DARUVIR 800-R / DARUVIR 600-R Tablets (Darunavir and Ritonavir )

Table of Content

To be sold by retail on prescription of R.M.P. only

Qualitative And Quantitative Composition

DARUVIR 800-R

Each film-coated tablet contains:

Darunavir Ethanolate,

eq. to Darunavir ........................... 800 mg

Ritonavir, IP.......................... 100 mg                                                             

Excipients ................................. q.s                  

Colours: Ferric oxide USP-NF Yellow and Titanium Dioxide IP

DARUVIR 600-R

Each film-coated tablet contains:

Darunavir Ethanolate,

eq. to Darunavir…..............….600 mg

Ritonavir, IP…………………….100 mg

Excipients ..................................... q.s

Colours:  Ferric Oxide USP-NF Yellow and Titanium Dioxide IP

Dosage Form(S) And Strength(S)

Film-coated, fixed-dose combination (FDC) of darunavir/ritonavir 800 mg/100 mg and 600 mg/100 mg tablets for oral use.          

Clinical Particulars

Therapeutic Indications

Darunavir and ritonavir Tablets are indicated for the treatment of Human Immunodeficiency Virus (HIV-1) infection in treatment-experienced adults and adolescents.

Posology and Method of Administration

Fixed dose combination (FDC) of DARUVIR 800-R/DARUVIR 600-R Tablets will be administered orally once daily with food.

Contraindications

  • Hypersensitivity to the active substance or to any of the excipients.
  • As this FDC is a fixed dose combination of darunavir and ritonavir, contraindications to any of darunavir or ritonavir is applicable for this FDC.
  • Co-administration of darunavir/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 are listed below:
  • Alpha 1-adrenoreceptor antagonist: alfuzosin
  • Antifungal: voriconazole
  • Antianginal: ranolazine
  • Anti-gout: colchicine, in patients with renal/and or hepatic impairment
  • Antimycobacterial: rifampin
  • Antipsychotics: lurasidone, pimozide,
  • Cardiac Disorders: dronedarone, ivabradine, ranolazine, amiodarone, , quinidine, flecainide, propafenone.
  • Ergot derivatives, e.g., dihydroergotamine, ergotamine, methylergonovine
  • GI motility agent: cisapride
  • Herbal product: St. John’s wort (Hypericum perforatum)
  • Hepatitis C direct-acting antiviral: elbasvir/grazoprevir
  • Lipid-modifying agents: lomitapide (Microsomal triglyceride transfer protein (MTTP) Inhibitor), lovastatin, simvastatin
  • Opioid Antagonist: naloxegol
  • PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension
  • Sedatives/hypnotics: orally administered midazolam, triazolam
  • Platelet aggregation inhibitor: ticagrelor, dabigatran
  • Anticancer Agents: apalutamide
  • Others; ivabradine, dapoxetine, domperidone, naloxegol, astemizole, terfenadine
  • Ritonavir is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.

Co-administration of ritonavir with several classes of drugs (including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations) is contraindicated and may result in potentially serious and/or life-threatening adverse events due to possible effects of ritonavir on the hepatic metabolism of these drugs. Voriconazole and St. John’s wort are exceptions in that co-administration of ritonavir and voriconazole results in a significant decrease in plasma concentrations of voriconazole, and co-administration of ritonavir with St. John’s wort may result in decreased ritonavir plasma concentrations.

Special Warnings and Precautions for Use

As this FDC is a fixed dose combination of darunavir and ritonavir, warnings and precautions to any of darunavir or ritonavir is applicable for this FDC.

Darunavir/Ritonavir

DARUVIR 800-R/DARUVIR 600-R Tablets must be co-administered with food to achieve the desired antiviral effect. Failure to administer DARUVIR 800-R/DARUVIR 600-R Tablets with food may result in a loss of efficacy of darunavir.

Hepatotoxicity

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir. During the clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse events.

Postmarketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities, including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir/ritonavir therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of darunavir/ritonavir treatment.

Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on darunavir/ritonavir should prompt consideration of interruption or discontinuation of treatment.

Severe Skin Reactions

During the clinical development program (N=3,063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson syndrome was rarely (less than 0.1%) reported during the clinical development program. During postmarketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported. Discontinue darunavir/ritonavir immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.

Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with darunavir/ritonavir (see Undesirable effects). Rash was mostly mild-to-moderate, often occurring within the first 4 weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using darunavir/ritonavir was 0.5%.

Rash occurred more commonly in treatment-experienced subjects receiving regimens containing darunavir/ritonavir + raltegravir compared with subjects receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir. However, rash that was considered drug-related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

Sulfa Allergy

Darunavir contains a sulfonamide moiety. Darunavir should be used with caution in patients with a known sulfonamide allergy. In clinical studies with darunavir/ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.

Risk of Serious Adverse Reactions due to Drug Interactions

Initiation of darunavir/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving darunavir/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of darunavir/ritonavir, respectively. These interactions may lead to the following:

  • Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
  • Clinically significant adverse reactions from greater exposures of darunavir/ritonavir.
  • Loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s).
  • Loss of therapeutic effect of darunavir/ritonavir and possible development of resistance from lower exposures of darunavir/ritonavir.

See Table 1 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations . Consider the potential for drug interactions prior to and during darunavir/ritonavir therapy; review concomitant medications during darunavir/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant drugs .

Diabetes Mellitus/Hyperglycemia

New-onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving PI therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these events have not been established.

Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance”, have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including darunavir/ritonavir. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia , or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.

Patients with Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia 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 between PI therapy and these episodes has not been established.

Ritonavir

Pancreatitis

Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made.

Allergic Reactions/Hypersensitivity

Allergic reactions, including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported. Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported. Discontinue treatment if severe reactions develop.

PR Interval Prolongation

Ritonavir prolongs the PR interval in some patients. Postmarketing cases of second- or third-degree atrioventricular block have been reported in patients.

Ritonavir should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended.

Lipid Disorders

Treatment with ritonavir therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides . Triglyceride and cholesterol testing should be performed prior to initiating ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug–drug interactions with ritonavir and HMG-CoA reductase inhibitors .

Resistance/Cross-resistance

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.

Laboratory Tests

Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating Darunavir and ritonavir Tablets and at periodic intervals or if any clinical signs or symptoms occur during therapy.

Drug Interactions

Darunavir

Potential for Darunavir/ritonavir to Affect Other Drugs

Darunavir co-administered with ritonavir is an inhibitor of CYP3A, CYP2D6, and P-gp. Co-administration of darunavir and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6, or are transported by P-gp may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events. Darunavir co-administered with ritonavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 1).

Potential for Other Drugs to Affect Darunavir

Darunavir and ritonavir are metabolized by CYP3A.In vitro data indicate that darunavir may be a P-gp substrate. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A, or P-gp may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (See Table 1).

Established and Other Potentially Significant Drug Interactions

Table 1 provides dosing recommendations as a result of drug interactions with darunavir/ritonavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. The Table 1 includes potentially significant interactions but is not all inclusive .

Table 1: Established and other potentially significant drug interactions: Alterations in dose or regimen may be recommended based on drug interaction studies or predicted interaction

Concomitant Drug Class: Drug Name

Effect on Concentration of Darunavir or Concomitant Drug

Clinical Comment

HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Didanosine

↔ darunavir

↔ didanosine

Didanosine should be administered 1 hour before or 2 hours after darunavir/ritonavir (which are administered with food).

HIV-1-Antiviral Agents: HIV Protease Inhibitors (PIs)

Indinavir

 

↑ darunavir

↑ indinavir

The appropriate dose of indinavir in combination with darunavir/ritonavir has not been established.

Lopinavir/ritonavir

↓ darunavir

↔ lopinavir

Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and darunavir, with or without ritonavir.

Saquinavir

↓ darunavir

 ↔saquinavir

Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and darunavir, with or without ritonavir.

Tipranavir

↑ tipranavir

See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir.

Other HIV protease inhibitors except atazanavir

 

As coadministration with darunavir/ritonavir has not been studied, coadministration is not recommended.

HIV-1-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibotor

Delavirdine

↑ ritonavir

Appropriate doses of this combination with respect to safety and efficacy have not been established.

HIV-1-Antiviral Agents: Integrase Inhibitors

Raltegravir

↓ raltegravir

 

The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.

HIV-1-Antiviral Agents: CCR5 Co-receptor Antagonists

Maraviroc

↑ maraviroc

When used in combination with darunavir/ritonavir, the dose of maraviroc should be 150 mg twice daily.

See the complete prescribing information for maraviroc for details on co-administration.

 

Other Agents

 

Alpha 1-adrenoreceptor antagonist:

Alfuzosin

 

 

↑ alfuzosin

 

 

 

 

 

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.

 

Anesthetic:

Meperidine

↓ meperidine /

↑normeperidine (metabolite)

Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).

Antialcoholics:

Disulfiram/

Metronidazole

 

Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

Antibacterial:

Clarithromycin

↔ darunavir

↑ clarithromycin

 

No dose adjustment of the combination is required for patients with normal renal function. For co-administration of clarithromycin and darunavir/ritonavir in patients with renal impairment, the following dose adjustments should be considered:

• For subjects with CLcr of 30-60 mL/min, the dose of clarithromycin should be reduced by 50%.

