Daruvir

Each film-coated tablet contains Darunavir ethanolate 325.23 mg corresponding to Daruvir 300 mg.

Daruvir also contains the following excipients: Tablet core: Microcrystalline cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate. Tablet film-coat: Polyvinyl alcohol (partially hydrolyzed), PEG 3350, titanium dioxide, talc.

Adult Patients

​Daruvir®, co-administered with cobicistat (Daruvir/cobicistat) or ritonavir (Daruvir/ritonavir), and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection.

This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from 2 controlled Daruvir/ritonavir Phase 3 trials of 48 weeks duration in antiretroviral treatment-naïve and treatment-experienced patients and 2 controlled Phase 2 trials of 96 weeks duration in clinically advanced, treatment-experienced adult patients.

Pediatric Patients

Daruvir, co-administered with ritonavir (Daruvir/ritonavir), and with other antiretroviral agents, is indicated for the treatment of HIV-1 infection in pediatric patients 3 years of age and older.

The indication for treatment-experienced pediatric patients 3 to less than 18 years of age is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from two open-label Phase 2 trials in antiretroviral treatment-experienced pediatric subjects (24-week analysis for one trial in patients 6 to less than 18 years of age; 48-week analysis for one trial in patients 3 to less than 6 years of age). The indication for treatment-naïve pediatric patients or antiretroviral treatment-experienced patients with no Daruvir resistance associated substitutions is based on one open-label Phase 2 trial of 48 weeks duration in antiretroviral treatment-naïve subjects 12 to less than 18 years of age and pharmacokinetic modeling and simulation for patients 3 to less than 12 years of age.

In treatment-experienced adult and pediatric patients, the following points should be considered when initiating therapy with Daruvir/ritonavir:

• ​Treatment history and, when available, genotypic or phenotypic testing should guide the use of Daruvir.
• ​The use of other active agents with Daruvir is associated with a greater likelihood of treatment response.

Daruvir is used in combination with ritonavir (Norvir®) and other medicines for the treatment of the infection caused by the human immunodeficiency virus (HIV). HIV is the virus that causes acquired immune deficiency syndrome (AIDS). Daruvir is given to patients who have already had previous treatment for HIV or who have never taken HIV medicines in the past.

Daruvir will not cure HIV infection or prevent AIDS. It helps keep HIV from reproducing and appears to slow down the destruction of the immune system. This may help delay problems that are usually related to AIDS or HIV disease from occurring. Daruvir will not keep you from spreading HIV to other people. People who receive Daruvir may continue to have other problems related to AIDS or HIV disease.

Daruvir is available only with your doctor's prescription.

Usual Adult Dose of Daruvir for HIV Infection:

Therapy-naive Patients and Therapy-experienced Patients with No Daruvir Resistance Associated Substitutions: Daruvir 800 mg plus ritonavir 100 mg orally once a day with food

Therapy-experienced Patients with At Least 1 Daruvir Resistance Associated Substitution (including V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V): Daruvir 600 mg plus ritonavir 100 mg orally twice a day with food

Comments:

-Genotypic testing is recommended for therapy-experienced patients; however, when genotypic testing is not possible, Daruvir 600 mg plus ritonavir 100 mg twice a day is recommended.

Use: In combination with ritonavir and other antiretroviral agents, for the treatment of HIV-1 infection

Usual Pediatric Dose for HIV Infection:

3 to less than 18 years:

Therapy-naive Patients and Therapy-experienced Patients with No Daruvir Resistance Associated Substitutions:

Oral suspension:

10 to less than 15 kg: Daruvir 35 mg/kg plus ritonavir 7 mg/kg orally once a day with food

-or-

10 to less than 11 kg: Daruvir 350 mg plus ritonavir 64 mg orally once a day with food

11 to less than 12 kg: Daruvir 385 mg plus ritonavir 64 mg orally once a day with food

12 to less than 13 kg: Daruvir 420 mg plus ritonavir 80 mg orally once a day with food

