Darunavir and Cobicistat

Darunavir and cobicistat are metabolised by the hepatic system. Separate trials of darunavir/ritonavir and cobicistat suggest no dose adjustment is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, darunavir/cobicistat should be used with caution in these patients.

Concomitant use of a HMG CoA reductase inhibitor and darunavir/cobicistat may increase plasma concentrations of the lipid lowering agent, which may lead to adverse events such as myopathy.

When administration of HMG CoA reductase inhibitors and darunavir/cobicistat is desired, it is recommended to start with the lowest dose and titrate up to the desired clinical effect while monitoring for safety.

Interaction – Geometric mean change (%):

Atorvastatin (10 mg once daily): AUC ↑ 290%, C_max ↑ 319%, C_min ND

Rosuvastatin (10 mg once daily): AUC ↑ 93%, C_max ↑ 277%, C_min ND

Based on theoretical considerations REZOLSTA is expected to increase the plasma concentrations of fluvastatin, pitavastatin and pravastatin (CYP3A inhibition and/or transport).

Caution should be exercised when clarithromycin is combined with darunavir/cobicistat.

For patients with renal impairment the Summary of Product Characteristics for clarithromycin should be consulted for the recommended dose.

Based on theoretical considerations clarithromycin is expected to increase darunavir and/or cobicistat plasma concentrations (CYP3A inhibition).

Concentrations of clarithromycin may be increased upon co-administration with darunavir/cobicistat (CYP3A inhibition).

Caution is warranted and clinical monitoring is recommended.

When co-administration is required, the daily dose of itraconazole should not exceed 200 mg.

Based on theoretical considerations darunavir/cobicistat is expected to increase these antifungal plasma concentrations, and darunavir and/or cobicistat plasma concentrations may be increased by the antifungals (CYP3A inhibition and/or P-gp inhibition).

Systemic dexamethasone should be used with caution when combined with darunavir/cobicistat.

Based on theoretical considerations (systemic) dexamethasone is expected to decrease darunavir and/or cobicistat plasma concentrations (CYP3A induction).

Co-administration of darunavir/cobicistat with rifabutin and rifapentine is not recommended.

If the combination is needed, the recommended dose of rifabutin is 150 mg 3 times per week on set days (for example Monday-Wednesday-Friday). Increased monitoring for rifabutin associated adverse reactions including neutropenia and uveitis is warranted due to an expected increase in exposure to rifabutin. Further dosage reduction of rifabutin has not been studied. It should be kept in mind that the twice weekly dosage of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifamycin resistance and a treatment failure.

Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV infected patients.

This recommendation is different from ritonavir-boosted darunavir. Consult the Summary of Product
Characteristics for darunavir for further details.

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.

There are no adequate and well controlled trials with darunavir, or cobicistat, in pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure, which may be associated with an increased risk of treatment failure and an increased risk of HIV transmission to the child. Therapy with darunavir/cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with darunavir/cobicistat should be switched to an alternative regimen.

It is not known whether darunavir or cobicistat are excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted in toxicity of the offspring. Studies in animals have demonstrated that cobicistat is excreted in milk.

Because of the potential for adverse reactions in breast-fed infants, women should be instructed not to breast-feed if they are receiving darunavir/cobicistat.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed.

Fertility

No human data on the effect of darunavir or cobicistat on fertility are available. There was no effect on mating or fertility in animals. Based on animal studies, no effect on mating or fertility is expected with darunavir/cobicistat.

Darunavir/cobicistat 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.

Summary of the safety profile

The overall safety profile of darunavir/cobicistat is based on available clinical trial data from darunavir boosted with either cobicistat or ritonavir, from cobicistat and from post-marketing data from darunavir/ritonavir.

As darunavir/cobicistat contains darunavir and cobicistat, the adverse reactions associated with each of the individual compounds may be expected.

The most frequent adverse reactions reported in the pooled data of the Phase III study GS-US-216-130 and the darunavir/cobicistat arm of Phase III study TMC114FD2HTX3001 were diarrhoea (23%), nausea (17%), rash (13%), and headache (10%). Serious adverse reactions were diabetes mellitus, (drug) hypersensitivity, immune reconstitution inflammatory syndrome, rash, Stevens-Johnson syndrome, and vomiting. All of these serious ADRs occurred in one (0.1%) subject except for rash in 4 (0.6%) subjects.

