lamivudine-zidovudine tablet generic combivir

Uses

Oral and IV zidovudine are used in conjunction with other antiretroviral agents for treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients. Oral and IV zidovudine are used for treatment of HIV-1 infection in pregnant women and for prevention of perinatal HIV transmission in a regimen that includes intrapartum IV zidovudine prophylaxis in the mother and oral or IV zidovudine prophylaxis in the neonate. In addition, oral zidovudine is used in conjunction with other antiretroviral agents for postexposure prophylaxis of HIV infection in health-care personnel and other individuals exposed occupationally via percutaneous injury or mucous membrane or skin contact with blood, tissue, or other body fluids associated with a risk for transmission of the virus.

Treatment of HIV Infection

Oral and IV zidovudine are used in conjunction with other antiretroviral agents for treatment of HIV-1 infection in adults, adolescents, and pediatric patients who are antiretroviral-naive (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated).

Zidovudine is used in multiple-drug regimens that include another HIV nucleoside reverse transcriptase inhibitor (NRTI) (dual NRTIs) and an HIV integrase strand transfer inhibitor (INSTI), HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV protease inhibitor (PI) in INSTI-, NNRTI-, or PI-based regimens.(See Dual NRTI Options under Treatment of HIV Infection: Antiretroviral-naive Adults and Adolescents, in Uses.)

If the dual NRTI option of lamivudine and zidovudine is used in conjunction with other antiretrovirals for treatment of HIV-1 infection, a fixed-combination preparation containing both drugs (lamivudine/zidovudine; Combivir) is commercially available and can be used in adults and adolescents weighing 30 kg or more to decrease pill burden and improve adherence.

Zidovudine has been used in triple NRTI regimens (i.e., single-class NRTI regimens) that include zidovudine and 2 other NRTIs. A fixed-combination preparation containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir) is commercially available and can be used in adults and adolescents weighing 40 kg or more to provide a triple NRTI regimen and to decrease pill burden and improve adherence.(See All-NRTI Regimens under Treatment of HIV Infection: Antiretroviral-naive Adults and Adolescents, in Uses.)

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario and selection of specific antiretroviral agents for use in such regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-naive Adults and Adolescents

Although monotherapy and 2-drug regimens that include only NRTIs are no longer recommended for treatment of HIV infection, early studies evaluating safety and efficacy of zidovudine for initial antiretroviral therapy in antiretroviral-naive HIV-infected adults used zidovudine monotherapy or 2-drug regimens of zidovudine and didanosine, lamivudine, or zalcitabine (no longer commercially available in the US). While results of these early studies indicated that zidovudine monotherapy or 2-drug NRTI regimens in antiretroviral-naive patients may be associated with initial declines in plasma HIV-1 RNA levels, subsequent studies showed that such regimens were less effective in providing durable suppression of HIV replication than 3-drug regimens that also included an agent from another class (i.e., PI or NNRTI).

Dual NRTI Options

For initial treatment regimens in antiretroviral-naive HIV-infected adults and adolescents, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that the dual NRTI option of tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) is the recommended dual NRTI option for use in most INSTI-, NNRTI-, and PI-based regimens recommended for initial treatment. These experts state that abacavir and lamivudine (or emtricitabine) also is a recommended dual NRTI option for use in initial treatment regimens in antiretroviral-naive adults and adolescents, but should be used only in those who are negative for human leukocyte antigen (HLA)-B*5701. These recommendations are based on safety and efficacy data from clinical trials, long-term clinical experience, and availability of fixed-combination preparations containing NRTIs.

The dual NRTI option of zidovudine and lamivudine is no longer recommended for initial treatment regimens in nonpregnant antiretroviral-naive adults and adolescents because it has greater toxicity than the dual NRTI options of tenofovir DF and emtricitabine or abacavir and lamivudine and requires twice-daily dosing. However, the dual NRTI option of zidovudine and lamivudine is one of several preferred dual NRTI options for initial treatment regimens in antiretroviral-naive pregnant women(see Pregnancy under Cautions: Pregnancy, Fertility, and Lactation) and for initial treatment regimens in pediatric patients(see Pediatric Patients under Uses: Treatment of HIV-1 Infection). When the dual NRTI option of lamivudine and zidovudine is used in conjunction with other antiretrovirals, the fixed-combination preparation containing both drugs (lamivudine/zidovudine; Combivir) can be used in adults and adolescents weighing 30 kg or more.

A dual NRTI option of zidovudine and stavudine should not be used at any time because of antagonistic antiretroviral effects.

All-NRTI Regimens

Zidovudine has been included in NRTI regimens that include 3 or 4 NRTIs (without any drugs from another class). However, triple and quadruple NRTI regimens are not usually recommended for treatment of HIV infection in antiretroviral-naive adults or adolescents because such regimens have inferior virologic efficacy or have not been adequately studied. In addition, regimens that only include NRTIs are not usually recommended in antiretroviral-experienced patients.(See Antiretroviral-experienced Adults and Adolescents under Uses: Treatment of HIV Infection.)

Zidovudine has been used in a triple NRTI regimen that includes abacavir, lamivudine, and zidovudine. The fixed-combination preparation containing these 3 NRTIs (abacavir/lamivudine/zidovudine; Trizivir) can be used in adults and adolescents weighing 40 kg or more. Abacavir/lamivudine/zidovudine is intended only for regimens that require all 3 drugs, and clinicians should consider that data are limited regarding use in patients with baseline viral loads exceeding 100,000 copies/mL. Although a triple NRTI regimen of abacavir, lamivudine, and zidovudine offers the advantages of fewer drug interactions, low pill burden and ease of administration (because of the commercially available fixed-combination preparation), and spares patients from potential adverse effects associated with PIs and NNRTIs, there is evidence that triple NRTI regimens have inferior virologic efficacy. Therefore, experts state that a triple NRTI regimen that includes abacavir, lamivudine, and zidovudine is not recommended for initial therapy in antiretroviral-naive adults and adolescents and should be used only when other regimens cannot be used.

A triple NRTI regimen of lamivudine, tenofovir DF, and zidovudine has been used and has been shown to have antiretroviral activity; however, this regimen should be used only when other regimens cannot be used.

A quadruple NRTI regimen of abacavir, lamivudine, tenofovir DF, and zidovudine is not recommended for initial therapy in antiretroviral-naive adults and adolescents because of inferior virologic activity. In an open-label pilot study, a quadruple NRTI regimen was compared with an NNRTI-based regimen of efavirenz with lamivudine and zidovudine and both regimens had similar efficacy and tolerability. However, a larger, open-label study comparing a similar quadruple NRTI regimen (abacavir, emtricitabine, tenofovir DF, zidovudine) with a standard NNRTI- or PI-based regimen found that substantially fewer patients receiving the quadruple NRTI regimen achieved HIV-1 RNA levels below 200 copies/mL.

Antiretroviral-experienced Adults and Adolescents

Although monotherapy or 2-drug regimens that include only NRTIs are no longer recommended for treatment of HIV infection, early studies evaluating the safety and efficacy of zidovudine in antiretroviral-experienced (previously treated) patients used such regimens. Subsequent studies indicated that regimens that include zidovudine, another NRTI (e.g., lamivudine, didanosine), and a PI (e.g., indinavir, ritonavir, saquinavir) or NNRTI (e.g., nevirapine) were more effective in increasing CD4 T-cell counts and decreasing plasma HIV-1 RNA levels in previously treated patients than zidovudine monotherapy or 2-drug NRTI regimens.

Zidovudine has been used in triple NRTI regimens in antiretroviral-experienced HIV-infected adults and adolescents, but triple NRTI regimens are not usually recommended because of inferior virologic efficacy or lack of data.

A triple NRTI regimen that includes abacavir (300 mg twice daily) and the fixed-combination preparation containing lamivudine and zidovudine (Combivir; 150 mg of lamivudine and 300 mg of zidovudine twice daily) has been evaluated in a 48-week, open-label study in HIV-infected patients who previously received antiretroviral regimens that included 1 or 2 NRTIs without any other antiretroviral agents. At the start of the study, 34% of patients had baseline plasma HIV-1 RNA levels less than 400 copies/mL and 11% had levels less than 50 copies/mL; the median CD4 T-cell count was 506/mm. At 48 weeks, 82% of patients had plasma HIV-1 RNA levels less than 400 copies/mL and 56% had levels less than 50 copies/mL (intent-to-treat analysis). Patients with baseline HIV-1 RNA levels less than 5000 copies/mL were more likely to achieve levels less than 400 copies/mL at week 48 than those with baseline levels exceeding 5000 copies/mL. At 48 weeks, the median change from baseline CD4 T-cell count was 66 cells/mm. While triple NRTI regimens are not generally recommended, some experts state that a regimen of the fixed combination of abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine) may be considered when other regimens cannot or should not be used (e.g., because of concerns regarding drug interactions, toxicity, adherence).

