Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Regular assessment of virological response is advised. In the setting of lack or loss of virological response, resistance testing should be performed.

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 section 4.5).

ART-experienced patients
REZOLSTA should not be used in treatment-experienced patients with one or more DRV-RAMs or HIV-1 RNA ≥ 100,000 copies/mL or CD4+ cell count < 100 cells x 106/l (see section 4.2).

Combinations with optimised background regimens (OBRs) other than ≥ 2 NRTIs have not been studied in this population. Limited data is available in patients with HIV-1 clades other than B (see section 5.1).



Pregnancy
Treatment with darunavir/cobicistat 800/150 mg during the second and third trimester has been shown to result in low darunavir exposure, with a reduction of around 90% in Cmin levels (see section 5.2).
Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in darunavir exposure may result in virological failure and an increased risk of mother to child transmission of HIV infection. Therefore, therapy with REZOLSTA should not be initiated during pregnancy, and women who become pregnant during therapy with REZOLSTA should be switched to an alternative regimen (see sections 4.2 and 4.6). Darunavir given with low dose ritonavir may be considered as an alternative.

Elderly
As limited information is available on the use of REZOLSTA in patients aged 65 and over, caution should be exercised, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2 and 5.2).

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. REZOLSTA 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 with 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/ritonavir (see section 4.8).

Sulphonamide allergy
Darunavir contains a sulphonamide moiety. REZOLSTA 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/ritonavir. During the 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 REZOLSTA 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 REZOLSTA 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 REZOLSTA, interruption or discontinuation of treatment should be considered promptly.

Patients with coexisting conditions

Hepatic impairment
The safety and efficacy of REZOLSTA, darunavir, or cobicistat have not been established in patients with severe underlying liver disorders. REZOLSTA is, therefore, contraindicated in patients with  severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, REZOLSTA should be used with caution in patients with mild or moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).

Renal impairment
Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine. This effect on serum creatinine, leading to a decrease in the estimated creatinine clearance, should be taken into consideration when REZOLSTA is administered to patients, in whom the estimated creatinine clearance is used to guide aspects of their clinical management, including adjusting doses of co-administered medicinal products. For more information consult the cobicistat Summary of Product Characteristics.

REZOLSTA should not be initiated in patients with creatinine clearance less than 70 mL/min when co-administered with one or more agent requiring dose adjustment based on creatinine clearance (e.g.
emtricitabine, lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate) or adefovir dipivoxil) (see sections 4.2, 4.8 and 5.2).

No special precautions or dose adjustments are required in patients with renal impairment. As darunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).

There are currently inadequate data to determine whether co-administration of tenofovir disoproxil and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil without cobicistat.

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 HIV PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with HIV 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 (IRIS)
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 trials with darunavir co-administered with low dose ritonavir.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis ) 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 section 4.8).

Interactions with medicinal products
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-glycoprotein (see section 4.5).

REZOLSTA should not be used in combination with another antiretroviral that requires pharmacoenhancement since dosing recommendations for such combination have not been established. REZOLSTA should not be used concurrently with products containing ritonavir or regimens containing ritonavir or cobicistat.

Unlike ritonavir, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. If switching from ritonavir as a pharmacoenhancer to cobicistat, caution is required during the first two weeks of treatment with REZOLSTA, particularly if doses of any concomitantly administered medicinal products have been titrated or adjusted during use of ritonavir as a pharmacoenhancer.

Paediatric population
REZOLSTA is not recommended for use in paediatric patients (3 to 17 years of age). REZOLSTA should not be used in paediatric patients below 3 years of age (see sections 4.2 and 5.3).

REZOLSTA contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7   Effects on ability to drive and use machines

REZOLSTA may have a minor influence on the ability to drive and use machines. Dizziness has been reported in some patients during treatment with regimens containing darunavir administered with cobicistat and should be borne in mind when considering a patient’s ability to drive or operate machinery.