REZOLSTA

Pregnancy

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.

REZOLSTA should be used during pregnancy only if the potential benefit justifies the potential risk.

Breast-feeding

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. Studies in animals have demonstrated that cobicistat is excreted in milk. Because of both the potential for HIV transmission and the potential for adverse reactions in breast-fed infants, mothers should be instructed not to breast-feed under any circumstances if they are receiving REZOLSTA.

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 REZOLSTA.

REZOLSTA 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 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 REZOLSTA 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. In many instances, it is unclear whether the reported adverse reactions are related to darunavir, ritonavir, cobicistat, the wide range of medicinal products used in the management of HIV disease, or as a result of the underlying disease process.

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

During the Phase III clinical trial GS-US-216-130 with darunavir/cobicistat (N = 313 treatment-naïve and treatment-experienced subjects), 66.5% of subjects experienced at least one adverse reaction. The mean treatment duration was 58.4 weeks. The most frequent adverse reactions reported were diarrhoea (28%), nausea (23%), and rash (16%). Serious adverse reactions were diabetes mellitus, (drug) hypersensitivity, immune reconstitution inflammatory syndrome, rash and vomiting. All of these serious ADRs occurred in one (0.3%) subject except for rash in 2 (0.6%) subjects.

During the darunavir/ritonavir clinical development program (N = 2613 treatment-experienced subjects who initiated therapy with darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent adverse reactions reported in clinical trials 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. No new safety findings were identified in the 192 week analysis of the ART treatment-naïve subjects in which the mean treatment duration of darunavir/ritonavir 800/100 mg once daily was 162.5 weeks.

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

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. In a single-arm trial investigating darunavir 800 mg once daily in combination with cobicistat 150 mg once daily and other antiretrovirals 2.2% 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) 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 (eGFR_CG) 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 eGFR_CG 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 eGFR_CG was noted at week 2, which remained stable through week 48. The mean eGFR_CG change from baseline was -9.6 ml/min at week 2, and -9.6 ml/min at week 48.

For more information consult the cobicistat Summary of Product Characteristics.

Paediatric population

The safety and efficacy of REZOLSTA in paediatric patients aged 3 to 17 years has not been established.

Other special populations

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

Limited information is available on the use of REZOLSTA 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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: [email protected]

Human experience of acute overdose with REZOLSTA or darunavir in combination with cobicistat is limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.

There is no specific antidote for overdose with REZOLSTA. Treatment of overdose with REZOLSTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir and cobicistat are highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substances.

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infection, combinations ATC code: J05AR14

REZOLSTA is a fixed-dose combination of the antiretroviral medicinal product darunavir and the pharmacokinetic enhancer cobicistat.

Mechanism of action

Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease (K_D of 4.5 x 10^-12M). It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus infected cells, thereby preventing the formation of mature infectious virus particles.

Cobicistat is a mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as darunavir, where bioavailability is limited and half-life is shortened due to CYP3A-dependent metabolism.

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.

Cobicistat has no detectable antiviral activity against HIV-1 and does not antagonise the antiviral effect of darunavir.

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.

The resistance profile of REZOLSTA is driven by darunavir. Cobicistat does not select any HIV resistance mutations, due to its lack of antiviral activity. The resistance profile of REZOLSTA is supported by two Phase III trials conducted with darunavir/ritonavir in treatment-naïve (ARTEMIS) and treatment-experienced (ODIN) patients and the analysis of 48 week data from trial GS-US-216-130 in treatment-naïve and treatment-experienced patients.

Low rates of developing resistant HIV-1 virus were observed in ART-naïve patients who are treated for the first time with REZOLSTA or darunavir/ritonavir 800/100 mg once daily in combination with other ART, and in ART-experienced patients with no darunavir RAMs receiving REZOLSTA or darunavir/ritonavir 800/100 mg once daily in combination with other ART. The table below shows the development of HIV-1 protease mutations and loss of susceptibility to HIV PIs in virologic failures at endpoint in the GS-US-216-130, ARTEMIS and ODIN trials.

Cross-resistance

In the virologic failures of the GS-US-216-130 trial no cross-resistance with other HIV PIs was observed. Refer to the table above for information on ARTEMIS and ODIN.

Clinical results

The antiretroviral effect of REZOLSTA is due to the darunavir component. The activity of cobicistat as a pharmacokinetic enhancer to darunavir has been demonstrated in pharmacokinetic trials. In these pharmacokinetic trials, the exposure of darunavir 800 mg boosted with cobicistat 150 mg was consistent with that observed when boosted with ritonavir 100 mg. Darunavir as a component of REZOLSTA is bioequivalent to darunavir 800 mg once daily in combination with cobicistat 150 mg once daily co-administered as single agents.