Pediatric Patients

Zidovudine is used in conjunction with other antiretrovirals for treatment of HIV-1 infection in children 4 weeks of age or older. In addition, the drug is used in neonates for prevention of perinatal HIV transmission as part of a regimen that includes intrapartum IV zidovudine prophylaxis in the mother and oral or IV zidovudine prophylaxis in the neonate.(See Uses: Prevention of Perinatal HIV Transmission.)

For initial treatment of HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a PI or NNRTI and 2 NRTIs (dual NRTIs). These experts state that the preferred dual NRTI options for initial treatment regimens in pediatric patients are zidovudine and either lamivudine or emtricitabine (can be used in pediatric patients of any age) or abacavir and either lamivudine or emtricitabine (can be used in those 3 months of age or older who are negative for HLA-B*5701).

When the dual NRTI option of lamivudine and zidovudine is used, the fixed-combination preparation containing both drugs (lamivudine/zidovudine; Combivir) can be used in pediatric patients weighing 30 kg or more.

Zidovudine and didanosine is an alternative (not a preferred) dual NRTI option that can be used in initial treatment regimens in children 2 weeks of age or older.

Zidovudine and abacavir is an alternative (not a preferred) dual NRTI option that can be used in initial treatment regimens in children 3 months of age or older who are negative for HLA-B*5701.

A dual NRTI option of zidovudine and stavudine should not be used at any time because of antagonistic antiretroviral effects.

Antiretroviral regimens that contain only NRTIs are not recommended for initial treatment in antiretroviral-naive children because of inferior virologic efficacy.

For further information on treatment of HIV infection in pediatric patients,

Prevention of Perinatal HIV Transmission

Zidovudine is used for treatment of HIV-1 infection in pregnant women and also is used for prophylaxis in pregnant HIV-infected women and their neonates to prevent perinatal transmission of HIV.

In the US, multiple-drug antiretroviral regimens are considered the standard of care for treatment of HIV-1 infection in pregnant women and for prevention of perinatal HIV transmission. The HHS Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that all pregnant HIV-infected women in the US should receive multiple-drug antiretroviral therapy, regardless of the woman's plasma HIV-1 RNA level or CD4 T-cell count. In addition, to decrease the risk of perinatal HIV transmission, the HHS panel states that pregnant HIV-infected women with plasma HIV-1 RNA levels exceeding 1000 copies/mL (or unknown HIV-1 RNA levels) near the time of delivery should receive an intrapartum IV zidovudine prophylaxis regimen and all neonates born to HIV-infected women (HIV-exposed neonates) should receive an oral or IV zidovudine prophylaxis regimen. In certain situations (e.g., infant born to a woman who did not receive antepartum or intrapartum antiretrovirals or received only intrapartum antiretrovirals), a 3-dose nevirapine prophylaxis regimen is recommended in the neonate in addition to the usual neonatal zidovudine prophylaxis regimen. Combined antepartum, intrapartum, and neonatal antiretroviral prophylaxis is recommended since this strategy reduces perinatal HIV transmission by several mechanisms, including lowering maternal antepartum viral load and providing pre- and postexposure prophylaxis in the infant. Maternal and neonatal regimens recommended for prevention of perinatal HIV transmission in the US may differ from those used in other countries (e.g., resource-limited countries).

Multiple-drug regimens in pregnant women are more effective than single-drug regimens in reducing perinatal transmission of HIV. The HHS panel recommends that all HIV-infected pregnant women in the US receive a potent multiple-drug antiretroviral regimen that includes at least 3 drugs. The choice of antiretrovirals to include in antenatal regimens should be individualized based on the woman's antiretroviral history, resistance testing, and the known risks of adverse effects and teratogenicity associated with the drugs. For initial treatment in antiretroviral-naive pregnant women, a regimen that includes 2 NRTIs (dual NRTIs) and a ritonavir-boosted PI or an NNRTI is recommended. The preferred dual NRTI options for use in pregnant women are abacavir and lamivudine, tenofovir DF and emtricitabine (or lamivudine), or lamivudine and zidovudine. Use of zidovudine alone during pregnancy for prevention of perinatal HIV transmission is not optimal, but may be an option in some HIV-infected pregnant women not currently receiving antiretroviral therapy who have plasma HIV-1 RNA levels less than 1000 copies/mL and wish to minimize fetal exposure to antiretrovirals.

All pregnant women in the US who have plasma HIV-1 RNA levels exceeding 1000 copies/mL (or unknown HIV-1 RNA levels) near the time of delivery should receive the intrapartum IV zidovudine prophylaxis regimen initiated at the onset of labor and continued until delivery. Scheduled cesarean delivery also is recommended for such women to help decrease the risk of perinatal HIV transmission. The intrapartum IV zidovudine prophylaxis regimen is not required in women who have been receiving a multiple-drug antiretroviral regimen and have plasma HIV-1 RNA levels that have consistently been 1000 copies/mL or lower during late pregnancy and/or near delivery, provided there are no concerns about adherence to or tolerance of the antiretroviral regimen.

In those who are currently receiving a multiple-drug antiretroviral regimen that is well tolerated and providing adequate virologic suppression, the regimen should be continued on schedule as much as possible during labor and delivery. If the intrapartum IV zidovudine prophylaxis is indicated and the current antiretroviral regimen includes oral zidovudine, IV zidovudine should be substituted for oral zidovudine until after delivery; other antiretrovirals included in the woman's regimen can be continued orally during labor.

All HIV-exposed neonates should receive the neonatal zidovudine prophylaxis regimen initiated as soon as possible after delivery (preferably within 6-12 hours). A 6-week neonatal zidovudine prophylaxis regimen is recommended to reduce the risk of perinatal HIV transmission; however a 4-week zidovudine prophylaxis regimen can be considered for infants born to mothers who were receiving a recommended multiple-drug antiretroviral regimen and have had consistent viral suppression during the pregnancy, provided there are no concerns about the mother's adherence to the treatment regimen. In situations when an HIV-infected woman received no antiretroviral therapy prior to and/or during labor, the HHS panel recommends that the neonate receive a 3-dose nevirapine regimen in addition to the 6-week zidovudine prophylaxis regimen. The HHS panel states that, for US patients, decisions to include any additional antiretrovirals for prophylaxis with the recommended intrapartum and neonatal zidovudine prophylaxis regimens should be made in consultation with a pediatric HIV specialist (preferably before delivery) and should be accompanied by maternal counseling regarding the potential risks and benefits. These experts also state that, because safety and dosage data are not available, use of antiretrovirals other than zidovudine and nevirapine cannot be recommended for prophylaxis in premature HIV-exposed neonates.

For information on the risk of perinatal transmission of HIV and some additional information regarding recommendations for use of antiretroviral agents for prevention of perinatal HIV transmission, In addition, clinicians can consult the National Perinatal HIV Hotline at 888-448-8765 for information regarding antiretroviral treatment of pregnant HIV-infected women and their infants and prevention of perinatal HIV transmission.

Postexposure Prophylaxis following Occupational Exposure to HIV

Oral zidovudine is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and other individuals exposed occupationally via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada). These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs). The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as emtricitabine/tenofovir DF; Truvada); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible. However, initiation of PEP should not be delayed while waiting for expert consultation.

For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure chemoprophylaxis, and recommendations regarding postexposure prophylaxis,

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Zidovudine is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals who have had exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.

For additional information on nonoccupational exposure to HIV and recommendations regarding postexposure prophylaxis,

Dosage and Administration

Reconstitution and Administration

Zidovudine is administered orally or by intermittent or continuous IV infusion. Zidovudine should not be administered by rapid or bolus IV injection and should not be given IM or subcutaneously.

Oral zidovudine therapy should replace parenteral zidovudine therapy as soon as feasible; the drug should be administered by IV infusion only until oral therapy can be substituted.

Oral Administration

Zidovudine capsules, solution, and tablets should be administered orally without regard to meals. Although food may decrease peak plasma concentrations of zidovudine, the area under the concentration-time curve (AUC) is not affected.

For children, zidovudine oral solution can be used. Alternatively, children who can reliably swallow an intact tablet or capsule may receive zidovudine tablets or capsules.