• For subjects with CLcr of < 30 mL/min, the dose of  clarithromycin should be reduced by 75%

Anticoagulants:

Direct Oral Anticoagulants (DOACs)

 

Apixaban

 

 

 

Rivaroxaban

 

 

 

Betrixaban

Dabigatran

Edoxaban

 

 

Other Anticoagulants

warfarin

↑apixaban

 

 

 

 

 

 

 

↑ rivaroxaban

 

 

 

↔ betrixaban

↔ dabigatran

↔ edoxaban

 

 

↓ warfarin

↔ darunavir

Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with darunavir depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information

 

 

Co-administration of darunavir /ritonavir and rivaroxaban is not recommended because it may lead to an increased bleeding risk

 

No dose adjustment is needed when betrixaban, dabigatran, or edoxaban is co-administered with darunavir.

 

 

Warfarin concentrations are decreased when co-administered with darunavir/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with darunavir/ritonavir.

Anticonvulsants:

Carbamazepine

 

 

 

 

 

 

Clonazepam

Ethosuximide

 

 

 

 

phenobarbital, Phenytoin

 

 

 

Divalproex, Lamotrigine

 

 

 

↔ darunavir

↑ carbamazepine

 

 

 

 

 

 

↑clonazepam

↑ ethosuximide

 

 

 

 

↔ darunavir

↓ phenytoin

↓ phenobarbital

 

↓ anticonvulsants

The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.

 

Clinical monitoring of anticonvulsants that are metabolized by CYP3A is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.

Phenytoin and phenobarbital levels should be monitored when co-administering with darunavir/ritonavir.

 

 

A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.

Antidepressants:

Selective Serotonin Reuptake Inhibitors (SSRIs):

Paroxetine, Sertraline

 

 

 

Tricyclic Antidepressants (TCAs):

Amitriptyline, Desipramine, Imipramine, Nortriptyline

 

 

Other: Trazadone

↓paroxetine,

↓sertraline

 

 

 

 

 

 

↑ amitriptyline,

↑ desipramine,

↑ imipramine,

↑ nortriptyline

 

↑ trazodone

If either sertraline or paroxetine is initiated in patients receiving darunavir/ritonavir, dose titrating the SSRI based on a clinical assessment of antidepressant response is recommended. Monitor for antidepressant response in patients on a stable dose of sertraline or paroxetine who start treatment with darunavir/ritonavir.

 

Use a lower dose of the tricyclic antidepressants and trazodone due to potential increased adverse events such as nausea, dizziness, hypotension and syncope.

Antiemetic:

Dronabinol

↑ dronabinol

A dose decrease of dronabinol may be needed when co-administered with ritonavir.

Antifungals:

ketoconazole,

Itraconazole,

Posaconazole

Isavuconazole

 

 

 

Voriconazole

↑ ketoconazole

↑ darunavir

↑ isavuconazole

↑ itraconazole

↔ posaconazole

 

 

 

↓ voriconazole

 

Monitor for increased darunavir/ritonavir adverse events with concomitant use of itraconazole, ketoconazole, or posaconazole. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg with monitoring for increased antifungal adverse events.

 

Voriconazole is not recommended for patients receiving darunavir/ritonavir unless an assessment comparing predicted benefit to risk ratio justifies the use of voriconazole.

Anti-Gout:

Colchicine        

↑ colchicine

Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions

For patients without renal or hepatic impairment:

  • Treatment of gout flares — co-administration of colchicine in patients on darunavir/ritonavir:

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half-tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.

Prophylaxis of gout flares — co-administration of colchicine in patients on darunavir/ritonavir:

If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

  • Treatment of familial Mediterranean fever — co-administration of colchicine in patients on darunavir/ritonavir:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Antimalarial:

Artemether/lumefantrine

↓ artemether

↓ dihydroartemisinin

↑ lumefantrine

↔ darunavir

The combination of darunavir and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation.

Antimycobacterial:

Rifampin

 

 

rifabutin

(The reference regimen for rifabutin was 300 mg once daily)

 

 

 

 

 

Rifapentine

 

 

Bedaquiline

 

↓ darunavir

↓ ritonavir

 

↑ darunavir

↑ rifabutin

↑25-O-desacetylrifabutin

 

 

 

 

 

↓ darunavir

 

 

↑ bedaquiline

 

Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance.

 

Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e. a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and a further dose reduction of rifabutin may be necessary.

 

Co-administration of darunavir /ritonavir with rifapentine is not recommended.

 

Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk.

Antineoplastics: Dasatinib, Nilotinib

 

 

 

 

Vinblastine, Vincristine

 

 

 

 

 

 

 

 

 

 

Kinase Inhibitors: Fostamatinib

 

 

 

Ibrutinib, Ivosidenib,
Neratinib, Abemaciclib, Apalutamide, Encorafenib, Venetoclax

 

↑ antineoplastics

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

↑ fostamatinib metabolite R406

 

 

 

↑ anticancer agents

↓ ritonavir

A decrease in the dosage or an adjustment of the dosing interval of dasatinib and nilotinib may be necessary for patients. Please refer to the dasatinib and nilotinib prescribing information for dosing instructions.

 

For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when darunavir/ritonavir is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.

 

Monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.

 

Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to ritonavir or to the class of protease inhibitors .

 

Avoid co-administration of encorafenib or ivosidenib with ritonavir due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with ritonavir cannot be avoided, modify dose as recommended in encorafenib USPI. If co­ administration of ivosidenib with ritonavir cannot be avoided, reduce ivosidenib dose to 250 mg once daily.

Avoid use of neratinib, venetoclax or ibrutinib with ritonavir.

Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.

Antiparasitic:
Atovaquone

↓ atovaquone

Clinical significance is unknown; however, increase in atovaquone dose may be needed.

Quinine

↑ quinine

A dose decrease of quinine may be needed when co-administered with ritonavir.

Antipsychotics:

Lurasidone

 

 

Pimozide

 

 

 

Quetiapine

 

 

 

 

 

 

 

 

 

 

 

 

 

e.g. Perphenazine, Risperidone, Thioridazone, Nefazodone

 

↑ lurasidone

 

 

↑ pimozide

 

 

 

↑ quetiapine

 

 

 

 

 

 

 

 

 

 

 

 

 

↑ antipsychotics

 

 

 

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions.

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

 

Initiation of darunavir with ritonavir inpatients taking quetiapine:

Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions.

Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking darunavir with ritonavir:

Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

 

A decrease in the dose of antipsychotics that are metabolized by CYP3A and CYP2D6 may be needed when co-administered with darunavir/ritonavir.

Bronchodilator:

Theophylline

↓ theophylline

Increased dosage of theophylline may be required; therapeutic monitoring should be considered.

Bupropion

↓ bupropion ↓ active metabolite, hydroxybupropion

Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.

Beta-blockers:

e.g. Carvedilol, Metoprolol, Timolol

↑ beta-blockers

Clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with darunavir/ritonavir and a lower dose of the beta blocker should be considered.

Calcium Channel  Blockers:

e.g.

Amlodipine, Diltiazem, Felodipine, Nifedipine,

Nicardipine, Verapamil

↑ calcium channel blockers

Clinical monitoring of patients is recommended.

Cardiac Disorders: Ranolazine, Ivabradine

 

 

Dronedarone

 

 

 

Other antiarrhythmics e.g. Amiodarone, Bepridil, Disopyramide, Flecainide, Lidocaine (systemic), Mexiletine, Propafenone, Quinidine

 

Digoxin

↑ ranolazine

↑ ivabradine

 

 

↑ dronedarone

 

 

 

↑ antiarrhythmics

 

 

 

 

↑ digoxin

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions

 

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

 

Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with darunavir/ritonavir

 

 

The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.

Systemic/Inhaled/Nasal/Ophthalmic Corticosteroid

Betamethasone, Budesonide, Ciclesonide,  Dexamethasone, Fluticasone, Methylprednisolone, Mometasone, Prednisone, Triamcinolone

↓ darunavir

↑ corticosteroids

 

 

Co-administration of darunavir/ritonavir with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to darunavir. Consider alternative corticosteroids.

Co-administration with corticosteroids of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use.

Endothelin-receptor antagonists:

Bosentan

↑ bosentan

Co-administration of bosentan in patients on darunavir/ritonavir:

In patients who have been receiving darunavir/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of darunavir /ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of darunavir/ritonavir. After at least 10 days following the initiation of darunavir/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Ergot derivatives:

e.g. Dihydroergotamine,

Ergotamine, Methylergonovine

↑ ergot derivatives

 

 

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

GI motility agent:

Cisapride

↑ cisapride

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

GnRH Receptor

Antagonists: Elagolix

↑ elagolix

↓ ritonavir

Concomitant use of elagolix 200 mg twice daily and ritonavir for more than 1 month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily and ritonavir to 6 months.

Hepatitis C Virus (HCV) Direct-acting Antivirals:

 

Elbasvir/grazoprevir

 

Glecaprevir/pibrentasvir

 

 

 

Simeprevir

 

↑elbasvir/

grazoprevir

 

 

↑ glecaprevir

↑ pibrentasvir

 

↑ simeprevir

↑ darunavir

 

Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations.

 

Co-administration of darunavir /ritonavir with glecaprevir/pibrentasvir is not recommended.

 

Co-administration of darunavir/ritonavir and simeprevir is not recommended.

Herbal product:

St. John’s wort (Hypericum perforatum)

↓ darunavir

Co-administration is contraindicated due to potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance

Hormonal contraceptives:

Ethinyl estradiol, Norethindrone, Drospirenone

 

↓ ethinyl estradiol

↓ norethindrone

drospirenone: effects unknown

Effective alternative (non-hormonal) contraceptive method or a barrier method of contraception is recommended.

