Cimduo
Lamivudine and Tenofovir Disoproxil Fumarate · Tablet, Film Coated · Oral
• Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and human immunodeficiency virus (HIV-1) and have discontinued lamivudine and tenofovir disoproxil fumarate. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment.…
Uses
1 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. CIMDUO is a two-drug combination of lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), both nucleo(t)side reverse transcriptase inhibitors and 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. ( 1 )
Dosage and administration
• Testing: Prior to initiation and during treatment with CIMDUO, patients should be tested for hepatitis B virus infection, and estimated creatinine clearance, urine glucose, and urine protein should be obtained. ( 2.1 )
• Recommended dose: One tablet taken orally once daily with or without food. ( 2.2 )
• Renal Impairment: Not recommended in patients with CrCL less than 50 mL/min or patients with end-stage renal disease requiring hemodialysis. ( 2.3 ) 2.1 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) ]. 2.2 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. 2.3 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) ] .
Dosage forms and strengths
Tablets: 300 mg of lamivudine and 300 mg of tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil). The tablets are white to off-white, film-coated, oval tablets debossed with “ M112 ” on one side and plain on the other side. Tablets: 300 mg lamivudine and 300 mg tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil). ( 3 )
Contraindications
4 CONTRAINDICATIONS CIMDUO is contraindicated in patients with a previous hypersensitivity reaction to any of the components contained in the formulation.
• CIMDUO is contraindicated in patients with previous hypersensitivity to any of the components of this product. ( 4 )
Warnings and precautions
• Lactic Acidosis/Severe Hepatomegaly with Steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.1 )
• New Onset or Worsening Renal Impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with tenofovir disoproxil fumarate, a component of CIMDUO. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose and urine protein before initiating treatment with tenofovir and periodically during treatment. Avoid administering CIMDUO with concurrent or recent use of nephrotoxic drugs. ( 5.3 )
• Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon- and ribavirin-based regimens. Monitor for treatment-associated toxicities. Discontinue CIMDUO, as medically appropriate, and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. ( 5.4 )
• Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue CIMDUO as clinically appropriate. ( 5.5 )
• Decreases in Bone Mineral Density (BMD): Observed in HIV-infected patients. Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. ( 5.6 )
• Immune Reconstitution Syndrome: Observed in HIV-infected patients. May necessitate further evaluation and treatment. ( 5.7 )
• Redistribution/Accumulation of Body Fat: Observed in HIV-infected patients receiving antiretroviral combination therapy. ( 5.8 )
• Triple Nucleoside-Only Regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification. ( 5.9 ) 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 (12.3) ] , 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.
Side effects
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) ] .
• Most common adverse reactions (> 10% with CIMDUO) are headache, pain, depression, diarrhea, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2-4) Reported in ≥ 5% in Any Treatment Group in Study 903 (0-144 Weeks) TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Body as a Whole Headache 14% 17% Pain 13% 12% Fever 8% 7% Abdominal pain 7% 12% Back pain 9% 8% Asthenia 6% 7% Digestive System Diarrhea 11% 13% Nausea 8% 9% Dyspepsia 4% 5% Vomiting 5% 9% Metabolic Disorders Lipodystrophy Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. 1% 8% Musculoskeletal Arthralgia 5% 7% Myalgia 3% 5% Nervous System Depression 11% 10% Insomnia 5% 8% Dizziness 3% 6% Peripheral neuropathy Peripheral neuropathy includes peripheral neuritis and neuropathy. 1% 5% Anxiety 6% 6% Respiratory Pneumonia 5% 5% Skin and Appendages Rash event Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. 18% 12% 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) TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Any ≥ Grade 3 Laboratory Abnormality 36% 42% Fasting Cholesterol (> 240 mg/dL) 19% 40% Creatine Kinase (M: > 990 U/L; F: > 845 U/L) 12% 12% Serum Amylase (> 175 U/L) 9% 8% AST (M: > 180 U/L; F: > 170 U/L) 5% 7% ALT (M: > 215 U/L; F: > 170 U/L) 4% 5% Hematuria (> 100 RBC/HPF) 7% 7% Neutrophils (< 750/mm 3 ) 3% 1% Fasting Triglycerides (> 750 mg/dL) 1% 9% 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.