IV Administration

Commercially available zidovudine concentrate for IV infusion containing 10 mg of the drug per mL must be diluted prior to administration. The appropriate dose of zidovudine should be withdrawn from the vial and diluted in 5% dextrose injection to provide a solution containing no more than 4 mg of the drug per mL.

Zidovudine solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit; if either is present, the solution should be discarded.

Rate of Administration

Intermittent IV infusions of zidovudine should be infused at a constant rate over 60 minutes. In neonates, intermittent IV infusions should be infused over 30 minutes.

Fixed Combinations Containing Zidovudine

For treatment of human immunodeficiency virus (HIV) infection, zidovudine is commercially available in fixed-combination tablets containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir) or fixed-combination tablets containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir).

Lamivudine/zidovudine tablets are administered orally twice daily without regard to meals. A fixed-combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine is bioequivalent to one 150-mg tablet of lamivudine and one 300-mg tablet of zidovudine given simultaneously. Lamivudine/zidovudine is used in conjunction with other antiretrovirals. The fixed combination should not be used in pediatric patients weighing less than 30 kg, patients with renal impairment (i.e., creatinine clearance 50 mL/minute or less), patients with hepatic impairment, patients who experience dose-limiting adverse effects, or others requiring dosage adjustment.

Abacavir/lamivudine/zidovudine tablets are administered orally twice daily without regard to meals. A fixed-combination tablet containing 300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine is bioequivalent to a 300-mg abacavir tablet, a 150-mg lamivudine tablet, and a 300-mg zidovudine tablet given simultaneously. Abacavir/lamivudine/zidovudine can be used alone as a complete treatment regimen or can be used in conjunction with other antiretrovirals. The fixed combination should not be used in pediatric patients, adolescents weighing less than 40 kg, patients with renal impairment (i.e., creatinine clearance 50 mL/minute or less), patients with hepatic impairment, or others requiring dosage adjustment.

Because the antiretroviral agents contained in lamivudine/zidovudine and abacavir/lamivudine/zidovudine also are available in single-entity or other fixed-combination preparations, care should be taken to ensure that therapy is not duplicated when any of these fixed combinations are used in conjunction with other antiretrovirals.(See Precautions Related to Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Dosage

Adult Dosage

Treatment of HIV Infection

The recommended oral dosage of zidovudine for treatment of HIV-1 infection in adults 18 years of age or older is 600 mg daily in divided doses. Oral zidovudine usually is given in a dosage of 300 mg twice daily or 200 mg 3 times daily.

When lamivudine/zidovudine (Combivir) is used, adults weighing 30 kg or more should receive 1 tablet (300 mg of zidovudine and 150 mg of lamivudine) twice daily.

When abacavir/lamivudine/zidovudine (Trizivir) is used, adults should receive 1 tablet (300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine) twice daily.

The usual adult IV dosage of zidovudine for treatment of HIV-1 infection is 1 mg/kg 5-6 times daily (5-6 mg/kg daily). Although the effectiveness of this dosage compared with effectiveness of higher dosage for improving the neurologic dysfunction associated with HIV infection is unknown, there is some evidence from a small, randomized study that higher dosage may be associated with greater improvement of neurologic symptoms in patients with preexisting neurologic disease.

Prevention of Perinatal HIV Transmission

For prevention of perinatal HIV transmission, HIV-infected pregnant women who have plasma HIV-1 RNA levels exceeding 1000 copies/mL (or have unknown plasma HIV-1 RNA levels) near the time of delivery should receive an intrapartum IV zidovudine prophylaxis regimen initiated at the start of labor, regardless of their current antiretroviral regimen. In those undergoing scheduled cesarean delivery, IV zidovudine should be started 3 hours before incision. In addition, all infants born to HIV-infected women should receive an oral or IV zidovudine prophylaxis regimen (see Prevention of Perinatal HIV Transmission under Dosage: Pediatric Dosage, in Dosage and Administration).

If the IV zidovudine prophylaxis regimen is indicated, the HIV-infected woman should receive an initial zidovudine dose of 2 mg/kg given by IV infusion over 1 hour followed by 1 mg/kg per hour given by continuous IV infusion until delivery.In those already receiving oral zidovudine as part of a multiple-drug antiretroviral regimen, IV zidovudine should be substituted for oral zidovudine until after delivery; other antiretrovirals included in the woman's regimen should be continued on schedule as much as possible during labor.

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel or other individuals, the recommended dosage of oral zidovudine is 300 mg twice daily. Zidovudine usually is used with lamivudine or emtricitabine in conjunction with a recommended HIV integrase strand transferase inhibitor (INSTI), HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV protease inhibitor (PI).(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

When lamivudine/zidovudine (Combivir) is used as the dual NRTI option in PEP regimens, adults should receive 1 tablet (150 mg of lamivudine and 300 mg of zidovudine) twice daily in conjunction with a recommended INSTI, NNRTI, or PI.(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

PEP should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP), adults may receive oral zidovudine in a dosage of 300 mg twice daily or 200 mg 3 times daily in conjunction with other antiretrovirals.(See Uses: Postexposure Prophylaxis following Nonoccupational Exposure to HIV.)

The nPEP regimen should be initiated as soon as possible following nonoccupational exposure to HIV (preferably within 72 hours) and continued for 28 days.

Pediatric Dosage

Treatment of HIV Infection

Dosage of zidovudine in pediatric patients usually is based on body weight or, alternatively, body surface area. To avoid medication errors, extra care should be used in calculating the dose, transcribing the medication order, and dispensing the prescription.

Zidovudine dosage for treatment of HIV-1 infection in children should not exceed adult dosage.(See Table 1.)

Table 1. Recommended Oral Zidovudine Dosage for Treatment of HIV-1 Infection in Pediatric Patients 4 Weeks of Age or Older Who Weigh 4 kg or More[1 ]

Body Weight (kg)	Dosage Regimen
4 to less than 9	12 mg/kg twice daily or 8 mg/kg three times daily
9 to less than 30	9 mg/kg twice daily or 6 mg/kg three times daily
30 or more	300 mg twice daily or 200 mg three times daily

If body surface area is used to calculate dosage, the recommended oral dosage of zidovudine for treatment of HIV-1 infection in pediatric patients 4 weeks of age or older is 240 mg/m twice daily or 160 mg/m three times daily.

When zidovudine is used for treatment of HIV-1 infection in full-term infants (gestational age 35 weeks or more) younger than 6 weeks of age, some experts recommend an oral dosage of 4 mg/kg every 12 hours or an IV dosage of 3 mg/kg every 12 hours.

Usual zidovudine dosage used in full-term neonates may be excessive in premature neonates. For treatment of HIV-1 infection in premature infants (gestational age 30 to less than 35 weeks) younger than 6 weeks of age, experts recommend an oral zidovudine dosage of 2 mg/kg or IV dosage of 1.5 mg/kg every 12 hours; at 15 days of age, the dosage should be increased to 3 mg/kg orally or 2.3 mg/kg IV every 12 hours. For premature infants (gestational age less than 30 weeks) younger than 6 weeks of age, experts recommend an oral zidovudine dosage of 2 mg/kg or IV dosage of 1.5 mg/kg every 12 hours; after 4 weeks of age, the dosage should be increased to 3 mg/kg orally or 2.3 mg/kg IV every 12 hours.

When lamivudine/zidovudine (Combivir) is used for treatment of HIV-1 infection, children and adolescents weighing 30 kg or more should receive 1 tablet (150 mg of lamivudine and 300 mg of zidovudine) twice daily.

When abacavir/lamivudine/zidovudine (Trizivir) is used for treatment of HIV-1 infection, adolescents weighing 40 kg or more should receive 1 tablet (300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine) twice daily.

Prevention of Perinatal HIV Transmission

For prevention of perinatal HIV transmission in full-term neonates (gestational age 35 weeks or more), experts recommend that oral zidovudine be given in a dosage of 4 mg/kg twice daily, initiated as soon as possible after birth (within 6-12 hours) and continued through 6 weeks of age. Full-term neonates unable to receive oral therapy should receive IV zidovudine in a dosage of 3 mg/kg every 12 hours given by IV infusion, initiated as soon as possible after birth (preferably within 6-12 hours) and continued through 6 weeks of age. A 4-week zidovudine regimen can be considered (instead of a 6-week regimen) for infants born to mothers who were receiving a recommended multiple-drug antiretroviral regimen and have had consistent viral suppression during the pregnancy, provided there are no concerns about the mother's adherence to the treatment regimen.

