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    Nucleoside and Nucleotide Reverse Transcriptase Inhibitor (NRTI) Combinations

    BOXED WARNING

    Anemia, bone marrow suppression, folate deficiency, neutropenia, radiation therapy, vitamin B12 deficiency

    Lamivudine, 3TC; zidovudine, ZDV should be used with extreme caution in patients with bone marrow suppression, especially neutropenia or anemia (e.g., neutrophil count < 1000 cells/mm3 or hemoglobin < 9.5 g/dL). Other patients that may be at increased risk for bone marrow toxicity include those with folate deficiency or vitamin B12 deficiency. Patients receiving cytotoxic drugs or radiation therapy are at risk for additive myelosuppressive effects. The HIV guidelines recommend monitoring complete blood counts (CBC) with differential at entry to care and before initiating or modifying treatment. For patients started on an antiretroviral regimen containing lamivudine; zidovudine, a follow-up CBC with differential should be obtained after 2—8 weeks of treatment, followed by periodic monitoring every 3—6 months or as clinically indicated.

    Alcoholism, females, hepatic disease, hepatotoxicity or lactic acidosis, obesity

    Because the dosage of zidovudine may require adjustment in patients with hepatic impairment, the use of lamivudine; zidovudine, a fixed dose product, is not recommended in patients with known hepatic disease. Additionally, lamivudine; zidovudine should be used with caution in patients with known risk factors for hepatic disease (e.g., alcoholism). Hepatotoxicity or lactic acidosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues, including zidovudine and lamivudine. A majority of these cases occurred in females; it is unknown if pregnant women are at increased risk. Clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly. Treatment with lamivudine; zidovudine should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked increases of hepatic enzymes. Obesity and prolonged exposure to nucleosides may be risk factors for hepatotoxicity. However, cases of lactic acidosis or liver problems have been reported in patients with no risk factors.

    Hepatitis B and HIV coinfection, hepatitis B exacerbation

    Perform hepatitis B virus (HBV) screening in any patient who presents with HIV infection to assure appropriate treatment. Patients who are coinfected with HIV and HBV should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Lamivudine-resistant HBV strains have been reported in coinfected patients receiving lamivudine as part of their anti-HIV treatment regimen. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. Patients with hepatitis B and HIV coinfection have been reported to experience clinical or laboratory evidence of hepatitis B exacerbation upon discontinuation of lamivudine. Typically, this was associated with a return of HBV DNA and ALT concentrations towards pre-treatment values, and with mild ALT flares (2-times the patient's baseline ALT) in about 20% of patients. A smaller percentage (2 to 4%) of hepatitis B patients discontinuing lamivudine have had clinically notable post-treatment recurrences of hepatitis (i.e., peak ALT 500 International Units/mL and elevation of serum bilirubin). Most events appear to be self-limiting, although fatalities have been reported. There is insufficient evidence to determine whether the re-initiation of lamivudine alters the course of post-treatment exacerbations of hepatitis. For patients who refuse a fully suppressive ARV regimen, but still require treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate. [32049] [46638] [34362]

    Myopathy

    Monitor patients for signs of myopathy and myositis as they have been reported, along with pathological changes similar to that produced by HIV, with prolonged use of zidovudine.

    DEA CLASS

    Rx

    DESCRIPTION

    Combination of 2 nucleoside reverse transcriptase inhibitors (NRTIs)
    Used for HIV infection in combination with other antiretroviral agents
    Black Box Warnings for hematologic toxicity, myopathy, lactic acidosis, severe hepatomegaly with steatosis, and exacerbations of hepatitis B upon treatment discontinuation

    COMMON BRAND NAMES

    Combivir

    HOW SUPPLIED

    Combivir/Lamivudine, Zidovudine Oral Tab: 150-300mg

    DOSAGE & INDICATIONS

    For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents.
    Oral dosage
    Adults weighing 30 kg or more

    1 tablet (lamivudine 150 mg; zidovudine 300 mg) PO twice daily. Assess patient for the ability to swallow tablets; if a patient is not able to reliably swallow tablets, use the liquid formulation of the individual components.

    Children and Adolescents weighing 30 kg or more

    1 tablet (lamivudine 150 mg; zidovudine 300 mg) PO twice daily. Assess children for the ability to swallow tablets; if a child is not able to reliably swallow tablets, use the liquid formulation of the individual components.