For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. No data are available to make recommendations on coadministration with other hormonal contraceptives.

Immunosuppressants:

e.g.

cyclosporine, Tacrolimus,

Sirolimus

 

Immunosuppressant/neoplastic:

Everolimus

Irinotecan

↑ immuno-suppressants

Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with darunavir/ritonavir.

 

 

Co-administration of everolimus and

darunavir/ritonavir is not recommended.

Discontinue darunavir/ritonavir at least 1 week prior to starting irinotecan therapy. Do not administer darunavir/ritonavir with irinotecan unless there are no therapeutic alternatives.

Inhaled Beta-Agonist: Salmeterol

↑ salmeterol

Co-administration of salmeterol and darunavir/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

Lipid Modifying Agents: 

HMG-CoA reductase inhibitors: Lovastatin, Simvastatin

 

Atorvastatin, Pravastatin, Rosuvastatin

 

 

 

 

Microsomal triglyceride transfer protein (MTTP) Inhibitor: Lomitapide

 

↑ lovastatin

↑ simvastatin

 

 

↑ HMG-CoA

reductase inhibitors

 

 

 

↑ lomitapide

Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

Co-administration of darunavir/ritonavir with HMG-Co A reductase inhibitors may lead to adverse events such as myopathy. Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for adverse events. Do not exceed atorvastatin 20 mg/day.

Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity.

Narcotic analgesics metabolized by CYP3A: e.g. Fentanyl,

 oxycodone

propoxyphene,

 

 

 

 

 

 

 

↑ fentanyl

 

 

 

↑ analgesics

 

 

 

 

Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized

narcotic analgesics (including potentially fatal respiratory depression) is recommended with coadministration. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with ritonavir.

A dose decrease may be needed for these drugs when co-administered with ritonavir.

Tramadol

↑ tramadol

A dose decrease may be needed for tramadol with concomitant use.

Narcotic Analgesic/Treatment of Opioid Dependence:

Buprenorphine,

buprenorphine/naloxone

 

 

methadone

 

↔ buprenorphine, naloxone

↑ norbuprenorphine

(metabolite)

 

 

 

↓ methadone

 

No dose adjustment for buprenorphine or buprenorphine /naloxone is required with concurrent administration of darunavir/ritonavir. Clinical monitoring is recommended if darunavir/ritonavir and buprenorphine or buprenorphine/naloxone are co-administered.

 

No adjustment of methadone dosage is required when initiating co-administration of darunavir/ritonavir. However, clinical monitoring is recommended as the dose of methadone maintenance therapy may need to be adjusted in some patients.

Opioid Antagonist Naloxegol

↑ naloxegol

Co-administration of darunavir/ritonavir and naloxegol is contraindicated due to potential for precipitating opioid withdrawal symptoms.

PDE-5 inhibitors:

e.g.

Avanafil

Sildenafil

Vardenafil

Tadalafil

↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with darunavir /ritonavir)

Co-administration with darunavir /ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism.

 

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):

Co-administration with sildenafil used for PAH is contraindicated due to potential for sildenafil associated adverse reactions (which include visual disturbances, hypotension, prolonged erection, and syncope).

 

The following dose adjustments are recommended for use of tadalafil with darunavir/ritonavir:

  • Co-administration of tadalafil in patients on darunavir/ritonavir:

In patients receiving darunavir /ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

  • Co-administration of darunavir /ritonavir in patients on tadalafil:

Avoid use of tadalafil during the initiation of darunavir/ritonavir. Stop tadalafil at least 24 hours prior to starting darunavir/ritonavir. After at least one week following the initiation of darunavir/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

 

Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.

 

Co-administration of darunavir /ritonavir and avanafil is not recommended.

Platelet aggregation inhibitor:

Ticagrelor

 

Clopidogrel

 

 

 

Prasugrel

 

↑ ticagrelor

 

↓ clopidogrel active metabolite

 

 

 

↔ prasugrel active metabolite

 

Co-administration of darunavir/ritonavir and ticagrelor is not recommended.

 

Co-administration of darunavir/ ritonavir and clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel.

No dose adjustment is needed when prasugrel is co-administered with darunavir /ritonavir.

Proton pump inhibitor:

Omeprazole

↓ omeprazole

↔ darunavir

 

When omeprazole is co-administered with darunavir/ritonavir, monitor patients for decreased efficacy of omeprazole. Consider increasing the

omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole.

Sedatives/Hypnotics:

Orally administered Midazolam, triazolam

 

 

 

 

 

 

 

Buspirone, Clorazepate,Diazepam, Estazolam, Flurazepam, Zoldipem

Parenterally administered Midazolam

 

 

 

 

 

 

 

 

 

Stimulant: Methamphetamine

 

↑ midazolam

↑ triazolam

 

 

 

 

 

 

 

↑ sedatives /hypnotics

 

 

 

 

 

 

 

 

 

 

 

↑ methamphetamine

 Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Co-administration of triazolam or orally administered midazolam with darunavir may cause large increases in the concentrations of these benzodiazepines.

 

Titration is recommended when co-administering darunavir/ritonavir with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for adverse events.

Co-administration of parenteral midazolam should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

 

Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.

Urinary antispasmodics Fesoterodine

 

 

Solifenacin

 

↑ fesoterodine

 

 

↑ solifenacin

When fesoterodine is co-administered with darunavir/ritonavir, do not exceed a fesoterodine dose of 4 mg once daily.

 

When solifenacin is co-administered with darunavir/ritonavir, do not exceed a solifenacin dose of 5 mg once daily.

↑ increase in concentrations

↓ decreased in concentrations

↔ No change in concentrations

Drugs without Clinically Significant Interactions with Darunavir

No dosage adjustments are recommended when darunavir/ritonavir is co-administered with the following medications: atazanavir, dolutegravir, efavirenz, etravirine, nevirapine, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, emtricitabine/tenofovir alafenamide, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), pitavastatin, raltegravir, ranitidine, or rilpivirine.

Ritonavir

Potential for Ritonavir to Affect Other Drugs

Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with ritonavir. Thus, co-administration of ritonavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 1.

Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.

These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with ritonavir. The healthcare provider should consult appropriate references for comprehensive information.

Use in Special Populations

Pregnant Women

Darunavir and ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No adequate and well-controlled studies of darunavir and ritonavir have been conducted in pregnant women.

Darunavir

Risk Summary

Available limited data from the APR show no difference in rate of overall birth defects for darunavir (2.7%) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) . The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation.

The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Studies in animals did not show evidence of developmental toxicity. Exposures (based on AUC) in rats were 3-fold higher, whereas in mice and rabbits, exposures were lower (less than 1-fold) than human exposures at the recommended daily dose .

Clinical Considerations

The recommended dosage in pregnant patients is darunavir 600 mg taken with ritonavir 100 mg twice daily with food.

Darunavir 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable darunavir 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom a change to twice daily darunavir 600 mg with ritonavir 100 mg may compromise tolerability or compliance .

Data

Human Data

Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was evaluated in a clinical trial of 36 pregnant women during the second and third trimesters, and postpartum. Eighteen subjects were enrolled in each BID and QD treatment arms. Twenty-nine subjects completed the trial through the postpartum period (6-12 weeks after delivery) and 7 subjects discontinued before trial completion, 5 subjects in the BID arm and 2 subjects in the QD arm.

The pharmacokinetic data demonstrate that exposure to darunavir and ritonavir as part of an antiretroviral regimen was lower during pregnancy compared with postpartum (6-12 weeks). Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen.

Virologic response was preserved. In the BID arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 39% (7/18) at baseline, 61% (11/18) through the third trimester visit, and 61% (11/18) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for 11% (2/18) of subjects and were missing for 5 subjects (1 subject discontinued prematurely due to virologic failure). In the QD arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 61% (11/18) at baseline, 83% (15/18) through the third trimester visit, and 78% (14/18) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for none of the subjects and were missing for 3 subjects (1 subject discontinued prematurely due to virologic failure).

Darunavir/ritonavir was well tolerated during pregnancy and postpartum. There were no new clinically relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1-infected adults.

Among the 31 infants with HIV test results available data, born to the 31 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 31 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum. All 31 infants received antiretroviral prophylactic treatment containing zidovudine.

Based on prospective reports to the APR of 615 live births following exposure to darunavir containing regimens during pregnancy (including 385 exposed in the first trimester and 230 exposed in the second/third trimester), there was no difference in rate of overall birth defects for darunavir compared with the background rate for major birth defects in a U.S. reference population of the MACDP.

The prevalence of birth defects in live births was 2.6% (95% CI: 1.2% to 4.7%) with first trimester exposure to darunavir containing regimens and 1.7% (95% CI: 0.5% to 4.4%) with second/third trimester exposure to darunavir containing regimens.

Animal Data

Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6-15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8-20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir.

Ritonavir

Risk Summary

Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Available data from the APR show no difference in the rate of overall birth defects for ritonavir compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) .

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with oral administration of ritonavir to pregnant rats and rabbits. During organogenesis in the rat and rabbit, systemic exposure (AUC) was approximately 1/3 lower than human exposure at the recommended daily dose. In the rat pre-and post-natal developmental study, maternal systemic exposure to ritonavir was approximately 1/2 of the exposure in humans at the recommended daily dose, based on a body surface area conversion factor .

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data

Based on prospective reports to the APR of approximately 6100 live births following exposure to ritonavir-containing regimens (including over 2800 live births exposed in the first trimester and over 3200 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7%-2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.3%-3.5%) following second and third trimester exposure to ritonavir-containing regimens.