For premature infants with gestational age of 30 weeks to less than 35 weeks, experts recommend an oral zidovudine dosage of 2 mg/kg or an IV dosage of 1.5 mg/kg every 12 hours initiated as soon as possible after birth (within 6-12 hours); at 15 days of age, dosage should be increased to 3 mg/kg orally or 2.3 mg/kg IV every 12 hours and continued through 6 weeks of age.

For premature neonates with gestational age less than 30 weeks, experts recommend an oral zidovudine dosage of 2 mg/kg or an IV dosage of 1.5 mg/kg every 12 hours initiated as soon as possible after birth (within 6-12 hours); after 4 weeks of age, dosage should be increased to 3 mg/kg orally or 2.3 mg/kg IV every 12 hours and continued through 6 weeks of age.

For prevention of perinatal HIV transmission in neonates born to HIV-infected women, the manufacturer recommends that oral zidovudine be given in a dosage of 2 mg/kg every 6 hours, initiated within 12 hours of birth, and continued through 6 weeks of age. The manufacturer states that neonates unable to receive oral therapy should receive IV zidovudine in a dosage of 1.5 mg/kg every 6 hours (given by IV infusion over 30 minutes) initiated within 12 hours of birth and continued through 6 weeks of age.

Although a 6-week neonatal zidovudine prophylaxis regimen usually is recommended to reduce the risk of perinatal HIV transmission, experts state that a 4-week zidovudine prophylaxis regimen can be considered for infants born to mothers who were receiving a recommended multiple-drug antiretroviral regimen and have had consistent viral suppression during the pregnancy.(See Uses: Prevention of Perinatal HIV Transmission.)

Decisions regarding the use of multiple-drug neonatal prophylaxis regimens that include other antiretrovirals in addition to zidovudine should be made in consultation with a pediatric HIV specialist.(See Uses: Prevention of Perinatal HIV Transmission.)

Dosage in Renal and Hepatic Impairment

Because zidovudine is eliminated principally by renal excretion following metabolism in the liver, dosage of the drug should be reduced in patients with severe renal impairment (i.e., creatinine clearance less than 15 mL/minute). Adults in end-stage renal disease maintained on hemodialysis or peritoneal dialysis should receive an oral zidovudine dosage of 100 mg every 6-8 hours or an IV dosage of 1 mg/kg every 6-8 hours.

Data are insufficient to recommend dosage adjustment for patients with mild to moderate impaired hepatic function or liver cirrhosis; however, a reduction in dosage may be necessary in these patients and frequent monitoring for hematologic toxicities is advised.

Lamivudine/zidovudine (Combivir) and abacavir/lamivudine/zidovudine (Trizivir) should not be used for treatment of HIV infection in patients with renal impairment (i.e., creatinine clearance less than 50 mL/minute) or in patients with any degree of hepatic impairment.

Cautions

The most common adverse effects of zidovudine in adults are headache, malaise, nausea, anorexia, and vomiting. Because HIV-infected patients receiving zidovudine generally have serious underlying disease with multiple baseline symptomatology and clinical abnormalities and because many adverse effects that occurred in zidovudine-treated patients also occurred in patients receiving placebo, many reported effects may not be directly attributable to zidovudine. The frequency and severity of adverse effects associated with use of zidovudine in adults are greater in patients with more advanced disease at the time of initiation of therapy. In one study in asymptomatic patients receiving 100 mg of the drug orally 5 times daily for an average of longer than 1 year (range: 4 months to 2 years), only nausea occurred more frequently in patients receiving zidovudine than in those receiving placebo. Adverse effects reported with use of zidovudine in women, IV drug users, and racial minorities are similar to those reported with use of the drug in white males.

Adverse systemic effects reported with IV zidovudine are similar to those reported with oral zidovudine. However, clinical experience with IV zidovudine has been more limited than experience with oral zidovudine and the drug has generally been administered IV only for short periods of time. Long-term IV zidovudine therapy (i.e., longer than 2-4 weeks) has not been evaluated in adults and may enhance adverse hematologic effects.

When the fixed combination containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir) or the fixed combination containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir) is used, the adverse effects, precautions, and contraindications associated with each of the individual components should be considered.(See Precautions Related to Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Hematologic Effects

The major adverse effect of oral or IV zidovudine in patients with advanced symptomatic HIV-1 infection is bone marrow toxicity resulting in severe anemia and/or neutropenia. These adverse hematologic effects have been severe enough to require blood transfusions and discontinuance of zidovudine or dosage modification in up to 41% of patients receiving the drug.

Hematologic toxicity is causally related to zidovudine therapy, being directly related to dosage and duration of therapy with the drug, and has been reported most frequently in patients with advanced symptomatic HIV infection or low pretreatment hemoglobin concentrations, neutrophil counts, and CD4 T-cell counts. Patients with low serum folate or vitamin B₁₂ concentrations may be at increased risk for developing bone marrow toxicity during zidovudine therapy. There also are limited data suggesting that bone marrow of patients with fulminant acquired immunodeficiency syndrome (AIDS) may be more sensitive to zidovudine-induced toxicity than that of patients with less advanced disease (e.g., AIDS-related complex [ARC]).

In patients with asymptomatic HIV infection or with early or advanced HIV disease and CD4 T-cell counts exceeding 200/mm who received zidovudine in a dosage of 500-1500 mg daily, anemia (hemoglobin concentration less than 8 g/dL) occurred in 1-4% and neutropenia (neutrophil count less than 750/mm) occurred in 1-10%. In patients with advanced HIV disease and CD4 T-cell counts of 200/mm or less who received zidovudine in a dosage of 600-1500 mg daily, anemia occurred in 29% and granulocytopenia occurred in 37-47%.

Anemia, as evidenced by a decrease in hemoglobin concentration, may occur as early as 2-4 weeks after initiation of zidovudine therapy, but occurs most commonly after 4-6 weeks of therapy. Granulocytopenia occurs most commonly after 6-8 weeks of therapy. Anemia and granulocytopenia usually resolve when zidovudine is discontinued or when dosage is decreased. Because of lithium's ability to stimulate neutrophilia (granulopoietic effect), the drug has been used with some success in a few patients with zidovudine-induced neutropenia. Biosynthetic hematopoietic agents, including filgrastim, a recombinant human granulocyte colony-stimulating factor (G-CSF), and sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), also have been used in an effort to correct or minimize zidovudine-induced neutropenia. (See Uses: Neutropenia Associated with HIV Infection and Antiretroviral Therapy, in and .) Severe, potentially fatal, but generally reversible, agranulocytosis or pancytopenia has occurred in some patients. Multiple blood transfusions may be required for treatment of severe anemia; however, a paradoxical erythrocytosis requiring phlebotomy has been reported rarely. Epoetin alfa, a recombinant human erythropoietin preparation, is used to treat the anemia associated with zidovudine. There is evidence that addition of epoetin alfa to the zidovudine regimen can increase and/or maintain the erythrocyte count as manifested by the hemoglobin concentration and hematocrit and decrease the need for red blood cell (RBC) transfusions; however, anemic zidovudine-treated patients with endogenous serum erythropoietin concentrations exceeding 500 mU/mL are unlikely to respond to epoetin alfa. In addition, epoetin alfa is not indicated for treatment of anemia in HIV-infected patients related to other factors (e.g., iron or folate deficiencies, hemolysis, GI bleeding). Epoetin alfa and filgrastim have been used concomitantly in a limited number of patients to ameliorate both severe anemia and granulocytopenia.

Zidovudine-induced anemia appears to result from impaired erythrocyte maturation; an increase in the mean corpuscular volume (MCV), which reflects megaloblastic changes, is often an early indicator of hematologic toxicity induced by the drug. Zidovudine-induced anemia is generally macrocytic and megaloblastic; however, a normocytic anemia associated with erythroid hypoplasia or aplasia has also been reported.

Exacerbation of anemia has been reported in HIV-infected patients coinfected with hepatitis C virus (HCV) who received zidovudine concomitantly with ribavirin; such concomitant use should be avoided. Concomitant use of zidovudine and myelosuppressive or cytotoxic drugs may increase the risk of hematologic toxicity.(See Drug Interactions.)

An increase in platelet count has occurred in some patients during zidovudine therapy, including some patients with HIV-associated thrombocytopenia. If an increase in platelet count occurs, it usually is evident during the first 1-2 weeks of therapy and may be maintained for at least the first 4-7 weeks of therapy. It has been suggested that the hematologic effects of zidovudine may be platelet sparing; however, thrombocytopenia has been reported rarely in patients receiving the drug. In one study, platelet counts decreased more than 50% from baseline values in 12% of patients receiving zidovudine and 5% of patients receiving placebo.

