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Lamivudine and Tenofovir Disoproxil Fumarate Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. DRUG INTERACTIONS
2. INDICATIONS AND USAGE 8. USE IN SPECIFIC POPULATIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. MECHANISM OF ACTION
5. WARNINGS AND PRECAUTIONS 11. PHARMACOKINETICS
6. ADVERSE REACTIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 


WARNING: POST TREATMENT ACUTE EXACERBATIONS OF HEPATITIS B

Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine or tenofovir disoproxil fumarate, components of CIMDUO. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment [see Warnings and Precautions (5.2)].


 

1. DESCRIPTION

CIMDUO tablets contain lamivudine (also known as 3TC), a synthetic nucleoside analogue with activity against HIV-1 and tenofovir disoproxil fumarate or tenofovir DF, a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester prodrug of tenofovir. In vivo tenofovir DF is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.

The chemical name of lamivudine is (-)-1-[2R,5S)-2-Hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has the following structural formula:

Empirical formula: C8H11N3O3S - Molecular weight: 229.26 g/mol

Lamivudine is a white to off-white solid with a solubility of approximately 70 mg per mL in water at 20°C.

The chemical name of tenofovir DF is 9-[(R)-2[[Bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has the following structural formula:

Empirical formula: C19H30N5O10P • C4H4O4 - Molecular weight: 635.51 g/mol

Tenofovir DF is a white to off-white powder with a solubility of 13.4 mg/mL in distilled water at 25°C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25°C.

CIMDUO tablets are for oral administration. Each film-coated tablet contains 300 mg of lamivudine and 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, and the following inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The tablet coating contains polyethylene glycol, titanium dioxide, polyvinyl alcohol and talc.

TEMIXYS is for oral administration. Each film coated tablet contains 300 mg of Lamivudine USP (also known as 3TC) and 300 mg of tenofovir disoproxil fumarate or tenofovir DF, a fumaric acid salt of bisisopropoxycabonyloxymethyl ester prodrug of tenofovir (equivalent to 245 mg of tenofovir disoproxil), as active ingredients. In addition, each tablet contains the following inactive ingredients: cellactose 80 (lactose monohydrate and powdered cellulose), colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, and a film-coating which contains hypromellose, polyethylene glycol and titanium dioxide.

2. INDICATIONS AND USAGE

CIMDUO (lamivudine and tenofovir disoproxil fumarate) 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 35 kg.

3. DOSAGE AND ADMINISTRATION

3.1 Testing Prior to Initiation and During Treatment with CIMDUO

Prior to initiation of CIMDUO, test patients for hepatitis B virus infection [see Warnings and Precautions (5.2)].

It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating CIMDUO and during therapy in all patients as clinically appropriate [see Warnings and Precautions (5.3)].

3.2 Recommended Dosage for Adult and Pediatric Patients Weighing at Least 35 kg

CIMDUO 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 CIMDUO in HIV-1-infected adult and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with or without food.

3.3 Not Recommended in Renal Impairment

Because CIMDUO is a fixed-dose combination tablet 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 [see Use in Specific Populations (8.6)].

4. CONTRAINDICATIONS

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

5. WARNINGS AND PRECAUTIONS

5.1 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 analogs and other antiretrovirals. Treatment 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).

5.2 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

Posttreatment Exacerbations of Hepatitis: All patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. Discontinuation of anti-HBV therapy, including 3TC and TDF, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue CIMDUO 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.

Important Differences Among Lamivudine-Containing Products: CIMDUO tablets contain a higher dose of the same active ingredient, 3TC, than EPIVIR-HBV® tablets. EPIVIR-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of 3TC in EPIVIR-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of 3TC have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV.

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.

5.3 New Onset or Worsening Renal Impairment

TDF, a component of CIMDUO 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 (6.2)].

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 tenofovir disoproxil fumarate, and periodically during TDF therapy.

Avoid CIMDUO with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) [see Drug Interactions (7.1)]. 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 TDF. 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.

5.4 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 CIMDUO. 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 HIV-1/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 > 6). See the full prescribing information for interferon and ribavirin.

5.5 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 CIMDUO, should be used with caution. Treatment with CIMDUO should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)].

5.6 Bone Effects

Bone Mineral Density (BMD): In clinical trials in HIV-1-infected adults, TDF was associated with slightly 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 (6.1)].

