Temixys

TEMIXYS is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35kg.

Testing Prior To Initiation And During Treatment With TEMIXYS

Prior to initiation treatment with TEMIXYS, test patients for hepatitis B virus infection .

It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating TEMIXYS and during therapy in all patients as clinically appropriate .

Recommended Dose In Adult And Pediatric Patients Weighing At Least 35 kg

TEMIXYS is a two-drug fixed-dose combination product containing 300 mg of lamivudine (3TC) and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of TEMIXYS in HIV-1 infected adult and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with or without food.

Not Recommended In Renal Impairment

Because TEMIXYS is a fixed-dose combination formulation and cannot be dose adjusted, it is not recommended for patients with impaired renal function (creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis .

TEMIXYS is contraindicated in patients with a previous hypersensitivity reaction to any of the components contained in the formulation.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 elevations).

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

Discontinuation 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 Ribavirin-Based Regimens

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 , 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).

Pancreatitis

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 .

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 .

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)) . 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 patients.

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 Effects

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 .

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.

Mineralization Defects

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 . 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 .

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) .

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 .

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 .

Risk of Pancreatitis

Advise parents or guardians to monitor pediatric patients for signs and symptoms of pancreatitis .

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 .

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 .

Drug Interactions

Do not administer TEMIXYS with HEPSERA .

Bone Effects

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 .

Pregnancy Registry

Advise patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in women exposed to lamivudine and tenofovir disoproxil fumarate tablets .

Storage

Instruct patients to store lamivudine and tenofovir disoproxil fumarate tablets in the original package and keep the bottle tightly closed. Do not remove desiccant.

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk .

Missed Dosage

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Lamivudine

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 mg.

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 therapeutic dose.

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

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.

Lamivudine

Risk Summary

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) .

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.

Data

Human Data

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).

Animal Data

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.

Lactation

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.

Lamivudine

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.

Pediatric Use

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).

Geriatric Use

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.

Renal Impairment

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 .

Drugs Affecting Renal Function

Tenofovir, a component of TEMIXYS, is primarily eliminated by the kidneys . Coadministration of TEMIXYS with drugs that are eliminated by active tubular secretion may increase serum concentrations of tenofovir and/or coadministered drug. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs . Drugs that decrease renal function may increase concentrations of tenofovir.

Do not administer TEMIXYS with HEPSERA (adefovir dipivoxil).

Established And Significant Interactions

Table 3 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with tenofovir DF .

Table 3: Established and Significant^a Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials

Drug Inhibiting Organic Cation Transporters

3TC, a component of TEMIXYS, is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim) . No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of 3TC.

Sorbitol

Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine .

The following adverse reactions are discussed in other sections of the labeling:

• Lactic acidosis and severe hepatomegaly with steatosis
• Exacerbations of hepatitis B
• Hepatic decompensation in patient co-infected with HIV-1 and hepatitis C
• Pancreatitis
• New onset or worsening renal impairment
• Immune reconstitution syndrome
• Bone Effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Lamivudine And Tenofovir Disoproxil Fumarate

Treatment-Naive Patients

Study 903 - Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial in which 600 treatment-naive subjects received TDF (N=299) or stavudine (N=301) in combination with 3TC and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness.

Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table1.

Table 1: Selected Treatment-Emergent Adverse Reactions^a (Grades 2-4) Reported in ≥5% in Any Treatment Group in Study 903 (0-144 Weeks)

Laboratory Abnormalities

With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with tenofovir disoproxil fumarate (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate and stavudine treatment arms. A summary of Grades 3-4 laboratory abnormalities is provided in Table 2.

Table 2: Grades 3-4 Laboratory Abnormalities Reported in ≥1% of tenofovir disoproxil fumarate-treated subjects in Study 903 (0-144 Weeks)

Pancreatitis

Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experiences pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents .

Changes In Bone Mineral Density

In HIV-1 infected adult subjects in Study 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving TDF + 3TC + EFV (-2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (-1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the TDF group vs. -2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24-48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of TDF-treated subjects vs. 21% of the d4T-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the TDF group and 6 subjects in the d4T group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the TDF group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range .

Postmarketing Experience

The following adverse reactions have been identified during post-approval use for each of the individual components of TEMIXYS. 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 3TC and TDF.

Lamivudine

Body as a Whole: Redistribution/accumulation of body fat.

Endocrine and Metabolic: Hyperglycemia.

General: Weakness.

Hemic and Lymphatic: Anemia (including pure red cell aplasia and severe anemias progressing on therapy).

Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis , posttreatment exacerbations of hepatitis B .