Aplastic anemia, hemolytic anemia, leukopenia, pancytopenia with marrow hypoplasia, and pure red cell aplasia have been reported in patients receiving zidovudine.

Lymphadenopathy has been reported in less than 5% of patients receiving zidovudine, but has not been directly attributed to the drug. Non-Hodgkin's lymphoma has been reported in patients with symptomatic HIV infection who have received long-term therapy with zidovudine either alone or in conjunction with other drugs (e.g., acyclovir). In one study in patients with AIDS or severe ARC, the incidence of non-Hodgkin's lymphoma was 14.5% in those who had received 13-35 months of regimens containing zidovudine. In this study, the estimated probabilities of developing non-Hodgkin's lymphoma were about 10, 29, and 46% by 24, 30, and 36 months of therapy, respectively. However, in another study in patients with AIDS or ARC receiving zidovudine, the probabilities of developing non-Hodgkin's lymphoma with continued therapy were substantially lower; the reasons for these differences are not known but may involve differences in antiretroviral therapy and severity of immunodeficiency at the start of therapy. In this study, the risk of developing non-Hodgkin's lymphoma appeared to be increased in patients with a history of Kaposi's sarcoma, cytomegalovirus infection, oral hairy leukoplakia, and possible herpes simplex infection. There also is some evidence that the risk of developing non-Hodgkin's lymphoma is increased by the degree of immunodeficiency (e.g., being increased substantially at CD4 T-cell counts less than 50/mm). Non-Hodgkin's lymphoma is a complication of HIV infection, and it has been suggested that prolonged survival secondary to antiretroviral and other therapy in the setting of profound immunodeficiency rather than a direct carcinogenic effect of zidovudine is more likely responsible for the increased incidence of developing non-Hodgkin's lymphoma observed to date in patients with HIV infection; however, the possibility that zidovudine may have a direct role in the development of these tumors cannot be excluded, and additional study is necessary.

Nervous System Effects

Headache, which may be severe, has been reported in up to 63% of patients receiving zidovudine, malaise has been reported in up to 53%, and asthenia has been reported in 9-69%. Agitation, dizziness, fatigue, insomnia, paresthesia, and somnolence have been reported in up to 8% of patients, most frequently in those who received high dosage of the drug. In a study in patients with asymptomatic HIV infection receiving oral zidovudine in a dosage of 500 mg daily, asthenia, dizziness, headache, or malaise occurred in 8.6, 17.9, 62.5, or 53.2% of patients, respectively; these same effects occurred in 5.8, 15.2, 52.6, or 44.9% of patients receiving placebo.

Seizures have been reported in patients receiving zidovudine, most frequently in patients with advanced HIV disease. Neuropathy also has been reported.

Although a definite causal relationship was not established, a manic syndrome consisting of irritability, depression, reduced cognition, hallucinations, euphoria, flight of ideas, and/or delusional states has been reported in several patients receiving zidovudine; lithium and/or other psychotherapeutic agents have reduced manifestations of this syndrome, even during continued zidovudine therapy. In several patients with AIDS or ARC receiving zidovudine therapy, acute, transient meningoencephalitis occurred when dosage of the drug was reduced; it has been suggested that the dosage reduction allowed an increase in HIV replication within the brain. In a patient with AIDS who received zidovudine in a dosage of 200 mg every 4 hours, a neurotoxic reaction consisting of headache, confusion, aphasia, twitching, and focal seizures occurred within 48 hours after initiation of the drug. Neurotoxicity resolved within 48 hours after discontinuance of zidovudine, recurred within 72 hours after reinitiation of therapy with the drug, and appeared to contribute to the patient's death 36 hours later. A fatal neurotoxic reaction with focal seizures has occurred in at least one other patient who received zidovudine in an oral dosage of 200 mg every 4 hours. Although a causal relationship was not clearly established, neurotoxic effects (e.g., tonic-clonic seizures) were temporally associated with zidovudine therapy in another patient with AIDS; autopsy findings revealed evidence of encephalopathy.

Anxiety, confusion, depression, emotional lability, nervousness, syncope, loss of mental acuity, vertigo, tremor, hyperalgesia, and back pain, have been reported in patients receiving zidovudine; however, a definite causal relationship to the drug has not been established. In several patients, confusion and tremor were associated with high plasma concentrations of the drug.

GI Effects

Nausea has been reported in up to 61% and anorexia, constipation, diarrhea, dyspepsia, abdominal cramping or pain, and vomiting in 5-25% of patients receiving zidovudine. Nausea occurs most frequently in patients with more advanced HIV disease and those receiving higher zidovudine dosage. In patients with symptomatic HIV infection or early HIV disease receiving oral zidovudine in a dosage of 1200 mg daily, nausea occurred in 61-68% of patients receiving zidovudine and in 41-46% of patients receiving placebo. In a study in patients with asymptomatic HIV infection receiving oral zidovudine in a dosage of 500 mg daily, nausea occurred in 51.4% of those receiving zidovudine and 29.9% of those receiving placebo. In other studies in asymptomatic HIV-infected patients receiving zidovudine in a dosage of 100 mg 5 times daily, nausea was reported in about 3%.

Bleeding gums, dysphagia, edema of the tongue, eructation, flatulence, mouth ulcer, oral mucosa pigmentation, rectal hemorrhage, and taste perversion have been reported in patients receiving zidovudine.

Esophageal ulceration, which was local in origin, has been reported in a few patients who swallowed their nightly doses of zidovudine capsules while in a recumbent position. To reduce the risk of esophageal irritation and ulceration, patients should be advised to swallow zidovudine capsules while in an upright position and with adequate amounts of fluid (e.g., at least 120 mL of water).

Musculoskeletal Effects

Myalgia and musculoskeletal pain have been reported in patients receiving zidovudine. In a study in patients with advanced HIV infection receiving high dosage of zidovudine (1500 mg daily), myalgia occurred in 8% of those receiving zidovudine and 2% of those receiving placebo. Myopathy and myositis with pathologic changes, similar to that produced by HIV infection, have been associated with prolonged use of zidovudine. Severe necrotizing myopathy, which generally affected the legs, and a polymyositis-like syndrome have been reported occasionally in patients receiving zidovudine. In most cases, the myopathy or polymyositis syndrome was apparent after 6.5-12 months of zidovudine therapy and was characterized by myalgias, muscle tenderness and weakness, weight loss, atrophy, and increased serum concentrations of muscle enzymes (e.g., creatine kinase, LDH). In many reported cases, myopathy resolved within 1-2 weeks when the drug was discontinued; in other cases, manifestations resolved over a 6-8 week period. Zidovudine-associated myopathy reportedly occurs in 6-18% of patients receiving the drug for more than 6 months. However, necrotizing, noninflammatory myopathy with microvesicular degeneration of muscle fibers, normal serum concentrations of muscle enzymes, and little pain also has been reported in patients with AIDS who were not receiving zidovudine and appears to be related to the HIV infection. Zidovudine-associated myopathy may not be clinically distinguishable from HIV-associated myopathy. Zidovudine appeared to be at least partially responsible for myopathy in many patients since symptoms resolved following discontinuance of the drug and repeat muscle biopsies showed improved arrangement of muscle-fiber cells and a decrease in inflammatory lesions. Histologic and electron microscopic evaluation of muscle biopsies from patients with myopathy indicate that inflammatory infiltrates may be present in either HIV-associated or zidovudine-associated myopathy. However, ragged-red fibers suggestive of abnormal mitochondria have been a consistent feature in muscle biopsies from patients with zidovudine-associated myopathy, whereas normal mitochondria generally were present in biopsies from patients with HIV-associated myopathy who had never received zidovudine. It has been suggested that zidovudine may inhibit γ-DNA polymerase and interfere with mitochondrial DNA replication causing the development of abnormal mitochondria and a resultant energy shortage within the muscle cell. It appears that zidovudine-associated myopathy in patients with HIV infection may be the result of both a direct effect of the drug on mitochondria as well as immune-mediated mechanisms.

Arthralgia, back pain, generalized pain, muscle spasm, tremor, and twitch have been reported in patients receiving zidovudine, but at a rate similar to that reported for placebo and a causal relationship to the drug has not been definitely established.

Dermatologic and Sensitivity Reactions

Diaphoresis, dyspnea, fever, rash, and taste perversion have been reported in 5-17% of patients receiving zidovudine, but a causal relationship was not definitely established since these effects also occurred in 3-15% of patients receiving placebo. In several reported cases, a causal relationship between low-grade fever (39-40°C) and zidovudine appeared to be demonstrated since fever started 5-7 days after initiation of therapy with the drug, persisted up to 5 days after the drug was discontinued, and recurred with rechallenge.

