LAMIVUDINE Drug Interactions: What You Need to Know

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> .

7.2 HIV-1 Protease Inhibitors TDF decreases the AUC and C min of atazanavir <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

Lamivudine and Zidovudine Tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the product. Lamivudine and Zidovudine Tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis, Stevens-Johnson syndrome). (4)

AND PRECAUTIONS Co-infected HIV-1/HBV Patients: Emergence of lamivudineresistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. (5.2) Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving interferon and ribavirin-based regimens. Monitor for treatment-associated toxicities. Discontinue LAMIVUDINE as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.3) Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.4) Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy. (5.5, 5.7) Lower virologic suppression rates and increased risk of viral resistance were observed in pediatric subjects who received LAMIVUDINE oral solution concomitantly with other antiretroviral oral solutions compared with those who received tablets. (5.6)

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 analogues and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering LAMIVUDINE to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors. Treatment with LAMIVUDINE 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 Patients with and Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Important

Differences among Lamivudine-containing Products LAMIVUDINE tablets contain a higher dose of the same active ingredient (lamivudine) than LAMIVUDINE-HBV tablets. LAMIVUDINE-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in LAMIVUDINE-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. If treatment with LAMIVUDINE-HBV 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. If a decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, LAMIVUDINE tablets, or another product containing the higher dose of lamivudine should be used as part of an appropriate combination regimen. Emergence of Lamivudine-resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV (see full prescribing information for LAMIVUDINE-HBV). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

5.3 Use with Interferon- and Ribavirin-based Regimens In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. 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 lamivudine in HIV-1/HCV co-infected patients <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , 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. Patients receiving interferon alfa with or without ribavirin and LAMIVUDINE should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of LAMIVUDINE should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). See the full prescribing information for interferon and ribavirin.

5.4 Pancreatitis In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, LAMIVUDINE should be used with caution. Treatment with LAMIVUDINE should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

5.5 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including LAMIVUDINE. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond 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’ 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.

5.6 Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution Pediatric subjects who received LAMIVUDINE oral solution concomitantly with other antiretroviral oral solutions at any time in the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving LAMIVUDINE tablets <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) , Microbiology (12.4) , Clinical Studies (14.2) ]</span>. LAMIVUDINE scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Consider more frequent monitoring of HIV-1 viral load when treating with LAMIVUDINE oral solution.

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

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 analogues and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering LAMIVUDINE to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors. Treatment with LAMIVUDINE 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 Patients with and Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Important

Differences among Lamivudine-containing Products LAMIVUDINE tablets contain a higher dose of the same active ingredient (lamivudine) than LAMIVUDINE-HBV tablets. LAMIVUDINE-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in LAMIVUDINE-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. If treatment with LAMIVUDINE-HBV 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. If a decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, LAMIVUDINE tablets, or another product containing the higher dose of lamivudine should be used as part of an appropriate combination regimen. Emergence of Lamivudine-resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV (see full prescribing information for LAMIVUDINE-HBV). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

5.3 Use with Interferon- and Ribavirin-based Regimens In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. 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 lamivudine in HIV-1/HCV co-infected patients <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , 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. Patients receiving interferon alfa with or without ribavirin and LAMIVUDINE should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of LAMIVUDINE should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). See the full prescribing information for interferon and ribavirin.

5.4 Pancreatitis In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, LAMIVUDINE should be used with caution. Treatment with LAMIVUDINE should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

5.5 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including LAMIVUDINE. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond 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’ 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.

5.6 Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution Pediatric subjects who received LAMIVUDINE oral solution concomitantly with other antiretroviral oral solutions at any time in the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving LAMIVUDINE tablets <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) , Microbiology (12.4) , Clinical Studies (14.2) ]</span>. LAMIVUDINE scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Consider more frequent monitoring of HIV-1 viral load when treating with LAMIVUDINE oral solution.

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