A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Trizivir Side Effects, and Drug Interactions - Abacavir Sulfate, Lamivudine, and Zidovudine
Trizivir Side Effects, and Drug Interactions - Abacavir Sulfate, Lamivudine, and Zidovudine
SIDE EFFECTS
Abacavir
Hypersensitivity Reaction: TRIZIVIR contains
abacavir sulfate (ZIAGEN), which has been associated with fatal hypersensitivity
reactions. Therapy with abacavir (as TRIZIVIR OR ZIAGEN) SHOULD NOT be restarted
following a hypersensitivity reaction because more severe symptoms will recur
within hours and may include life-threatening hypotension and death. Patients
developing signs or symptoms of hypersensitivity should discontinue treatment
as soon as a hypersensitivity reaction is first suspected, and should seek medical
evaluation immediately. To avoid a delay in diagnosis and minimize the risk
of a life-threatening hypersensitivity reaction, TRIZIVIR should be permanently
discontinued if hypersensitivity cannot be ruled out, even when other diagnoses
are possible (e.g., acute onset respiratory diseases, gastroenteritis, or reactions
to other medications).
Severe or fatal hypersensitivity reactions can occur within
hours after reintroduction of abacavir (as TRIZIVIR or ZIAGEN) in patients who
have no identified history or unrecognized symptoms of hypersensitivity to abacavir
therapy (see WARNINGS and PRECAUTIONS:
Information for Patients).
When therapy with abacavir (as TRIZIVIR or ZIAGEN) has been
discontinued for reasons other than symptoms of a hypersensitivity reaction,
and if reinitiation of therapy is under consideration, the reason for discontinuation
should be evaluated to ensure that the patient did not have symptoms of a hypersensitivity
reaction. If hypersensitivity cannot be ruled out, abacavir (as TRIZIVIR or
ZIAGEN) should NOT be reintroduced. If symptoms consistent with hypersensitivity
are not identified, reintroduction can be undertaken with continued monitoring
for symptoms of hypersensitivity reaction. Patients should be made aware that
a hypersensitivity reaction can occur with reintroduction of abacavir (as TRIZIVIR
or ZIAGEN), and that reintroduction of abacavir (as TRIZIVIR or ZIAGEN) should
be undertaken only if medical care can be readily accessed by the patient or
others (see WARNINGS).
In clinical studies, approximately 5% of adult and pediatric
patients receiving abacavir developed a hypersensitivity reaction. This reaction
is characterized by the appearance of symptoms indicating multi-organ/body system
involvement. Symptoms usually appear within the first 6 weeks of treatment with
abacavir, although these reactions may occur at any time during therapy. Frequently
observed signs and symptoms include fever, skin rash, fatigue, and gastrointestinal
symptoms such as nausea, vomiting, diarrhea, or abdominal pain. Other signs
and symptoms include malaise, lethargy, myalgia, myolysis, arthralgia, edema,
cough, abnormal chest x-ray findings (predominantly infiltrates, which can be
localized), dyspnea, headache, and paresthesia. Some patients who experienced
a hypersensitivity reaction were initially thought to have acute onset or worsening
respiratory disease. The diagnosis of hypersensitivity
reaction should be carefully considered for patients presenting with symptoms
of acute onset respiratory diseases, even if alternative respiratory diagnoses
(pneumonia, bronchitis, flu-like illness) are possible.
Physical findings include lymphadenopathy, mucous membrane
lesions (conjunctivitis and mouth ulcerations), and rash. The rash usually appears
maculopapular or urticarial but may be variable in appearance. There have been
reports of erythema multiforme. Hypersensitivity reactions have occurred without
rash.
Laboratory abnormalities include elevated liver function tests,
increased creatine phosphokinase or creatinine, and lymphopenia. Anaphylaxis,
liver failure, renal failure, hypotension, adult respiratory distress syndrome,
respiratory failure, and death have occurred in association with hypersensitivity
reactions. Symptoms worsen with continued therapy but often resolve upon discontinuation
of abacavir.
Risk factors that may predict the occurrence or severity of
hypersensitivity to abacavir have not been identified.