13 to less than 14 kg: Daruvir 455 mg plus ritonavir 80 mg orally once a day with food

14 to less than 15 kg: Daruvir 490 mg plus ritonavir 96 mg orally once a day with food

Tablets and oral suspension:

15 to less than 30 kg: Daruvir 600 mg plus ritonavir 100 mg orally once a day with food

30 to less than 40 kg: Daruvir 675 mg plus ritonavir 100 mg orally once a day with food

40 kg or more: Daruvir 800 mg plus ritonavir 100 mg orally once a day with food

Therapy-experienced Patients with At Least 1 Daruvir Resistance Associated Substitution (including V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V):

Oral suspension:

10 to less than 15 kg: Daruvir 20 mg/kg plus ritonavir 3 mg/kg orally twice a day with food

-or-

10 to less than 11 kg: Daruvir 200 mg plus ritonavir 32 mg orally twice a day with food

11 to less than 12 kg: Daruvir 220 mg plus ritonavir 32 mg orally twice a day with food

12 to less than 13 kg: Daruvir 240 mg plus ritonavir 40 mg orally twice a day with food

13 to less than 14 kg: Daruvir 260 mg plus ritonavir 40 mg orally twice a day with food

14 to less than 15 kg: Daruvir 280 mg plus ritonavir 48 mg orally twice a day with food

Tablets and oral suspension:

15 to less than 30 kg: Daruvir 375 mg plus ritonavir 48 mg orally twice a day with food

30 to less than 40 kg: Daruvir 450 mg plus ritonavir 60 mg orally twice a day with food

40 kg or more: Daruvir 600 mg plus ritonavir 100 mg orally twice a day with food

Comments:

-Special vigilance recommended during dose selection, medication order transcription, dispensing information, and dosing instructions to reduce risk for medication errors, overdose, and underdose.

-Dose should not exceed the recommended adult dose.

Use: In combination with ritonavir and other antiretroviral agents, for the treatment of HIV-1 infection

See also:
What is the most important information I should know about Daruvir?

Co-administration of Daruvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These drugs and other contraindicated drugs (which may lead to reduced efficacy of Daruvir) are listed in Table 6. Due to the need for co-administration of Daruvir with ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications.

Table 6: Drugs That Are Contraindicated With Daruvir/ritonavir

Use Daruvir suspension as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Daruvir suspension. Talk to your pharmacist if you have questions about this information.
• Take Daruvir suspension by mouth with food. Ritonavir should be taken at the same time as Daruvir suspension.
• Shake well before each use.
• Use the oral dosing syringe that comes with Daruvir suspension to measure your dose. Ask your pharmacist for help if you are unsure of how to measure your dose.
• If you also take didanosine, do not take it within 1 hour before or 2 hours after taking Daruvir suspension. Check with your doctor if you have questions.
• Taking Daruvir suspension at the same time(s) each day will help you remember to take it.
• Take Daruvir suspension on a regular schedule to get the most benefit from it.
• Continue to take Daruvir suspension even if you feel well. Do not miss any doses.
• If you take Daruvir suspension 1 time per day and you miss a dose by less than 12 hours, take it as soon as possible and go back to your regular dosing schedule. If you miss a dose by more than 12 hours, skip the missed dose and go back to your regular dosing schedule. If you take Daruvir suspension 2 times per day and miss a dose by less than 6 hours, take it as soon as possible and go back to your regular dosing schedule. If you miss a dose of Daruvir suspension by more than 6 hours, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Daruvir suspension.

This drug is used with other HIV medications to help control HIV infection. It helps to decrease the amount of HIV in your body so your immune system can work better. This lowers your chance of getting HIV complications (such as new infections, cancer) and improves your quality of life.

Daruvir belongs to a class of drugs known as protease inhibitors. Daruvir must be given with certain other medications (such as cobicistat, ritonavir) to increase ("boost") the levels of Daruvir. This helps Daruvir work better.

