Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate

Dosage Forms

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

Tablet, oral:

Complera: Emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir disoproxil fumarate 300 mg

Pharmacology

Mechanism of Action

Non-nucleoside, nucleoside, and nucleotide reverse transcriptase inhibitor combination; rilpivirine binds to reverse transcriptase and does not require intracellular phosphorylation for antiviral activity; emtricitabine is a cytosine analogue while tenofovir disoproxil fumarate (TDF) is an analog of adenosine 5'-monophosphate. Each drug interferes with HIV viral RNA dependent DNA polymerase activities resulting in inhibition of viral replication.

Use: Labeled Indications

HIV-1 infection: Treatment of HIV-1 infection (as a complete regimen) in adult and pediatric patients >35 kg as initial therapy in antiretroviral treatment-naive patients with HIV-1 RNA ≤100,000 copies/mL at the start of therapy, and in certain virologically suppressed (HIV-1 RNA <50 copies/mL) patients on a stable antiretroviral regimen for ≥6 months with no treatment failure or substitutions due to resistance to emtricitabine, rilpivirine, or tenofovir disoproxil fumarate in order to replace their current antiretroviral treatment regimen.

Contraindications

Concurrent use of carbamazepine, systemic dexamethasone (>1 dose), oxcarbazepine, phenobarbital, phenytoin, proton pump inhibitors (PPIs) (eg, dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), rifampin, rifapentine, and/or St John's wort.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to emtricitabine, rilpivirine, tenofovir disoproxil fumarate or any component of the formulation.

Dosage and Administration

Dosing: Adult

HIV-1 infection: Oral: One tablet once daily

Missed dose: If ≤12 hours, take dose as soon as possible; if >12 hours, resume at next regularly scheduled time.

Dosage adjustment for concomitant therapy with rifabutin: One tablet once daily plus rilpivirine 25 mg

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

HIV-1 infection, treatment: Note: Products are a fixed-dose combination; use not recommended in other weight groups. Gene mutation and antiretroviral resistance patterns should be evaluated (refer to https://www.iasusa.org/ for more information) when necessary.

Children and Adolescents weighing ≥35 kg: Oral: One tablet (emtricitabine 200 mg, rilpivirine 25 mg, tenofovir disoproxil fumarate 300 mg) once daily

Dosing adjustment for concomitant therapy with rifabutin: Children and Adolescents weighing ≥35 kg: Oral: One tablet (emtricitabine 200 mg, rilpivirine 25 mg, tenofovir disoproxil fumarate 300 mg) once daily plus an additional rilpivirine 25 mg once daily

Administration

Oral: Administer with food. A protein drink is not a substitute for food.

Dietary Considerations

Take with food. Consider calcium and vitamin D supplementation.

Storage

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Dispense in original container.

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

Antacids: May decrease the serum concentration of Rilpivirine. Management: Administer antacids at least 2 hours before or 4 hours after rilpivirine. Administer antacids at least 6 hours before or 4 hours after the rilpivirine/dolutegravir combination product. Consider therapy modification

Antihepaciviral Combination Products: May increase the serum concentration of Rilpivirine. Avoid combination

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

CarBAMazepine: May decrease the serum concentration of Rilpivirine. Avoid combination

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

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Rilpivirine. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Darunavir: May increase the serum concentration of Rilpivirine. 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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

DexAMETHasone (Systemic): May decrease the serum concentration of Rilpivirine. Avoid combination

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

Efavirenz: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Efavirenz. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Efavirenz. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ergonovine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Ergonovine. Specifically, this would be most likely with delavrdine, while other Non-Nucleoside Reverse Transcriptase Inhibitors may be more likely to decrease the concentration of Ergonovine. Avoid combination

Etravirine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Etravirine. This has been observed with the NNRTIs efavirenz and nevirapine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Etravirine. This has been observed with delavirdine. Avoid combination

Fosphenytoin: May decrease the serum concentration of Rilpivirine. 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

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Histamine H2 Receptor Antagonists: May decrease the serum concentration of Rilpivirine. Management: Administer histamine H2 receptor antagonists at least 12 hours before or 4 hours after rilpivirine. Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Rilpivirine. Rilpivirine may decrease the serum concentration of Ketoconazole (Systemic). Monitor therapy

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

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

Levomethadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Levomethadone. Management: Levomethadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Monitor therapy

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

Lopinavir: May increase the serum concentration of Rilpivirine. Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Macrolide Antibiotics: May increase the serum concentration of Rilpivirine. Management: Consider the use of azithromycin or another non-macrolide alternative when appropriate to avoid this potential interaction. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Methadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