Hypersensitivity: Anaphylaxis, urticaria.

Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.

Skin: Alopecia, pruritus.

Tenofovir Disoproxil Fumarate

Immune System Disorders: allergic reaction, including angioedema.

Metabolism and Nutrition Disorders: lactic acidosis, hypokalemia, hypophosphatemia.

Respiratory, Thoracic, and Mediastinal Disorders: dyspnea.

Gastrointestinal Disorders: pancreatitis, increased amylase, abdominal pain.

Hepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT).

Skin and Subcutaneous Tissue Disorders: rash.

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy.

Renal and Urinary Disorders: acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria.

General Disorders and Administration Site Conditions: asthenia.

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Lamivudine

There is no known specific treatment for overdose with 3TC. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. Because a negligible amount of 3TC was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a 3TC overdose event.

Tenofovir Disoproxil Fumarate

Limited clinical experience at doses higher than the therapeutic dose of TDF is available.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

Mechanism Of Action

TEMIXYS is fixed dose combination of antiviral drugs, 3TC, 300 mg and TDF, 300 mg with antiviral activity against HIV-1 .

Pharmacokinetics

Lamivudine

After oral administration of 2 mg/kg of 3TC twice a day to 9 adults with HIV-1, the peak serum 3TC concentration (Cmax) was 1.5 ± 0.5 mcg/mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg and absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. Binding of 3TC to human plasma proteins is low (< 36%). Within 12 hours after a single oral dose of 3TC in 6 HIV-l-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. The majority of 3TC is eliminated unchanged in urine by active organic cationic secretion and the observed mean elimination half-life (t½) ranged from 5 to 7 hours in most single-dose studies with serum sampling for 24 hours after dosing.

Tenofovir Disoproxil Fumarate

Following oral administration of a single 300 mg dose of TDF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and Cmax and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng•hr/mL, respectively. The oral bioavailability of tenofovir from TDF in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01 to 25 mcg/mL. Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine.

Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 243 ± 33 mL/min (mean ± SD). Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.

Specific Populations

Geriatric Patients

The pharmacokinetics of lamivudine and tenofovir disoproxil fumarate have not been studied in patients over 65 years of age.

Gender

There are no significant or clinically relevant gender differences in the pharmacokinetics of lamivudine and tenofovir.

Race Lamivudine

There are no significant or clinically relevant racial differences in 3TC pharmacokinetics. Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.

Patients With Renal Impairment

.

Lamivudine

The pharmacokinetic of lamivudine are altered in subjects with impaired renal function (Table 4).

Table 4: Pharmacokinetic Parameters (Mean ± SD) after a Single 300-mg Oral Dose of 3TC in Subjects with Varying Degrees of Renal Function

Tenofovir Disoproxil Fumarate

The pharmacokinetics of tenofovir are altered in subjects with renal impairment . In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-∞ of tenofovir were increased (Table 5).

Table 5: Pharmacokinetic Parameters (Mean ± SD) of Tenofovir in Subjects after a Single 300 mg Oral Dose of TDF in Subjects with Varying Degrees of Renal Function

Patients With Hepatic Impairment

Lamivudine: The pharmacokinetics of lamivudine were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.

Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg single dose of TDF have been studied in non-HIV infected subjects with moderate to severe (Child-Pugh B to C) hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects.

Assessment of Drug Interactions:

Lamivudine

Effect of Lamivudine on the Pharmacokinetics of Other Agents: Based on in vitro study results, 3TC at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein 1 (MATE1), MATE2-K, organic cation transporter 1 (OCT1), OCT2, or OCT3.

Effect of Other Agents on the Pharmacokinetics of 3TC: 3TC is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase 3TC plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of 3TC is needed.

3TC is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of 3TC. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of 3TC.

Interferon Alfa: There was no significant pharmacokinetic interaction between 3TC and interferon alfa in a trial of 19 healthy male subjects .

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of 3TC, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and 3TC (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects .

Sorbitol (Excipient): 3TC and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of 3TC oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of 3TC with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(024), 14%, 32%, and 36% in the AUC(∞), and 28%, 52%, and 55% in the Cmax of 3TC, respectively.

Trimethoprim/Sulfamethoxazole: 3TC and TMP/SMX were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of 3TC and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of 3TC 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with 3TC resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ±13% in lamivudine oral clearance, and a decrease of 30% ± 36% in 3TC renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with 3TC. There is no information regarding the effect on 3TC pharmacokinetics of higher doses of TMP/SMX such as those used in treat PCP.

Tenofovir Disoproxil Fumarate: At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP-mediated interactions involving tenofovir with other medicinal products is low.

