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While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Regular assessment of virological response is advised. In the setting of lack or loss of virological response, resistance testing should be performed.
Patients receiving antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection.
Darunavir binds predominantly to α1-acid glycoprotein. This protein binding is concentration-dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products highly bound to α1-acid glycoprotein cannot be ruled out (see Interactions).
ART-experienced patients-once daily dosing: Darunavir used in combination with low dose ritonavir once daily in ART-experienced patients should not be used in patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA ≥100,000 copies/ml or CD4+ cell count <100 cells x 106/l (see Dosage & Administration). Combinations with optimised background regimen (OBRs) other than ≥2 NRTIs have not been studied in this population. Limited data are available in patients with HIV-1 clades other than B (see Pharmacology: Pharmacodynamics under Actions).
Severe skin reactions: During the darunavir/ritonavir clinical development program (N=3,063), severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson Syndrome has been rarely (<0.1%) reported, and during post-marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported. Darunavir should be discontinued immediately if signs or symptoms of severe skin reactions develop. These can include, but are not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
Rash occurred more commonly in treatment-experienced patients receiving regimens containing Darunavir/ritonavir + raltegravir compared to patients receiving Darunavir/ritonavir without raltegravir or raltegravir without Darunavir (see Adverse Reactions).
Darunavir contains a sulphonamide moiety. Darunavir should be used with caution in patients with a known sulphonamide allergy.
Hepatotoxicity: Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with Darunavir. During the darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral 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 and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.
Appropriate laboratory testing should be conducted prior to initiating therapy with Darunavir used in combination with low dose 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 used in combination with low dose ritonavir treatment.
If there is 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 using Darunavir used in combination with low dose ritonavir, interruption or discontinuation of treatment should be considered promptly.
Patients with coexisting conditions: Hepatic impairment: The safety and efficacy of Darunavir have not been established in patients with severe underlying liver disorders and Darunavir is therefore contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, Darunavir should be
used with caution in patients with mild or moderate hepatic impairment (see Dosage & Administration, Contraindications and Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No special precautions or dose adjustments for darunavir/ritonavir are required 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 haemodialysis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these patients (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Haemophiliac patients: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding.
Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Immune reconstitution inflammatory syndrome: In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 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, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with Darunavir co-administered with low dose ritonavir.
Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see Adverse Reactions).
Interactions with medicinal products: Pharmacokinetic enhancer and concomitant medications: Concomitant use of darunavir/ritonavir with lopinavir/ritonavir, rifampicin and herbal products containing St John's wort, Hypericum perforatum, is contraindicated (see Interactions).
Unlike ritonavir, cobicistat does not have inducing effects on enzymes or transport proteins (see Interactions). If switching the pharmacoenhancer from ritonavir to cobicistat, caution is required during the first two weeks of treatment with darunavir/cobicistat, particularly if doses of any concomitantly administered medicinal products have been titrated or adjusted during use of ritonavir as a pharmacoenhancer. A dose reduction of the co-administered drug may be needed in these cases.
Efavirenz in combination with Darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with Darunavir/ritonavir, the Darunavir/ritonavir 600/100 mg twice daily regimen should be used.
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-glycoprotein (P-gp; see Contraindications and Interactions).
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 (see Adverse Reactions).
Use in Pregnancy: Darunavir should be used during pregnancy only if the potential benefit justifies the potential risk. Caution should be used in pregnant women with concomitant medications which may further decrease darunavir exposure (see Interactions and Pharmacology: Pharmacokinetics under Actions).
Use in Children: Darunavir is not recommended for use in paediatric patients below 3 years of age or less than 15 kg body weight (see Dosage & Administration and Pharmacology: Toxicology: Preclinical safety data under Actions).
Use in the Elderly: As limited information is available on the use of Darunavir in patients aged 65 and over, caution should be exercised in the administration of Darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
