Included as part of the PRECAUTIONS section.
Lactic Acidosis And Severe Hepatomegaly With Steatosis
Lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with the use of nucleoside analogues
alone or in combination with other antiretrovirals. Treatment with TEMIXYS
should be suspended in any patient who develops clinical or laboratory findings
suggestive of lactic acidosis or pronounced hepatotoxicity (which may include
hepatomegaly and steatosis even in the absence of marked transaminase
Severe Acute Exacerbation Of Hepatitis B In Patients
Coinfected With HIV-1 And HBV
All patients with HIV-1 should be tested for the presence
of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy.
Posttreatment Exacerbations Of Hepatitis
of anti-HBV therapy, including 3TC and TDF may be associated with severe acute
exacerbations of hepatitis. Patients infected with HBV who discontinue TEMIXYS
should be closely monitored with both clinical and laboratory follow-up for at
least several months after stopping treatment. If appropriate, resumption of
anti-hepatitis B therapy may be warranted.
If treatment with EPIVIR-HBV, TDF or a tenofovir
alafenamide (TAF)-containing product is prescribed for chronic hepatitis B for
a patient with unrecognized or untreated HIV-1 infection, rapid emergence of
HIV-1 resistance is likely to result because of the subtherapeutic dose and the
inappropriateness of monotherapy HIV-1 treatment.
Risk Of Hepatic Decompensation When Used With Interferon-And
In vitro studies have shown ribavirin can reduce the
phosphorylation of pyrimidine nucleoside analogues such as 3TC, a component of
TEMIXYS. Although no evidence of a pharmacokinetic or pharmacodynamic
interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when
ribavirin was coadministered with 3TC in HIV1/HCV co-infected patients [see CLINICAL
PHARMACOLOGY], hepatic decompensation (some fatal) has occurred in
HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for
HIV-1 and interferon alfa with or without ribavirin. Patients receiving
interferon alfa with or without ribavirin and 3TC should be closely monitored
for treatment-associated toxicities, especially hepatic decompensation.
Discontinuation of 3TC should be considered as medically
appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin,
or both should also be considered if worsening clinical toxicities are
observed, including hepatic decompensation (e.g., Child-Pugh greater than 6).
See the full prescribing information for interferon and ribavirin.
In pediatric patients with a history of prior
antiretroviral nucleoside exposure, a history of pancreatitis, or other
significant risk factors for the development of pancreatitis, 3TC, a component
of TEMIXYS, should be used with caution. Treatment with TEMIXYS should be
stopped immediately if clinical signs, symptoms, or laboratory abnormalities
suggestive of pancreatitis occur [see ADVERSE REACTIONS].
New Onset Or Worsening Renal Impairment
TDF, a component of TEMIXYS, is principally eliminated by
the kidney. Renal impairment, including cases of acute renal failure and Fanconi
syndrome (renal tubular injury with severe hypophosphatemia), has been reported
with the use of TDF [see ADVERSE REACTIONS].
It is recommended that estimated creatinine clearance be
assessed in all patients prior to initiating therapy and as clinically
appropriate during therapy with TDF. In patients at risk of renal dysfunction,
it is recommended that estimated creatinine clearance, serum phosphorus, urine
glucose, and urine protein be assessed prior to initiation of TDF, and
periodically during TDF therapy.
Avoid TEMIXYS with concurrent or recent use of a
nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory
drugs (NSAIDs)) [see DRUG INTERACTIONS]. Cases of acute renal failure
after initiation of high dose or multiple NSAIDs have been reported in
HIV-infected patients with risk factors for renal dysfunction who appeared
stable on tenofovir disoproxil fumarate. Some patients required hospitalization
and renal replacement therapy. Alternatives to NSAIDs should be considered, if
needed, in patients at risk for renal dysfunction.
Persistent or worsening bone pain, pain in extremities,
fractures and/or muscular pain or weakness may be manifestations of proximal
renal tubulopathy and should prompt an evaluation of renal function in at-risk
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in
HIV-infected patients treated with combination antiretroviral therapy,
including 3TC and TDF. During the initial phase of combination antiretroviral
treatment, patients whose immune system responds may develop an inflammatory
response to indolent or residual opportunistic infections (such as Mycobacterium
avium infection, cytomegalovirus, Pneumocystis jiroveci 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.
Bone Mineral Density (BMD)
In clinical trials in HIV-1 infected adults, TDF was
associated with greater decreases in BMD and increases in biochemical markers
of bone metabolism, suggesting increased bone turnover relative to comparators.
Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in
subjects receiving TDF [see ADVERSE REACTIONS].
The effects of TDF-associated changes in BMD and
biochemical markers on long-term bone health and future fracture risk are
unknown. Assessment of BMD should be considered for adults and pediatric
patients who have a history of pathologic bone fracture or other risk factors
for osteoporosis or bone loss. Although the effect of supplementation with
calcium and vitamin D was not studied, such supplementation may be beneficial for
all patients. If bone abnormalities are suspected, then appropriate
consultation should be obtained.