Daruvir is not a cure for HIV infection. To decrease your risk of spreading HIV disease to others, do all of the following: (1) continue to take all HIV medications exactly as prescribed by your doctor, (2) always use an effective barrier method (latex or polyurethane condoms/dental dams) during all sexual activity, and (3) do not share personal items (such as needles/syringes, toothbrushes, and razors) that may have contacted blood or other body fluids. Consult your doctor or pharmacist for more details.

This medication is not recommended for use in children younger than 3 years due to the increased risk of serious side effects.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This product may also be used to lessen the risk of HIV infection after contact with the virus (for example, due to a needle stick). Ask your doctor for more details.

How to use Daruvir

Read the Patient Information Leaflet if available from your pharmacist before you start taking Daruvir and each time you get a refill. If you are using the liquid form of this medication, carefully read the Instructions for Use provided with the medication. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with food as directed by your doctor. Daruvir must be taken at the same time as certain other medications, usually once or twice a day. The manufacturer recommends to swallow the tablets whole with a drink such as water or milk. If you cannot swallow whole tablets, ask your doctor if you can still use the tablets or if you should use the liquid form.

If you are using the liquid form of this medication, shake the bottle well before each dose. Carefully measure the dose using a special measuring device/spoon. Do not use a household spoon because you may not get the correct dose.

The dosage is based on your age, laboratory tests, medical condition, and response to treatment. In children, the dosage is also based on body weight.

It is very important to continue taking this medication (and other HIV medications) exactly as prescribed by your doctor.

This medication works best when the amount of drug in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals. To help you remember, take it at the same time(s) each day.

Do not take more or less of this drug than prescribed or stop taking it (or other HIV medicines) even for a short time unless directed to do so by your doctor. Skipping or changing your dose without approval from your doctor may cause the amount of virus to increase, make the infection more difficult to treat (resistant), or worsen side effects.

See also:
What other drugs will affect Daruvir?

Daruvir and ritonavir are both inhibitors of the CYP3A isoform. Co-administration of Daruvir and ritonavir with medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect and adverse events.

Daruvir/rtv should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These medicinal products include astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide and the ergot alkaloids (eg, ergotamine, dihydroergotamine, ergonovine and methylergonovine).

Rifampicin is a potent inducer of CYP-450 metabolism. Daruvir/rtv should not be used in combination with rifampicin, as co-administration may cause significant decreases in Daruvir plasma concentrations. This may result in loss of therapeutic effect to Daruvir.

Daruvir/rtv should not be used concomitantly with products containing St. John's Wort (Hypericum perforatum) because co-administration may cause significant decreases in Daruvir plasma concentrations. This may result in loss of therapeutic effect to Daruvir.

Antiretroviral Medicinal Products: Nucleoside/Nucleotide Reverse Transcriptase Inhibitors [N(t)RTIs]: Didanosine: Daruvir/rtv (600/100 mg twice daily) did not significantly affect didanosine exposure. The combination of Daruvir co-administered with low dose ritonavir and didanosine can be used without dose adjustments.

As it is recommended that didanosine be administered on an empty stomach, didanosine should be administered 1 hr before or 2 hrs after Daruvir/rtv (which are administered with food).

Tenofovir: The results of an interaction trial with tenofovir (tenofovir disoproxil fumarate 300 mg once daily) demonstrated that the systemic exposure of tenofovir was increased by 22% when co-administered with Daruvir/rtv (300/100 mg twice daily). This finding is not considered to be clinically relevant. There was no change in the urinary excretion of tenofovir or Daruvir during co-administration. Tenofovir did not have a significant influence on Daruvir exposure. No dose adjustments of Daruvir, ritonavir or tenofovir disoproxil fumarate are required when these drugs are co-administered.

Other NRTIs: Based on the different elimination pathways of the other NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally excreted, no drug interactions are expected for these medicinal compounds and Daruvir/rtv.