Hypersensitivity reactions have been reported rarely in patients receiving zidovudine. Anaphylaxis, angioedema, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. In most reported cases, hypersensitivity reactions consisted of fever, rash, and pruritus; nausea, vomiting, anorexia, weakness, confusion, and elevated serum hepatic enzymes occurred in some patients. Cutaneous leukocytoclastic vasculitis, characterized by distinctive dermal perivascular inflammation without visceral involvement, has been reported in at least 2 patients receiving zidovudine. The vasculitis was associated with fever and appeared to be a hypersensitivity reaction. In addition, severe reactions consisting of pruritic rash on the abdomen, back, and extremities with fever, nausea, headache, vomiting, lymphocytopenia, and elevated liver enzymes have been reported in at least 2 otherwise healthy adults receiving zidovudine in conjunction with zalcitabine (no longer commercially available in the US) for postexposure prophylaxis of HIV following occupational exposure to the virus.

Pigmentation of fingernails and toenails has been reported occasionally in patients receiving zidovudine. A dark, bluish discoloration at the base of the fingernails was evident 2-6 weeks after initiation of zidovudine therapy in black patients with HIV infection; similar discoloration of the toenails occurred after 4 more weeks of therapy with the drug. A similar, but brownish-gray pigmentation of fingernails and toenails has also been reported in other patients (including some whites) receiving zidovudine. In some reported cases, pigmentation involved the entire nail; in other cases, there were transverse or longitudinal bands of color. Zidovudine-associated nail discoloration has been reported more frequently in black patients than in white or Hispanic patients, reportedly occurring in 67-81% of black patients compared with 20-31% of white or Hispanic patients. The cause of this nail pigmentation is unknown but may result from injury to the nail bed, matrix, and/or plate; increased stimulation of matrix melanocytes by zidovudine may be involved. Diffuse hyperpigmented macular skin lesions and hyperpigmentation of the oral mucosa also have been reported in several patients who had pigmentation of the nails during zidovudine therapy. It has been suggested that such hyperpigmentation may be an early indication of zidovudine hypersensitivity; however, this observation was based on limited data. Patients should be informed that discoloration of nails may occur during zidovudine therapy.

Other adverse dermatologic effects, including acne, changes in skin pigmentation, pruritus, and urticaria, have been reported in patients receiving zidovudine, but a causal relationship has not been established.

Hepatic Effects and Lactic Acidosis

Lactic acidosis (in the absence of hypoxemia) and severe hepatomegaly with steatosis, including some fatalities, have been reported in patients receiving zidovudine. Although lactic acidosis and severe hepatomegaly appear to be related, they have been reported both separately and together. Manifestations of hepatotoxicity included fever, malaise, weakness, nausea, vomiting, diarrhea, epigastric pain, and rapidly increasing serum transaminase concentrations. In fatalities associated with enlarged fatty liver, massive hepatomegaly with severe, diffuse macrovesicular steatosis of the liver were present without associated necrosis; most fatalities were reported in women, many of whom were mildly to moderately obese. Manifestations of lactic acidosis generally developed rapidly and included tachypnea and dyspnea, without evidence of systemic hypoxemia or tissue hypoxia. In fatalities associated with lactic acidosis, some of the deaths resulted from cardiovascular collapse secondary to progressive lactic acidosis; in other cases, lactic acidosis persisted or improved although the patient died within the next 15 months of other complications.

The mechanism for the development of lactic acidosis and severe hepatomegaly with steatosis in patients receiving zidovudine is unknown, and the causal role of the drug in the development of these adverse effects has not been fully elucidated. In most reported cases of lactic acidosis or hepatomegaly with steatosis, patients had received at least 6 months of zidovudine therapy. Similar cases of lactic acidosis and severe hepatomegaly with steatosis have been reported rarely in patients receiving other HIV nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., abacavir, didanosine, stavudine). However, it is unclear whether these adverse effects are a direct result of nucleoside antiviral therapy since adverse hepatic effects, including hepatomegaly and mild to moderate macrovesicular steatosis, have been described in some AIDS patients in the absence of antiretroviral therapy or any apparent underlying etiology. Because results of in vitro studies indicate that the active metabolites of zidovudine and other nucleoside antiviral agents can exert an inhibitory effect on γ-polymerase, an enzyme involved in mitochondrial DNA synthesis, it has been suggested that this effect may be a factor in the development of lactic acidosis, as well as other adverse effects, in patients receiving the drugs.(See Mechanism of Action: Cytotoxic Effects.)

There also have been rare reports of zidovudine-associated hepatitis, including cholestatic hepatitis that recurred on rechallenge, and fulminant hepatic failure in patients who received zidovudine. Increases in liver function test results, including serum AST (SGOT), LDH, and alkaline phosphatase concentrations, have been reported in some patients receiving zidovudine and have been reported in up to 3% of patients with asymptomatic HIV infection. In some reported cases, serum concentrations of these enzymes increased within 2-3 weeks after initiating zidovudine therapy but returned to pretreatment values when therapy with the drug was withheld and did not increase when therapy was restarted. Mild drug-associated increases in total bilirubin concentrations have been reported rarely in asymptomatic HIV-infected patients receiving zidovudine.

Hepatic decompensation, sometimes fatal, has been reported in HIV-infected patients coinfected with HCV who received antiretroviral therapy concomitantly with interferon alfa (or peginterferon alfa) with or without ribavirin.(See Drug Interactions.)

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (''buffalo hump''), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving antiretroviral agents, including zidovudine. The mechanisms responsible for these adipogenic effects and the long-term consequences of these effects are unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome) have been reported to occur in the setting of immune reconstitution; the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Other Adverse Effects

Adverse respiratory effects, including dyspnea, epistaxis, hoarseness, pharyngitis, rhinitis, and sinusitis, and adverse urinary effects, including dysuria, polyuria, urinary frequency, and urinary hesitancy, have been reported in patients receiving zidovudine; however a causal relationship was not established.

Other adverse effects reported in patients receiving zidovudine include amblyopia, hearing loss, photophobia, body odor, chills, edema of the lip, macular edema, pancreatitis, flu syndrome, cardiomyopathy, chest pain, rhabdomyolysis, and vasodilation.

IV administration of zidovudine may cause local reactions including pain and slight irritation at the infusion site. Phlebitis also has been reported rarely with IV zidovudine. Breast enlargement has been reported rarely in female patients and bilateral gynecomastia has been reported rarely in male patients receiving zidovudine.

Precautions and Contraindications

Zidovudine and fixed combinations containing zidovudine (lamivudine/zidovudine, abacavir/lamivudine/zidovudine) are contraindicated in patients who have had potentially life-threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to the drug or any ingredient in the formulation.(See Precautions Related to Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Precautions Related to Hematologic Effects

Zidovudine therapy may be associated with hematologic toxicity, including neutropenia and/or severe anemia, especially in patients with advanced HIV disease. Blood cell counts and indices of anemia (e.g., hemoglobin, mean corpuscular volume) should be performed prior to initiation of zidovudine therapy to establish baseline values and should then be monitored during therapy with the drug. Patients with advanced HIV disease or low baseline values for blood cell counts and indices of anemia should be monitored frequently (at least every 2 weeks); periodic monitoring (once monthly for the first 3 months and then, if stable, once every 3 months) is recommended for patients with asymptomatic or early symptomatic HIV infection.

If significant anemia (hemoglobin less than 7.5 g/dL or reduction of more than 25% from baseline) and/or neutropenia (granulocyte count less than 750 cells/mm or reduction of more than 50% from baseline) occurs, interruption of zidovudine therapy may be necessary until there is evidence of bone marrow recovery. In patients who develop significant anemia, dosage interruption does not necessarily eliminate the need for blood transfusions. If marrow recovery occurs following dosage interruption, reinitiation of zidovudine therapy may be appropriate using adjunctive measures (e.g., epoetin alfa), depending on hematologic indices such as serum erythropoetin level and patient tolerance.

Patients should be informed that the major adverse effects of zidovudine are anemia and/or neutropenia. The frequency and severity of these toxicities are greater in patients with more advanced disease and in those who initiate therapy later in the course of their infection. Patients should be told of the extreme importance of having their blood cell counts followed closely while receiving zidovudine therapy, especially those with advanced symptomatic HIV infection. Patients also should be told that if toxicity develops, they may require transfusions or discontinuance of the drug and they should be cautioned about concomitant use of other drugs that may potentiate zidovudine toxicity.