While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair.

Animal Data

Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on gestation days 6 through 17 and 6 through 19, respectively). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at doses producing systemic exposures (AUC) equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dose, at an exposure equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. A slight increase in the incidence of cryptorchidism was also noted in rats (at a maternally toxic dose) at an exposure approximately 1/5 lower than human exposure at the recommended daily dose. Developmental toxicity was observed in rabbits (resorptions, decreased litter size and decreased fetal weights) at maternally toxic doses approximately 1.8 times higher than the recommended daily dose, based on a body surface area conversion factor. In pre-and postnatal development study in rats, ritonavir was administered at doses of 0, 15, 35, and 60 mg/kg/day from gestation day 6 through postnatal day20. At doses of 60 mg/kg/day, no developmental toxicity was noted with ritonavir dosage equivalent to 1/2 of the recommended daily dose, based on a body surface area conversion factor.

Lactating Women

The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV. There are no data on the presence of darunavir in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir is secreted into the milk of lactating rats.  Limited published data reports that ritonavir is present in human milk.There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production.

Because of both the potential for HIV transmission, developing viral resistance and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving darunavir and ritonavir.

Animal Data

Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is secreted in the milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 50% of those obtained in humans at the recommended clinical dose with ritonavir.

Females and Males of Reproductive Potential

Contraception

Use of darunavir and ritonavir may reduce the efficacy of combined hormonal contraceptives and the progestin only pill. Advise patients to use an effective alternative (non-hormonal) contraceptive method or add a barrier method of contraception. For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia .

Pediatric Patients

The safety and effectiveness of DARUVIR 800-R and DARUVIR 600-R Tablets have not been established in pediatric patients less than 12 years of age.

In clinical trial TMC114-C230, the safety, pharmacokinetic profile and virologic and immunologic responses of darunavir/ritonavir administered once daily were evaluated in treatment-naïve HIV-1-infected pediatric subjects 12 to less than 18 years of age (12 subjects). Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable with those observed in adults.

Geriatric Patients

Clinical studies of darunavir/ritonavir did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of darunavir/ritonavir in elderly patients, reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy.

Patients with Hepatic Impairment

No dose adjustment of darunavir/ritonavir is necessary for patients with either mild or moderate hepatic impairment. No pharmacokinetic or safety data are available regarding the use of darunavir/ritonavir in subjects with severe hepatic impairment. Therefore, darunavir/ritonavir is not recommended for use in patients with severe hepatic impairment.

Patients with Renal Impairment

Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-infected subjects with moderate renal impairment (CrCL between 30–60 mL/min, n=20). No pharmacokinetic data are available in HIV-1-infected patients with severe renal impairment or end-stage renal disease; however, because the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis.    

Effects on Ability to Drive and Use Machines

Darunavir in combination with 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 low-dose ritonavir and should be borne in mind when considering a patient's ability to drive or operate machinery.

Undesirable Effects

The following adverse reactions are discussed in other sections of labeling:

  • Hepatotoxicity
  • Severe Skin Reactions
  • Diabetes Mellitus/Hyperglycemia
  • Fat Redistribution
  • Immune Reconstitution Syndrome
  • Hemophilia
  • Drug Interactions
  • Pancreatitis
  • Allergic Reactions /Hypersensitivity

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Treatment-naïve Adults: Study TMC114-C211

The safety assessment is based on all safety data from the Phase 3 trial TMC114-C211 comparing darunavir/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day in 689 antiretroviral treatment-naïve HIV-1-infected adult subjects. The total mean exposure for subjects in the darunavir/ritonavir 800/100 mg once daily arm and in the lopinavir/ritonavir 800/200 mg per day arm was 162.5 and 153.5 weeks, respectively.

The majority of the adverse drug reactions (ADRs) reported during treatment with darunavir/ritonavir 800/100 mg once daily were mild in severity. The most common clinical ADRs to darunavir/ritonavir 800/100 mg once daily (greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, headache, abdominal pain and rash. 2.3% of subjects in the darunavir/ritonavir arm discontinued treatment due to ADRs.

ADRs to darunavir/ritonavir 800/100 mg once daily of at least moderate intensity (greater than or equal to Grade 2) in antiretroviral treatment-naïve HIV-1-infected adult subjects are presented in Table 2 and subsequent text below the table

Table 2: Selected clinical adverse drug reactions to darunavir/ritonavir 800/100 mg once daily* of at least moderate intensity (≥Grade 2) occurring in ≥2% of antiretroviral treatment-naïve hiv-1-infected adult subjects (Trial TMC114-C211)

System Organ Class, Preferred Term, %

Darunavir/Ritonavir 800/100 mg once daily + TDF/FTC

n=343

Lopinavir/ritonavir 800/200 mg per day + TDF/FTC

n=346

Gastrointestinal Disorders

Abdominal pain

6%

6%

Diarrhoea

9%

16%

Nausea

4%

4%

Vomiting

2%

4%

General Disorders and Administration Site Conditions

Fatigue

<1%

3%

Metabolism and Nutrition Disorders

Anorexia

2%

<1%

Nervous System Disorders

 

Headache

7%

6%

Skin and Subcutaneous Tissue Disorders

Rash

6%

7%

       

n = total number of subjects per treatment group; TDF = tenofovir disoproxil fumarate

FTC = emtricitabine

 * Excluding laboratory abnormalities reported as ADRs

Less Common Adverse Reactions

Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving darunavir/ritonavir 800/100 mg once daily are listed below by body system:

Gastrointestinal Disorders: acute pancreatitis, dyspepsia, flatulence

General Disorders and Administration Site Conditions: asthenia

Hepatobiliary Disorders: acute hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity)

Immune System Disorders: (drug) hypersensitivity, immune reconstitution syndrome

Metabolism and Nutrition Disorders: diabetes mellitus

Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis

Psychiatric Disorders: abnormal dreams

Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson Syndrome, urticaria

Laboratory abnormalities

Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-naïve adult subjects treated with darunavir/ritonavir 800/100 mg once daily are presented in Table 3.

Table 3: Grade 2 to 4 laboratory abnormalities observed in antiretroviral treatment-naïve HIV-1-infected adult subjects* (Trial TMC114-C211)

Laboratory Parameter Preferred Term, %

Limit

Darunavir/Ritonavir 800/100 mg once daily + TDF/FTC

Lopinavir/ritonavir 800/200 mg per day + TDF/FTC

 

 

Biochemistry

 

 

 

 

Alanine Aminotransferase

Grade 2

>2.5 to ≤5.0 × ULN

9%

9%

 

Grade 3

>5.0 to ≤10.0 × ULN

3%

3%

 

Grade 4

>10.0 × ULN

<1%

3%

 

Aspartate Aminotransferase

Grade 2

>2.5 to ≤5.0 × ULN

7%

10%

 

Grade 3

>5.0 to ≤10.0 × ULN

4%

2%

 

Grade 4

>10.0 × ULN

1%

3%

 

Alkaline Phosphatase

Grade 2

>2.5 to ≤5.0 × ULN

1%

1%

 

Grade 3

>5.0 to ≤10.0 × ULN

0%

<1%

 

Grade 4

>10.0 × ULN

0%

0%

 

Hyperbilirubinaemia

Grade 2

>1.5 to ≤2.5 ×ULN

<1%

5%

 

Grade 3

>2.5 to ≤5.0 ×ULN

<1%

<1%

 

Grade 4

>5.0 ×ULN

0%

0%

 

Triglycerides

Grade 2

5.65–8.48 mmol/L

500–750 mg/dL

3%

10%

 

Grade 3

8.49–13.56 mmol/L

751–1,200 mg/dL

2%

5%

 

Grade 4

>13.56 mmol/L

>1,200 mg/dL

1%

1%

 

Total Cholesterol

Grade 2

6.20–7.77 mmol/L

240–300 mg/dL

23%

27%

 

Grade 3

>7.77 mmol/L

>300 mg/dL

1%

5%

 

Low-density Lipoprotein Cholesterol

Grade 2

4.13–4.90 mmol/L

160–190 mg/dL

14%

12%

 

Grade 3

≥4.91 mmol/L

>191 mg/dL

9%

6%

 

Elevated Glucose Levels

Grade 2

6.95–13.88 mmol/L

126–250 mg/dL

11%

10%

 

Grade 3

13.89–27.75 mmol/L

251–500 mg/dL

1%

<1%

 

Grade 4

>27.75 mmol/L

>500 mg/dL

0%

0%

 

Pancreatic Lipase

Grade 2

>1.5 to ≤3.0 × ULN

3%

2%

 

Grade 3

>3.0 to ≤5.0 × ULN

<1%

1%

 

Grade  4

>5.0 × ULN

0%

<1%

 

Pancreatic Amylase

Grade 2

>1.5 to ≤2.0 × ULN

5%

2%

 

Grade 3

>2.0 to ≤5.0 × ULN

5%

4%

 

Grade 4

>5.0 × ULN

0%

<1%

 

n = Total number of subjects per treatment group

TDF = tenofovir disoproxil fumarate

FTC = emtricitabine

*Grade 4 data not applicable in division of AIDS grading scale.

Treatment-Experienced Adults: Study TMC114-C214

The safety assessment is based on all safety data from the Phase 3 trial TMC114-C214 comparing darunavir/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in 595 antiretroviral treatment-experienced HIV-1-infected adult subjects. The total mean exposure for subjects in the darunavir/ritonavir 600/100 mg twice daily arm and in the lopinavir/ritonavir 400/100 mg twice-daily arm was 80.7 and 76.4 weeks, respectively.

