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Lamivudine and Tenofovir Disoproxil Fumarate

Medically reviewed on Nov 15, 2018

Pronunciation

See also: Atripla

(la MI vyoo deen & ten OF oh vir dye soe PROX il FUE ma rate)

Index Terms

  • Cimduo
  • Tenofovir Disoproxil Fumarate and Lamivudine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Cimduo: Lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg

Brand Names: U.S.

  • Cimduo

Pharmacologic Category

  • Antiretroviral, Reverse Transcriptase Inhibitor, Nucleoside (Anti-HIV)
  • Antiretroviral, Reverse Transcriptase Inhibitor, Nucleotide (Anti-HIV)

Pharmacology

Lamivudine: Cytosine analog that is phosphorylated intracellularly to its active 5’-triphosphate metabolite. The principal mode of action is inhibition of HIV reverse transcription via viral DNA chain termination; inhibits RNA- and DNA-dependent DNA polymerase activities of reverse transcriptase.

Tenofovir disoproxil fumarate: Nucleotide reverse transcriptase inhibitor; analog of adenosine 5' monophosphate that interferes with the HIV viral RNA dependent DNA polymerase resulting in inhibition of viral replication. TDF is first converted intracellularly by hydrolysis to tenofovir and subsequently phosphorylated to the active tenofovir diphosphate.

Use: Labeled Indications

HIV-1 infection: Treatment of HIV-1 infection in combination with other antiretroviral agents in adult and pediatric patients weighing ≥35 kg.

Contraindications

Hypersensitivity to lamivudine, tenofovir disoproxil fumarate, or any component of the formulation

Dosing: Adult

HIV-infection: Oral: One tablet once daily in combination with other antiretroviral agents

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

HIV-infection: Children and Adolescents ≥35 kg: Oral: Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl <50 mL/minute: Use is not recommended.

End-stage renal disease (ESRD) requiring hemodialysis: Use is not recommended.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Administration

Oral: May administer with or without food.

Dietary Considerations

Consider calcium and vitamin D supplementation

Storage

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).

Drug Interactions

Acyclovir-Valacyclovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir. Monitor therapy

Adefovir: May diminish the therapeutic effect of Tenofovir Products. Adefovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Adefovir. Avoid combination

Aminoglycosides: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Aminoglycosides. Monitor therapy

Atazanavir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Must use boosted atazanavir in adults; give combo (atazanavir/ritonavir or atazanavir/cobicistat with tenofovir) as a single daily dose with food. Pediatric patients, pregnant patients, and users of H2-blockers require other dose changes. Consider therapy modification

Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Monitor therapy

Cidofovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Cidofovir. Monitor therapy

Cobicistat: May enhance the adverse/toxic effect of Tenofovir Products. More specifically, cobicistat may impair proper tenofovir monitoring and dosing. Monitor therapy

Darunavir: Tenofovir Disoproxil Fumarate may increase the serum concentration of Darunavir. Darunavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Diclofenac (Systemic): May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to this combination whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Didanosine: Tenofovir Disoproxil Fumarate may diminish the therapeutic effect of Didanosine. Tenofovir Disoproxil Fumarate may increase the serum concentration of Didanosine. Management: Avoid concomitant treatment with tenofovir disoproxil fumarate and didanosine. Consider altering even existing, stable treatment to avoid this combination. Avoid combination

Emtricitabine: LamiVUDine may enhance the adverse/toxic effect of Emtricitabine. Avoid combination

Ganciclovir-Valganciclovir: Tenofovir Products may increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Tenofovir Products. Monitor therapy

Ledipasvir: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Avoidance of this combination is recommended under some circumstances. Refer to full monograph for details. Consider therapy modification

Lopinavir: May enhance the nephrotoxic effect of Tenofovir Disoproxil Fumarate. Lopinavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

Simeprevir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Sorbitol: May decrease the serum concentration of LamiVUDine. Management: When possible, avoid chronic coadministration of sorbitol-containing solutions with lamivudine, but if this combination cannot be avoided, monitor patients more closely for possible therapeutic failure associated with decreased lamivudine exposure. Consider therapy modification

Telaprevir: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Tipranavir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Trimethoprim: May increase the serum concentration of LamiVUDine. Monitor therapy

Velpatasvir: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Voxilaprevir: Tenofovir Disoproxil Fumarate may increase the serum concentration of Voxilaprevir. Monitor therapy

Adverse Reactions

See individual agents.

ALERT: U.S. Boxed 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 HIV-1 and have discontinued lamivudine or tenofovir disoproxil fumarate. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment.

Warnings/Precautions

Concerns related to adverse effects:

• Decreased bone mineral density: In clinical trials, tenofovir disoproxil fumarate has been associated with decreases in bone mineral density in HIV-1 infected adults and increases in bone metabolism markers. Serum parathyroid hormone and 1,25 vitamin D levels were also higher. Consider monitoring of bone density in adults with a history of pathologic fractures or with other risk factors for bone loss or osteoporosis. Consider calcium and vitamin D supplementation for all patients; effect of supplementation has not been studied, but may be beneficial. Long-term bone health and fracture risk are unknown. If abnormalities are suspected, expert assessment is recommended.

