Adverse reactions : תופעות לוואי

4.8       Undesirable effects

Summary of the safety profile
During the clinical development program (N=2,613 treatment-experienced subjects who initiated therapy with PREZISTA/rtv 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 PREZISTA/rtv 800/100 mg once daily in treatment-naïve subjects was similar to that seen with PREZISTA/rtv 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 treatment- naïve subjects in which the mean treatment duration of PREZISTA/rtv 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 observed with darunavir/ritonavir in clinical trials and post-marketing 
MedDRA system Organ Class                 Adverse reaction
Frequency category
Infections and infestations uncommon                                  herpes simplex
Blood and lymphatic system disorders uncommon                                  thrombocytopenia, neutropenia, anaemia, leukopenia rare                                      increased eosinophil count
Immune system disorders uncommon                                  immune reconstitution inflammatory syndrome, (drug) hypersensitivity
Endocrine disorders uncommon                                  hypothyroidism, increased blood thyroid stimulating hormone
Metabolism and nutrition disorders common                                    diabetes mellitus, hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia uncommon                                  gout, anorexia, decreased appetite, decreased weight, increased weight,
hyperglycaemia, insulin resistance,
decreased high density lipoprotein,
increased appetite, polydipsia,
increased blood lactate dehydrogenase
Psychiatric disorders common                                    insomnia uncommon                                  depression, disorientation, anxiety, sleep disorder, abnormal dreams, nightmare,
decreased libido

rare                                        confusional state, altered mood, restlessness
Nervous system disorders common                                      headache, peripheral neuropathy, dizziness uncommon                                    lethargy, paraesthesia, hypoaesthesia, dysgeusia, disturbance in attention,
memory impairment, somnolence rare                                        syncope, convulsion, ageusia, sleep phase rhythm disturbance
Eye disorders uncommon                                    conjunctival hyperaemia, dry eye rare                                        visual disturbance
Ear and labyrinth disorders uncommon                                    vertigo
Cardiac disorders uncommon                                    myocardial infarction, angina pectoris, prolonged electrocardiogram QT,
tachycardia rare                                        acute myocardial infarction, sinus bradycardia, palpitations
Vascular disorders uncommon                                  hypertension, flushing
Respiratory, thoracic and mediastinal disorders uncommon                                  dyspnoea, cough, epistaxis, throat irritation rare                                      rhinorrhoea
Gastrointestinal disorders very common                               diarrhoea common                                    vomiting, nausea, abdominal pain, increased blood amylase, dyspepsia,
abdominal distension, flatulence uncommon                                  pancreatitis, gastritis, gastrooesophageal reflux disease, aphthous stomatitis,
retching, dry mouth, abdominal discomfort,
constipation, increased lipase, eructation,
oral dysaesthesia rare                                      stomatitis, haematemesis, cheilitis, dry lip, coated tongue
Hepatobiliary disorders common                                    increased alanine aminotransferase uncommon                                  hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased transaminase, increased aspartate aminotransferase, increased blood bilirubin, increased blood alkaline phosphatase, increased gamma- glutamyltransferase,
Skin and subcutaneous tissue disorders common                                    rash (including macular, maculopapular, papular,erythematous and pruritic rash),
pruritus uncommon                                  angioedema, generalised rash, allergic dermatitis, urticaria, eczema, erythema,
hyperhidrosis, night sweats, alopecia,


acne, dry skin, nail pigmentation rare                                      DRESS, Stevens-Johnson syndrome, erythema multiforme, dermatitis,
seborrhoeic dermatitis, skin lesion,
xeroderma not known                                 toxic epidermal necrolysis, acute generalized exanthematous pustulosis
Musculoskeletal and connective tissue disorders uncommon                                  myalgia, osteonecrosis, muscle spasms, muscular weakness, arthralgia, pain in extremity, osteoporosis, increased blood creatine phosphokinase rare                                      musculoskeletal stiffness, arthritis, joint stiffness
Renal and urinary disorders uncommon                                  acute renal failure, renal failure, nephrolithiasis, increased blood creatinine,
proteinuria, bilirubinuria, dysuria, nocturia,
pollakiuria rare                                      decreased creatinine renal clearance Reproductive system and breast disorders uncommon                                  erectile dysfunction, gynaecomastia General disorders and administration site conditions common                                    asthenia, fatigue uncommon                                  pyrexia, chest pain, peripheral oedema, malaise,
feeling hot, irritability, pain rare                                      chills, abnormal feeling, xerosis 
Description of selected adverse reactions
Rash
In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in section 4.4.
During the clinical development program of raltegravir in treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing PREZISTA/ritonavir +raltegravir compared to those containing PREZISTA/ritonavir without raltegravir or raltegravir without PREZISTA/ritonavir. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4).

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 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) 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).

Other special populations
Patients co-infected with hepatitis B and/or hepatitis C virus
Among 1,968 treatment-experienced patients receiving PREZISTA 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