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Etravirine: An interaction trial between Daruvir/rtv (600/100 mg twice daily) and etravirine, there was a 37% decrease in etravirine exposure in the presence of Daruvir/rtv and no relevant change in exposure to Daruvir. Therefore, Daruvir/rtv can be co-administered with etravirine 200 mg twice daily without dose adjustments.

Efavirenz: An interaction trial between Daruvir/rtv (300/100 mg twice daily) and efavirenz (600 mg once daily) has been performed. In the presence of efavirenz, a decrease of 13% for Daruvir exposure was observed. Exposure to efavirenz was increased by 21% when administered in combination with Daruvir/rtv. Since this difference is considered not to be clinically relevant, the combination of Daruvir/rtv and efavirenz can be used without dose adjustments.

Nevirapine: The results of an interaction trial with Daruvir/rtv (400/100 mg twice daily) and nevirapine (200 mg twice daily) demonstrated that Daruvir exposure was not affected when administered concomitantly with nevirapine. Exposure to nevirapine increased by 27% (compared to historical controls) when administered in combination with Daruvir/rtv. Since this difference is not considered to be clinically relevant, the combination of Daruvir/rtv and nevirapine can be used without dose adjustments.

Protease Inhibitors (PIs): Ritonavir: The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of Daruvir when a single dose of Daruvir 600 mg was given orally in combination with ritonavir at 100 mg twice daily. Therefore, Daruvir should only be used in combination with low dose of ritonavir as a pharmacokinetic enhancer.

Lopinavir/Ritonavir: Results of interaction trials with Daruvir with or without ritonavir and lopinavir/ritonavir (1200 mg Daruvir twice daily with or without 100 mg ritonavir twice daily and lopinavir/ritonavir 400/100 mg twice daily or 533/133.3 mg twice daily) demonstrated a decrease in the exposure (AUC) of Daruvir by 40%. The appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer Daruvir/rtv with lopinavir/ritonavir.

Saquinavir: In an interaction trial between Daruvir (400 mg twice daily), saquinavir (1000 mg twice daily) and ritonavir (100 mg twice daily), Daruvir exposure was decreased by 26% in the presence of saquinavir/rtv; saquinavir exposure was not affected by the presence of Daruvir/rtv. It is not recommended to combine saquinavir and Daruvir, with or without low-dose ritonavir.

Atazanavir: An interaction trial between Daruvir/rtv (400/100 mg twice daily) and atazanavir (300 mg once daily) demonstrated that systemic exposure to Daruvir and atazanavir was not significantly affected when co-administered. Atazanavir can be co-administered with Daruvir/rtv.

Indinavir: In an interaction trial between Daruvir/rtv (400/100 mg twice daily) and indinavir (800 mg twice daily), Daruvir exposure was increased by 24% in the presence of indinavir/rtv; indinavir exposure was increased by 23% in the presence of Daruvir/rtv. When used in combination with Daruvir/rtv, dose adjustment of indinavir from 800 mg to 600 mg twice daily may be warranted in case of intolerance.

Other Protease Inhibitors: The co-administration of Daruvir/rtv and PIs other than lopinavir/ritonavir, saquinavir, atazanavir and indinavir have not been studied. Therefore, such co-administration is not recommended.

CCR5 antagonist: When used in combination with Daruvir/rtv, the dose of maraviroc should be 150 mg twice daily. An interaction trial between Daruvir/rtv (600/100 twice daily) and maraviroc (150 mg twice daily) demonstrated that in the presence of Daruvir/rtv the exposure of maraviroc was increased by 305%. There was no apparent effect of maraviroc on Daruvir/ritonavir exposure.

Other Medicinal Products: Antiarrhythmics (bepridil, systemic lidocaine, quinidine and amiodarone): Exposure to bepridil, lidocaine, quinidine and amiodarone may be increased when co-administered with Daruvir/rtv. Caution is warranted and therapeutic drug monitoring of antiarrhythmics is recommended when available.