Majority of the adverse drug reactions reported during treatment with darunavir/ritonavir 600/100 mg twice daily were mild in severity. The most common clinical adverse drug reactions to darunavir/ritonavir 600/100 mg twice daily (≥5%) of at least moderate intensity (≥Grade 2) were diarrhoea, nausea, rash, abdominal pain and vomiting. Of the subjects in the darunavir/ritonavir arm, 4.7% discontinued treatment due to adverse drug reactions.

Adverse drug reactions to darunavir/ritonavir 600/100 mg twice daily of at least moderate intensity (≥Grade 2) in antiretroviral treatment-experienced HIV-1-infected adult subjects are presented in Table 4 and subsequent text below the table

Table 4: Selected clinical adverse drug reactions to darunavir/ritonavir 600/100 mg twice daily* of at least moderate intensity (≥Grade 2) occurring in ≥2% of antiretroviral treatment-experienced hiv-1-infected adult subjects (Trial TMC114-C214)

System Organ Class, Preferred Term, %

Darunavir/Ritonavir 600/100 mg twice daily + OBR

n=298

Lopinavir/ritonavir 400/100 mg twice daily + OBR

n=297

Gastrointestinal Disorders

Abdominal distension

2%

<1%

Abdominal pain

6%

3%

Diarrhoea

14%

20%

Dyspepsia

2%

1%

Nausea

7%

6%

Vomiting

5%

3%

General Disorders and Administration Site Conditions

Asthenia

3%

1%

Fatigue

2%

1%

Metabolism and Nutrition Disorders

Anorexia

2%

2%

Diabetes mellitus

2%

<1%

Nervous System Disorders

Headache

3%

3%

Skin and Subcutaneous Tissue Disorders

Rash

7%

3%

n = total number of subjects per treatment group

OBR = optimized background regimen

* Excluding laboratory abnormalities reported as adverse drug reactions

Less Common Adverse Reactions

Treatment-emergent adverse drug reactions of at least moderate intensity (≥Grade 2) occurring in less than 2% of antiretroviral treatment-experienced subjects receiving darunavir/ritonavir 600/100 mg twice daily are listed below by body system:

Gastrointestinal Disorders: Acute pancreatitis, flatulence

Musculoskeletal and Connective Tissue Disorders: Myalgia

Psychiatric Disorders: Abnormal dreams

Skin and Subcutaneous Tissue Disorders: Pruritus, urticaria

Laboratory abnormalities

Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-experienced adult subjects treated with darunavir/ritonavir 600/100 mg twice daily are presented in Table 5.

Table 5: Grade 2 to 4 laboratory abnormalities observed in antiretroviral treatment-experienced HIV-1-infected adult subjects* (TMC114-C214)

Laboratory Parameter Preferred Term, %

Limit

Darunavir/

Ritonavir 600/100 mg twice daily + OBR

lopinavir/ritonavir 400/100 mg Twice daily + OBR

Biochemistry

 

 

 

Alanine Aminotransferase

Grade 2

>2.5 to ≤5.0 × ULN

7%

5%

Grade 3

>5.0 to ≤10.0 × ULN

2%

2%

Grade 4

>10.0 × ULN

1%

2%

Aspartate Aminotransferase

Grade 2

>2.5 to ≤5.0 × ULN

6%

6%

Grade 3

>5.0 to ≤10.0 × ULN

2%

2%

Grade 4

>10.0 × ULN

<1%

2%

Alkaline Phosphatase

Grade 2

>2.5 to ≤5.0 × ULN

<1%

0%

Grade 3

>5.0 to ≤10.0 × ULN

<1%

<1%

Grade 4

>10.0 × ULN

0%

0%

Hyperbilirubinaemia

Grade 2

>1.5 to ≤2.5 ×ULN

<1%

2%

Grade 3

>2.5 to ≤5.0 ×ULN

<1%

<1%

Grade 4

>5.0 ×ULN

<1%

0%

Triglycerides

Grade 2

5.65–8.48 mmol/L

500–750 mg/dL

10%

11%

Grade 3

8.49–13.56 mmol/L

751–1,200 mg/dL

7%

10%

Grade 4

>13.56 mmol/L

>1,200 mg/dL

3%

6%

Total Cholesterol

Grade 2

6.20–7.77 mmol/L

240–300 mg/dL

25%

23%

Grade 3

>7.77 mmol/L

>300 mg/dL

10%

14%

Low-density Lipoprotein Cholesterol

Grade 2

4.13–4.90 mmol/L

160–190 mg/dL

14%

14%

Grade 3

≥4.91 mmol/L

>191 mg/dL

8%

9%

Elevated Glucose Levels

Grade 2

6.95–13.88 mmol/L

126–250 mg/dL

10%

11%

Grade 3

13.89–27.75 mmol/L

251–500 mg/dL

<1%

<1%

Grade 4

>27.75 mmol/L

>500 mg/dL

<1%

0%

Pancreatic Lipase

Grade 2

>1.5 to ≤3.0 × ULN

3%

4%

Grade 3

>3.0 to ≤5.0 × ULN

2%

<1%

Grade  4

>5.0 × ULN

<1%

0%

Pancreatic Amylase

Grade 2

>1.5 to ≤2.0 × ULN

6%

7%

Grade 3

>2.0 to ≤5.0 × ULN

7%

3%

Grade 4

>5.0 × ULN

0%

0%

n = Total number of subjects per treatment group

OBR = optimized background regimen

*Grade 4 data not applicable in division of AIDS grading scale.

Serious Adverse Drug Reactions

The following serious adverse drug reactions of at least moderate intensity (greater than or equal to Grade 2) occurred in the Phase 2b studies and Phase 3 studies with darunavir/ritonavir: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhoea, fatigue, headache, hepatic enzyme increased, hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, immune reconstitution syndrome, low-density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson syndrome, and vomiting.

Adverse Reactions of Ritonavir in Adults

The safety of ritonavir alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table 6 lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving ritonavir  in combined Phase II/IV studies.

The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia.

Table 6. Treatment-emergent adverse reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving ritonavir in combined phase ii/iv studies (n = 1,755)

Adverse Reactions

n

%

Eye disorders

Blurred vision

113

6.4

Gastrointestinal disorders

Abdominal Pain (upper and lower)*

464

26.4

Diarrhea including severe with electrolyte imbalance*

1,192

67.9

Dyspepsia

201

11.5

Flatulence

142

8.1

Gastrointestinal hemorrhage*

41

2.3

Gastroesophageal reflux disease (GERD)

19

1.1

Nausea

1,007

57.4

Vomiting*

559

31.9

General disorders and administration site conditions

Fatigue including asthenia*

811

46.2

Hepatobiliary disorders

Blood bilirubin increased (including jaundice)*

25

1.4

Hepatitis (including increased AST, ALT, GGT)*

153

8.7

Immune system disorders

Hypersensitivity including urticaria and face edema*

114

8.2

Metabolism and nutrition disorders

Edema and peripheral edema*

110

6.3

Gout*

24

1.4

Hypercholesterolemia*

52

3.0

Hypertriglyceridemia*

158

9.0

Lipodystrophy acquired*

51

2.9

Musculoskeletal and connective tissue disorders

Arthralgia and back pain*

326

18.6

Myopathy/creatine phosphokinase increased*

66

3.8

Myalgia

156

8.9

Nervous system disorders

 

Dizziness*

274

15.6

Dysgeusia*

285

16.2

Paresthesia (including oral paresthesia)*

889

50.7

Peripheral neuropathy

178

10.1

Syncope*

58

3.3

Psychiatric disorders

 

Confusion*

52

3.0

 

Disturbance in attention

44

2.5

 

Renal and urinary disorders

 

Increased urination*

74

4.2

 

Respiratory, thoracic and mediastinal disorders

 

Coughing*

380

21.7

 

Oropharyngeal Pain*

279

15.9

 

Skin and subcutaneous tissue disorders

 

Acne*

67

3.8

 

Pruritus*

214

12.2

 

Rash (includes erythematous and maculopapular)*

475

27.1

 

Vascular disorders

 

Flushing, feeling hot*

232

13.2

 

Hypertension*

58

3.3

 

Hypotension including orthostatic hypotension*

30

1.7

 

Peripheral coldness*

21

1.2

 

* Represents a medical concept including several similar MedDRA PTs

 

Laboratory Abnormalities in Adults

Table 7 shows the percentage of adult patients who developed marked laboratory abnormalities.

Table 7: Percentage of adult patients, by study and treatment group, with chemistry and hematology abnormalities

 

 

Study 245 Naive Patients

Study 247 Advanced Patients

Study 462 PI-Naive Patients

Variable

Limit

RTV + ZDV

RTV

ZDV

RTV

Placebo

RTV + SQV

Chemistry

High

Cholesterol

> 240 mg/dL

30.7

44.8

9.3

36.5

8.0

65.2

CPK

> 1000 IU/L

9.6

12.1

11.0

9.1

6.3

9.9

GGT

> 300 IU/L

1.8

5.2

1.7

19.6

11.3

9.2

SGOT (AST)

> 180 IU/L

5.3

9.5

2.5

6.4

7.0

7.8

SGPT (ALT)

> 215 IU/L

5.3

7.8

3.4

8.5

4.4

9.2

Triglycerides

> 800 mg/dL

9.6

17.2

3.4

33.6

9.4

23.4

Triglycerides

> 1500 mg/dL

1.8

2.6

-

12.6

0.4

11.3

Triglycerides Fasting

> 1500 mg/dL

1.5

1.3

-

9.9

0.3

-

Uric Acid

> 12 mg/dL

-

-

-

3.8

0.2

1.4

Hematology

Low

Hematocrit

< 30%

2.6

-

0.8

17.3

22.0

0.7

Hemoglobin

< 8.0 g/dL

0.9

-

-

3.8

3.9

-

Neutrophils

≤ 0.5 x 109/L

-

-

-

6.0

8.3

-

RBC

< 3.0 x 1012/L

1.8

-

5.9

18.6

24.4

-

WBC

< 2.5 x 109/L

-

0.9

6.8

36.9

59.4

3.5

-Indicates no events reported.