    For human immunodeficiency virus (HIV) prophylaxis†.
    For human immunodeficiency virus (HIV) prophylaxis† after occupational exposure.
    Oral dosage
    Adults

    As an acceptable alternative to preferred regimens, guidelines recommend 1 tablet (lamivudine 150 mg; zidovudine 300 mg) PO twice daily in combination with one of the following ritonavir-boosted protease inhibitors: atazanavir, darunavir, fosamprenavir, or lopinavir; recommended duration of therapy is 28 days. A 3-drug regimen is recommended; however, the use of a 2-drug regimen would be preferred to discontinuing prophylaxis completely if tolerability is a concern. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).

    For human immunodeficiency virus (HIV) prophylaxis† after nonoccupational exposure, including sexual assault.
    NOTE: Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis.
    Oral dosage
    Adults

    1 tablet (lamivudine 150 mg; zidovudine 300 mg) PO twice daily in combination with raltegravir or dolutegravir for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in adults with renal dysfunction (CrCl 59 mL/minute or less). Lamivudine; zidovudine in combination with darunavir/ritonavir is an alternative regimen. However, because lamivudine and zidovudine require different dose adjustments in the presence of renal impairment, fixed dose lamivudine; zidovudine is not recommended in patients with CrCl of 50 mL/minute or less; the individual components should be used. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Adolescents

    1 tablet (lamivudine 150 mg; zidovudine 300 mg) PO twice daily in combination with raltegravir or dolutegravir for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in adolescents with renal dysfunction (CrCl 59 mL/minute or less). Lamivudine; zidovudine in combination with darunavir/ritonavir is an alternative regimen. However, because lamivudine and zidovudine require different dose adjustments in the presence of renal impairment, fixed dose lamivudine; zidovudine is not recommended in patients with CrCl of 50 mL/minute or less; the individual components should be used. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children weighing 30 kg or more

    1 tablet (lamivudine 150 mg; zidovudine 300 mg) PO twice daily in combination with raltegravir or lopinavir/ritonavir for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Lamivudine 300 mg/day PO and zidovudine 600 mg/day PO.

    Geriatric

    Lamivudine 300 mg/day PO and zidovudine 600 mg/day PO.

    Adolescents

    >= 30 kg: Lamivudine 300 mg/day PO and zidovudine 600 mg/day PO.
    < 30 kg: Combination product not recommended.

    Children

    >= 30 kg: Lamivudine 300 mg/day PO and zidovudine 600 mg/day PO.
    < 30 kg: Combination product not recommended.

    Infants

    Combination product not recommended.

    Neonates

    Combination product not recommended.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Because zidovudine may require a dose adjustment in the presence of hepatic impairment, Combivir is not recommended for patients with impaired hepatic function.

    Renal Impairment

    CrCl <= 50 mL/min: Because lamivudine and zidovudine require dose adjustment in the presence of renal insufficiency, Combivir is not recommended for patients with impaired renal function.

    ADMINISTRATION

    Hazardous Drugs Classification
    Zidovudine is classified as a hazardous drug.
    NIOSH 2016 List: Group 2
    NIOSH (Draft) 2020 List: Table 2
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.

    Oral Administration

    Some formulations may be administered with or without food, while other formulations require administration on an empty stomach. Refer to the product labeling for specific recommendations.

    STORAGE

    Combivir:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U.
     
    Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered; as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Health care providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities. [46638]

    Children, infants, neonates

    Lamivudine, 3TC; zidovudine, ZDV (Combivir) should not be administered to neonates, infants, or children weighing less than 30 kg because it is a fixed-dose combination that cannot be adjusted for this patient population. Lamivudine, 3TC; zidovudine, ZDV (Combivir) should also not be used in any patients who weigh less than 30 kg because reduced doses of lamivudine are recommended for patients with low body weight.

    Renal failure, renal impairment

    Because lamivudine and zidovudine require dose adjustment in the presence of renal insufficiency, lamivudine, 3TC; zidovudine, ZDV (Combivir) is not recommended for patients with renal impairment or renal failure (i.e., CrCl <= 50 mL/min).

    Anemia, bone marrow suppression, folate deficiency, neutropenia, radiation therapy, vitamin B12 deficiency

    Lamivudine, 3TC; zidovudine, ZDV should be used with extreme caution in patients with bone marrow suppression, especially neutropenia or anemia (e.g., neutrophil count < 1000 cells/mm3 or hemoglobin < 9.5 g/dL). Other patients that may be at increased risk for bone marrow toxicity include those with folate deficiency or vitamin B12 deficiency. Patients receiving cytotoxic drugs or radiation therapy are at risk for additive myelosuppressive effects. The HIV guidelines recommend monitoring complete blood counts (CBC) with differential at entry to care and before initiating or modifying treatment. For patients started on an antiretroviral regimen containing lamivudine; zidovudine, a follow-up CBC with differential should be obtained after 2—8 weeks of treatment, followed by periodic monitoring every 3—6 months or as clinically indicated.

