EMTRICITABINE Drug Interactions: What You Need to Know

INTERACTIONS

• Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. ( 7.1 )
• Consult the Full Prescribing Information prior to and during treatment for important drug interactions. ( 4 , 5.7 , 7 )

7.1 Not Recommended with Other Antiretroviral Medications Because emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Comprehensive information regarding potential drug-drug interactions with other antiretroviral medications is not provided. This section describes clinically relevant drug interactions with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Drug interaction studies were conducted with the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (FTC, RPV, and TDF as single agents) or with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets as a combination product <span class="opacity-50 text-xs">[see Dosage and Administration (2) , Contraindications (4) , and Clinical Pharmacology (12.3) ]</span> .

7.2 Drugs Inducing or Inhibiting CYP3A Enzymes Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV <span class="opacity-50 text-xs">[see Contraindications (4) , Warnings and Precautions (5.7) , and Clinical Pharmacology (12.3) ]</span> . Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV.

7.3 Drugs Increasing Gastric pH Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Use of RPV with proton pump inhibitors is contraindicated and use of RPV with H2-receptor antagonists requires staggered administration <span class="opacity-50 text-xs">[see Contraindications (4) and Clinical Pharmacology (12.3) ]</span> .

7.4 Drugs Affecting Renal Function Because FTC and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion, coadministration of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of FTC, tenofovir, and/or other renally eliminated drugs. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> .

7.5 QT Prolonging Drugs There is limited information available on the potential for a pharmacodynamic interaction between RPV and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, 75 mg once daily and 300 mg once daily doses of RPV (3 times and 12 times the dose in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets) have been shown to prolong the QTc interval of the electrocardiogram <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) and Clinical Pharmacology (12.2) ]</span> . Consider alternatives to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets when coadministered with a drug with a known risk of Torsade de Pointes.

7.6 Significant Drug Interactions Important drug interaction information for emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets is summarized in Table 4. The drug interactions described are based on studies conducted with FTC, RPV, or TDF as individual medications or with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets as a combination product, or are potential drug interactions <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) , Tables 9–14]</span> . For list of contraindicated drugs, <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

Table

4 Significant This table is not all inclusive.

Drug Interactions Concomitant Drug

Class: Drug Name Effect on Concentration Increase = ↑; Decrease = ↓; No Effect = ↔ Clinical Comment Antacids: antacids (e.g., aluminum, magnesium hydroxide, or calcium carbonate) ↔ RPV (antacids taken at least 2 hours before or at least 4 hours after RPV) ↓ RPV (concomitant intake) Administer antacids at least 2 hours before or at least 4 hours after emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. Antimycobacterials: rifampin rifapentine ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. rifabutin ↓ RPV The interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. If emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with rifabutin, an additional 25 mg tablet of RPV (Edurant) once per day is recommended to be taken concomitantly with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and with a meal for the duration of rifabutin coadministration.

Azole Antifungal

Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole ↑ RPV , This interaction study has been performed with a dose higher than the recommended dose for RPV assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended dose of RPV 25 mg once daily. ↓ ketoconazole , No dose adjustment is required when emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment) ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir sofosbuvir/velpatasvir/ voxilaprevir ↑ tenofovir Patients receiving emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets concomitantly with HARVONI ® (ledipasvir/sofosbuvir), EPCLUSA ® (sofosbuvir/velpatasvir), or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with TDF. H 2 -Receptor Antagonists: cimetidine famotidine nizatidine ranitidine ↔ RPV , (famotidine taken 12 hours before RPV or 4 hours after RPV) ↓ RPV , (famotidine taken 2 hours before RPV) Administer H 2 -receptor antagonists at least 12 hours before or at least 4 hours after emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.

Herbal

Products: St John’s wort ( Hypericum perforatum ) ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin ↑ RPV ↔ clarithromycin ↔ erythromycin ↔ telithromycin Where possible, alternatives such as azithromycin should be considered.