Because exacerbation of anemia has been reported in HIV-infected patients coinfected with HCV who received zidovudine concomitantly with ribavirin, concomitant use of these drugs should be avoided. Clinicians should consider that concomitant use of zidovudine and myelosuppressive or cytotoxic drugs (e.g., ganciclovir, interferon alfa, ribavirin) may increase the risk of hematologic toxicity.(See Drug Interactions.)

Precautions Related to Use of Fixed Combinations

When lamivudine/zidovudine or abacavir/lamivudine/zidovudine is used, the usual cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination must be considered. Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, pediatric patients, geriatric patients) should be considered for each drug.

Because the antiretrovirals contained in lamivudine/zidovudine and abacavir/lamivudine/zidovudine also are available in single-entity or other fixed-combination preparations, care should be taken to ensure that therapy is not duplicated if one of these fixed combinations is used in conjunction with other antiretrovirals.

Multiple zidovudine-containing preparations should not be used concomitantly.

Lamivudine/zidovudine and abacavir/lamivudine/zidovudine should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1000 cells/mm or hemoglobin less than 9.5 g/dL.(See Precautions Related to Hematologic Effects under Cautions: Precautions and Contraindications.)

If lamivudine/zidovudine or abacavir/lamivudine/zidovudine is used, clinicians should consider that severe, acute exacerbations of hepatitis B virus (HBV) infection have been reported when lamivudine was discontinued from antiretroviral regimens in HIV-infected patients coinfected with HBV. Although a causal relationship to lamivudine discontinuance has not been established, patients receiving lamivudine-containing preparations should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with the drug. Emergence of lamivudine-resistant HBV also has been reported in HIV-infected patients coinfected with HBV who were receiving lamivudine-containing antiretroviral regimens for treatment of HIV.

If abacavir/lamivudine/zidovudine is used, clinicians should consider that abacavir has been associated with serious and sometimes fatal hypersensitivity reactions. Because individuals with the human leukocyte antigen (HLA)-B*5701 allele are at high risk for abacavir hypersensitivity reactions, screening for the HLA-B*5701 allele is recommended prior to initiation of abacavir-containing preparations. Abacavir/lamivudine/zidovudine should be discontinued as soon as a hypersensitivity reaction is suspected. Regardless of the patient's HLA-B*5701 status, the fixed combinations should be permanently discontinued if hypersensitivity cannot be ruled out.

Other Precautions

Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving HIV NRTIs, including zidovudine, alone or in conjunction with other antiretroviral agents. Most reported cases have involved women; obesity and long-term therapy with NRTIs also may be risk factors. Zidovudine should be used with caution in any patient with hepatomegaly, hepatitis, or other known risk factor for liver disease, and such patients should be monitored closely while receiving the drug. Lactic acidosis should be considered whenever a patient receiving zidovudine develops unexplained tachypnea, dyspnea, or a decrease in serum bicarbonate concentrations. If such manifestations occur, zidovudine should be discontinued until a diagnosis of lactic acidosis has been excluded. The clinical importance of increased serum aminotransferase (transaminase) concentrations suggesting hepatic injury in HIV-infected patients prior to initiation of zidovudine therapy or during therapy with the drug is unclear. Zidovudine therapy should be discontinued in patients with rapidly increasing serum aminotransferase concentrations, progressive hepatomegaly, or metabolic/lactic acidosis of unknown etiology. Patients should be instructed to notify their physician if they experience muscle weakness, shortness of breath, manifestations of hepatitis or pancreatitis, or any other unexplained adverse effect while receiving zidovudine. Clinicians are encouraged to report any cases of unexplained lactic acidosis and/or massive hepatomegaly in HIV-infected patients (without regard to whether or not the patient is receiving antiretroviral therapy) to the manufacturer or the US Food and Drug Administration (FDA).

HIV-infected patients coinfected with HCV should be informed that hepatic decompensation (sometimes fatal) has been reported when antiretrovirals were used concomitantly with interferon alfa (or peginterferon alfa) with or without ribavirin and that they should be closely monitored for toxicity, especially hepatic decompensation, neutropenia, and anemia.(See Drug Interactions.)

Because myopathy or myositis with pathologic changes (similar to that produced by HIV disease) has been reported in individuals who received long-term zidovudine therapy, patients should be informed about these adverse effects and questioned during routine visits about symptoms such as myalgia, loss of muscle mass, weight loss, and proximal muscle weakness. Elevations in serum concentrations of muscle enzymes (e.g., creatine kinase, LDH) may occur weeks before symptoms of myopathy and some clinicians recommend that serum creatine kinase concentrations be determined every 3 months in patients who have received zidovudine for 6-12 months or longer. Depending on the severity of musculoskeletal manifestations, interruption of zidovudine therapy or, preferably, dosage reduction should be considered in patients who develop myopathy during therapy with the drug. If manifestations of myopathy persist following discontinuance of zidovudine therapy, the drug probably should be reinstated since the myopathy may be related to the HIV infection. In patients with mild manifestations of myopathy, use of a nonsteroidal anti-inflammatory agent may be beneficial; the risks and benefits of corticosteroids for treatment of myopathy in patients with HIV infection have not been evaluated to date.

Patients should be advised that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are as yet unknown.(See Cautions: Adipogenic Effects.)

Zidovudine in conjunction with other antiretroviral agents is not a cure for HIV infection, and patients receiving the drugs may continue to develop opportunistic infections and other complications associated with HIV disease. Patients should be informed of the critical nature of compliance with HIV therapy and the importance of remaining under the care of a clinician. Patients should be advised to take their antiretroviral regimen exactly as prescribed and to not alter or discontinue the regimen without consulting a clinician.

Patients should be advised that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Patients should continue to practice safer sex (e.g., use latex or polyurethane condoms to minimize sexual contact with body fluids), never share personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reuse or share needles.

Zidovudine should always be administered in conjunction with other antiretroviral agents and should not be used alone for treatment of HIV infection. The usual precautions and contraindications of the other antiretrovirals in the regimen should be considered during concomitant therapy.

Because zidovudine is eliminated principally by renal excretion following metabolism in the liver, patients with impaired renal or hepatic function or decreased hepatic blood flow may be at increased risk of toxicity from the drug. A reduction in zidovudine dosage is recommended in patients with severe renal impairment.(See Dosage: Dosage in Renal and Hepatic Impairment.) Although data are limited regarding use of zidovudine in patients with hepatic impairment, those with severe hepatic impairment may be at increased risk of hematologic toxicity. Patients with hemophilia often have compromised hepatic function because of an increased incidence of HCV; however, zidovudine has been well tolerated in such patients who have asymptomatic HIV infection.

Pediatric Precautions

Zidovudine generally has been well tolerated when used in neonates and children. The major adverse effects reported in children are similar to those reported in adults and include bone marrow toxicity resulting in anemia and/or neutropenia. The reported incidence of anemia and granulocytopenia among children with advanced HIV infection receiving zidovudine is similar to that reported for adults with AIDS or advanced ARC. In children 3 months to 12 years of age with advanced HIV infection who received a mean of 267 days (range: 3-855 days) of zidovudine therapy, anemia (hemoglobin less than 7.5 g/dL) occurred in 23% and granulocytopenia (granulocytes less than 750/mm) occurred in 39% of patients. Management of these adverse effects included dosage modification, temporary discontinuance of the drug, and/or blood transfusions. Most children had macrocytosis.

In one randomized, double-blind, placebo-controlled trial evaluating use of zidovudine for prevention of maternal-fetal transmission of HIV, the most common adverse effects in neonates were anemia (hemoglobin less than 9 g/dL) and neutropenia (less than 1000/mm). Anemia occurred in 22% of infants who received zidovudine (2 mg/kg orally every 6 hours for 6 weeks beginning within 12 hours of birth) and in 12% of infants who received placebo. Mean hemoglobin concentrations in infants receiving zidovudine were less than 1 g/dL lower than hemoglobin concentrations in infants receiving placebo. No infants with anemia required transfusion and all hemoglobin concentrations spontaneously returned to normal within 6 weeks after completion of zidovudine therapy. Neutropenia was reported in 21% of infants who received zidovudine and 27% of infants who received placebo. The long-term consequences of in utero and infant exposure to zidovudine are unknown.(See Cautions: Pregnancy, Fertility, and Lactation.)

Lamivudine/zidovudine (Combivir) should not be used in pediatric patients or adolescents weighing less than 30 kg.