• Fat redistribution: May cause redistribution/accumulation of body fat (eg, central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, cushingoid appearance).

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Lactic acidosis/hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with use of nucleoside analogues, alone or in combination with other antiretrovirals. Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (marked transaminase elevation may/may not accompany hepatomegaly and steatosis).

• Osteomalacia and renal dysfunction: May cause osteomalacia with proximal renal tubulopathy. Bone pain, extremity pain, fractures, arthralgias, weakness, and muscle pain have been reported. In patients at risk for renal dysfunction, persistent or worsening bone or muscle symptoms should be evaluated for hypophosphatemia and osteomalacia.

• Renal toxicity: Tenofovir disoproxil fumarate may cause renal toxicity (acute renal failure and/or Fanconi syndrome); avoid use with concurrent or recent nephrotoxic therapy (including high dose or multiple NSAID use). Acute renal failure has occurred in HIV-infected patients with risk factors for renal impairment who were on a stable tenofovir disoproxil fumarate regimen to which a high dose or multiple NSAID therapy was added. Consider alternatives to NSAIDS in patients taking tenofovir disoproxil fumarate and at risk for renal impairment. Calculate CrCl prior to initiation of therapy and as clinically appropriate during therapy. In patients at risk for renal dysfunction, assess serum phosphorus, urine glucose, and urine protein prior to and periodically during treatment. IDSA guidelines recommend discontinuing tenofovir disoproxil fumarate (and substituting with alternative antiretroviral therapy) in HIV-infected patients who develop a decline in GFR (a >25% decrease in GFR from baseline and to a level of <60 mL/minute/1.73 m2) during use, particularly in presence of proximal tubular dysfunction (eg, euglycemic glycosuria, increased urinary phosphorus excretion and hypophosphatemia, proteinuria [new onset or worsening]) (IDSA [Lucas 2014]).

Disease-related concerns:

• Chronic hepatitis B: [US Boxed Warning]: Severe acute exacerbations of hepatitis B have been reported in patients coinfected with hepatitis B virus (HBV) and HIV-1, following discontinuation of antiretroviral therapy. Closely monitor hepatic function in these patients; if appropriate, antihepatitis B therapy may be warranted. All patients with HIV should be tested for HBV prior to initiation of treatment.

• Renal impairment: Do not use in patients with CrCl <50 mL/minute or requiring hemodialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Interferon alfa: Use with caution in combination with interferon alfa with or without ribavirin in HIV/HCV coinfected patients; monitor closely for hepatic decompensation, anemia, or neutropenia; dose reduction or discontinuation of interferon and/or ribavirin may be required if toxicity evident.

Special populations:

• Pediatric: Use with caution in pediatric patients with a history of prior antiretroviral nucleoside exposure or pancreatitis, or other significant risk factors for development of pancreatitis.

Other warnings/precautions:

• Appropriate use: Not recommended as a component of a triple nucleoside regimen due to potential for early virological failure. Clinical trials in HIV-infected patients whose regimens contained only three nucleoside reverse transcriptase inhibitors (NRTI) show less efficacy, early virologic failure and high rates of resistance substitutions. Triple drug regimens with two NRTIs in combination with a non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, or a HIV-1 protease inhibitor are usually more effective.

Monitoring Parameters

CD4 count, HIV RNA plasma levels; serum creatinine, serum phosphorous, urine glucose, urine protein (prior to initiation and as clinically indicated during therapy); hepatic function tests, bone density (patients with a history of bone fracture or have risk factors for bone loss); testing for HBV is recommended prior to the initiation of antiretroviral therapy. Patients with HIV and HBV coinfection should be monitored for several months following therapy discontinuation.

Pregnancy Considerations

Lamivudine and tenofovir disoproxil fumarate have a high level of transfer across the human placenta.

The Health and Human Services (HHS) Perinatal HIV Guidelines consider lamivudine in combination with tenofovir disoproxil fumarate to be one of the preferred NRTI backbone for initial therapy in antiretroviral-naive pregnant females. The guidelines also consider lamivudine plus tenofovir disoproxil fumarate to be a recommended dual NRTI backbone in regimens for HIV/HBV-coinfected pregnant females.

In general, females who become pregnant on a stable antiretroviral therapy (ART) regimen may continue that regimen if viral suppression is effective, appropriate drug exposure can be achieved, contraindications for use in pregnancy are not present, and the regimen is well tolerated (HHS [perinatal] 2017).

Refer to individual monographs.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, headache, or diarrhea. Have patient report immediately to prescriber signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), bone pain, muscle pain, muscle weakness, painful extremities, change in body fat, depression, or signs of infection (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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