SIDE EFFECTS
Lamivudine Plus Zidovudine Administered As Separate
Formulations
In four randomized, controlled trials of EPIVIR 300 mg
per day plus RETROVIR 600 mg per day, the following selected
clinical and laboratory adverse events were observed (see
Tables 4 and 5).
Table 4: Selected Clinical Adverse Events (³5%
Frequency) in Four Controlled Clinical Trials With EPIVIR
300 mg/day and RETROVIR 600 mg/day
|
Adverse Event
|
EPIVIR plus RETROVIR |
|
(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 three of the 656 adult patients
(< 0.5%) who received EPIVIR in controlled clinical
trials. Selected laboratory abnormalities observed during
therapy are listed in Table 5.
Table 5: Frequencies of Selected Laboratory Abnormalities
Among Adults in Four Controlled Clinical Trials of EPIVIR
300 mg/day plus RETROVIR 600 mg/day*
Test
(Abnormal Level) |
EPIVIR plus RETROVIR |
|
% (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 EPIVIR and/or RETROVIR. 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 their seriousness, frequency of reporting,
causal connection to EPIVIR and/or RETROVIR, or a combination
of these factors.
Cardiovascular: Cardiomyopathy
Endocrine and Metabolic: Gynecomastia,
hyperglycemia.
Gastrointestinal: Oral mucosal
pigmentation, stomatitis.
General: Vasculitis, weakness.
Hemic and Lymphatic: Aplastic
anemia, anemia, lymphadenopathy, pure red cell aplasia,
splenomegaly.
Hepatic and Pancreatic: Lactic
acidosis and hepatic steatosis, 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
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). No data are available regarding
the potential for interactions with other drugs that have
renal clearance mechanisms similar to that of lamivudine.
Lamivudine and zalcitabine may inhibit the intracellular
phosphorylation of one another. Therefore, use of COMBIVIR
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 COMBIVIR with stavudine should be
avoided since an antagonistic relationship with zidovudine
has been demonstrated in vitro. In addition, concomitant
use of zidovudine with doxorubicin or ribavirin should
be avoided because an antagonistic relationship has been
demonstrated in vitro.
See CLINICAL PHARMACOLOGY for additional drug interactions.
Carcinogenesis, Mutagenesis, and Impairment
of Fertility: Carcinogenicity
Lamivudine: Long-term carcinogenicity
studies with lamivudine in mice and rats showed no evidence
of carcinogenic potential at exposures up to 10 times
(mice) and 58 times (rats) those observed in humans at
the recommended therapeutic dose for HIV infection.
Pregnancy
Lamivudine
Reproduction studies with orally administered lamivudine
have been performed in rats and rabbits at doses up to
4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing
plasma levels up to approximately 35 times that for the
adult HIV dose. No evidence of teratogenicity due to lamivudine
was observed.
Evidence of early embryolethality was seen in the rabbit
at exposure levels similar to those observed in humans,
but there was no indication of this effect in the rat
at exposure levels up to 35 times that in humans. Studies
in pregnant rats and rabbits showed that lamivudine is
transferred to the fetus through the placenta.
Nursing Mothers
The Centers for Disease Control and Prevention recommend
that HIV-infected mothers not breastfeed their infants
to avoid risking postnatal transmission of HIV infection.
No specific studies of lamivudine and zidovudine excretion
in breast milk after dosing with COMBIVIR have been performed,
although zidovudine is excreted in breast milk after dosing
with RETROVIR (see CLINICAL PHARMACOLOGY: Pharmacokinetics:
Nursing Mothers). Although it is not known if lamivudine
is excreted in human milk, a study in which lactating
rats were administered 45 mg/kg of lamivudine showed that
lamivudine concentrations in milk were slightly greater
than those in plasma.
Because of both the potential for HIV transmission and
the potential for serious adverse reactions in nursing
infants, mothers should be instructed not to breastfeed
if they are receiving COMBIVIR.
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