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Patients should be advised that current antiretroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV. Appropriate precautions should continue to be employed.
PREZISTA/rtv is not approved for use in antiretroviral treatment in naive patients and in children.
Severe skin reactions: During the darunavir/ritonavir clinical development program (N = 3063), severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. Stevens-Johnson Syndrome has been rarely (< 0.1%) reported: during post-marketing experience, toxic epidermal necrolysis, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported very rarely (< 0.01%). Discontinue PREZISTA 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 patients treated with PREZISTA/rtv (see Adverse Reactions). Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in patients using PREZISTA/rtv was 0.5%.
Rash occurred more commonly in treatment-experienced subjects receiving regimens containing PREZISTA/rtv + raltegravir compared to subjects receiving PREZISTA/rtv without raltegravir or raltegravir without PREZISTA/rtv. 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.
Darunavir contains a sulfonamide moiety. PREZISTA should be used with caution in patients with a known sulfonamide allergy. In clinical studies with PREZISTA/rtv, the incidence and severity of rash was similar in patients with or without a history of sulfonamide allergy.
Patients with coexisting conditions: Hepatic impairment: There are no data regarding the use of PREZISTA in patients with severe hepatic impairment; therefore, specific dosage recommendations cannot be made. PREZISTA should be used with caution in patients with severe hepatic impairment. Based on data that demonstrated that the steady-state pharmacokinetic parameters of darunavir in subjects with mild and moderate hepatic impairment were comparable with those in healthy subjects, no dose adjustment is required in patients with mild or moderate hepatic impairment (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Hepatotoxicity: Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv. During the darunavir/ritonavir clinical development program (N = 3063), hepatitis was reported in 0.5% of patients receiving combination therapy with PREZISTA/rtv. 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.
Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA 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 PREZISTA 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 PREZISTA should prompt consideration of interruption or discontinuation of treatment.
Renal impairment: Since 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 (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Hemophiliac patients: 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 has been suggested, although the mechanism of action has not been elucidated. Hemophiliac patients should therefore be made aware of the possibility of increased bleeding.
Metabolic disorders: Hyperglycemia/Diabetes mellitus: New onset diabetes mellitus, hyperglycemia, or exacerbation of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including PIs. In some of these patients the hyperglycemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycemia.
Consideration should be given to measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate. (see Adverse Reactions).
Immune reconstitution inflammatory syndrome: In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders such as Graves' disease 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 treatment (see Adverse Reactions).
Interactions with medicinal products: Darunavir when used in combination with ritonavir is an inhibitor of CYP3A, CYP2D6 and P-gp. Co-administration of PREZISTA and ritonavir with medicinal products primarily metabolized by CYP3A, CYP2D6, or transported by P-gp may result in increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect and adverse events (see Contraindications and Interactions).
Darunavir and ritonavir are metabolized by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lower plasma concentrations of darunavir and ritonavir. Co-administration with other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (see Interactions). Co-administration of PREZISTA/rtv 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 Interactions).
Effects on Ability to Drive and Use Machines: No trials on the effects of PREZISTA in combination with ritonavir on the ability to drive or use machines have been performed. However, dizziness has been reported in some patients during treatment with regimens containing PREZISTA and should be borne in mind when considering a patient's ability to drive or operate machinery (see Adverse Reactions).
Use in the Elderly: As limited information is available on the use of PREZISTA in patients aged 65 and over, caution should be exercised in the administration of PREZISTA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see Pharmacology: Pharmacokinetics under Actions).
The absolute oral bioavailability of a single 600 mg dose of PREZISTA alone was approximately 37% and increased to approximately 82% in the presence of 100 mg ritonavir b.i.d. The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg PREZISTA was given orally in combination with ritonavir at 100 mg b.i.d. Therefore, PREZISTA should only be used in combination with low dose ritonavir as a pharmacokinetic enhancer (see Pharmacology: Pharmacokinetics under Actions).
Increasing the dose of ritonavir did not significantly affect darunavir concentrations. It is not recommended to alter the dose of ritonavir.