Digoxin: An interaction trial with Daruvir/rtv (600/100 mg twice daily) and a single dose of digoxin (0.4 mg) showed an increase of digoxin AUC_last of 77% [ratio of Least Square Means (LSM) was 1.77 with a 90% CI of 0.9-3.5]. It is recommended that the lowest dose of digoxin should initially be prescribed and digoxin dose should be titrated to obtain the desired clinical effect when co-administered with Daruvir/rtv. Serum digoxin concentrations should be monitored to assist in the titration.

Anticoagulants: Warfarin concentrations may be affected when co-administered with Daruvir/rtv. It is recommended that the international normalized ratio (INR) is monitored when warfarin is combined with Daruvir/rtv.

Anticonvulsants (Phenobarbital, Phenytoin and Carbamazepine): Phenobarbital and phenytoin are inducers of CYP-450 enzymes. Daruvir/rtv should not be used in combination with these medicines, as co-administration may cause significant decreases in Daruvir plasma concentrations. This may result in loss of therapeutic effect to Daruvir.

Carbamezepine: An interaction trial between Daruvir/rtv (600/100 mg twice daily) and carbamazepine (200 mg twice daily) showed that the exposure to Daruvir, co-administered with ritonavir, was unaffected by carbamazepine. Ritonavir exposure (AUC_{12 hr}) was decreased by 49%. For carbamazepine, AUC_{12 hr} was increased by 45%. No dose adjustment for Daruvir/rtv is recommended. If there is a need to combine Daruvir/rtv 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 cabamazepine dose may need to be reduced by 25-50% in the presence of Daruvir/rtv.

Calcium-Channel Blockers: The exposure to calcium-channel blockers (eg, felodipine, nifedipine, nicardipine) may increase when Daruvir/rtv are used concomitantly. Caution is warranted and careful clinical monitoring is recommended.

Clarithromycin: An interaction trial between Daruvir/rtv (400/100 mg twice daily) and clarithromycin (500 mg twice daily) showed an increase in exposure to clarithromycin by 57%, while exposure to Daruvir was not affected. For patients with renal impairment, a dose reduction of clarithromycin should be considered.

Dexamethasone: Systemic dexamethasone induces CYP3A and thereby may decrease Daruvir exposure. This may result in loss of therapeutic effect. Therefore this combination should be used with caution.

Fluticasone Propionate: Concomitant use of inhaled fluticasone propionate and Daruvir/rtv may increase plasma concentrations of fluticasone propionate. Alternatives should be considered, particularly for long-term use.

HMG-CoA Reductase Inhibitors: HMG-CoA reductase inhibitors eg, lovastatin and simvastatin, which are highly dependent on CYP3A metabolism are therefore expected to have markedly increased plasma concentrations when co-administered with Daruvir/rtv. Increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis. Concomitant use of Daruvir/rtv with lovastatin and simvastatin is therefore not recommended.

The results of an interaction trial with atorvastatin show that atorvastatin (10 mg once daily) in combination with Daruvir/rtv (300/100 mg twice daily) provides an exposure to atorvastatin, which is only 15% lower than that obtained with atorvastatin (40 mg once daily) alone. When administration of atorvastatin and Daruvir/rtv 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.

Daruvir/rtv (600/100 mg twice daily) increased exposure to a single dose of pravastatin (40 mg) by approximately 80%, but only in a subset of subjects. When administration of pravastatin and Daruvir/rtv is required, it is recommended to start with the lowest possible dose of pravastatin and titrate up to the desired clinical effects while monitoring safety.

H₂-Receptor Antagonists and Proton Pump Inhibitors: Co-administration of omeprazole (20 mg once daily) or ranitidine (150 mg twice daily) and Daruvir/rtv (400/100 mg twice daily) did not affect the exposure to Daruvir. Based on these results, Daruvir/rtv can be co-administered with H₂-receptor antagonists and proton pump inhibitors without dose adjustments.