RTV: Ritonavir

ZDV: Zidovudine

SQV: Saquinavir

                   

Patients co-infected with hepatitis B and/or hepatitis C virus

In subjects co-infected with hepatitis B or C virus receiving darunavir/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving darunavir/ritonavir 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.

Postmarketing Experience

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

Body as a Whole

Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration.

Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.

Cardiovascular System
First-degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported .

Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded.

Endocrine System

Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co- administered with fluticasone propionate or budesonide.

Nervous System
There have been postmarketing reports of seizure. Also, see Cardiovascular System.

Renal and Urinary Disorders

Nephrolithiasis

Skin and subcutaneous tissue disorders
Toxic epidermal necrolysis (TEN) has been reported. In addition, acute generalized exanthematous pustulosis and drug rash with eosinophilia and systemic symptoms have been reported rarely.

Redistribution of body fat has been reported.

Rarely, rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and darunavir/ritonavir) has been reported.

Reporting of Side Effects

If your patient experiences any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Program of India by calling (PvPI) on 1800 180 3024 or you can report to Cipla Ltd. on 18002677779.  

By reporting side effects you can help provide more information on the safety of this product

Overdose

Human experience of acute overdose with darunavir/ritonavir is limited.

Acute Overdosage -Human Overdose Experience

Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg per day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose.

The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice.

No specific antidote is available for overdose with darunavir/ritonavir. Treatment of overdose with darunavir/ritonavir consists of general supportive measures, including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir/ritonavir is highly protein-bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway.  Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. 

Pharmacological Properties

Mechanism of Action

Darunavir

Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles. Darunavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M (A, B, C, D, E, F, G), and group O primary isolates with EC50 values ranging from less than 0.1 to 4.3 nM. The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum. Darunavir did not show antagonism when studied in combination with the PIs amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine, rilpivirine, efavirenz, etravirine, or nevirapine, and the fusion inhibitor enfuvirtide.

Ritonavir

Ritonavir is a peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of non-infectious immature HIV particles.The activity of ritonavir was assessed in acutely infected lymphoblastoid cell lines and in peripheral blood lymphocytes. The concentration of drug that inhibits 50% (EC50) value of viral replication ranged from 3.8 to 153 nM depending upon the HIV-1 isolate and the cells employed. The average EC50 value for low passage clinical isolates was 22 nM (n = 13). In MT4 cells, ritonavir demonstrated additive effects against HIV-1 in combination with either didanosine (ddI) or zidovudine (ZDV). Studies which measured cytotoxicity of ritonavir on several cell lines showed that greater than 20 μM was required to inhibit cellular growth by 50% resulting in a cell culture therapeutic index of at least 1000.

Pharmacodynamic Properties

Darunavir

Antiviral Activity in Vitro

Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/ml). Darunavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from < 0.1 to 4.3 nM.

These EC50 values are well below the 50% cellular toxicity concentration range of 87 µM to > 100 µM.

Resistance

In vitro selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years). The selected viruses were unable to grow in the presence of darunavir concentrations above 400 nM. Viruses selected in these conditions and showing decreased susceptibility to darunavir (range: 23-50-fold) harboured 2 to 4 amino acid substitutions in the protease gene. The decreased susceptibility to darunavir of the emerging viruses in the selection experiment could not be explained by the emergence of these protease mutations.

Ritonavir

Ritonavir dosed as a pharmacokinetic enhancer

Pharmacokinetic enhancement by ritonavir is based on ritonavir's activity as a potent inhibitor of CYP3A- mediated metabolism. The degree of enhancement is related to the metabolic pathway of the co-administered protease inhibitor and the impact of the co-administered protease inhibitor on the metabolism of ritonavir. Maximal inhibition of metabolism of the co-administered protease inhibitor is generally achieved with ritonavir doses of 100 mg daily to 200 mg twice daily, and is dependent on the co-administered protease inhibitor. For additional information on the effect of ritonavir on co-administered protease inhibitor metabolism.

Ritonavir dosed as an antiretroviral agent

Ritonavir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to the production of HIV particles with immature morphology that are unable to initiate new rounds of infection. Ritonavir has selective affinity for the HIV protease and has little inhibitory activity against human aspartyl proteases.

Ritonavir was the first protease inhibitor (approved in 1996) for which efficacy was proven in a study with clinical endpoints. However, due to ritonavir's metabolic inhibitory properties its use as a pharmacokinetic enhancer of other protease inhibitors is the prevalent use of ritonavir in clinical practice.

Effects on the Electrocardiogram

In a thorough QT/QTc study in 40 healthy subjects, Darunavir/ritonavir doses of 1.33 times the maximum recommended dose did not affect the QT/QTc interval.

QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once- daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state.

PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec in the 12-hour interval post dose. Maximum PR interval was 252 msec and no second or third degree heart block was observed.

Resistance

Ritonavir-resistant isolates of HIV-1 have been selected in vitro and isolated from patients treated with therapeutic doses of ritonavir.

Reduction in the antiretroviral activity of ritonavir is primarily associated with the protease mutations V82A/F/T/S and I84V. Accumulation of other mutations in the protease gene (including at positions 20, 33, 36, 46, 54, 71, and 90) can also contribute to ritonavir resistance. In general, as mutations associated with ritonavir resistance accumulate, susceptibility to select other PIs may decrease due to cross-resistance.

Pharmacokinetic Properties

Pharmacokinetics in Adults

General

Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a single dose of darunavir 600 mg was given orally in combination with 100 mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir. Therefore, darunavir 800 should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir.

The pharmacokinetics of darunavir, co-administered with low-dose ritonavir (100 mg), has been evaluated in healthy adult volunteers and in HIV-1-infected subjects. Table 8 displays the population pharmacokinetic estimates of darunavir after oral administration of darunavir/ritonavir 600/100 mg twice daily (based on sparse sampling in 285 patients in study TMC114-C214, 278 patients in Study TMC114-C229 and 119 patients from Studies TMC114-C202 and TMC114-C213) and darunavir/ritonavir 800/100 mg once daily (based on sparse sampling in 335 patients in Study TMC114-C211 and 280 patients in Study TMC114-C229) to HIV-1-infected patients.

The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD4 greater than or equal to 50 cells per μL). See Table 9 for ritonavir pharmacokinetic characteristics.

Table 8: Population pharmacokinetic estimates of darunavir with darunavir/ritonavir 800/100 mg once daily (Study TMC114-C211, 48-week analysis and study TMC114-C229, 48-week analysis) and darunavir/ritonavir 600/100 mg twice daily (Study TMC114-C214, 48-week analysis, study TMC114-C229, 48-week analysis and integrated data from Studies TMC114-C213 and TMC114-C202, primary 24-week analysis)

Parameter

darunavir/Ritonavir 800/100 mg once daily

darunavir/Ritonavir

600/100 mg twice daily

TMC114-C211

N=335

TMC114-C229

N=280

TMC114-C214

N=285

TMC114-C229 N=278

TMC114-C213 and TMC114-C202 (integrated data)

N=119

AUC24h (ng·h/mL)*

Mean ± Standard Deviation

93,026 ± 27,050

93,334 ± 28,626

1,16,796 ± 33,594

1,14,302 ± 32,681

1,24,698 ± 32,286

Median (Range)

87,854

(45,000–2,19,240)

87,788 (45,456–2,36,920)

1,11,632

(64,874–3,55,360)

1,09,401 (48,934–3,23,820)

1,23,336

(67,714–2,12,980)

C0h (ng/mL)

Mean ± Standard Deviation

2,282 ± 1,168

2,160 ± 1,201

3,490 ± 1,401

3,386 ± 1,372

3,578 ± 1,151

Median (Range)

2,041 (368–7,242)

1,896

(184-7,881)

3,307 (1,517–13,198)

3,197 (250–11,865)

3,539

(1,255–7,368)

N = number of subjects with data

*AUC24h is calculated as AUC12h*2

Absorption and Bioavailability

Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a Tmax of approximately 2.5–4 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively. In vivo data suggests that darunavir/ritonavir is an inhibitor of the P-glycoprotein (P-gp) transporters.

Effects of Food on Oral Absorption

Darunavir

When darunavir tablets were administered with food, the Cmax and AUC of darunavir, co-administered with ritonavir, is approximately 40% higher relative to the fasting state. Within the range of meals studied, darunavir exposure is similar. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 gm fat) to 928 Kcal (56 gm fat).

Ritonavir

Following the administration of a 100 mg tablet dose of Ritonavir, Cmax and AUCinf of ritonavir were decreased by 21-23% under moderate fat (857 Kcal, 30% from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.

Distribution

Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).

Metabolism

In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after a single-dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least three oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV-1.

Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that CYP3A is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M–2.

