Adverse reactions : תופעות לוואי

4.8   Undesirable effects

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.

As REZOLSTA 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 REZOLSTA 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

MedDRA system organ class                           Adverse reaction
Frequency category
Immune system disorders
Common                                              (drug) hypersensitivity 
Uncommon                                            immune reconstitution inflammatory syndrome Metabolism and nutrition disorders
Common                                              anorexia, hypercholesterolaemia, hypertriglyceridaemia
 diabetes mellitus, dyslipidaemia,
Uncommon                                            hyperglycaemia, hyperlipidaemia Psychiatric disorders
Common                                              abnormal dreams
Nervous system disorders
Very common                                         headache
Gastrointestinal disorders
Very common                                         diarrhoea, nausea 
Common                                              vomiting, abdominal pain, abdominal distension, dyspepsia, flatulence
Uncommon                                            pancreatitis acute, pancreatic enzymes increased 
Hepatobiliary disorders
Common                                              hepatic enzyme increased 
Uncommon                                            hepatitis*, cytolytic hepatitis* Skin and subcutaneous tissue disorders
Very common                                         rash (including macular, maculopapular, papular, erythematous, pruritic rash, generalised rash, and allergic dermatitis)

Common                                              pruritus

Uncommon                                            Stevens-Johnson syndrome#, angioedema, urticaria

Rare                                                drug reaction with eosinophilia and systemic symptoms*
Not known                                           toxic epidermal necrolysis*, acute generalised exanthematous pustulosis*
Musculoskeletal and connective tissue disorders
Common                                            myalgia
Uncommon                                          osteonecrosis*
Renal and urinary disorders
Rare                                              crystal nephropathy*§ Reproductive system and breast disorders
Uncommon                                          gynaecomastia*
General disorders and administration site conditions
Common                                            fatigue, asthenia


Investigations
Common                                              increased blood creatinine 
*     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 (see Severe skin reactions in Section 4.4).
§
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 (see section 4.4). 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 REZOLSTA 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 (see section 4.4).

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 (see section 4.4).

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 (see section 4.4).

Bleeding in haemophiliac patients
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors (see section 4.4).

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 REZOLSTA 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 and efficacy of REZOLSTA in paediatric patients aged 3 to 11 years, or weighing < 40 kg, have not been established, no data are available. Rezolsta is not indicated for paediatric patients aged 12 to 17 years (see sections 4.4 and 5.3).

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 (see section 4.4).

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.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il