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

OXcarbazepine: May decrease the serum concentration of Rilpivirine. Avoid combination

PHENobarbital: May decrease the serum concentration of Rilpivirine. Avoid combination

Phenytoin: May decrease the serum concentration of Rilpivirine. Avoid combination

Primidone: May decrease the serum concentration of Rilpivirine. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of Rilpivirine. Avoid combination

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Reverse Transcriptase Inhibitors (Non-Nucleoside): May increase the serum concentration of Rilpivirine. This mechanism applies to coadministration of delavirdine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Rilpivirine. This mechanism applies to coadministration of efavirenz, etravirine, and nevirapine. Avoid combination

Rifabutin: May decrease the serum concentration of Rilpivirine. Management: Increase the rilpivirine adult dose to 50 mg/day during rifabutin treatment. Decrease back to 25 mg/day following rifabutin discontinuation. Use of rifabutin with the emtricitabine/rilpivirine/tenofovir alafenamide combination product is not recommended. Consider therapy modification

Rifamycin Derivatives: May decrease the serum concentration of Rilpivirine. Exceptions: Rifabutin. Avoid combination

Saquinavir: May enhance the arrhythmogenic effect of Rilpivirine. Saquinavir may increase the serum concentration of Rilpivirine. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

St John's Wort: May decrease the serum concentration of Reverse Transcriptase Inhibitors (Non-Nucleoside). Specifically, St. Johns Wort may increase the metabolism of Reverse Transcriptase Inhibitors (Non-Nucleoside). Avoid combination

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Observed in patients receiving the same doses of emtricitabine, rilpivirine, and tenofovir as the combination product; also see individual agents.

>10%:

Endocrine & metabolic: Increased serum cholesterol (≤14%), increased LDL cholesterol (1% to 13%)

Hepatic: Increased serum alanine aminotransferase (1% to 19%), increased serum aspartate aminotransferase (1% to 16%)

1% to 10%:

Central nervous system: Depression (2% to 9%), headache (2%), insomnia (2%), abnormal dreams (1%), dizziness (1%)

Dermatologic: Skin rash (1%)

Endocrine & metabolic: Adrenocortical insufficiency (7%), increased serum triglycerides (1%)

Gastrointestinal: Nausea (1%)

Hepatic: Increased serum bilirubin (1% to 6%)

Renal: Increased serum creatinine (≤6%)

Frequency not defined:

Central nervous system: Anxiety, drowsiness, fatigue, sleep disorder

Gastrointestinal: Abdominal distress, abdominal pain, cholecystitis, cholelithiasis, decreased appetite, diarrhea, vomiting

Renal: Glomerulonephritis (membranous and mesangioproliferative), nephrolithiasis

<1%, postmarketing, and/or case reports: DRESS syndrome, hypersensitivity reaction, immune reconstitution syndrome, severe dermatological reaction, suicidal ideation, suicidal tendencies, weight gain

Warnings/Precautions

Concerns related to adverse effects:

• Cardiac effects: In healthy subjects, supratherapeutic dosages of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram; use caution when coadministering with drugs with a known risk of torsades de pointes.
• 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. Decreases in bone mineral density have also been observed in clinical trials of HIV-1 infected pediatric patients. Observations in chronic hepatitis B infected pediatric patients (aged 12 to 18 years) were similar. In all pediatric clinical trials, skeletal growth (height) appears unaffected. Consider monitoring of bone density in adult 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. Long-term bone health and fracture risk unknown. If abnormalities are suspected, expert assessment is recommended.
• Depressive disorders: Rilpivirine may cause depression, depressed mood, dysphoria, major depression, mood changes, negative thoughts, suicide attempts, or suicidal ideation. Promptly evaluate patients with severe depressive symptoms and reevaluate risk versus benefit of continued combination therapy.
• Hepatotoxicity: Hepatotoxicity has been reported with rilpivirine-containing regimens. Patients with hepatitis B or C or increased baseline liver function tests may be at greater risk, although some cases have occurred in patients with no preexisting disease or hepatic disease risk factors. Evaluate liver function tests in patients with increased baseline liver function tests or with hepatitis B or C prior to treatment initiation and periodically during therapy; also consider evaluation of patients with no preexisting hepatic disease or hepatic disease risk factors.
• Hypersensitivity: Hypersensitivity and severe skin reactions have been reported, including severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia, or drug reaction with eosinophilia and systemic symptoms (DRESS) with regimens containing rilpivirine. Some skin reactions were accompanied by constitutional symptoms (eg, fever); other skin reactions were associated with organ dysfunction (eg, hepatic serum biochemistry elevations). In clinical trials, treatment-related rashes ≥ grade 2 were reported in 1% of patients. Most rashes were Grade 1 or 2 and occurred within the first 4 to 6 weeks of therapy. Monitor laboratory parameters and clinical status; discontinue if any severe hypersensitivity or skin rash develop.
• 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, sometimes fatal, have been reported with the use of nucleoside analogs, 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: Tenofovir disoproxil fumarate 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: 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. Assess serum creatinine, estimated CrCl, urine protein, and urine glucose prior to initiation of therapy and as clinically appropriate during therapy. Monitor serum phosphorus in patients with chronic kidney disease. IDSA guidelines recommend discontinuing tenofovir (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]: Safety and efficacy during coinfection of HIV-1 and HBV have not been established; acute, severe exacerbations of HBV have been reported following discontinuation of antiretroviral therapy. Not indicated for treatment of chronic hepatitis B. Closely monitor hepatic function with clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue this therapy. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced hepatic disease or cirrhosis (post-treatment exacerbation of hepatitis may lead to hepatic decompensation or liver failure). All patients with HIV should be tested for HBV prior to initiation of treatment.
• Renal impairment: Use is not recommended in patients with CrCl <50 mL/minute.