Immunosuppressants (Cyclosporin, Tacrolimus, Sirolimus): Exposure to cyclosporine, tacrolimus or sirolimus may be increased when co-administered with Daruvir/rtv. Therapeutic drug monitoring of the immunosuppressive agent is recommended when co-administered with Daruvir/rtv.

Ketoconazole, Itraconazole and Voriconazole: Ketoconazole, itraconazole and voriconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole or voriconazole and Daruvir/rtv may increase plasma concentrations of Daruvir. Simultaneously, plasma concentrations of ketoconazole or itraconazole may be increased by Daruvir/rtv. This was confirmed in an interaction trial where the concomitant administration of ketoconazole (200 mg twice daily) with Daruvir/rtv (400/100 mg twice daily) increased exposure of ketoconazole and Daruvir by 212 and 42%, respectively. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. Plasma concentrations of voriconazole may be decreased in the presence of Daruvir/ritonavir. Voriconazole should not be administered to patients receiving Daruvir/rtv unless an assessment of the benefit/risk ratio justifies the use of voriconazole.

Methadone: An interaction trial investigating the effect of Daruvir/rtv (600/100 mg twice daily) on a stable methadone maintenance therapy showed an AUC decrease of 16% for R-methadone. Based on pharmacokinetic and clinical findings, no adjustment of methadone dosage is required when initiating co-administration of Daruvir/rtv. However, clinical monitoring is recommended as maintenance therapy may need to be adjusted in some patients.

Buprenorphine or Naloxone: The results of an interaction trial with Daruvir/rtv and buprenorphine/naloxone demonstrated that buprenorphine exposure was not affected when administered with Daruvir/rtv. Exposure of the active metabolite, norbuprenorphine, increased by 46%. No dose adjustment for buprenorphine was required. Careful clinical monitoring is recommended if Daruvir/rtv and buprenorphine are co-administered.

Estrogen-Based Contraceptives: The results of an interaction trial between Daruvir/rtv (600/100 mg twice daily) and ethinylestradiol and norethindrone demonstrated that at steady-state systemic exposures to ethinylestradiol and norethindrone are decreased by 44% and 14%, respectively. Therefore, alternative methods of nonhormonal contraception are recommended.

PDE-5 Inhibitors: In an interaction trial, a comparable systemic exposure to sildenafil was observed for a single intake of sildenafil 100 mg alone and a single intake of sildenafil 25 mg co-administered with Daruvir/rtv (400/100 mg twice daily). Concomitant use of PDE-5 inhibitors with Daruvir/rtv should be done with caution. If concomitant use of Daruvir/rtv with sildenafil, vardenafil or tadalafil is indicated, sildenafil at a single dose not exceeding 25 mg in 48 hrs, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hrs or tadalafil at a single dose not exceeding 10 mg dose in 72 hrs is recommended.

Rifabutin: Rifabutin is substrate of CYP-450 enzymes. In an interaction trial, an increase of systemic exposure to Daruvir by 57% was observed when Daruvir/rtv (600/100 mg twice daily) was administered with rifabutin (150 mg once every other day). Based on the safety profile of Daruvir/rtv, the increase in Daruvir exposure in the presence of rifabutin does not warrant a dose adjustment for Daruvir/rtv. The interaction trial showed a comparable systemic exposure for rifabutin between treatment at 300 mg once daily, alone and at 150 mg once every other day in combination with Daruvir/rtv (600/100 mg twice daily) with an increase in exposure to the active metabolite 25-O-desacetylrifabutin. A dosage reduction of rifabutin by 75% of the usual dose 300 mg/day (ie, rifabutin 150 mg once every other day) and increased monitoring for rifabutin-related adverse events is warranted in patients receiving the combination.

Selective Serotonin Re-uptake Inhibitors (SSRIs): In an interaction trial between paroxetine (20 mg once daily) or sertraline (50 mg once daily) and Daruvir/rtv (400/100 mg twice daily), the exposure to Daruvir was not affected by the presence of sertraline or paroxetine. Exposure to sertraline and paroxetine was decreased by 49% and 39%, respectively, in the presence of Daruvir/rtv. If SSRIs are co-administered with Daruvir/rtv, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with Daruvir/rtv should be monitored for antidepressant response.