The most frequent adverse reactions reported during the darunavir/ritonavir clinical development program and as spontaneous reports are diarrhoea, nausea, rash, headache, and vomiting. The most frequent serious reactions are acute renal failure, myocardial infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis, and pyrexia.

In the 96 week analysis, the safety profile of darunavir/ritonavir 800/100 mg once daily in treatment-naïve subjects was similar to that seen with darunavir/ritonavir 600/100 mg twice daily in treatment-experienced subjects except for nausea which was observed more frequently in treatment-naïve subjects. This was driven by mild intensity nausea.

Tabulated list of adverse reactions

Adverse reactions are listed by system organ class (SOC) and frequency category. Within each frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and not known (frequency cannot be estimated from the available data).

Adverse reactions with darunavir/cobicistat in adult patients:

^* These adverse drug reactions have not been reported in clinical trial experience with darunavir/cobicistat but have been noted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.
^# When also taking into account the clinical trial data of DRV/COBI/emtricitabine/tenofovir alafenamide, Stevens-Johnson syndrome occurred rarely (in 1 out of 2,551 subjects) consistent with the DRV/rtv clinical trial program.
^§ Adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics (Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determined using the “Rule of 3”.

Description of selected adverse reactions

Rash

In clinical trials with darunavir/ritonavir and darunavir/cobicistat, rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The pooled data of a single-arm trial investigating darunavir 800 mg once daily in combination with cobicistat 150 mg once daily and other antiretrovirals and one arm of a trial in which darunavir/cobicistat 800/150 mg once daily and other antiretrovirals were administered, showed that 1.9% of patients discontinued treatment due to rash.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

Musculoskeletal abnormalities

Increased CPK, myalgia, myositis and, rarely, rhabdomyolysis have been reported with the use of HIV protease inhibitors, particularly in combination with NRTIs.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.

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 infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Bleeding in haemophiliac patients

There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors.

Decrease estimated creatinine clearance

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of renal tubular secretion of creatinine. An increase in serum creatinine due to the inhibitory effect of cobicistat generally does not exceed 0.4 mg/dL.

The effect of cobicistat on serum creatinine was investigated in a Phase I trial in subjects with normal renal function (eGFR ≥80 mL/min, n=12) and mild to moderate renal impairment (eGFR:50-79 mL/min, n=18). Change of estimated glomerular filtration rate calculated by Cockcroft-Gault method (eGFRCG) from baseline was observed within 7 days after start of treatment with cobicistat 150 mg among subjects with normal renal function (-9.9 ± 13.1 mL/min) and mild to moderate renal impairment (-11.9 ± 7.0 mL/min). These decreases in eGFRCG were reversible after cobicistat was discontinued and did not affect the actual glomerular filtration rate, as determined by the clearance of probe drug iohexol.

In the Phase III single-arm trial (GS-US-216-130), a decrease in eGFRCG was noted at week 2, which remained stable through week 48. The mean eGFRCG change from baseline was –9.6 mL/min at week 2, and –9.6 mL/min at week 48. In the darunavir/cobicistat arm of Phase III trial TMC114FD2HTX3001, mean eGFRCG change from baseline was -11.1 mL/min at week 48 and mean eGFRcystatin C change from baseline was +2.9 mL/min/1.73 m² at week 48.

For more information consult the cobicistat Summary of Product Characteristics.

Paediatric population

The safety of components of darunavir/cobicistat was evaluated in adolescents aged 12 to less than 18 years, weighing at least 40 kg through the clinical trial GS-US-216-0128 (treatment-experienced, virologically suppressed, N=7). Safety analyses of this study in adolescent subjects did not identify new safety concerns compared to the known safety profile of darunavir and cobicistat in adult subjects.

Other special populations

Patients co-infected with hepatitis B and/or hepatitis C virus Limited information is available on the use of darunavir/cobicistat in patients co-infected with hepatitis B and/or C virus. Among 1,968 treatment-experienced patients receiving darunavir co-administered with ritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.