Cases of osteomalacia associated with proximal renal
tubulopathy, manifested as bone pain or pain in extremities and which may
contribute to fractures, have been reported in association with the use of TDF [see
ADVERSE REACTIONS]. Arthralgias and muscle pain or weakness have also
been reported in cases of proximal renal tubulopathy. Hypophosphatemia and
osteomalacia secondary to proximal renal tubulopathy should be considered in
patients at risk of renal dysfunction who present with persistent or worsening
bone or muscle symptoms while receiving products containing tenofovir
disoproxil fumarate [see New Onset or Worsening Renal Impairment].
Early Virologic Failure
Clinical trials in HIV-infected subjects have
demonstrated that certain regimens that only contain three nucleoside reverse
transcriptase inhibitors (NRTI) are generally less effective than triple drug
regimens containing two NRTIs in combination with either a non-nucleoside
reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular,
early virological failure and high rates of resistance substitutions have been
reported. Triple nucleoside regimens should therefore be used with caution.
Patients on a therapy utilizing a triple nucleosideonly regimen should be
carefully monitored and considered for treatment modification.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (PATIENT INFORMATION).
Lactic Acidosis And Severe Hepatomegaly
Inform patients that lactic acidosis and severe
hepatomegaly with steatosis, including fatal cases, have been reported. TEMIXYS
should be suspended in any patients who develop clinical symptoms suggestive of
lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting,
unusual or unexpected stomach discomfort, and weakness) [see WARNINGS AND PRECAUTIONS].
Patients With Hepatitis B Or C-infection
Inform patients co-infected with HIV-1 and HBV that
deterioration of liver disease has occurred in some cases when treatment with
lamivudine and tenofovir disoproxil fumarate were discontinued. Advise patients
to discuss any changes in regimen with their healthcare provider [see WARNINGS AND PRECAUTIONS].
Inform patients with HIV-1/HCV co-infection that hepatic
decompensation (some fatal) has occurred in HIV1/HCV co-infected patients
receiving combination antiretroviral therapy for HIV-1 and interferon alfa with
or without ribavirin [see WARNINGS AND PRECAUTIONS].
Risk of Pancreatitis
Advise parents or guardians to monitor pediatric patients
for signs and symptoms of pancreatitis [see WARNINGS
New Onset Or Worsening Renal Impairment
Inform patients that renal impairment, including cases of
acute renal failure and Fanconi syndrome, has been reported. Advise patients
with impaired renal function (i.e., creatinine clearance less than 50 mL/min)
or patients with end-stage renal disease (ESRD) requiring hemodialysis to avoid
TEMIXYS with concurrent or recent use of a nephrotoxic agent (e.g., high-dose
or multiple NSAIDs) for patients [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Immune Reconstitution Syndrome
Advise patients to inform their healthcare provider
immediately of any signs and symptoms of infection as inflammation from
previous infection may occur soon after combination antiretroviral therapy [see WARNINGS AND PRECAUTIONS].
Do not administer TEMIXYS with HEPSERA [see DRUG
Inform patients that decreases in bone mineral density
have been observed with the use of TEMIXYS. Bone mineral density monitoring
should be considered in patients who have a history of pathologic bone fracture
or at risk for osteopenia [see WARNINGS AND
Advise patients that there is an antiretroviral pregnancy
registry to monitor fetal outcomes in women exposed to lamivudine and tenofovir
disoproxil fumarate tablets [see Use In Specific Populations].
Instruct patients to store lamivudine and tenofovir
disoproxil fumarate tablets in the original package and keep the bottle tightly
closed. Do not remove desiccant.
Instruct women with HIV-1 infection not to breastfeed
because HIV-1 can be passed to the baby in the breast milk [see Use In Specific
Instruct patients that if they miss a dose of TEMIXYS, to
take it as soon as they remember. Advise patients not to double their next dose
or take more than the prescribed dose.
TEMIXYS is a registered trademark of Celltrion, Inc.
Other brands listed are the trademarks of their respective owners and are not
trademarks of Celltrion, Inc.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term carcinogenicity studies with 3TC in mice and
rats showed no evidence of carcinogenic potential at exposures up to 10 times
(mice) and 58 times (rats) the human exposures at the recommended dose of 300
3TC was not mutagenic in a microbial mutagenicity assay,
in an in vitro cell transformation assay, in a rat micronucleus test, in a rat
bone marrow cytogenetic assay, and in assay for unscheduled DNA synthesis in
rat liver. 3TC showed no evidence of in vivo genotoxic activity in the rat at
oral doses of up to 2000 mg per kg, producing plasma levels of 35 to 45 times
those in humans at the recommended dose for HIV-1 infection.
In a study of reproductive performance, 3TC administered
to rats at doses up to 4,000 mg per kg per day, producing plasma levels 47 to
70 times those in humans, revealed no evidence of impaired fertility and no
effect on the survival, growth, and development to weaning of the offspring.
Tenofovir Disoproxil Fumarate
Long-term oral carcinogenicity studies of TDF in mice and
rats were carried out at exposures up to approximately 16 times (mice) and 5
times (rats) those observed in humans at the therapeutic dose for HIV-1
infection. At the high dose in female mice, liver adenomas were increased at
exposures 16 times that in humans. In rats, the study was negative for
carcinogenic findings at exposures up to 5 times that observed in humans at the
TDF was mutagenic in the in vitro mouse lymphoma assay
and negative in an in vitro bacterial mutagenicity test (Ames test). In an in
vivo mouse micronucleus assay, TDF was negative when administered to male mice.