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 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 [see Adverse Reactions (6.2)]. 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 TDF [see Warnings and Precautions (5.3)].

5.7 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 jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barre 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.

5.8 Fat Redistribution

In HIV-infected patients, redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.9 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 nucleoside-only regimen should be carefully monitored and considered for treatment modification.

6. ADVERSE REACTIONS

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

• Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.1)].

• Exacerbations of Hepatitis B [see Boxed Warning, Warnings and Precautions (5.2)].

• New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3)].

• Hepatic Decompensation in Patients Co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions (5.4)].

• Pancreatitis [see Warnings and Precautions (5.5)].

• Decreases in Bone Mineral Density [see Warnings and Precautions (5.6)].

• Immune Reconstitution Syndrome [see Warnings and Precautions (5.7)].

• Fat Redistribution [see Warnings and Precautions (5.8)].

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed in 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-Naïve Patients

Study 903 -Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve subjects received TDF (N = 299) or stavudine (d4T) (N = 301) in combination with 3TC and EFV for 144 weeks 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 moderate to severe adverse reactions are summarized in Table 1.

Table 1. Selected Adverse Reactionsa (Grades 2-4) Reported in ≥ 5% in Any Treatment Group in Study 903 (0-144 Weeks)

a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.

b Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.

c Peripheral neuropathy includes peripheral neuritis and neuropathy.

d Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.

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 TDF (19% and 1%) respectively, laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir disoproxil fumarate and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 2.

Table 2. Grade 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-experienced pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents [see Warnings and Precautions (5.5)].

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 [see Warnings and Precautions (5.6)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use for each of the individual components of CIMDUO (3TC and TDF). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish 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 [see Warnings and Precautions (5.8)].

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 exacerbation of hepatitis B [see Boxed Warning, Warnings and Precautions (5.1, 5.2)].

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.

Renal and Urinary Disorders: renal insufficiency, 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 [see Warnings and Precautions (5.3)].

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.

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.

7. DRUG INTERACTIONS

7.1 Drugs Affecting Renal Function

Since tenofovir is primarily eliminated by the kidneys [see Clinical Pharmacology], coadministration of CIMDUO with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.3)].

7.2 HIV-1 Protease Inhibitors

TDF decreases the AUC and Cmin of atazanavir [see Clinical Pharmacology]. When coadministered with CIMDUO, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. TDF should not be coadministered with atazanavir without ritonavir.

Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations [see Clinical Pharmacology]. Patients receiving CIMDUO concomitantly with lopinavir/ritonavir, atazanavir and ritonavir, or darunavir and ritonavir should be monitored for tenofovir-associated adverse reactions. CIMDUO should be discontinued in patients who develop tenofovir-associated adverse reactions.

7.3 Hepatitis C Antiviral Agents

Coadministration of TDF, a component of CIMDUO, and EPCLUSA® (sofosbuvir/velpatasvir) or HARVONI® (ledipasvir/sofosbuvir) has been shown to increase tenofovir exposure [see Clinical Pharmacology].

In patients receiving TDF concomitantly with sofosbuvir/velpatasvir, monitor for adverse reactions associated with TDF.

In patients receiving CIMDUO concomitantly with ledipasvir/sofosbuvir without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, monitor for adverse reactions associated with tenofovir.

In patients receiving CIMDUO concomitantly with ledipasvir/sofosbuvir and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for adverse reactions associated with tenofovir.

7.4 Drugs Inhibiting Organic Cation Transporters

3TC, a component of CIMDUO, 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) [see Clinical Pharmacology]. No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of 3TC.

7.5 Sorbitol

Coadministration of single doses of 3TC and sorbitol resulted in a sorbitol dose-dependent reduction in 3TC exposures. When possible, avoid use of sorbitol-containing medicines with 3TC [see Clinical Pharmacology].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIMDUO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

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 the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data).

3TC produced embryonic toxicity in rabbits at a dose that 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.

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 4,300 exposed in the first trimester), there was no difference between 3TC 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 3.7%).

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 3TC 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 lamivudine crosses the placenta in humans. Amniotic fluid concentrations of lamivudine 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 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.

8.2 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 CIMDUO), had measurable concentrations of 3TC. There is no 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 postpartum week show that tenofovir is excreted in human milk at low levels. The impact of this exposure in breastfed infants is unknown and the effects 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 CIMDUO.

8.4 Pediatric Use

The safety and effectiveness of CIMDUO as a fixed-dose tablet 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).