    Alcoholism, females, hepatic disease, hepatotoxicity or lactic acidosis, obesity

    Because the dosage of zidovudine may require adjustment in patients with hepatic impairment, the use of lamivudine; zidovudine, a fixed dose product, is not recommended in patients with known hepatic disease. Additionally, lamivudine; zidovudine should be used with caution in patients with known risk factors for hepatic disease (e.g., alcoholism). Hepatotoxicity or lactic acidosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues, including zidovudine and lamivudine. A majority of these cases occurred in females; it is unknown if pregnant women are at increased risk. Clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly. Treatment with lamivudine; zidovudine should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked increases of hepatic enzymes. Obesity and prolonged exposure to nucleosides may be risk factors for hepatotoxicity. However, cases of lactic acidosis or liver problems have been reported in patients with no risk factors.

    Hepatitis B and HIV coinfection, hepatitis B exacerbation

    Perform hepatitis B virus (HBV) screening in any patient who presents with HIV infection to assure appropriate treatment. Patients who are coinfected with HIV and HBV should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Lamivudine-resistant HBV strains have been reported in coinfected patients receiving lamivudine as part of their anti-HIV treatment regimen. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. Patients with hepatitis B and HIV coinfection have been reported to experience clinical or laboratory evidence of hepatitis B exacerbation upon discontinuation of lamivudine. Typically, this was associated with a return of HBV DNA and ALT concentrations towards pre-treatment values, and with mild ALT flares (2-times the patient's baseline ALT) in about 20% of patients. A smaller percentage (2 to 4%) of hepatitis B patients discontinuing lamivudine have had clinically notable post-treatment recurrences of hepatitis (i.e., peak ALT 500 International Units/mL and elevation of serum bilirubin). Most events appear to be self-limiting, although fatalities have been reported. There is insufficient evidence to determine whether the re-initiation of lamivudine alters the course of post-treatment exacerbations of hepatitis. For patients who refuse a fully suppressive ARV regimen, but still require treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate. [32049] [46638] [34362]

    Dental disease, dental work

    Lamivudine; zidovudine (Combivir) should be used with caution in patients with dental disease. Zidovudine can cause myelosuppression, which may increase the risk for infection. If hematologic toxicity develops while the patient is receiving lamivudine; zidovudine (Combivir), dental work should be deferred until blood counts return to normal.

    Hepatitis C and HIV coinfection

    HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experienced with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.

    Pancreatitis

    Lamivudine; zidovudine should be used with caution in patients with a history of pancreatitis or significant risk factors for the development of pancreatitis. There appears to be a significant risk of pancreatitis in pediatric patients treated with lamivudine. Lamivudine; zidovudine (Combivir) should be terminated if any clinical signs or symptoms of pancreatitis develop, or if laboratory abnormalities suggest pancreatitis.

    Peripheral neuropathy

    Patients with peripheral neuropathy can experience exacerbations during lamivudine; zidovudine (Combivir) therapy.[24551]

    Pregnancy

    Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations more than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations more than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. HIV guidelines recommend the use of lamivudine; zidovudine as an alternative 2-NRTI backbone in women who are pregnant or trying to conceive. Available data from the Antiretroviral Pregnancy Registry, which includes first trimester exposures to lamivudine (more than 5,430 exposures) and zidovudine (more than 4,220 exposures), have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When exposure occurred in the first trimester, the prevalence of defects was 3.1% (95% CI: 2.7 to 3.6) for lamivudine and 3.2% (95% CI: 2.7 to 3.8) for zidovudine. Nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in-utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy, and any new symptoms should be evaluated thoroughly. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to lamivudine; zidovudine; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263; fax 1-800-800-1052.[27468] [23512]