Elimination

A mass balance study in healthy volunteers showed that after single-dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in the feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice-daily ritonavir, was 32.8 L/h and 5.9 L/h, respectively.

In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance.

Table 9: Ritonavir pharmacokinetic characteristics

Parameter

N

Values (Mean ± SD)

Vβ/F

91

0.41 ± 0.25 L/kg

 

3 - 5 h

CL/F SS

10

8.8 ± 3.2 L/h

CL/F

91

4.6 ± 1.6 L/h

CLR

62

<0.1 L/h

RBC/Plasma Ratio

 

0.14

Percent Bound*

 

98 to 99%

SS = steady state; patients taking ritonavir 600 mg q12h.
Single ritonavir 600 mg dose.
* Primarily bound to human serum albumin and alpha-1 acid glycoprotein over the ritonavir concentration range of 0.01 to 30 µg/mL.

Special Populations

Hepatic Impairment

Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple-dose co-administration of daruanvir/ritonavir 600/100 mg twice daily to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A; n=8), and moderate hepatic impairment (Child-Pugh Class B; n=8). Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. The effect of severe hepatic impairment on the pharmacokinetics of darunavir or ritonavir has not been evaluated.

Hepatitis B or Hepatitis C Virus Co-infection

The 48-week analysis of the data from Studies TMC114-C211 and TMC114-C214 in HIV-1-infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.

Renal Impairment

Results from a mass balance study with 14C-darunavir/ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged drug. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1-infected subjects with moderate renal impairment (CrCL between 30 to 60 mL/min, n=20). There are no pharmacokinetic data available in HIV-1-infected patients with severe renal impairment or end-stage renal disease.

Ritonavir pharmacokinetics has not been studied in patients with renal impairment; however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Gender and Race

Population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-1-infected females compared with males. This difference is not clinically relevant. Population pharmacokinetic analysis of darunavir in HIV-1-infected subjects indicated that race had no apparent effect on the exposure to darunavir.

A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences. Pharmacokinetic differences due to race have not been identified.

Geriatric Patients

Population pharmacokinetic analysis in HIV-1-infected subjects showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV-1-infected subjects (n=12, age ≥65 years).

Pregnancy and Postpartum

The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum (see Table 10, Table 11 and Figure 1).

Table 10: Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg twice daily as part of an antiretroviral regimen, during the 2nd trimester of pregnancy, the 3rd trimester of pregnancy and postpartum

Pharmacokinetics of total darunavir (mean ± standard deviation)

2nd Trimester of pregnancy (n=12)*

3rd Trimester of pregnancy (n=12)

Postpartum (6-12 Weeks) (n=12)

Cmax, ng/mL

4668 ± 1097

5328 ± 1631

6659 ± 2364

AUC24h, ng.h/mL

78740 ± 19194

91760 ± 34720

113780 ± 52680

Cmin, ng/mL

1922 ± 825

26 61 ± 1269

2851 ± 2216

* n=11 for AUC24h                                                                    

AUC24h is calculated as AUC12h*2

Table 11: Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 800/100 mg once daily as part of an antiretroviral regimen, during the 2nd trimester of pregnancy, the 3rd trimester of pregnancy and postpartum

Pharmacokinetics of total darunavir (mean ± standard deviation)

2nd Trimester of pregnancy (n=17)

3rd Trimester of pregnancy (n=15)

Postpartum (6-12 Weeks) (n=16)

Cmax, ng/mL

4964 ± 1505

5132 ± 1198

7310 ± 1704

AUC24h, ng.h/mL

62289 ± 16234

61112 ± 13790

92116 ± 29241

Cmin, ng/mL

1248 ± 542

1075 ± 594

1473 ± 1141

Due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum, unbound darunavir exposures were less reduced during pregnancy as compared to postpartum. Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen (see Figure 1).

 Darunavir/ritonavir twice daily                                                                                            Darunavir/ritonavir once daily    

Legend: 90% CI: 90% confidence interval;GMR: geometric mean ratio. Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.

Figure 1: Pharmacokinetic results (within-subject comparison) of total and unbound darunavir after administration of darunavir/ritonavir at 600/100 mg twice daily or 800/100 mg once daily as part of an antiretroviral regimen, during the 2nd and 3rd trimester of pregnancy compared to postpartum

Based on evaluation of the published literature, ritonavir exposures are reduced during pregnancy relative to postpartum.

Nonclinical Properties

Animal Toxicology or Pharmacology

Darunavir

Animal toxicology studies have been conducted at exposures up to clinical exposure levels with darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.

In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment with darunavir. In rodents the target organs identified were the haematopoietic system, the blood coagulation system, liver and thyroid. A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated partial thromboplastin time.

Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and thyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a small increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the pancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicity findings or target organs were identified up to exposures equivalent to clinical exposure at the recommended dose.

In a study conducted in rats, the number of corpora lutea and implantations were decreased in the presence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavir treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The exposure levels were lower than those with the recommended clinical dose in humans. In a pre- and postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening of eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pups that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation. These effects may be secondary to pup exposure to the active substance via the milk and/or maternal toxicity. No post weaning functions were affected with darunavir alone or in combination with ritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed with convulsions in some animals. Exposure in plasma, liver and brain was considerably higher than in adult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, the exposure was comparable to that in adult rats. The increased exposure was likely at least partly due to immaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalities were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats.

Ritonavir

Repeated dose toxicity studies in animals identified major target organs as the liver, retina, thyroid gland and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and were accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigment epithelium (RPE) and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have not been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary to phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced ocular changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir. Clinical investigation in humans has revealed no clinically significant alteration in thyroid function tests. Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted in rats and are felt to be attributable to species-specific spontaneous disease. Furthermore, no clinically significant renal abnormalities were noted in clinical trials.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Darunavir

Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg was administered to rats. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas were observed in males and females of both species as well as an increase in thyroid follicular cell adenomas in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).

Ritonavir

Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg per kg per day, there was a dose-dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 0.3-fold for males that of the exposure in humans with the recommended therapeutic dose (600 mg twice daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg per kg per day there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 6% that of the exposure in humans with the recommended therapeutic dose. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known.

Mutagenesis

Darunavir

Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reserve mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.

Ritonavir

Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a maternally toxic dosage. Developmental toxicity in rabbits (embryolethality, decreased litter size and decreased foetal weights) occurred at a maternally toxic dosage.

Ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Long term carcinogenicity studies of ritonavir in mice and rats revealed tumourigenic potential specific for these species, but are regarded as of no relevance for humans.

Impairment of Fertility

Darunavir

No effects on fertility or early embryonic development were observed with darunavir in rats.

Ritonavir

Ritonavir produced no effects on fertility in rats at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed therapeutic dose. Higher dosages were not feasible due to hepatic toxicity.

Description

Darunavir

Darunavir is an inhibitor of the human immunodeficiency virus (HIV-1) protease. It has a molecular weight of 593.73 and chemical name is (2-methylpropyl)amino]-2-hydroxy-1(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofurofuran-3-yl ester monoethanolate. The molecular formula is C27H37N3O7S • C2H5OH and it is represented by the following structural formula:

Darunavir ethanolate has is a white to off-white powder with a solubility of approximately 0.15 mg/mL in water at 20°C.

Ritonavir

Ritonavir is an inhibitor of HIV protease with activity against the human immunodeficiency virus (HIV). Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1--3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, . Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95. Ritonavir has the following structural formula:

Ritonavir is a white -to -light-tan powder. Ritonavir has a bitter metallic taste. It is freely soluble in methanol and ethanol, soluble in isopropanol, and practically insoluble in water.

Pharmaceutical Particulars

Incompatibilities

None.

Shelf-Life

24 months

Packaging Information

DARUVIR 800-R: HDPE container of 30 Tablets

DARUVIR 600-R: HDPE container of 60 Tablets

Storage and Handling Instructions

Store at a temperature below 30°C. Protect from moisture. Keep the container tightly closed. Keep out of the reach of children.

Patient Counseling Information

What is the most important information I should know about DARUVIR 800-R/DARUVIR 600-R Tablets?

Ask your healthcare provider or pharmacist about medicines that should not be taken with DARUVIR 800-R/DARUVIR 600-R Tablets.

  • DARUVIR 800-R/DARUVIR 600-R Tablets may cause liver problems. Some people taking DARUVIR 800-R/DARUVIR 600-R Tablets have developed liver problems, which may be life-threatening. Your healthcare provider should do blood tests before and during your DARUVIR 800-R/DARUVIR 600-R Tablets treatment. If you have chronic hepatitis B or C infection, your healthcare provider should check your blood tests more often because you have an increased chance of developing liver problems. Tell your healthcare provider if you have any of the below signs and symptoms of liver problems.
  • dark (tea colored) urine
  • yellowing of your skin or whites of your eyes
  • pale colored stools (bowel movements)
  • nausea
  • vomiting
  • pain or tenderness on your right side below your ribs
  • loss of appetite
  • tiredness
  • DARUVIR 800-R/DARUVIR 600-R Tablets may cause severe or life-threatening skin reactions or rash. Sometimes these skin reactions and skin rashes can become severe and require treatment in a hospital. Tell your healthcare provider right away if you develop a rash. Stop taking DARUVIR 800-R/DARUVIR 600-R Tablets and tell your healthcare provider right away if you have any skin changes with symptoms below:
  • fever
  • tiredness
  • muscle or joint pain
  • blisters or skin lesions
  • mouth sores or ulcers
  • Red or inflamed eyes, like “pink eye” (conjunctivitis) Rash occurred more often in people taking DARUVIR 800-R/DARUVIR 600-R Tablets and raltegravir together than with either drug separately,but was generally mild.