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.

Other warnings/precautions:

• Appropriate use: Patients with increased HIV-1 viral loads (HIV-1 RNA >100,000 copies/mL) or CD4+ cell counts <200 cells/mm³ at treatment initiation are more likely to develop treatment failure (Cohen 2011; HHS [adult] 2015; Molina 2011). Therefore, rilpivirine-based regimens should not be used in adolescent and adult HIV-1 patients with a pre-ART CD4 count <200 cells/mm³ and/or HIV RNA >100,000 copies/mL (HHS [adult] 2015). Rilpivirine resistance patterns are very similar to those of etravirine (including cross resistance with single substitutions at K101P, Y181I, and Y181V) (Azijn 2010). When used to replace an antiretroviral treatment regimen in virologically-suppressed patients currently on a stable regimen, patients must have no history of virologic failure; prior to regimen replacement, must have been suppressed for at least 6 months; must be currently on their first or second antiretroviral regimen, and have no history of resistance to emtricitabine, rilpivirine, or tenofovir.
• Monitoring: If used as therapy replacement in virologically suppressed patients meeting criteria, additional HIV-1 RNA and regimen tolerability monitoring is recommended to assess potential virologic failure or rebound.

Monitoring Parameters

CBC with differential, reticulocyte count, creatine kinase, CD4 count, HIV RNA plasma levels; serum phosphorus (chronic kidney disease patients), serum creatinine, estimated creatine clearance, 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); fever, skin reactions, and/or hypersensitivity reactions; testing for HBV is recommended prior to the initiation of antiretroviral therapy; weight (children). If used as therapy replacement in virologically suppressed patients meeting criteria, additional HIV-1 RNA and regimen tolerability monitoring is recommended to assess potential virologic failure or rebound.

Patients with HIV and HBV coinfection should be monitored for several months following tenofovir discontinuation.

Pregnancy

Pregnancy Considerations

The Health and Human Services (HHS) perinatal HIV guidelines recommend this fixed-dose combination an alternative regimen for initial use in pregnant females living with HIV who are antiretroviral naive, 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. More frequent monitoring is recommended during pregnancy. This combination should not be used in pregnant females with a pretreatment HIV RNA ≤100,000 copies/mL or CD4 cell count ≥200 cells/mm³ (HHS [perinatal] 2019).

Refer to individual monographs for additional information.

Patient Education

What is this drug used for?

• It is used to treat HIV infection.

Frequently reported side effects of this drug

• Headache
• Nausea
• Vomiting
• Trouble sleeping
• Diarrhea
• Dizziness
• Abdominal pain
• Nightmares
• Stuffy nose
• Common cold symptoms
• Joint pain
• Back pain
• Fatigue
• Loss of strength and energy

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Lactic acidosis like 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.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.
• Burning or numbness feeling
• Bone pain
• Muscle pain
• Muscle weakness
• Painful extremities
• Severe skin problems like red, blistered, or swollen skin; peeling skin; itchy or painful skin.
• Mouth or throat sores
• Difficulty swallowing
• Severe eye irritation
• Infection
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.