8.5 Geriatric Use

Clinical studies of CIMDUO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of CIMDUO in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

CIMDUO 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 Administration (3.3)].

9. OVERDOSAGE

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 300 mg is available.

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

10. MECHANISM OF ACTION

CIMDUO is a fixed-dose combination of antiviral drugs 3TC and TDF with antiviral activity against HIV-1.

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 μM) 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 HIV-1 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 see the full prescribing information for VIREAD® for information regarding the inhibitory activity of TDF against HBV.

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) substitution in reverse transcriptase.

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 tenofovir disoproxil fumarate regimen.

Cross-Resistance:

Lamivudine: Cross-resistance among NRTIs has been observed. 3TC-resistant HIV-1 isolates 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 NRTIs has been observed. 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 substitution also showed reduced susceptibility to FTC and 3TC. HIV-1 isolates from subjects (N = 20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid 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.

11. 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 (t1/2) 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.

Special Populations:

Race:

Lamivudine: There are no significant or clinically relevant racial differences in lamivudine 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.

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

Geriatric Patients: The pharmacokinetics of lamivudine and tenofovir have not been studied in patients over 65 years of age.

Patients with Renal Impairment: [See Use in Specific Populations (8.6).]

Lamivudine: The pharmacokinetics of lamivudine are altered in subjects with renal impairment (Table 3).

Table 3. 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 [see Warnings and Precautions (5.3)]. 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 4. 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: [See Drug Interactions (7).]

Lamivudine:

Effect of 3TC 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 [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.4)].

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(0-24), 14%, 32%, and 36% in the AUC(∞), and 28%, 52%, and 55% in the Cmax of lamivudine.

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 3TC AUC, a decrease of 29% ± 13% in 3TC 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 TDF with other medicinal products is low.

TDF has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 5 and 6 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of TDF on the pharmacokinetics of coadministered drug. Coadministration of TDF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of TDF with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with TDF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (Table 5). The mechanism of this interaction is unknown.

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

Table 5. Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovira in the Presence of the Coadministered Drug

a Subjects received TDF 300 mg once daily.

b Increase = ↑; Decrease = ↓; No Effect = ↔

c Reyataz® (atazanavir) Prescribing Information.

d Prezista® (darunavir) Prescribing Information.

e Data generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provide similar results.

f Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/TDF.

g Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/TDF.

h Study conducted with ATRIPLA® (efavirenz/emtricitabine/tenofovir DF) coadministered with HARVONI.

i Study conducted with COMPLERA® (emtricitabine/rilpivirine/tenofovir DF) coadministered with HARVONI.

j Study conducted with TRUVADA® (emtricitabine/tenofovir DF) + dolutegravir coadministered with HARVONI.

k Study conducted with ATRIPLA coadministered with SOVALDI® (sofosbuvir).

l Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/tenofovir DF.

m Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/tenofovir DF.

n Study conducted with ATRIPLA coadministered with EPCLUSA (sofosbuvir/velpatasvir).

o Study conducted with STRIBILD® (elvitegravir/cobicistat/emtricitabine/tenofovir DF) coadministered with EPCLUSA.

p Study conducted with COMPLERA coadministered with EPCLUSA.

q Administered as raltegravir + emtricitabine/tenofovir DF.

r Aptivus® (tipranavir) Prescribing Information.

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

Table 6. Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TDF

a Increase = ↑; Decrease = ↓; No Effect = ↔; NA = Not Applicable

b Reyataz (atazanavir) Prescribing Information.

c In HIV-infected subjects, addition of TDF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3-and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.

d Prezista (darunavir) Prescribing Information.

e Videx EC® Prescribing Information. Subjects received didanosine enteric-coated capsules.

f 373 kcal, 8.2 g fat

g Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions.

h Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered.

i Aptivus (tipranavir) Prescribing Information.

12. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

CIMDUO (lamivudine and tenofovir disoproxil fumarate) tablets 300 mg/300 mg are white to off-white, film-coated, oval tablets debossed with “M112” on one side and plain on the other side. They are supplied as follows:

NDC 49502-450-93 cartons containing bottles of 30 tablets with desiccant, induction seal and child-resistant cap.

NDC 49502-450-77 cartons containing bottles of 90 tablets with desiccant, induction seal and child-resistant cap.

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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.

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Dispense in original container.

Rx only

Rev 11/18