Special Warning : אזהרת שימוש

5      WARNINGS AND PRECAUTIONS
5.1    Risk of Serious Adverse Reactions Due to Drug Interactions
Initiation of LEXIVA/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving LEXIVA/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of LEXIVA/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 LEXIVA/ritonavir.
• Loss of therapeutic effect of LEXIVA/ritonavir and possible development of resistance.


See Table 6 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 therapy with LEXIVA/ritonavir; review concomitant medications during therapy with LEXIVA/ritonavir; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4), Drug Interactions (7)].
5.2    Skin Reactions
Severe and life-threatening skin reactions, including 1 case of Stevens-Johnson syndrome among 700 subjects treated with LEXIVA in clinical trials. Treatment with LEXIVA should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms [see Adverse Reactions (6)].
5.3    Sulfa Allergy
LEXIVA should be used with caution in patients with a known sulfonamide allergy.
Fosamprenavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and fosamprenavir is unknown. In a clinical trial of LEXIVA used as the sole protease inhibitor, rash occurred in 2 of 10 subjects (20%) with a history of sulfonamide allergy compared with 42 of 126 subjects (33%) with no history of sulfonamide allergy. In 2 clinical trials of LEXIVA plus low-dose ritonavir, rash occurred in 8 of 50 subjects (16%) with a history of sulfonamide allergy compared with 50 of 412 subjects (12%) with no history of sulfonamide allergy.
5.4    Hepatic Toxicity
Use of LEXIVA with ritonavir at higher-than-recommended dosages may result in transaminase elevations and should not be used [see Dosage and Administration (2), Overdosage (9)]. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing or worsening of transaminase elevations. Appropriate laboratory testing should be conducted prior to initiating therapy with LEXIVA and patients should be monitored closely during treatment.
5.5    Diabetes/Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-1-infected patients receiving protease inhibitor 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 protease inhibitor 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 protease inhibitor therapy and these events have not been established.


5.6    Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including LEXIVA. 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.
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 treatment.
5.7    Increase in Body Fat
Increased of body fathas been observed in patients receivingprotease inhibitors, including LEXIVA. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
5.8    Lipid Elevations
Treatment with LEXIVA plus ritonavir has resulted in increases in the concentration of triglycerides and cholesterol [see Adverse Reactions (6)]. Triglyceride and cholesterol testing should be performed prior to initiating therapy with LEXIVA and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate [see Drug Interactions (7)].
5.9    Hemolytic Anemia
Acute hemolytic anemia has been reported in a patient treated with amprenavir.
5.10   Patients with Hemophilia
There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients, additional factor VIII was required. In many of the reported cases, treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established.
5.11   Nephrolithiasis
Cases of nephrolithiasis were reported during postmarketing surveillance in HIV-1-infected patients receiving LEXIVA. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.
5.12   Resistance/Cross-Resistance
Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored, it is unknown what effect therapy with LEXIVA will have on the activity of 

subsequently administered protease inhibitors. LEXIVA has been studied in patients who have experienced treatment failure with protease inhibitors [see Clinical Studies (13.2)].

6      ADVERSE REACTIONS
• Severe or life-threatening skin reactions have been reported with the use of LEXIVA [see Warnings and Precautions (5.2)].
• The most common moderate to severe adverse reactions in clinical trials of LEXIVA were diarrhea, rash, nausea, vomiting, and headache.
• Treatment discontinuation due to adverse events occurred in 6.4% of subjects receiving LEXIVA and in 5.9% of subjects receiving comparator treatments. The most common adverse reactions leading to discontinuation of LEXIVA (incidence less than or equal to 1% of subjects) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash.
6.1    Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adult Trials
The data for the 3 active-controlled clinical trials described below reflect exposure of 700 HIV-1–infected subjects to LEXIVA tablets, including 599 subjects exposed to LEXIVA for greater than 24 weeks, and 409 subjects exposed for greater than 48 weeks. The population age ranged from 17 to 72 years. Of these subjects, 26% were female, 51% white, 31% black, 16% American Hispanic, and 70% were antiretroviral-naive. Sixty-one percent received LEXIVA 1,400 mg once daily plus ritonavir 200 mg once daily; 24% received LEXIVA 1,400 mg twice daily; and 15% received LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily.
Selected adverse reactions reported during the clinical efficacy trials of LEXIVA are shown in Tables 2 and 3. Each table presents adverse reactions of moderate or severe intensity in subjects treated with combination therapy for up to 48 weeks.