    Breast-feeding

    The manufacturer recommends mothers be instructed to discontinue breast-feeding if they are receiving lamivudine; zidovudine. The Centers for Disease Control and Prevention recommend all mothers with HIV within the United States avoid breast-feeding as a method of preventing postnatal transmission of HIV. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy. If a mother with HIV opts to breast-feed, the infant should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, health care workers may contact the Perinatal HIV Hotline (888-448-8765).[42452] Lamivudine was found to be secreted in human breast milk during a study involving 20 breast-feeding women with HIV who were administered either 300 mg of lamivudine twice daily as a single agent (n = 10) or lamivudine 150 mg twice daily in combination with zidovudine (n = 10). The mean breast milk concentrations of lamivudine in the respective groups were similar at 1.22 mcg/mL (range less than 0.5 to 6.09 mcg/mL) and 0.9 mcg/mL (range less than 0.5 to 8.2 mcg/mL). Zidovudine, administered as 300 mg PO twice daily, was found to be secreted in human breast milk during a study involving 18 breast-feeding women with HIV. Data from this study revealed higher median zidovudine concentrations in the breast milk (207 ng/mL) than in the serum of the mothers (58 ng/mL). Other antiretroviral mediations whose passage into human breast milk have been evaluated include nevirapine and nelfinavir.

    Human immunodeficiency virus (HIV) infection resistance

    Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. Resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, resistance can develop when lamivudine; zidovudine is used either alone or in combination with other agents.

    Autoimmune disease, Graves' disease, Guillain-Barre syndrome, immune reconstitution syndrome

    Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Combivir. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis carinii pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

    Myopathy

    Monitor patients for signs of myopathy and myositis as they have been reported, along with pathological changes similar to that produced by HIV, with prolonged use of zidovudine.

    In utero exposure

    In utero exposure to zidovudine-containing products has been associated with mitochondrial toxicity in newborns. Hyperlactatemia can occur after delivery, but it is transient and asymptomatic in most cases. While routine monitoring of serum lactate is not recommended for all newborns, evaluation for a mitochondrial disorder, including serum lactate measurement, should be considered for those newborns who develop clinical symptoms, particularly neurologic symptoms. In symptomatic infants with significantly abnormal lactate concentrations (more than 5 mmol/L), discontinue ARV prophylaxis and consult a pediatric HIV expert. Data are limited concerning potential toxicities in infants whose mothers received combination ARV therapy. More intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised in these infants. Current clinical guidelines recommend long-term follow-up for all children exposed to ARVs in utero. It is recommended that health care providers who are treating the newborns of women with HIV report cases of prenatal ARV exposure to the Antiretroviral Pregnancy Registry (telephone 800-258-4263; fax 800-800-1052); the Antiretroviral Pregnancy Registry is also accessible via the Internet.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / 0.3-0.3
    hepatotoxicity / Delayed / Incidence not known
    lactic acidosis / Delayed / Incidence not known
    hepatitis B exacerbation / Delayed / Incidence not known
    red cell aplasia / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known

    Moderate

    peripheral neuropathy / Delayed / 12.0-12.0
    depression / Delayed / 9.0-9.0
    neutropenia / Delayed / 7.2-7.2
    hyperamylasemia / Delayed / 4.2-4.2
    elevated hepatic enzymes / Delayed / 1.7-3.7
    anemia / Delayed / 2.9-2.9
    hyperbilirubinemia / Delayed / 0.8-0.8
    thrombocytopenia / Delayed / 0.4-0.4
    hepatomegaly / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    splenomegaly / Delayed / Incidence not known
    bone marrow suppression / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    lipodystrophy / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known

