir co-administered with low dose ritonavir with saquinavir.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4.
#darunavir AUC ↓ 26%, Cmin ↓ 42%, Cmax ↓ 17%
saquinavir: AUC ↓ 6%, Cmin ↓ 18%, Cmax ↓ 6%
Saquinavir: comparison of saquinavir/ritonavir 1,000/100 mg twice daily vs. saquinavir/darunavir/ritonavir 1,000/400/100 mg twice daily
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with saquinavir 1,000 mg twice daily.
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen.
Concomitant use of PDE-5 inhibitors for the treatment of erectile dysfunction with boosted darunavir should be done with caution. If concomitant use of boosted darunavir with sildenafil, vardenafil or tadalafil is indicated, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours or tadalafil at a single dose not exceeding 10 mg in 72 hours is recommended.
In an interaction study#, a comparable systemic exposure to sildenafil was observed for a single intake of 100 mg sildenafil alone and a single intake of 25 mg sildenafil co-administered with darunavir and low dose ritonavir.
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen.
It is not recommended to co-administer boosted darunavir and simeprevir.
simeprevir AUC: ↑159%
simeprevir Cmin: ↑358%
simeprevir Cmax: ↑79%
darunavir AUC: ↑18%
darunavir Cmin: ↑31%
darunavir Cmax: ↔
The dose of simeprevir in this interaction study was 50 mg when co-administered in combination with darunavir/ritonavir, compared to 150 mg in the simeprevir alone treatment group.
Monitoring of renal function may be indicated when boosted darunavir is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.
Darunavir/cobicistat: Cobicistat decreases the estimated creatinine clearance due to inhibition of tubular secretion of creatinine. This should be taken into consideration if darunavir with cobicistat is administered to patients in whom the estimated creatinine clearance is used to adjust doses of co-administered tenofovir disoproxil.
enofovir: AUC ↑22%, Cmin ↑37%, Cmax ↑24%
#darunavir: AUC ↑21%, Cmin ↑24%, Cmax ↑16%
(↑ tenofovir from effect on MDR-1 transport in the renal tubules)
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen.
Voriconazole should not be combined with boosted darunavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Not studied. Ritonavir may decrease plasma concentrations of voriconazole (induction of CYP450 enzymes).
Concentrations of voriconazole may increase or decrease when co-administered with darunavir co-administered with cobicistat (inhibition of CYP450 enzymes).
It is recommended that the international normalised ratio (INR) be monitored when warfarin is combined with boosted darunavir.
Warfarin concentrations may be affected when co-administered with boosted darunavir.
There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding.
Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.
There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding.
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.
There are no adequate and well controlled studies on pregnancy outcome with darunavir in pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Darunavir co-administered low dose ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk.
Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure, which may be associated with an increased risk of treatment failure and an increased risk of HIV transmission to the child. Therapy with darunavir/cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with darunavir/cobicistat should be switched to an alternative regimen.
It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk and at high levels (1 000 mg/kg/day) resulted in toxicity of the offspring.
Because of the potential for adverse reactions in breast-fed infants, women should be instructed not to breast-feed if they are receiving darunavir.
In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed.
No human data on the effect of darunavir on fertility are available. There was no effect on mating or fertility with darunavir treatment in rats.
Darunavir in combination with cobicistat or ritonavir has no or negligible influence on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing darunavir co-administered with cobicistat or low dose ritonavir and should be borne in mind when considering a patient’s ability to drive or operate machinery.
During the clinical development program (N=2 613 treatment-experienced subjects who initiated therapy with darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent adverse reactions reported in clinical studies and as spontaneous reports are diarrhoea, nausea, rash, headache and vomiting. The most frequent serious reactions are acute renal failure, myocardial infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis and pyrexia.
In the 96 week analysis, the safety profile of darunavir/ritonavir 800/100 mg once daily in treatmentnaïve subjects was similar to that seen with darunavir/ritonavir 600/100 mg twice daily in treatmentexperienced subjects except for nausea which was observed more frequently in treatment-naïve subjects. This was driven by mild intensity nausea. No new safety findings were identified in the 192 week analysis of the treatment-naïve subjects in which the mean treatment duration of darunavir/ritonavir 800/100 mg once daily was 162.5 weeks.
During the Phase III clinical studies GS-US-216-130 with darunavir/cobicistat (N=313 treatment-naïve and treatment-experienced subjects), 66.5% of subjects experienced at least one adverse reaction. The mean treatment duration was 58.4 weeks. The most frequent adverse reactions reported were diarrhoea (28%), nausea (23%), and rash (16%). Serious adverse reactions are diabetes mellitus, (drug) hypersensitivity, immune reconstitution inflammatory syndrome, rash and vomiting.
For information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Adverse reactions are listed by system organ class (SOC) and frequency category. Within each frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000) and not known (frequency cannot be estimated from the available data).