Selected clinical adverse events with a ³5%
frequency during therapy with ZIAGEN 300 mg twice daily, EPIVIR 150 mg twice
daily, and RETROVIR 300 mg twice daily compared with EPIVIR 150 mg twice daily
and RETROVIR 300 mg twice daily from CNAAB3003 are listed in Table 4.
|
Table 4. Selected Clinical Adverse Events Grades 1-4
(³5% Frequency) in Therapy-Naïve
Adults (CNAAB3003) Through 16 Weeks of Treatment
|
|
Adverse Event
|
ZIAGEN/Lamivudine/Zidovudine (n = 83)
|
Lamivudine/Zidovudine (n = 81)
|
|
Nausea
|
47%
|
41%
|
|
Nausea and vomiting
|
16%
|
11%
|
|
Diarrhea
|
12%
|
11%
|
|
Loss of appetite/anorexia
|
11%
|
10%
|
|
Insomnia and other sleep disorders
|
7%
|
5%
|
Selected clinical adverse events with a ³5%
frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice
daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times
daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from
CNAAB3005 are listed in Table 5.
|
Table 5. Selected Clinical Adverse Events Grades 1-4 (³5%
Frequency) in Therapy-Naïve Adults (CNAAB3005) Through 48 Weeks of
Treatment
|
|
Adverse Event
|
ZIAGEN/Lamivudine/Zidovudine
(n = 262)
|
Indinavir/Lamivudine/Zidovudine
(n = 264)
|
|
Nausea
|
60%
|
61%
|
|
Nausea and vomiting
|
30%
|
27%
|
|
Diarrhea
|
26%
|
27%
|
|
Loss of appetite/anorexia
|
15%
|
11%
|
|
Insomnia and other sleep Disorders
|
13%
|
12%
|
|
Fever and/or chills
|
20%
|
13%
|
|
Headache
|
28%
|
25%
|
|
Malaise and/or fatigue
|
44%
|
41%
|
Five subjects in the abacavir arm of study CNAAB3005 experienced
worsening of pre-existing depression compared to none in the indinavir arm.
The background rates of pre-existing depression were similar in the 2 treatment
arms.
Laboratory Abnormalities : Laboratory abnormalities
(anemia, neutropenia, liver function test abnormalities, and CPK elevations)
were observed with similar frequencies in the 2 treatment groups in studies
CNAAB3003 and CNAAB3006. Mild elevations of blood glucose were more frequent
in subjects receiving abacavir. In study CNAAB3003, triglyceride elevations
(all grades) were more common on the abacavir arm (25%) than on the placebo
arm (11%). In study CNAAB3005, hyperglycemia and disorders of lipid metabolism
occurred with similar frequency in the abacavir and indinavir treatment arms.
Other Adverse Events : In addition to adverse
events in Tables 4 and 5, other adverse events observed in the expanded access
program for abacavir were pancreatitis and increased GGT.
Lamivudine Plus Zidovudine
In 4 randomized, controlled trials of lamivudine 300 mg per
day plus zidovudine 600 mg per day, the following selected clinical and laboratory
adverse events were observed (see Tables 6 and 7).
|
Table 6. Selected Clinical Adverse Events (³5%
Frequency) in 4 Controlled Clinical Trials With Lamivudine 300 mg/day
and Zidovudine 600 mg/day
|
|
Adverse Event
|
Lamivudine plus Zidovudine (n = 251)
|
|
Body as a whole
|
|
Headache
|
35%
|
|
Malaise & fatigue
|
27%
|
|
Fever or chills
|
10%
|
|
Digestive
|
|
Nausea
|
33%
|
|
Diarrhea
|
18%
|
|
Nausea & vomiting
|
13%
|
|
Anorexia and/or decreased appetite
|
10%
|
|
Abdominal pain
|
9%
|
|
Abdominal cramps
|
6%
|
|
Dyspepsia
|
5%
|
|
Nervous system
|
|
Neuropathy
|
12%
|
|
Insomnia & other sleep disorders
|
11%
|
|
Dizziness
|
10%
|
|
Depressive disorders
|
9%
|
|
Respiratory
|
|
Nasal signs & symptoms
|
20%
|
|
Cough
|
18%
|
|
Skin
|
|
Skin rashes
|
9%
|
|
Musculoskeletal
|
|
Musculoskeletal pain
|
12%
|
|
Myalgia
|
8%
|
|
Arthralgia
|
5%
|
Pancreatitis was observed in 3 of the 656 adult patients (<0.5%)
who received lamivudine in controlled clinical trials.