TDF has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 6 and 7 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of TDF on the pharmacokinetics of coadministered drug.

TDF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When TDF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed.

No clinically significant drug interactions have been observed between TDF and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir.

Table 6: Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir^a in the Presence of the Coadministered Drug

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TDF: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine.

Table 7: Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TDF

Microbiology

Mechanism Of Action

Lamivudine

3TC is a synthetic nucleoside analogue with activity against HIV-1 and HBV. Intracellularly, 3TC is phosphorylated to its active 5’-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.

Tenofovir Disoproxil Fumarate

TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase by competing with the natural substrate deoxyadenosine 5’-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Antiviral Activity

Lamivudine

The antiviral activity of 3TC against HIV-1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC50 values were in the range of 3 to 15,000 nM. (1 μM = 0.23 mcg/mL). The median EC50 values of 3TC were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 3 to 120 nM in PBMCs. 3TC was not antagonistic to all tested anti-HIV agents. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of 3TC by 3.5-fold in MT-4 cells.

Tenofovir Disoproxil Fumarate

The antiviral activity of tenofovir against laboratory and clinical isolates of HIV1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 (50% effective concentration) values for tenofovir were in the range of 0.04 μM to 8.5 μM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5 μM to 2.2 μM) and strain-specific activity against HIV-2 (EC50 values ranged from 1.6 μM to 5.5 μM). Please

Resistance

Lamivudine

3TC-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that resistance was predominantly due to a methionine to valine or isoleucine (M184V/I).

Tenofovir Disoproxil Fumarate

HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2- to 4-fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir. K65R substitutions developed in some subjects failing a TDF regimen.

Cross-Resistance

Lamivudine

Cross-resistance among certain reverse transcriptase inhibitors has been observed. 3TC-resistant HIV-1 isolate were cross-resistant in cell culture to didanosine (ddI). Cross-resistance is also expected with abacavir and emtricitabine as these select M184V substitutions.

Tenofovir Disoproxil Fumarate

Cross resistance among certain reverse transcriptase inhibitors has been recognized. The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected subjects treated with abacavir or didanosine. HIV-1 isolates with the K65R also showed reduced susceptibility to emtricitabine and 3TC. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudineassociated reverse transcriptase substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.

Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.

Animal Toxicology And/Or Pharmacology

Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6 fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2-20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

Clinical Studies

Clinical Efficacy In Adults With HIV-1 Infection

Treatment-Naïve Adult Patients Trial 903

Data through 144 weeks are reported for Trial 903, a double-blind, active-controlled multicenter trial comparing TDF 300 mg + 3TC 300 mg + EFV 600 mg vs stavudine (d4T) 40 mg + 3TC 300 mg + and EFV 600 mg in 600 antiretroviral-naïve subjects. Subjects had a mean age of 36 years (range 18-64); 74% were male, 64% were Caucasian, and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm³ (range 3-956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417-5,130,000). Subjects were stratified by baseline HIV-1 RNA and CD4+ cell count. Forty-three percent of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4+ cell counts <200 cells/mm³. Treatment outcomes through 48 and 144 weeks are presented in Table 9.

Table 9: Outcomes of Randomized Treatment at Week 48 and 144 (Study 903)

Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4+ cell count (< or ≥200 cells/mm³). Through 144 weeks of therapy, 62% and 58% of subjects in the TDF and d4T arms, respectively, achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4+ cell count was 263 cells/mm³ for the TDF arm and 283 cells/mm³ for the d4T arm.

Through 144 weeks, 11 subjects in the TDF group and 9 subjects in the d4T group experienced a new CDC Class C event.

Dosage Forms And Strengths

TEMIXYS contains 300 mg of lamivudine and 300 mg of tenofovir disoproxil fumarate.

The tablets are white, oblong shape, film-coated tablets debossed with “C 0” on one side and plain on the other side.

Storage And Handling

TEMIXYS (lamivudine and tenofovir disoproxil fumarate) tablets 300 mg/300 mg are white, oblong shape, film-coated tablets debossed with “C 0” on one side and plain on the other side.

They are supplied as follows:

Bottles of 30 tablets with a desiccant and closed with a child-resistant closure NDC 32228-004-01

Store below 30°C (86 °F).

Keep bottles tightly closed to protect from moisture.

Dispense and store only in original bottle.

Manufactured by: CELLTRION PHARM, INC., 82, 2sandan-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungcheongbuk-do, 28117, Republic of Korea Distributed by: CELLTRION, INC. 23 Academy-ro, Yeonsu-gu, Incheon, 22014, Republic of Korea. Revised: Nov 2018