Table 1. Adverse reactions observed with darunavir/ritonavir in clinical studies and post-marketing:
| MedDRA system organ class Frequency category | Adverse reaction |
|---|---|
| Infections and infestations | |
| uncommon | herpes simplex |
| Blood and lymphatic system disorders | |
| uncommon | thrombocytopenia, neutropenia, anaemia, leukopenia |
| rare | increased eosinophil count |
| Immune system disorders | |
| uncommon | immune reconstitution inflammatory syndrome, (drug) hypersensitivity |
| Endocrine disorders | |
| uncommon | hypothyroidism, increased blood thyroid stimulating hormone |
| Metabolism and nutrition disorders | |
| common | diabetes mellitus, hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia |
| uncommon | gout, anorexia, decreased appetite, decreased weight, increased weight, hyperglycaemia, insulin resistance, decreased high density lipoprotein, increased appetite, polydipsia, increased blood lactate dehydrogenase |
| Psychiatric disorders | |
| common | insomnia |
| uncommon | depression, disorientation, anxiety, sleep disorder, abnormal dreams, nightmare, decreased libido |
| rare | confusional state, altered mood, restlessness |
| Nervous system disorders | |
| common | headache, peripheral neuropathy, dizziness |
| uncommon | lethargy, paraesthesia, hypoaesthesia, dysgeusia, disturbance in attention, memory impairment, somnolence |
| rare | syncope, convulsion, ageusia, sleep phase rhythm disturbance |
| Eye disorders | |
| uncommon | conjunctival hyperaemia, dry eye |
| rare | visual disturbance |
| Ear and labyrinth disorders | |
| uncommon | vertigo |
| Cardiac disorders | |
| uncommon | myocardial infarction, angina pectoris, prolonged electrocardiogram QT, tachycardia rare acute myocardial infarction, sinus bradycardia, palpitations |
| Vascular disorders | |
| uncommon | hypertension, flushing |
| Respiratory, thoracic and mediastinal disorders | |
| uncommon | dyspnoea, cough, epistaxis, throat irritation |
| rare | rhinorrhoea |
| Gastrointestinal disorders | |
| very common | diarrhoea |
| common | vomiting, nausea, abdominal pain, increased blood amylase, dyspepsia, abdominal distension, flatulence |
| uncommon | pancreatitis, gastritis, gastrooesophageal reflux disease, aphthous stomatitis, retching, dry mouth, abdominal discomfort, constipation, increased lipase, eructation, oral dysaesthesia |
| rare | stomatitis, haematemesis, cheilitis, dry lip, coated tongue |
| Hepatobiliary disorders | |
| common | increased alanine aminotransferase |
| uncommon | hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased transaminase, increased aspartate aminotransferase, increased blood bilirubin, increased blood alkaline phosphatase, increased gamma-glutamyltransferase |
| Skin and subcutaneous tissue disorders | |
| common | rash (including macular, maculopapular, papular, erythematous and pruritic rash), pruritus |
| uncommon | angioedema, generalised rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, nail pigmentation |
| rare | DRESS, Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrhoeic dermatitis, skin lesion, xeroderma |
| not known | toxic epidermal necrolysis, acute generalised exanthematous pustulosis |
| Musculoskeletal and connective tissue disorders | |
| uncommon | myalgia, osteonecrosis, muscle spasms, muscular weakness, arthralgia, pain in extremity, osteoporosis, increased blood creatine phosphokinase |
| rare | musculoskeletal stiffness, arthritis, joint stiffness |
| Renal and urinary disorders | |
| uncommon | acute renal failure, renal failure, nephrolithiasis, increased blood creatinine, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria rare decreased creatinine renal clearance |
| rare | crystal nephropathy§ |
| Reproductive system and breast disorders | |
| uncommon | erectile dysfunction, gynaecomastia |
| General disorders and administration site conditions | |
| common | asthenia, fatigue |
| uncommon | pyrexia, chest pain, peripheral oedema, malaise, feeling hot, irritability, pain |
| rare | chills, abnormal feeling, xerosis |
§ adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics (Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determined using the “Rule of 3”.
Table 2. Adverse reactions observed with darunavir/cobicistat in adult patients:
| MedDRA system organ class Frequency category | Adverse reaction |
|---|---|
| Immune system disorders | |
| common (drug) | hypersensitivity |
| uncommon | immune reconstitution inflammatory syndrome |
| Metabolism and nutrition disorders | |
| common | anorexia, diabetes mellitus, hypercholesterolaemia, hypertriglyceridaemia, hyperlipidaemia |
| Psychiatric disorders | |
| common | abnormal dreams |
| Nervous system disorders | |
| very common | headache |
| Gastrointestinal disorders | |
| very common | diarrhoea, nausea |
| common | vomiting, abdominal pain, abdominal distension, dyspepsia, flatulence, pancreatic enzymes increased |
| uncommon | pancreatitis acute |
| Hepatobiliary disorders | |
| common | hepatic enzyme increased |
| uncommon | hepatitis*, cytolytic hepatitis* |
| Skin and subcutaneous tissue disorders | |
| very common | rash (including macular, maculopapular, papular, erythematous, pruritic rash, generalised rash, and allergic dermatitis) |
| common | angioedema, pruritus, urticaria |
| rare | drug reaction with eosinophilia and systemic symptoms*, Stevens-Johnson syndrome* |
| not known | toxic epidermal necrolysis*, acute generalised exanthematous pustulosis* |
| Musculoskeletal and connective tissue disorders | |
| common | myalgia |
| uncommon | osteonecrosis* |
| Renal and urinary disorders | |
| rare | crystal nephropathy§* |
| Reproductive system and breast disorders | |
| uncommon | gynaecomastia* |
| General disorders and administration site conditions | |
| common | fatigue |
| uncommon | asthenia |
| Investigations | |
| common | increased blood creatinine |
* these adverse drug reactions have not been reported in clinical study experience with darunavir/cobicistat but have been noted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.
§ adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics (Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determined using the “Rule of 3”.
In clinical studies, rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. In a single arm study investigating darunavir 800 mg once daily in combination with cobicistat 150 mg once daily and other antiretrovirals 2.2% of patients discontinued treatment due to rash.
During the clinical development program of raltegravir in treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing darunavir/ritonavir + raltegravir compared to those containing darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy.
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of protease inhibitors, particularly in combination with NRTIs.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors.
The safety assessment of darunavir with ritonavir in paediatric patients is based on the 48-week analysis of safety data from three Phase II studies. The following patient populations were evaluated:
Overall, the safety profile in these paediatric patients was similar to that observed in the adult population.
Among 1 968 treatment-experienced patients receiving darunavir co-administered with ritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis.
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