Narcotic

Analgesics: methadone ↓ R(−) methadone ↓ S(+) methadone ↔ RPV ↔ methadone (when used with tenofovir) No dose adjustments are required when initiating coadministration of methadone with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

Proton Pump

Inhibitors: e.g., dexlansoprazole esomeprazole lansoprazole omeprazole pantoprazole rabeprazole ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.

7.7 Drugs with No Observed Interactions with Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets No clinically significant drug interactions have been observed between FTC and the following medications: famciclovir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF. No clinically significant drug interactions have been observed between TDF and the following medications: entecavir, methadone, oral contraceptives, ribavirin, sofosbuvir, or tacrolimus in studies conducted in healthy subjects. No clinically significant drug interactions have been observed between RPV and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinyl estradiol, ledipasvir/sofosbuvir, norethindrone, sildenafil, simeprevir, sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF. RPV did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are contraindicated when coadministered with the following drugs; coadministration may result in loss of virologic response and possible resistance to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets or to the class of NNRTIs [see Warnings and Precautions (5.7) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ] :

• Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• Antimycobacterials: rifampin, rifapentine
• Glucocorticoid (systemic): dexamethasone (more than a single-dose)
• Herbal Products: St John’s wort ( Hypericum perforatum )
• Proton Pump Inhibitors: e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are contraindicated when coadministered with drugs which may result in loss of virologic response and possible resistance to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. ( 4 )

AND PRECAUTIONS New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with TRUVADA. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose and urine protein before initiating treatment with TRUVADA and periodically during treatment. Avoid administering Truvada with concurrent or recent use of nephrotoxic drugs. ( 5.3 ) Coadministration with Other Products: Do not use with drugs containing emtricitabine, tenofovir alafenamide or tenofovir disoproxil fumarate including ATRIPLA, COMPLERA, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, VIREAD; or with drugs containing lamivudine. Do not administer in combination with HEPSERA. ( 5.4 ) Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. ( 5.5 ) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. ( 5.6 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.7 ) Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification. ( 5.8 ) Comprehensive management to reduce the risk of acquiring HIV-1: Use as part of a comprehensive prevention strategy including other prevention measures; strictly adhere to dosing schedule. ( 5.9 ) Management to reduce the risk of acquiring HIV-1 drug resistance: Prior to initiating TRUVADA for PrEP - if clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm negative HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection. While using TRUVADA for PrEP - HIV-1 screening tests should be repeated at least every 3 months. ( 5.9 )

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, a component of TRUVADA, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient or uninfected individual with known risk factors for liver disease; however, cases have also been reported in HIV-1 infected patients with no known risk factors. Treatment with TRUVADA should be suspended in any patient or uninfected individual 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 HBV Infection It is recommended that all individuals be tested for the presence of chronic hepatitis B virus (HBV) before initiating TRUVADA. TRUVADA is not approved for the treatment of chronic HBV infection and the safety and efficacy of TRUVADA have not been established in patients infected with HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are infected with HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted. HBV-uninfected individuals should be offered vaccination.

5.3 New Onset or Worsening Renal Impairment Emtricitabine and tenofovir are 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 VIREAD <span class="opacity-50 text-xs">[see Adverse Reactions (6.3) ]</span> . It is recommended that estimated creatinine clearance be assessed in all individuals prior to initiating therapy and as clinically appropriate during therapy with TRUVADA. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA ® , it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of TRUVADA, and periodically during TRUVADA therapy. TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) <span class="opacity-50 text-xs">[see Drug Interactions (7.4) ]</span> . 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 tenofovir disoproxil fumarate (tenofovir DF). 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. Treatment of HIV-1 Infection Dosing interval adjustment of TRUVADA and close monitoring of renal function are recommended in all patients with estimated creatinine clearance 30–49 mL/min <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . No safety or efficacy data are available in patients with renal impairment who received TRUVADA using these dosing guidelines, so the potential benefit of TRUVADA therapy should be assessed against the potential risk of renal toxicity. TRUVADA should not be administered to patients with estimated creatinine clearance below 30 mL/min or patients requiring hemodialysis. Pre-exposure Prophylaxis TRUVADA for a PrEP indication should not be used if estimated creatinine clearance is less than 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> .