Drug interactions
• Atazanavir: Atazanavir should be coadministered with ritonavir when coadministered with CIMDUO. ( 7.2 )
• HIV-1 Protease Inhibitors: Monitor for evidence of tenofovir toxicity when CIMDUO is coadministrated with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. ( 7.2 )
• Sorbitol: Avoid chronic administration of sorbitol with CIMDUO.( 7.5 ) 7.1 Drugs Affecting Renal Function Since tenofovir is primarily eliminated by the kidneys [see Clinical Pharmacology (12.3) ] , 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 C min of atazanavir [see Clinical Pharmacology (12.3) ] . 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 (12.3) ] . 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 (12.3) ] . 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 (12.3) ] . 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 (12.3) ] .
Use in specific populations
• Lactation: Breastfeeding not recommended due to potential for HIV transmission. ( 8.2 ) 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 (2.3) ] .
Pregnancy
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.
Pediatric use
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).
Geriatric use
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.
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.
Description
11 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-[2 R ,5 S ) - 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 a molecular formula of C 8 H 11 N 3 O 3 S and a molecular weight of 229.26 g per mol. It has the following structural formula: 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 a molecular formula of C 19 H 30 N 5 O 10 P
• C 4 H 4 O 4 and a molecular weight of 635.51. It has the following structural formula: 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. Lamivudine Structural Formula Tenofovir Structural Formula
Mechanism of action
12.1 Mechanism of Action CIMDUO is a fixed-dose combination of antiviral drugs 3TC and TDF with antiviral activity against HIV-1 [see Microbiology (12.4) ]. 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.
How supplied
(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 Store at 20°C to 25°C (68°F 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.
Patient 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. Treatment with CIMDUO should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [see Warnings and Precautions (5.1) ] . Post Treatment Acute Exacerbation of Hepatitis B in Patients with HBV Co-Infection: Severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or coinfected with HBV and HIV-1 and have discontinued 3TC and TDF, components of CIMDUO. Test patients with HIV-1 for hepatitis B virus (HBV) before initiating antiretroviral therapy. In patients with chronic hepatitis B, it is important to obtain HIV antibody testing prior to initiating 3TC and TDF, components of CIMDUO [see Warnings and Precautions (5.2) ] . 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 CIMDUO with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) for patients [see Dosage and Administration (2.3) , Warnings and Precautions (5.3) ] . Risk of Hepatic Decompensation in Patients with HIV-1/HCV Co-Infection: Inform patients with HIV-1/HCV co-infection that 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 [see Warnings and Precautions (5.4) ]. Pancreatitis: Advise patients or guardians to monitor pediatric patients for signs and symptoms of pancreatitis [see Warnings and Precautions (5.5) ] . Decreases in Bone Mineral Density: Advise patients that decreases in bone mineral density have been observed with the use of 3TC and TDF, components of CIMDUO, in patients with HIV [see Warnings and Precautions (5.6) ] . Immune Reconstitution Syndrome: Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.7) ]. Fat Redistribution: Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including CIMDUO, and that the cause and long‑term health effects of these conditions are not known at this time [see Warnings and Precautions (5.8) ] . Administration Instructions: Inform patients that it is important to take CIMDUO once daily on a regular dosing schedule and to avoid missing doses as it can result in development of resistance. Advise patients if a dose is missed, take it as soon as possible unless it is almost time for the next dose [see Dosage and Administration (2.2) ] . Pregnancy Registry: Advise patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in women exposed to CIMDUO [see Use in Specific Populations (8.1) ] . Lactation: Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2) ] . Rx only Manufactured for: Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Laboratories Limited Hyderabad — 500 096, India © 2021 Viatris Inc. CIMDUO is a registered trademark of Mylan Pharmaceuticals Inc., a Viatris Company. Other brands listed are the registered trademarks of their respective owners and are not trademarks of Mylan Laboratories Limited or Mylan Pharmaceuticals Inc.
Label text from the FDA structured product label by Viatris Specialty LLC (revised Feb 15, 2021). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Lamivudine in 1 product
- Tenofovir Disoproxil Fumarate in 1 product
Cimduo NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 49502-450 | Lamivudine 300 mg/1; Tenofovir Disoproxil Fumarate 300 mg/1 Tablet, Film Coated | Viatris Specialty LLC | NDA |
Frequently asked questions
What is Cimduo used for?
1 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. CIMDUO is a two-drug combination of lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), both nucleo(t)side reverse…
What are the side effects of Cimduo?
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… See the full label for the complete list.
Who makes Cimduo?
Cimduo is listed by 1 labeler in the FDA NDC directory, including Viatris Specialty LLC.