What are DARUVIR 800-R/DARUVIR 600-R Tablets?

DARUVIR 800-R/DARUVIR 600-R Tablets are prescription HIV-1 (Human Immunodeficiency Virus-type 1) medicine used with ritonavir and other antiretroviral medicines to treat HIV-1 infection in adults and adolescents. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

DARUVIR 800-R/DARUVIR 600-R Tablets should not be used in children less than 12 years of age. When used with other antiretroviral medicines to treat HIV-1 infection, DARUVIR 800-R/DARUVIR 600-R Tablets may help:

  • Reduce the amount of HIV-1 in your blood. This is called “viral load”.
  • Increase the number of CD4+ (T) cells in your blood that help fight off other infections.

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

DARUVIR 800-R/DARUVIR 600-R Tablets does not cure HIV-1 infection or AIDS. You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.

Avoid doing things that can spread HIV-1 infection to others:

  • Do not share or re-use needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Ask your healthcare provider if you have any questions on how to prevent passing HIV to other people.

Who should not take DARUVIR 800-R/DARUVIR 600-R Tablets?

Do not take DARUVIR 800-R/DARUVIR 600-R Tablets with any medicine that contains:

  • are allergic to darunavir/ritonavir or any of the ingredients in DARUVIR-800 - R or DARUVIR 600- R.
  • alfuzosin
  • amiodarone
  • apalutamide
  • cisapride
  • colchicine, if you have liver or kidney problems
  • dronedarone
  • elbasvir and grazoprevir 
  • ergot-containing medicines:
  • dihydroergotamine
  • ergotamine tartrate
  • methylergonovine
  • flecainide
  • ivabradine
  • lomitapide
  • lovastatin
  • lurasidone
  • midazolam, when taken by mouth
  • naloxegol
  • pimozide
  • propafenone
  • ranolazine
  • rifampin
  • sildenafil, when used for the treatment of pulmonary arterial hypertension (PAH)
  • simvastatin
  • St. John’s wort (Hypericum perforatum)
  • triazolam
  • quinidine
  • voriconazole

Serious problems can happen if you take any of these medicines with DARUVIR 800-R/DARUVIR 600-R Tablets.

What should I tell my healthcare provider before taking DARUVIR 800-R/DARUVIR 600-R Tablets?

Before taking DARUVIR 800-R/DARUVIR 600-R Tablets, tell your healthcare provider if you:

  • have liver problems, including hepatitis B or hepatitis C
  • are allergic to sulfa medicines
  • have high blood sugar (diabetes)
  • have bleeding problems or hemophilia
  • have any other medical conditions
  • Are pregnant or plan to become pregnant. Tell your healthcare provider if you become pregnant while taking DARUVIR 800-R/DARUVIR 600-R Tablets. Ritonavir a component of DARUVIR 800-R/DARUVIR 600-R Tablets may reduce how well hormonal birth control works. Females who may become pregnant should use another effective form of birth control or an additional barrier method of birth control during treatment with DARUVIR 800-R/DARUVIR 600-R Tablets.
  • Are breastfeeding or plan to breastfeed. Do not breastfeed if you take DARUVIR 800-R/DARUVIR 600-R Tablets.
  • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
  • It is not known if DARUVIR 800-R/DARUVIR 600-R Tablets can pass into your breast milk.
  • Talk to your healthcare provider about the best way to feed your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with DARUVIR 800-R/DARUVIR 600-R Tablets. Keep a list of your medicines to show your healthcare provider and pharmacist.

  • You can ask your healthcare provider or pharmacist for a list of medicines that interact with DARUVIR 800-R/DARUVIR 600-R Tablets.
  • Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take DARUVIR 800-R/DARUVIR 600-R Tablets with other medicines.

How should I take DARUVIR 800-R/DARUVIR 600-R Tablets?

  • Take DARUVIR 800-R/DARUVIR 600-R Tablets exactly as your healthcare provider tells you.
  • Do not change your dose or stop treatment with DARUVIR 800-R/DARUVIR 600-R Tablets without talking to your healthcare provider.
  • Take DARUVIR 800-R/DARUVIR 600-R Tablets with food.
  • Swallow DARUVIR 800-R/DARUVIR 600-R Tablets whole. Do not chew, break, or crush tablets before swallowing.
  • It is important that you do not miss or skip doses of DARUVIR 800-R/DARUVIR 600-R Tablets during treatment. If you miss a dose of DARUVIR 800-R/DARUVIR 600-R Tablets, take it as soon as possible and then take your next scheduled dose at its regular time. If it is almost time for your next dose, wait and take the next dose at the regular time. Do not double the next dose.
  • Do not run out of DARUVIR 800-R/DARUVIR 600-R Tablets. Get your DARUVIR 800-R/DARUVIR 600-R Tablets prescription refilled from your healthcare provider or pharmacy before you run out.
  • If you take too much DARUVIR 800-R/DARUVIR 600-R Tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of DARUVIR 800-R/DARUVIR 600-R Tablets ?

  • See “What is the most important information I should know about DARUVIR 800-R/DARUVIR 600-R Tablets?”

DARUVIR 800-R/DARUVIR 600-R Tablets may cause serious side effects, including:

  • Liver problems. Some people taking darunavir/ritonavir in combination with other antiviral medicines have developed liver problems which may be life-threatening. Your healthcare provider should do regular blood tests during your combination treatment with DARUVIR 800-R/DARUVIR 600-R Tablets. If you have chronic hepatitis B or C infection, your healthcare provider should check your blood tests more often because you have an increased chance of developing liver problems. Tell your healthcare provider right away if you get any of the following signs and symptoms of liver problems:
  • loss of appetite
  • yellowing of your skin or whites of your eyes
  • pain or tenderness on your right side below your ribs
  • itchy skin
  • Diabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors including DARUVIR 800-R/DARUVIR 600-R Tablets can get high blood sugar, develop diabetes, or your diabetes can get worse. Tell your healthcare provider if you notice an increase in thirst or urinate often while taking DARUVIR 800-R/DARUVIR 600-R Tablets.
  • Changes in body fat can happen in people who take HIV-1 medicines. The changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.
  • Inflammation of your pancreas (pancreatitis). DARUVIR 800-R/DARUVIR 600-R Tablets can cause serious pancreas problems, which may lead to death. Tell your healthcare provider right away if you have signs or symptoms of pancreatitis such as:
  • Nausea
  • Vomiting
  • Stomach (abdomen) pain
  • Changes in your immune system (Immune Reconstitution Syndrome)) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.
  • Allergic reactions. Sometimes these allergic reactions can become severe and require treatment in a hospital. Call your healthcare provider right away if you develop a rash. Stop taking DARUVIR 800-R/DARUVIR 600-R Tablets and get medical help right away if you have any of the following symptoms of a severe allergic reaction:
  • trouble breathing
  • sweating
  • wheezing
  •  swelling of your face, lips or tongue
  • dizziness or fainting
  • muscle or joint pain
  • throat tightness or hoarseness
  •  blisters or skin lesions
  • fast heartbeat or pounding in your chest (tachycardia)
  • mouth sores or ulcers
  • Changes in the electrical activity of your heart called PR prolongation. PR prolongation can cause irregular heartbeats. Tell your healthcare provider right away if you have symptoms such as:
  • dizziness
  • feel faint or pass out
  • lightheadedness
  •  abnormal heart beat
  • Increase in cholesterol and triglyceride levels. Treatment with DARUVIR 800-R/DARUVIR 600-R Tablets may increase your blood levels of cholesterol and triglycerides. Your healthcare provider should do blood tests before you start your treatment with DARUVIR 800-R/DARUVIR 600-R Tablets and regularly to check for an increase in your cholesterol and triglycerides levels.
  • Kidney stones
  • Increased bleeding for hemophiliacs. Some people with hemophilia have increased bleeding with protease inhibitors including DARUVIR 800-R/DARUVIR 600-R Tablets.
  • The most common side effects of DARUVIR 800-R/DARUVIR 600-R Tablets include: 
  • diarrhea
  • nausea
  • rash
  • headache
  • stomach-area (abdominal) pain
  • vomiting
  • feeling weak or tired
  • tingling feeling or numbness in hands or feet or around the lips

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of DARUVIR 800-R/DARUVIR 600-R Tablets.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779.  By reporting side effects, you can help provide more information on the safety of this product.

How should I store DARUVIR 800-R/DARUVIR 600-R Tablets?

Store at a temperature below 30°C. Protect from moisture. Keep the container tightly closed. Keep out of the reach of children.

General information about the safe and effective use of DARUVIR 800-R/DARUVIR 600-R Tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use DARUVIR 800-R/DARUVIR 600-R Tablets for a condition for which it was not prescribed.

Do not give DARUVIR 800-R/DARUVIR 600-R Tablets to other people even if they have the same condition you have. It may harm them.

Details of the Manufacturer

Hetero Labs Limited (Unit-I),

Village: Kalyanpur, Chakkan Road,

Tehsil: Baddi, Distt.: Solan,

Himachal Pradesh - 173 205

Marketed By

Cipla Ltd.

Regd. Office: Cipla House,

Peninsula Business Park,

Ganpatrao Kadam Marg, Lower Parel, Mumbai - 400 013, India

Details of Permission or Licence Number with Date

MF-234/2017 dated 02nd Nov 2017

Date of Revision

12/05/2021