The evidence of efficacy of REZOLSTA once daily is based on the analysis of 48 week data from trial GS-US-216-130 in ART-naïve and ART-experienced patients and two Phase III trials ARTEMIS and ODIN conducted with darunavir/ritonavir 800/100 mg q.d. in ART-naïve and ART-experienced patients, respectively.

Description of clinical studies of REZOLSTA in adults

Efficacy of darunavir 800 mg once daily co-administered with 150 mg cobicistat once daily in ART-naïve and ART-experienced patients

GS-US-216-130 is a single-arm, open-label, Phase III trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of darunavir with cobicistat in 313 HIV-1 infected adult patients (295 treatment-naïve and 18 treatment-experienced). These patients received darunavir 800 mg once daily in combination with cobicistat 150 mg once daily with an investigator selected optimised background regimen (OBR) consisting of 2 active NRTIs.

HIV-1 infected patients who were eligible for this trial had a screening genotype showing no darunavir RAMs and plasma HIV-1 RNA > 1000 copies/ml. The table below shows the efficacy data of the 48 week analyses from the GS-US-216-130 trial:

Description of clinical studies of darunavir/ritonavir in adults

Efficacy of darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in ART-naïve patients

The evidence of efficacy of darunavir/ritonavir 800/100 mg once daily is based on the analyses of 192 week data from the randomised, controlled, open-label Phase III trial ARTEMIS in antiretroviral treatment-naïve HIV-1 infected patients comparing darunavir/ritonavir 800/100 mg once daily with lopinavir/ritonavir 800/200 mg per day (given as a twice-daily or as a once-daily regimen). Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily and emtricitabine 200 mg once daily.

The table below shows the efficacy data of the 48 week and 96 week analyses from the ARTEMIS trial:

Non-inferiority in virologic response to the darunavir/ritonavir treatment, defined as the percentage of patients with plasma HIV-1 RNA level < 50 copies/ml, was demonstrated (at the pre-defined 12% non-inferiority margin) for both Intent-To-Treat (ITT) and On Protocol (OP) populations in the 48 week analysis. These results were confirmed in the analyses of data at 96 weeks of treatment in the ARTEMIS trial. These results were sustained up to 192 weeks of treatment in the ARTEMIS trial.

Efficacy of darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in ART-experienced patients

ODIN is a Phase III, randomised, open-label trial comparing darunavir/ritonavir 800/100 mg once daily versus darunavir/ritonavir 600/100 mg twice daily in ART-experienced HIV-1 infected patients with screening genotype resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V) and a screening HIV-1 RNA > 1,000 copies/ml. Efficacy analysis is based on 48 weeks of treatment (see table below). Both arms used an optimised background regimen (OBR) of > 2 NRTIs.

At 48 weeks, virologic response, defined as the percentage of patients with plasma HIV-1 RNA level < 50 copies/ml, with darunavir/ritonavir 800/100 mg once daily treatment was demonstrated to be non-inferior (at the pre-defined 12% non-inferiority margin) compared to darunavir/ritonavir 600/100 mg twice daily for both ITT and OP populations.

REZOLSTA 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. Limited data is available in patients with HIV-1 clades other than B.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with REZOLSTA in all subsets of the paediatric population in the condition of treatment of HIV-1 infection.

Darunavir exposure was shown to be comparable in a bioavailability trial between REZOLSTA and darunavir/ritonavir 800/100 mg q.d. at steady-state and fed conditions in healthy subjects.

The bioequivalence between REZOLSTA and darunavir/cobicistat 800/150 mg co-administered as single agents was established under fed and fasted conditions in healthy subjects.

Absorption

Darunavir

The absolute oral bioavailability of a single 600 mg dose of darunavir alone is approximately 37%.

Darunavir was rapidly absorbed following oral administration of REZOLSTA in healthy volunteers. Maximum plasma concentration of darunavir in the presence of cobicistat is generally achieved within 3 to 4.5 hours. Following oral administration of REZOLSTA in healthy volunteers, maximum plasma concentrations of cobicistat were observed 2 to 5 hours post-dose.

When administered with food, the relative exposure of darunavir is 1.7-fold higher as compared to intake without food. Therefore, REZOLSTA tablets should be taken with food. The type of food does not affect exposure to REZOLSTA.

Distribution

Darunavir

Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma α₁-acid glycoprotein.

Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 l (Mean ± SD) and increased to 131 ± 49.9 l (Mean ± SD) in the presence of 100 mg twice-daily ritonavir.

Cobicistat

Cobicistat is 97 to 98% bound to human plasma proteins and the mean plasma to blood-drug concentration ratio was approximately 2.

Biotransformation

Darunavir

In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme CYP3A4. A ¹⁴C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due to the parent active substance. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild type HIV.

Cobicistat

Cobicistat is metabolised via CYP3A (major)- and CYP2D6 (minor)-mediated oxidation and does not undergo glucuronidation. Following oral administration of ¹⁴C-cobicistat, 99% of circulating radioactivity in plasma was unchanged cobicistat. Low levels of metabolites are observed in urine and feces and do not contribute to the CYP3A inhibitory activity of cobicistat.

Elimination

Darunavir

After a 400/100 mg ¹⁴C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the administered dose of ¹⁴C-darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.

The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 l/h and 5.9 l/h, respectively.

Cobicistat

Following oral administration of ¹⁴C-cobicistat, 86% and 8.2% of the dose were recovered in feces and urine, respectively. The median terminal plasma half-life of cobicistat following administration of REZOLSTA is approximately 3-4 hours.

Special populations

Paediatric population

The pharmacokinetics of REZOLSTA in paediatric patients have not been investigated.

Elderly

Darunavir

Limited information is available in this population. Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (n = 12, age > 65 years). However, only limited data were available in patients above the age of 65 years.

Cobicistat

Pharmacokinetics of cobicistat have not been fully evaluated in older people (65 years of age and older).

Gender

Darunavir

Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV infected females compared to males. This difference is not clinically relevant.

Cobicistat

No clinically relevant pharmacokinetic differences due to gender have been identified for cobicistat.

Renal impairment

REZOLSTA has not been investigated in patients with renal impairment.

Darunavir

Results from a mass balance study with ¹⁴C-darunavir with ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine unchanged.

Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n = 20).

Cobicistat

A trial of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with severe renal impairment (estimated creatinine clearance below 30 ml/min). No meaningful differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects, consistent with low renal clearance of cobicistat.

Hepatic impairment

REZOLSTA has not been investigated in patients with hepatic impairment.

Darunavir

Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose trial with darunavir/ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n = 8) and moderate (Child-Pugh Class B, n = 8) hepatic impairment were comparable with those in healthy subjects. However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown, therefore, darunavir/ritonavir should be used with caution. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied.

Cobicistat

Cobicistat is primarily metabolised and eliminated by the liver. A trial of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with moderate hepatic impairment (Child-Pugh Class B). No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate impairment and healthy subjects. No dosage adjustment of REZOLSTA is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied.

Hepatitis B and/or hepatitis C virus co-infection

There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or 8).

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.

Due to uncertainties regarding the rate of development of the human blood brain barrier and liver enzymes REZOLSTA should not be used in paediatric patients below 3 years of age.

Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1,000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences of hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. The observed hepatocellular and thyroid tumours 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 (based on AUC) to darunavir when co-administered with ritonavir 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.

After 2 years administration of darunavir at exposures at or below the human exposure, kidney changes were observed in mice (nephrosis) and rats (chronic progressive nephropathy).

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

Cobicistat

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction and development. No teratogenic effects were observed in rats and rabbit developmental toxicity studies. In rats, ossification changes in the spinal column and sternebrae of fetuses occurred at a dose that produced significant maternal toxicity.

Ex vivo rabbit studies and in vivo dog studies suggest that cobicistat has a low potential for QT prolongation, and may slightly prolong the PR interval and decrease left ventricular function at mean concentrations at least 10-fold higher than the human exposure at the recommended 150 mg daily dose.

A long term carcinogenicity study of cobicistat in rats revealed tumourigenic potential specific for this species, that is regarded as of no relevance for humans. A long term carcinogenicity study in mice did not show any carcinogenic potential.

Tablet core

Hypromellose

Colloidal silicon dioxide

Silicified microcrystalline cellulose

Crospovidone

Magnesium stearate

Tablet film-coat

Polyvinyl alcohol- partially hydrolysed

Macrogol 3350

Titanium dioxide

Talc

Iron oxide red

Iron oxide black

Not applicable

2 years

6 weeks after opening the bottle.

This medicinal product does not require any special storage conditions.

White, high density polyethylene (HDPE) bottle containing 30 tablets, fitted with polypropylene (PP) child resistant closure with induction seal.

Pack size of one bottle.

No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/14/967/001

Date of first authorisation: 19 November 2014

15 February 2018