    Mild

    headache / Early / 35.0-35.0
    nausea / Early / 33.0-33.0
    malaise / Early / 27.0-27.0
    fatigue / Early / 27.0-27.0
    diarrhea / Early / 18.0-18.0
    cough / Delayed / 18.0-18.0
    vomiting / Early / 13.0-13.0
    musculoskeletal pain / Early / 12.0-12.0
    insomnia / Early / 11.0-11.0
    dizziness / Early / 10.0-10.0
    anorexia / Delayed / 10.0-10.0
    fever / Early / 10.0-10.0
    chills / Rapid / 10.0-10.0
    abdominal pain / Early / 9.0-9.0
    rash / Early / 9.0-9.0
    myalgia / Early / 8.0-8.0
    dyspepsia / Early / 5.0-5.0
    arthralgia / Delayed / 5.0-5.0
    paresthesias / Delayed / Incidence not known
    weakness / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Aspirin: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Aspirin; Diphenhydramine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Caffeine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Caffeine; Dihydrocodeine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Caffeine; Pyrilamine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Chlorpheniramine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Codeine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Dextromethorphan: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Diphenhydramine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Guaifenesin; Phenylephrine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Hydrocodone: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Oxycodone: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Pamabrom; Pyrilamine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Pentazocine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acetaminophen; Pseudoephedrine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals (i.e., anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs)) are at risk of developing 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 analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir 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).
    Alogliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Amiloride: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Administer clarithromycin and zidovudine at least 2 hours apart. Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine may result in decreased steady-state zidovudine concentrations. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
    Amphotericin B lipid complex (ABLC): (Moderate) The use of ABLC with zidovudine, ZDV has lead to an increase in myelotoxicity and nephrotoxicity in dogs. If these medications are used concomitantly, monitor renal and hematologic function closely.
    Atovaquone: (Minor) Atovaquone appears to increase the AUC of zidovudine by inhibiting the glucuronidation of zidovudine. Inhibition of zidovudine metabolism by atovaquone could result in an increase in zidovudine-induced adverse effects.
    Atovaquone; Proguanil: (Minor) Atovaquone appears to increase the AUC of zidovudine by inhibiting the glucuronidation of zidovudine. Inhibition of zidovudine metabolism by atovaquone could result in an increase in zidovudine-induced adverse effects.
    Azathioprine: (Moderate) Azathioprine may interact with other drugs that are myelosuppressive, such as azathioprine. A significant toxicity of zidovudine, ZDV is myelosuppression and resulting neutropenia and anemia.
    Benzhydrocodone; Acetaminophen: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive. (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like zidovudine; the risk of peripheral neuropathy may be additive.
    Butalbital; Acetaminophen: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Butalbital; Acetaminophen; Caffeine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Cabozantinib: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Canagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Cidofovir: (Major) Concomitant use of probenecid with zidovudine may produce substantially higher serum concentrations of zidovudine. Because cidofovir must be given concomitantly with probenecid, the manufacturer of cidofovir recommends that on the days of concomitant cidofovir and probenecid therapy, zidovudine should either be discontinued temporarily or the zidovudine dosage should be reduced by 50%. Limited data suggest that probenecid may inhibit glucuronidation and/or reduce renal excretion of zidovudine.
    Clarithromycin: (Moderate) Administer clarithromycin and zidovudine at least 2 hours apart. Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine may result in decreased steady-state zidovudine concentrations. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
    Clofarabine: (Moderate) Concomitant use of clofarabine and zidovudine, ZDV may result in altered clofarabine levels because both agents are substrates of OAT1 and OAT3. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OAT1 and OAT3 substrates.
    Cyclophosphamide: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with zidovudine is necessary as there is an increased risk of hematologic toxicity and immunosuppression.
    Dapagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Dapsone: (Minor) Zidovudine, ZDV should be given with caution to patients also receiving dapsone due to the risk of additive hematologic toxicity.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Minor) Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown.
    Dofetilide: (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
    Donepezil; Memantine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    Doxorubicin Liposomal: (Major) Avoid concomitant administration of zidovudine, ZDV, and doxorubicin as an antagonistic relationship has been demonstrated in vitro.
    Doxorubicin: (Major) Avoid concomitant administration of zidovudine, ZDV, and doxorubicin as an antagonistic relationship has been demonstrated in vitro.
    Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Empagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Emtricitabine: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    Emtricitabine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    Ertugliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Fluconazole: (Minor) During concomitant administration with fluconazole, the clearance of zidovudine may be reduced. Although the clinical significance of this interaction has not been established, patients receiving fluconazole with zidovudine should be closely monitored for zidovudine-induced adverse effects, especially hematologic toxicity. Zidovudine dosage reduction may be considered.