Incompatibilities: None known.

See also:
What are the possible side effects of Daruvir?

The safety assessment is based on all safety data from the studies TMC114-C213 and TMC114-C202 and the TMC114-C215/C208 analysis reported with the recommended dose Daruvir/rtv 600/100 mg twice daily in the 458 subjects who initiated treatment with the recommended dose (de novo subjects). In Studies TMC114-C213 and TMC114-C202, the mean exposure in weeks for subjects in the Daruvir/rtv 600/100 mg twice daily arm and comparator PI arm was 63.5 and 31.5, respectively. The mean exposure in weeks for subjects in the TMC114-C215/C208 analysis was 23.9.

The most common treatment-emergent adverse events (>10%) reported in the de novo subjects, regardless of causality or frequency, were diarrhea, nausea, headache and nasopharyngitis. For subjects in the Daruvir/rtv 600/100 mg twice daily arm and the comparator PI arm in the pooled analysis for studies TMC114-C213 and the TMC114-C202, diarrhea was reported in 19.8% and 28.2%, nausea in 18.3% and 12.9%, headache in 15.3% and 20.2%, and nasopharyngitis in 13.7% and 10.5% of subjects, respectively. In the randomized trials, rates of discontinuation of therapy due to adverse events were 9% in subjects receiving Daruvir/rtv and in 5% of subjects in the comparator PI arm.

Due to the need for co-administration of Daruvir with 100 mg of ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.

Drug-related clinical adverse events of moderate or severe intensity (Grade 2) occurring in 2% of subjects treated with Daruvir/rtv for 1-96 weeks are presented in Table 4.

Treatment-emergent adverse events occurring in <2% of de novo subjects (n=458) receiving Daruvir/rtv, considered at least possibly related to treatment and of at least moderate intensity are listed as follows by body system:

Body as a Whole: Folliculitis, asthenia, pyrexia, fatigue, rigors, hyperthermia, peripheral edema.

Cardiovascular System: Myocardial infarction, tachycardia, hypertension.

Digestive System: Flatulence, abdominal distension, dry mouth, dyspepsia, abdominal pain, nausea, constipation.

Metabolic and Nutritional Disorders: Anorexia, hypercholesterolemia, hyperlipidemia, diabetes mellitus, decreased appetite, obesity, fat redistribution, hyponatremia, polydipsia.

Musculoskeletal System: Arthralgia, pain in extremity, myalgia, osteopenia, osteoporosis.

Nervous System: Peripheral neuropathy, hypoesthesia, memory impairment, paresthesia, somnolence, transient ischemic attack, confusional state, disorientation, irritability, altered mood, nightmare, anxiety, headache.

Respiratory System: Dyspnea, cough, hiccups.

Skin and Appendages: Lipoatrophy, night sweats, allergic dermatitis, eczema, toxic skin eruption, alopecia, dermatitis medicamentosa, hyperhidrosis, skin inflammation, maculopapular rash, erythema multiforme, Stevens-Johnson syndrome (reported in another ongoing clinical study).

Special Senses: Vertigo.

Urogenital System: Acute renal failure, renal insufficiency, nephrolithiasis, polyuria, gynecomastia.

Laboratory Abnormalities: The percentages of adult subjects treated with Daruvir/rtv 600/100 mg twice daily with treatment-emergent Grade 2-4 laboratory abnormalities are presented in Table 5.

Special Populations: Patients co-infected with hepatitis B and/or hepatitis C virus: In patients co-infected with hepatitis B or C virus receiving Daruvir/rtv, the incidence of adverse events and clinical chemistry abnormalities was not higher than patients receiving Daruvir/rtv who were not co-infected, except for increased hepatic enzymes. The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection. Standard clinical monitoring of patients with chronic hepatitis B and/or C is considered adequate.