Table 2. Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects
APV30001a                           APV30002a
LEXIVA
Nelfinavir       1,400 mg q.d./  Nelfinavir
LEXIVA             1,250 mg          Ritonavir     1,250 mg
1,400 mg b.i.d.         b.i.d.         200 mg q.d.       b.i.d.
Adverse Reaction            (n = 166)           (n = 83)          (n = 322)     (n = 327) Gastrointestinal
Diarrhea                      5%                 18%               10%           18% Nausea                        7%                  4%                7%            5% Vomiting                      2%                  4%                6%            4% Abdominal pain                1%                  0%                2%            2% Skin
Rash                          8%                  2%                3%            2% General disorders
Fatigue                       2%                  1%                4%            2% Nervous system
Headache                      2%                  4%                3%            3% a
All subjects also received abacavir and lamivudine twice daily.

Table 3. Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects (Trial APV30003) LEXIVA 700 mg b.i.d./       Lopinavir 400 mg b.i.d./
Ritonavir 100 mg b.i.d.   a Ritonavir 100 mg b.i.d.a
Adverse Reaction                       (n = 106)                  (n = 103) Gastrointestinal
Diarrhea                                      13%                       11% Nausea                                         3%                        9% Vomiting                                       3%                        5% Abdominal pain                                <1%                        2% Skin
Rash                                           3%                        0% Nervous system
Headache                                       4%                        2% a
All subjects also received 2 reverse transcriptase inhibitors.
Skin rash (without regard to causality) occurred in approximately 19% of subjects treated with LEXIVA in the pivotal efficacy trials. Rashes were usually maculopapular and of mild or moderate intensity, some with pruritus. Rash had a median onset of 11 days after initiation of LEXIVA and had a median duration of 13 days. Skin rash led to discontinuation of LEXIVA in less than 1% of subjects. In some subjects with mild or moderate rash, dosing with LEXIVA was often continued without interruption; if interrupted, reintroduction of LEXIVA generally did not result in rash recurrence.
The percentages of subjects with Grade 3 or 4 laboratory abnormalities in the clinical efficacy trials of LEXIVA are presented in Tables 4 and 5.

Table 4. Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects in Trials APV30001 and APV30002
APV30001a                       APV30002a
LEXIVA
1,400 mg q.d./ Nelfinavir
LEXIVA          Nelfinavir       Ritonavir    1,250 mg
1,400 mg b.i.d. 1,250 mg b.i.d. 200 mg q.d.        b.i.d.
Laboratory Abnormality          (n = 166)         (n = 83)        (n = 322)   (n = 327) ALT (>5 x ULN)                      6%               5%               8%           8% AST (>5 x ULN)                      6%               6%               6%           7% Serum lipase (>2 x ULN)             8%               4%               6%           4% b
Triglycerides                       0%               1%               6%           2% (>750 mg/dL)
Neutrophil count, absolute          3%               6%               3%           4% 3
(<750 cells/mm ) a
All subjects also received abacavir and lamivudine twice daily.
b
Fasting specimens.
ULN = Upper limit of normal.
The incidence of Grade 3 or 4 hyperglycemia in antiretroviral-naive subjects who received LEXIVA in the pivotal trials was less than 1%.



Table 5. Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects in Trial APV30003
LEXIVA 700 mg b.i.d./       Lopinavir 400 mg b.i.d./
Ritonavir 100 mg b.i.d. a   Ritonavir 100 mg b.i.d.a
Laboratory Abnormality                     (n = 104)                  (n = 103) b                                         c
Triglycerides (>750 mg/dL)                         11%                         6%c Serum lipase (>2 x ULN)                             5%                        12% ALT (>5 x ULN)                                      4%                         4% AST (>5 x ULN)                                      4%                         2% c
Glucose (>251 mg/dL)                                2%                         2%c a
All subjects also received 2 reverse transcriptase inhibitors.
b
Fasting specimens.
c n = 100 for LEXIVA plus ritonavir, n = 98 for lopinavir plus ritonavir.
ULN = Upper limit of normal.
6.2    Postmarketing Experience
The following adverse reactions have been identified during postapproval use of LEXIVA.
Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to LEXIVA.
Cardiac Disorders
Myocardial infarction.
Metabolism and Nutrition Disorders
Hypercholesterolemia.
Nervous System Disorders
Oral paresthesia.
Skin and Subcutaneous Tissue Disorders
Angioedema.
Urogenital
Nephrolithiasis.

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
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.health.gov.il).
Additionally, you should also report to GSK Israel (il.safety@gsk.com).

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