    Flucytosine: (Moderate) Zidovudine, ZDV should be used cautiously with other drugs that can cause bone marrow suppression, such as flucytosine, because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage of zidovudine may be warranted.
    Foscarnet: (Minor) Concurrent use of foscarnet and zidovudine, ZDV may be associated with a higher incidence of anemia; clinicians should follow normal recommendations for blood count monitoring and other parameters.
    Fosphenytoin: (Minor) Coadministration with zidovudine may result in either increased or decreased phenytoin concentrations.
    Ganciclovir: (Major) Coadministration of ganciclovir and zidovudine may increase the hematologic toxicity (e.g., neutropenia, anemia) of zidovudine. Some patients may not tolerate concomitant therapy with these drugs at full dosage. If concomitant use is necessary, monitor hematologic parameters closely.
    Glipizide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Glyburide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Indinavir: (Moderate) When indinavir and zidovudine, ZDV were administered concurrently, the AUC of indinavir and zidovudine was increased by 13% +/- 48% and 17% +/- 23%, respectively. Dosage adjustments are not recommended when zidovudine is administered with indinavir.
    Interferon Alfa-2b; Ribavirin: (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. (Moderate) Use zidovudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin may antagonize the cell culture antiviral activity of zidovudine against HIV; however, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
    Interferons: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance. (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Rifampin can accelerate the metabolism of zidovudine, causing a decrease in AUC of approximately 50%. However the effectiveness of zidovudine against HIV does not appear to be altered and no dosage adjustments are required.
    Isoniazid, INH; Rifampin: (Minor) Rifampin can accelerate the metabolism of zidovudine, causing a decrease in AUC of approximately 50%. However the effectiveness of zidovudine against HIV does not appear to be altered and no dosage adjustments are required.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Administer clarithromycin and zidovudine at least 2 hours apart. Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine may result in decreased steady-state zidovudine concentrations. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
    Leflunomide: (Moderate) Closely monitor for zidovudine-induced side effects such as hematologic toxicity when these drugs are used together. In some patients, a dosage reduction of zidovudine may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with zidovudine, a substrate of OAT3, may increase zidovudine plasma concentrations.
    Linagliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Lopinavir; Ritonavir: (Minor) Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown.
    Memantine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Metformin; Repaglinide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Metformin; Rosiglitazone: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Metformin; Saxagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Metformin; Sitagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Methadone: (Moderate) Methadone increases exposure zidovudine, ZDV. Patients should be monitored for zidovudine toxicity during concurrent methadone treatment; however, the manufacturer of zidovudine states that routine dosage adjustment of zidovudine is not required during coadministration of methadone. Patients who receive both methadone and zidovudine may experience symptoms characteristic of opiate withdrawal and attribute the cause to decreased methadone levels due to zidovudine. However, it is more likely patients are actually experiencing zidovudine side effects due to increased levels since zidovudine has no effect on methadone metabolism. In one pharmacokinetic study (n=9), coadministration of methadone increased the AUC of zidovudine by about 43% (range: 16-64%). It appears methadone inhibits zidovudine glucuronidation and, to a lesser extent, decreases zidovudine renal clearance.
    Nirmatrelvir; Ritonavir: (Minor) Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown.
    Ombitasvir; Paritaprevir; Ritonavir: (Minor) Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown.
    Omeprazole; Amoxicillin; Rifabutin: (Minor) Rifabutin may accelerate the metabolism of zidovudine. However the effectiveness of zidovudine against HIV does not appear to be altered and no dosage adjustments are required. The CDC currently considers the nucleoside reverse transcriptase inhibitors, including zidovudine, compatible for concomitant use with rifamycins, including rifampin, rifabutin and rifapentine.
    Orlistat: (Moderate) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
    Phenytoin: (Minor) Coadministration with zidovudine has resulted in altered phenytoin concentrations. Reports have varied, with increased and decreased phenytoin concentrations being reported. Use combination with caution.
    Pioglitazone; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Probenecid: (Major) Concomitant use of probenecid with zidovudine, ZDV may produce substantially higher serum concentrations of zidovudine.
    Probenecid; Colchicine: (Major) Concomitant use of probenecid with zidovudine, ZDV may produce substantially higher serum concentrations of zidovudine.
    Procainamide: (Moderate) Cationic drugs that are eliminated by renal tubular secretion such as procainamide may compete with lamivudine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of the response to lamivudine and/or procainamide is recommended to individualize dosage. In selected individuals, procainamide serum concentration monitoring may be appropriate.