5.4 Coadministration with Other Products TRUVADA is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. Do not coadminister TRUVADA with other drugs containing emtricitabine or tenofovir disoproxil fumarate, or containing tenofovir alafenamide, including ATRIPLA, COMPLERA, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, or VIREAD. Due to similarities between emtricitabine and lamivudine, do not coadminister TRUVADA with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Dutrebis (lamivudine/raltegravir) , Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), Triumeq (abacavir sulfate/dolutegravir/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine). Do not coadminister TRUVADA with HEPSERA (adefovir dipivoxil) Do not coadminister TRUVADA with HEPSERA (adefovir dipivoxil) .

5.5 Bone Effects of Tenofovir DF Bone Mineral Density: In clinical trials in HIV-1 infected adults and in a clinical trial of HIV-1 uninfected individuals, tenofovir DF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) and VIREAD prescribing information ]</span> . Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF. Clinical trials evaluating tenofovir DF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir DF treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. For more information, consult the VIREAD prescribing information. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. If bone abnormalities are suspected then appropriate consultation should be obtained.

Mineralization

Defects: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF [see Adverse Reactions (6.3) ] . Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF [see Warnings and Precautions (5.3) ].

5.6 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and &quot;cushingoid appearance&quot; have been observed in HIV-1 infected patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.7 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including TRUVADA. During the initial phase of combination antiretroviral treatment, HIV-1 infected patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves&apos; disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.8 Early Virologic Failure Clinical trials in HIV-1 infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virologic failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

5.9 Comprehensive Management to Reduce the Risk of Acquiring HIV-1 Use TRUVADA for pre-exposure prophylaxis only as part of a comprehensive prevention strategy that includes other prevention measures, such as safer sex practices, because TRUVADA is not always effective in preventing the acquisition of HIV-1 <span class="opacity-50 text-xs">[see Clinical Studies (14.2 and 14.3) ]</span> . Counsel uninfected individuals about safer sex practices that include consistent and correct use of condoms, knowledge of their HIV-1 status and that of their partner(s), and regular testing for other sexually transmitted infections that can facilitate HIV-1 transmission (such as syphilis and gonorrhea). Inform uninfected individuals about and support their efforts in reducing sexual risk behavior. Use TRUVADA to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-negative. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only TRUVADA, because TRUVADA alone does not constitute a complete treatment regimen for HIV-1 treatment <span class="opacity-50 text-xs">[see Microbiology (12.4) ]</span> ; therefore, care should be taken to minimize drug exposure in HIV-infected individuals. Many HIV-1 tests, such as rapid tests, detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating TRUVADA for a PrEP indication, evaluate seronegative individuals for current or recent signs or symptoms consistent with acute viral infections (e.g., fever, fatigue, myalgia, skin rash, etc.) and ask about potential exposure events (e.g., unprotected, or condom broke during sex with an HIV-1 infected partner) that may have occurred within the last month. If clinical symptoms consistent with acute viral infection are present and recent (&lt;1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection. While using TRUVADA for a PrEP indication, HIV-1 screening tests should be repeated at least every 3 months. If symptoms consistent with acute HIV-1 infection develop following a potential exposure event, PrEP should be discontinued until negative infection status is confirmed using a test approved by the FDA as an aid in the diagnosis of HIV-1, including acute or primary HIV-1 infection. Counsel uninfected individuals to strictly adhere to the recommended TRUVADA dosing schedule. The effectiveness of TRUVADA in reducing the risk of acquiring HIV-1 is strongly correlated with adherence as demonstrated by measurable drug levels in clinical trials <span class="opacity-50 text-xs">[see Clinical Studies (14.2 and 14.3) ]</span> .