Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
5.1 General
PREZISTA must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer PREZISTA with ritonavir and food may result in a loss of efficacy of darunavir.

Please refer to ritonavir prescribing information for additional information on precautionary measures.

5.2 Hepatotoxicity
Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv.
During the clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy with PREZISTA/rtv. 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 events. 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 PREZISTA/rtv 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 PREZISTA/rtv 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 PREZISTA/rtv, interruption or discontinuation of treatment should be considered promptly.

5.3 Severe Skin Reactions
During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (<0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported. Discontinue PREZISTA/rtv 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 (all grades, regardless of causality) occurred in 10.3% of subjects treated with PREZISTA/rtv [also see Adverse Reactions (6)]. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using PREZISTA/rtv was 0.5%.

Rash occurred more commonly in treatment-experienced subjects receiving regimens containing PREZISTA/rtv + raltegravir compared to subjects receiving PREZISTA/rtv without raltegravir or raltegravir without PREZISTA/rtv. However, rash that was considered drug related occurred at similar rates for all three groups.
These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

5.4 Sulfa Allergy
Darunavir contains a sulfonamide moiety. PREZISTA should be used with caution in patients with a known sulfonamide allergy. In clinical studies with PREZISTA/ritonavir, the incidence and severity of rash was similar in subjects with or without a history of sulfonamide allergy.

5.5 Drug Interactions
Initiation of PREZISTA/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PREZISTA/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PREZISTA/ritonavir, respectively. These interactions may lead to:
• Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.
• Clinically significant adverse reactions from greater exposures of PREZISTA/ritonavir.
• Loss of therapeutic effect of PREZISTA/ritonavir and possible development of resistance.
See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during PREZISTA/ritonavir therapy; review concomitant medications during PREZISTA/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant drugs [see Contraindications (4) and Drug Interactions (7)].

5.6 Diabetes Mellitus / Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy.
Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these events have not been established.

5.7 Fat Redistribution
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.8 Immune reconstitution syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including PREZISTA. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
In addition,reactivation of herpes simplex and herpes zoster has been observed in clinical studies with PREZISTA co-administered with low dose ritonavir.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.

5.9 Hemophilia
There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with 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.

5.10 Resistance/Cross-Resistance
Because the potential for HIV cross-resistance among PIs has not been fully explored in PREZISTA/ritonavir treated patients, the effect therapy with PREZISTA will have on the activity of subsequently administered PIs is unknown [see Microbiology (11.4)].

5.11 Pediatric Patients
Do not administer PREZISTA/ritonavir in pediatric patients below 3 years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age [see Use in Specific Populations (8.1 and 8.3), Clinical Pharmacology (11.3), and Nonclinical Toxicology (12.2)].
Prezista Tabs are intended only for pediatric patients ≥6years old weighing ≥20 Kg.

5.12 Osteonecrosis
Although the etiology 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.

5.13 Elderly
As limited information is available on the use of PREZISTA in patients aged 65 and over, caution should be exercised in the administration of PREZISTA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy.

5.14 Renal impairment
No special precautions or dose adjustments are required in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these patients

6 ADVERSE REACTIONS

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 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-naive 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).


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 syndrome, (drug) hypersensitivity
Endocrine disorders uncommon                                          hypothyroidism, increased blood thyroid stimulating hormone
Metabolism and nutrition disorders common                                            lipodystrophy (including lipohypertrophy, lipodystrophy, lipoatrophy), 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, hepatotoxicity
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 5.3.

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 .

Lipodystrophy
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) .

Metabolic abnormalities
Combination antiretroviral therapy has also been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia .

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 .

Immune reconstitution 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 .

Paediatric population
The safety assessment in paediatric patients is based on the 48-week analysis of safety data from three Phase II trials. The following patient populations were evaluated:
* 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at least 20 kg who received PREZISTA tablets with low dose ritonavir twice daily in combination with other antiretroviral agents.
* 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received PREZISTA oral suspension with low dose ritonavir twice daily in combination with other antiretroviral agents.
* 12 ART-naïve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 40 kg who received PREZISTA tablets with low dose ritonavir once daily in combination with other antiretroviral agents.

Overall, the safety profile in these paediatric patients was similar to that observed in the adult population.

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 .

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@mo h.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).

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