    Pyrimethamine: (Major) Pyrimethamine should be used cautiously with zidovudine, ZDV because of the potential for the development of blood dyscrasias including megaloblastic anemia, agranulocytosis, or thrombocytopenia. Monitor CBCs routinely in patients receiving both drugs simultaneously; if signs of folate deficiency develop, pyrimethamine should be discontinued.
    Ribavirin: (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. (Moderate) Use zidovudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin may antagonize the cell culture antiviral activity of zidovudine against HIV; however, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
    Rifabutin: (Minor) Rifabutin may accelerate the metabolism of zidovudine. However the effectiveness of zidovudine against HIV does not appear to be altered and no dosage adjustments are required. The CDC currently considers the nucleoside reverse transcriptase inhibitors, including zidovudine, compatible for concomitant use with rifamycins, including rifampin, rifabutin and rifapentine.
    Rifampin: (Minor) Rifampin can accelerate the metabolism of zidovudine, causing a decrease in AUC of approximately 50%. However the effectiveness of zidovudine against HIV does not appear to be altered and no dosage adjustments are required.
    Rifapentine: (Minor) Rifapentine appears to increase the glucuronidation of zidovudine, ZDV similar to other rifamycins. This may cause a decrease in zidovudine AUC. However, the effectiveness of zidovudine against HIV does not appear to be altered. The activity of zidovudine is dependent on the intracellular concentration of the triphosphate metabolite which is not correlated with plasma concentrations of the parent compound. The CDC currently considers the nucleoside reverse transcriptase inhibitors (NRTIs), including zidovudine, compatible for concomitant use with rifamycins (including rifampin, rifabutin and rifapentine). No dosing adjustments are necessary.
    Ritonavir: (Minor) Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown.
    Sorbitol: (Major) Avoid coadministration of lamivudine oral solution and sorbitol if possible due to sorbitol dose-dependent reduction in lamivudine exposure. An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol. Consider more frequent monitoring of viral load when treating with lamivudine oral solution. In a drug interaction study in 16 healthy adult patients, coadministration of a single 300 mg dose of lamivudine oral solution with sorbitol 3.2 g, 10.2 g, or 13.4 g resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC24 and 28%, 52%, and 55% in the Cmax of lamivudine.
    Stavudine, d4T: (Contraindicated) Zidovudine, ZDV, may competitively inhibit the intracellular phosphorylation of stavudine, d4T. Therefore, use of these drugs together is not recommended. At a molar ratio of 20:1 (stavudine:zidovudine), an antagonistic antiviral effect was detected, while at molar ratios of 100:1 and 500:1, antiviral effects were additive. Administration of zidovudine is recommended during labor and delivery in HIV-infected women; for women who are receiving a stavudine-containing regimen, discontinue stavudine during labor while intravenous zidovudine is being administered. Following delivery, the previous anti-retroviral regimen can be resumed.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Concomitant use of trimethoprim and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.
    Sulfonamides: (Moderate) Concomitant use of sulfonamides and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.
    Telbivudine: (Moderate) The risk of myopathy may be increased if zidovudine is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Teriflunomide: (Major) Zidovudine, ZDV should be used cautiously with other drugs that can cause bone marrow suppression including teriflunomide because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage or discontinuation of zidovudine may be warranted. Teriflunomide, an organic anion transporter OAT3 renal updake inhibitor, may cause elevated concentrations of zidovudine, an OAT3 substrate.
    Tipranavir: (Moderate) Concurrent administration of tipranavir and ritonavir with zidovudine results in decreased zidovudine concentrations. The clinical significance of this interaction has not been established, and no recommendations for zidovudine dosage adjustments are available.
    Tramadol; Acetaminophen: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Trimethoprim: (Moderate) Concomitant use of trimethoprim and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.
    Trospium: (Moderate) Trospium is eliminated by active tubular secretion and has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion including lamivudine. In theory, coadministration of trospium with lamivudine may increase the serum concentrations of trospium or lamivudine due to competition for the drug elimination pathway.
    Valganciclovir: (Major) Zidovudine should be used cautiously with other drugs that can cause bone marrow suppression, such as valganciclovir, because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage of zidovudine may be warranted. Occasionally, discontinuation of therapy or the addition of a hematopoietic colony stimulating factor may be necessary.
    Valproic Acid, Divalproex Sodium: (Minor) Concomitant administration of valproic acid and oral zidovudine may result in increase in the area under the concentration-time curve of zidovudine and a decrease in the AUC of its glucuronide metabolite. This interaction does not appear to be clinically significant unless the patient is experiencing hematologic toxicities. The dose of zidovudine may be reduced in patients who are experiencing pronounced anemia while receiving chronic coadministration of zidovudine and valproic acid.
    Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Administer clarithromycin and zidovudine at least 2 hours apart. Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine may result in decreased steady-state zidovudine concentrations. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
    Voriconazole: (Minor) Concomitant administration of voriconazole and zidovudine may result in a reduction in the clearance of zidovudine.