There were no effects on fertility, mating performance or
early embryonic development when TDF was administered to male rats at a dose
equivalent to 10 times the human dose based on body surface area comparisons
for 28 days prior to mating and to female rats for 15 days prior to mating
through day seven of gestation. There was, however, an alteration of the
estrous cycle in female rats.
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to TEMIXYS during pregnancy. Healthcare
providers are encouraged to register patients by calling the Antiretroviral
Pregnancy Registry (APR) at 1-800-258-4263.
Available data from the APR show no difference in the
risk of overall major birth defects for 3TC compared to the background rate for
major birth defects of 2.7% in U.S. reference population of the Metropolitan
Atlanta Congenital Defects Program (MACDP) (see Data).
3TC produced embryonic toxicity in rabbits at a dose the
produced similar human exposures as the recommended clinical dose. The
relevance of animal findings to human pregnancy registry data is not known.
There are no adequate and well-controlled studies with TDF in pregnant women. Because
animal reproduction studies are not always predictive of human response, TDF
should be used during pregnancy only if clearly needed.
Lamivudine: Based on prospective reports from the APR of
over 11,000 exposures to 3TC during pregnancy resulting in live births
(including over 4,500 exposed in the first trimester), there was no difference
between lamivudine and overall birth defects compared with the background birth
defect rate of 2.7% in the U.S. reference population of the MACDP. The
prevalence of defects in the first trimester was 3.1% (95% CI: 2.6% to 3.6%).
3TC pharmacokinetics were studied in pregnant women
during 2 clinical trials conducted in South Africa. The trials assessed
pharmacokinetics in 16 women at 36 weeks gestation using 150 mg 3TC twice daily
with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice
daily with zidovudine, and 10 women at 38 weeks gestation using 3TC 300 mg
twice daily without other antiretrovirals. These trials were not designed or
powered to provide efficacy information. 3TC pharmacokinetics in pregnant women
were similar to those seen in non-pregnant adults and in postpartum women. 3TC
concentrations were generally similar in maternal, neonatal, and umbilical cord
serum samples. In a subset of subjects, amniotic fluid specimens were collected
following natural rupture of membranes and confirmed that 3TC crosses the
placenta in humans. Amniotic fluid concentrations of 3TC were typically 2 times
greater than maternal serum levels and ranged from 1.2 to 2.5 mcg per mL (150
mg twice daily) and 2.1 to 5.2 mcg per mL (300 mg twice daily).
Lamivudine: Studies in pregnant rats showed that 3TC is
transferred to the fetus through the placenta. Reproduction studies with orally
administered 3TC have been performed in rats and rabbits at doses producing
plasma levels up to approximately 35 times that for the recommended adult HIV
dose. No evidence of teratogenicity due to 3TC was observed. Evidence of early
embryo-lethality 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 those in humans.
Tenofovir Disoproxil Fumarate: Reproduction studies have
been performed in rats and rabbits at doses up to 14 and 19 times the human
dose based on body surface area comparisons and revealed no evidence of impaired
fertility or harm to the fetus due to tenofovir.
The Centers for Disease Control and Prevention recommend
that HIV-1 infected mothers not breastfeed their infants to avoid risking
postnatal transmission of HIV-1 infection.
3TC is excreted into human milk. Samples of breast milk
obtained from 20 mothers receiving 3TC monotherapy 300 mg twice daily (2 times
the dose in TEMIXYS) had measurable concentrations of 3TC. There is not
information on the effects of 3TC on the breastfed infant or the effects of 3TC
on milk production.
Tenofovir Disoproxil Fumarate
Samples of breast milk obtained from five HIV-1 infected
mothers in the first post-partum week show that tenofovir is excreted in human
milk at low levels. The impact of this exposure in breastfed infants is unknown
and the effect of TDF on milk production is unknown.
Because of the potential for 1) HIV transmission (in
HIV-negative infants); 2) developing viral resistance (in HIV-positive
infants); and 3) adverse reactions in a breastfed infant similar to those seen
in adults, instruct mothers not to breastfeed if they are receiving TEMIXYS.
The safety and effectiveness of TEMIXYS as a fixed dose
formulation in pediatric patients infected with HIV-1 and weighing at least 35
kg have been established based on clinical studies using the individual
components (lamivudine and tenofovir disoproxil fumarate).
Clinical trials of lamivudine and tenofovir disoproxil
fumarate did not include sufficient numbers of subjects aged 65 years and over
to determine whether they respond differently from younger subjects. In
general, caution should be exercised in administration of TEMIXYS in elderly
patients reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or other drug therapy.
TEMIXYS is not recommended for patients with impaired
renal function (i.e., creatinine clearance less than 50 mL/min) or patients
with end-stage renal disease (ESRD) requiring hemodialysis because it is a
fixed-dose combination formulation that cannot be adjusted [see DOSAGE AND