Adverse reactions : תופעות לוואי

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).