    PREGNANCY AND LACTATION

    Pregnancy

    Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations more than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations more than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. HIV guidelines recommend the use of lamivudine; zidovudine as an alternative 2-NRTI backbone in women who are pregnant or trying to conceive. Available data from the Antiretroviral Pregnancy Registry, which includes first trimester exposures to lamivudine (more than 5,430 exposures) and zidovudine (more than 4,220 exposures), have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When exposure occurred in the first trimester, the prevalence of defects was 3.1% (95% CI: 2.7 to 3.6) for lamivudine and 3.2% (95% CI: 2.7 to 3.8) for zidovudine. Nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in-utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy, and any new symptoms should be evaluated thoroughly. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to lamivudine; zidovudine; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263; fax 1-800-800-1052.[27468] [23512]

    The manufacturer recommends mothers be instructed to discontinue breast-feeding if they are receiving lamivudine; zidovudine. The Centers for Disease Control and Prevention recommend all mothers with HIV within the United States avoid breast-feeding as a method of preventing postnatal transmission of HIV. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy. If a mother with HIV opts to breast-feed, the infant should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, health care workers may contact the Perinatal HIV Hotline (888-448-8765).[42452] Lamivudine was found to be secreted in human breast milk during a study involving 20 breast-feeding women with HIV who were administered either 300 mg of lamivudine twice daily as a single agent (n = 10) or lamivudine 150 mg twice daily in combination with zidovudine (n = 10). The mean breast milk concentrations of lamivudine in the respective groups were similar at 1.22 mcg/mL (range less than 0.5 to 6.09 mcg/mL) and 0.9 mcg/mL (range less than 0.5 to 8.2 mcg/mL). Zidovudine, administered as 300 mg PO twice daily, was found to be secreted in human breast milk during a study involving 18 breast-feeding women with HIV. Data from this study revealed higher median zidovudine concentrations in the breast milk (207 ng/mL) than in the serum of the mothers (58 ng/mL). Other antiretroviral mediations whose passage into human breast milk have been evaluated include nevirapine and nelfinavir.

    MECHANISM OF ACTION

    Lamivudine and zidovudine are synthetic nucleoside analogs. Lamivudine is an analog of cytidine, and zidovudine is an analog of thymidine. Intracellularly, lamivudine and zidovudine are phosphorylated to their active 5'-triphosphate metabolites, lamivudine triphosphate (L-TP) and zidovudine triphosphate (ZDV-TP), respectively. Both L-TP and ZDV-TP inhibit reverse transcriptase via DNA chain termination after incorporation of the nucleoside analog. L-TP is a weak inhibitor of mammalian DNA polymerases alpha and beta, and mitochondrial DNA polymerase-gamma. ZDV-TP is a weak inhibitor of the mammalian DNA polymerase-alpha and mitochondrial DNA polymerase-gamma and has been reported to be incorporated into the DNA of cells in culture. The relationship between in vitro susceptibility of HIV to lamivudine or zidovudine and the inhibition of HIV replication in humans has not been established. In MT-4 cells with HIV-1, lamivudine in combination with zidovudine has synergistic antiretroviral activity.[32049]
     
    HIV-1 isolates from patients who receive combination therapy with lamivudine plus zidovudine can become phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients with a zidovudine-resistant virus at baseline, treatment with lamivudine plus zidovudine restored phenotypic sensitivity to zidovudine by week 12. HIV-1 strains with resistance to both lamivudine and zidovudine have been isolated from patients after prolonged lamivudine/zidovudine therapy. Genotypic analysis has shown that resistance to lamivudine is due to mutations in the HIV-1 reverse transcriptase gene at codon 184 from methionine to either isoleucine or valine. Genotypic analysis of isolates resistant to zidovudine showed thymine analog mutation substitutions in HIV-1 RT (M41L, D67N, K70R, L210W, T215Y or F, K219E/R/H/Q/N). In general, higher levels of resistance are associated with a greater number of mutations. Cross-resistance between lamivudine and zidovudine has not been reported.[32049]

    PHARMACOKINETICS

    Lamivudine; zidovudine (Combivir) is administered orally.
    Lamivudine: Lamivudine is minimally bound to plasma proteins (less than 36%) and is extensively distributed. Approximately 70% of an IV dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). The elimination half-life of lamivudine is about 5 to 7 hours.
    Zidovudine: Binding of zidovudine to plasma proteins is low (about 38%), and distribution is extensive. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite is 3'-azido-3'-deoxy-5'-O'-beta-D-glucopyranuronosylthymidine (GZDV). GZDV area under the curve is about 3-fold greater than the zidovudine AUC. Following oral administration, urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose, respectively. A second metabolite of zidovudine, 3'-amino-3'-deoxythymidine (AMT), has also been identified in plasma. The elimination half-life of zidovudine is about 0.5 to 3 hour in patients with normal renal function.[32049]
     
    Affected cytochrome P450 isoenzymes: none

    Oral Route

    One lamivudine; zidovudine (Combivir) tablet has been shown to be bioequivalent to 1 lamivudine (EPIVIR) 150 mg tablet and 1 zidovudine (Retrovir) 300 mg tablet following single-dose administration to fasting healthy subjects.
    Lamivudine: Following oral administration, lamivudine is rapidly absorbed with a bioavailability of about 86%.
    Zidovudine: Zidovudine is rapidly absorbed following oral administration with a bioavailability of about 64%.