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. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and tenofovir disoproxil fumarate and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
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
Temixys: Lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg
Pharmacology
Mechanism of Action
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
Dosage and Administration
Dosing: Adult
HIV-infection: Oral: One tablet once daily in combination with other antiretroviral agents
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Note: Use in combination with other antiretroviral agents.
HIV-1 infection, treatment:
Children and Adolescents weighing <35 kg: Not recommended; product is a fixed-dose combination
Children and Adolescents weighing ≥35 kg: Oral: 1 tablet daily
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
Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination
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
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. Voxilaprevir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy
Adverse Reactions
See individual agents.
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. Effects on long-term bone health and future fracture risk, including long-term effects on skeletal growth in pediatric patients and effects of extended duration in younger children, are unknown. In all pediatric clinical trials, skeletal growth (height) was not affected. Consider monitoring of bone density in adults and pediatric patients 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. If abnormalities are suspected, expert assessment is recommended.
- 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 nonsteroidal anti-inflammatory drug [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 estimated CrCl and assess serum creatinine, urine glucose, and urine protein prior to treatment initiation and during therapy in all patients. Assess serum phosphorus in patients with chronic kidney disease. 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 with both clinical and laboratory follow up for at least several months in patients who are coinfected with HIV-1 and HBV; if appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis. 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.
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.
Monitoring Parameters
CD4 count, HIV RNA plasma levels; serum creatinine, serum phosphorous (in patients with chronic kidney disease), urine glucose, urine protein, and estimated creatinine clearance (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 hepatitis B virus (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
Pregnancy Considerations
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. This combination is also preferred for pregnant females who have had antiretroviral therapy (ART) in the past but are restarting, who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen), and who are not yet pregnant but are trying to conceive. Females who become pregnant while taking this combination may continue if viral suppression is effective and the regimen is well tolerated. The guidelines also consider lamivudine plus tenofovir disoproxil fumarate to be a recommended dual NRTI backbone in regimens for HIV/HBV-coinfected pregnant females (HHS [perinatal] 2019).
Refer to individual monographs for additional information.
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 (unable to pass urine, blood in the urine, 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 yellow skin), signs of lactic acidosis (fast breathing, fast heartbeat, 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.