Selected laboratory abnormalities observed during therapy are
listed in Table 7.
|
Table 7. Frequencies of Selected Laboratory Abnormalities
Among Adults in 4 Controlled Clinical Trials of Lamivudine 300 mg/day
plus Zidovudine 600 mg/day*
|
|
Test (Abnormal Level)
|
Lamivudine plus Zidovudine % (n)
|
|
Neutropenia (ANC <750/mm3)
|
7.2% (237)
|
|
Anemia (Hgb <8.0 g/dL)
|
2.9% (241)
|
|
Thrombocytopenia (platelets <50,000/mm3)
|
0.4% (240)
|
|
ALT (>5.0 x ULN)
|
3.7% (241)
|
|
AST (>5.0 x ULN)
|
1.7% (241)
|
|
Bilirubin (>2.5 x ULN)
|
0.8% (241)
|
|
Amylase (>2.0 x ULN)
|
4.2% (72)
|
|
ULN = Upper limit of normal.
|
|
ANC = Absolute neutrophil count.
|
|
n = Number of patients assessed.
|
|
*Frequencies of these laboratory abnormalities were higher
in patients with mild laboratory abnormalities at baseline.
|
Observed During Clinical Practice
The following events have been identified during post-approval
use of abacavir, lamivudine, and/or zidovudine. Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot be made. These
events have been chosen for inclusion due to a combination of their seriousness,
frequency of reporting, or potential causal connection to lamivudine and/or
zidovudine.
Abacavir : Suspected Stevens-Johnson syndrome
(SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving
abacavir primarily in combination with medications known to be associated with
SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms
between hypersensitivity to abacavir and SJS and TEN, and the possibility of
multiple drug sensitivities in some patients, abacavir should be discontinued
and not restarted in such cases.
There have also been reports of erythema multiforme with abacavir
use.
Abacavir, Lamivudine, and Zidovudine
Body as a Whole : Redistribution/accumulation
of body fat (see PRECAUTIONS: Fat Redistribution).
Cardiovascular : Cardiomyopathy.
Digestive : Stomatitis.
Endocrine and Metabolic : Gynecomastia, hyperglycemia.
Gastrointestinal : Oral mucosal pigmentation.
General : Vasculitis, weakness.
Hemic and Lymphatic : Aplastic anemia, anemia,
lymphadenopathy, pure red cell aplasia, splenomegaly.
Hepatic and Pancreatic : Lactic acidosis and
hepatic steatosis, pancreatitis, posttreatment exacerbation of hepatitis B (see
WARNINGS).
Hypersensitivity : Sensitization reactions (including
anaphylaxis), urticaria.
Musculoskeletal : Muscle weakness, CPK elevation,
rhabdomyolysis.
Nervous : Paresthesia, peripheral neuropathy,
seizures.
Respiratory : Abnormal breath sounds/wheezing.
Skin : Alopecia, erythema multiforme, Stevens-Johnson
syndrome.
DRUG INTERACTIONS
TRIZIVIR : No clinically significant changes
to pharmacokinetic parameters were observed for abacavir, lamivudine, or zidovudine
when administered together.
Abacavir : Abacavir has no effect on the pharmacokinetic
properties of ethanol. Ethanol decreases the elimination of abacavir causing
an increase in overall exposure (see CLINICAL PHARMACOLOGY:
Drug Interactions).
The addition of methadone has no clinically significant effect
on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected
subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with
600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone
clearance increased 22% (90% CI 6% to 42%). This alteration will not
result in a methadone dose modification in the majority of patients; however,
an increased methadone dose may be required in a small number of patients.
Lamivudine : Trimethoprim (TMP) 160 mg/sulfamethoxazole
(SMX) 800 mg once daily has been shown to increase lamivudine exposure (AUC).
The effect of higher doses of TMP/SMX on lamivudine pharmacokinetics has not
been investigated (see CLINICAL PHARMACOLOGY).
Lamivudine and zalcitabine may inhibit the intracellular phosphorylation
of one another. Therefore, use of TRIZIVIR in combination with zalcitabine is
not recommended.
Zidovudine : Coadministration of ganciclovir,
interferon-alpha, and other bone marrow suppressive or cytotoxic agents may
increase the hematologic toxicity of zidovudine. Concomitant use of zidovudine
with stavudine should be avoided since an antagonistic relationship has been
demonstrated in vitro. In addition, concomitant use of zidovudine with doxorubicin
or ribavirin should be avoided because an antagonistic relationship has also
been demonstrated in vitro.
See CLINICAL PHARMACOLOGY
for additional drug interactions.
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