Abacavir/lamivudine/zidovudine (Trizivir) should not be used in pediatric patients or in adolescents weighing less than 40 kg.

Geriatric Precautions

While clinical experience to date has not revealed age-related differences in response to zidovudine, clinical studies evaluating zidovudine have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults. Dosage of zidovudine for geriatric patients should be selected carefully because of limited experience with the drug in this age group and because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Mutagenicity and Carcinogenicity

Zidovudine was mutagenic in a 5178Y/TK mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests following repeated doses. Zidovudine was negative in a cytogenetic study in rats given a single dose.

In carcinogenicity studies in mice, late-appearing (after 19 months) vaginal neoplasms (nonmetastasizing squamous cell carcinomas, squamous cell papilloma, squamous polyps) occurred in some of those receiving the highest zidovudine dosage (120 mg/kg daily and then 40 mg/kg daily after 90 days). One mouse receiving an intermediate dosage (60 mg/kg daily and then 30 mg/kg daily) developed vaginal squamous cell papilloma late in the study, but no vaginal neoplasms were observed in mice receiving the lowest dosage studied. In a similar study in rats, late-appearing (after 20 months) nonmetastasizing vaginal squamous cell carcinoma occurred in some rats receiving the highest oral dosages (600 mg/kg daily initially, 450 mg/kg daily starting on day 91, and then 300 mg/kg daily starting on day 279); no vaginal neoplasms occurred in rats receiving low or intermediate dosages. There were no other drug-related neoplasms observed in either sex of either species studied. At dosages that produced tumors in mice or rats, the estimated drug exposure (as measured by AUC) were approximately 3 or 24 times, respectively, the estimated human exposure at a dosage of 100 mg every 4 hours.

Transplacental carcinogenicity studies have been conducted in rodents. In one study in mice, zidovudine 20 or 40 mg/kg daily (zidovudine exposure equivalent to about 3 times the estimated human exposure at recommended dosages) was administered to the mother from gestation day 10 through parturition and lactation and then administered postnatally to the offspring for 24 months. An increased incidence of vaginal tumors was observed after 24 months; however, there was no observable increase in the incidence of tumors of the lung, liver, or any other organ in either male or female mice. In another study in pregnant mice, zidovudine was administered at maximally tolerated dosages of 12.5 or 25 mg daily (approximately 1000 mg/kg nonpregnant body weight or approximately 450 mg/kg of term body weight) from days 12-18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice who received the higher zidovudine dosage. The clinical importance of these carcinogenic effects in rodents is not known.

Pregnancy, Fertility, and Lactation

Pregnancy

There is no evidence of human teratogenicity with zidovudine.

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that zidovudine and lamivudine is one of several preferred dual NRTI options for initial regimens used for treatment of HIV infection in antiretroviral-naive pregnant women.

Reproduction studies in rats and rabbits using oral zidovudine in dosages up to 500 mg/kg daily have not revealed evidence of teratogenicity. However, there was evidence of embryo and fetal toxicity (an increased incidence of fetal resorptions) in rats given the drug in dosages of 150 or 450 mg/kg daily and rabbits given 500 mg/kg daily Peak plasma concentrations of zidovudine attained in rats and rabbits in these teratology studies were 66-226 and 12-87 times higher, respectively, than mean steady-state peak plasma concentrations of zidovudine attained in humans receiving 100 mg of the drug every 4 hours. In an additional study in rats, there was no evidence of teratogenicity with zidovudine dosages up to 600 mg/kg daily; however, a dosage of 3000 mg/kg daily (the oral median lethal dose of the drug in rats is 3683 mg/kg daily) caused marked maternal toxicity and an increase in the incidence of fetal malformations; this dosage resulted in peak plasma zidovudine concentrations 350 times the peak human plasma concentrations and is associated with an estimated AUC in rats that is 300 time the daily AUC in humans receiving a dosage of 600 mg daily. In one in vitro study in fertilized mouse oocytes, exposure to zidovudine resulted in a dose-dependent reduction in blastocyst formation. Transplacental carcinogenicity studies have been performed in mice.(See Cautions: Mutagenicity and Carcinogenicity.)

Zidovudine and its glucuronide metabolite cross the human placenta and are distributed into amniotic fluid, cord blood, and fetal blood and fetal liver, muscle, and CNS tissue. Pregnancy is not a contraindication for use of antiretroviral therapy. Zidovudine is well tolerated in pregnant women; safety of zidovudine in mother and infant has been demonstrated in short-term studies.

Zidovudine has been used throughout pregnancy in some HIV-infected women without evidence of teratogenicity or harm to the fetus. In one retrospective study of 43 HIV-infected women who received zidovudine during their pregnancies, there was no evidence of teratogenic effects in the neonates, no cases of fetal death or stillbirth, and no association between treatment with the drug and premature birth. In several neonates, however, there was evidence of anemia and intrauterine growth retardation that was possibly related to the mothers' zidovudine therapy. Data obtained from study PACTG 076, a randomized, double-blind, placebo-controlled study evaluating a 3-part zidovudine regimen for prevention of maternal-fetal transmission of HIV indicated that similar rates of congenital abnormalities occurred in infants with or without in utero exposure to zidovudine; abnormalities were either problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound prior to or immediately after initiation of study drug. In addition, there were no differences in growth, neurodevelopment, or immunologic status between uninfected infants born to mothers who received zidovudine and those born to mothers who received placebo (median follow-up 4.2 years).

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including zidovudine, the Antiretroviral Pregnancy Registry was established. Clinicians are encouraged to contact the registry at 800-258-4263 or http://www.APRegistry.com to enroll such women. Data obtained through the pregnancy registry indicate that there is no increased risk for congenital abnormalities among infants born to women who receive zidovudine during pregnancy compared with the general population. The prevalence of birth defects was 3.3% following first trimester exposures to zidovudine; the birth defect rate among pregnant women in the US reference population is 2.7%.

Fertility

There was no evidence that zidovudine affected fertility (conception rates) when the drug was given to male and female rats in dosages up to 7 times the usual adult dosage based on body surface area.

Lactation

Zidovudine is distributed into human milk. Potential toxicities of antiretroviral agents in infants exposed to the drugs via breast milk are unknown. In addition, efficacy of antiretroviral therapy for prevention of postpartum transmission of HIV through breast milk is unknown.

Because of the risk of transmission of HIV to an uninfected infant through breast milk, the HHS Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission and the US Centers for Disease Control and Prevention (CDC) recommend that HIV-infected women not breast-feed infants, regardless of antiretroviral therapy. Therefore, because of the potential for HIV transmission and the potential for serious adverse effects from zidovudine in nursing infants, women should be instructed not to breast-feed while they are receiving zidovudine.

Drug Interactions

The following drug interactions are based on studies using zidovudine. Drug interaction studies have not been performed using the fixed combination containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir) or the fixed combination containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir). When a fixed combination is used, interactions associated with each drug in the fixed combination should be considered.

Acyclovir

Neurotoxicity (profound drowsiness and lethargy), which recurred on rechallenge, has been reported in at least one HIV-infected patient who received acyclovir and zidovudine concomitantly Neurotoxicity was evident within 30-60 days after initiation of IV acyclovir therapy, persisted with some improvement when acyclovir was administered orally, and resolved following discontinuance of acyclovir in this patient. Acyclovir and zidovudine have been used concomitantly in other HIV-infected patients without evidence of increased toxicity.

Although the clinical importance is unclear, there is some evidence that acyclovir may potentiate the antiretroviral effect of zidovudine in vitro; acyclovir alone has only minimal antiretroviral activity.

Antifungal Agents

Fluconazole

Concomitant use of fluconazole appears to interfere with the metabolism and clearance of zidovudine. In one study in HIV-infected men who received zidovudine (200 mg every 8 hours) alone or in conjunction with fluconazole (400 mg daily), the area under the concentration-time curve (AUC) of zidovudine was increased 74% (range: 28-173%), peak serum zidovudine concentrations were increased 84% (range: -1 to 227%), and the terminal elimination half-life of the drug was increased 128% (range: -4 to 189%) in patients receiving concomitant fluconazole.

Although the clinical importance of this effect is unknown, it has been suggested that patients receiving concomitant zidovudine and fluconazole therapy be monitored closely for zidovudine-associated adverse effects. Routine zidovudine dosage modifications are not warranted in patients receiving concomitant fluconazole; however, a reduction in zidovudine dosage may be considered if a patient experiences substantial anemia or other severe zidovudine-associated adverse effect while receiving the drugs concomitantly.

Antimycobacterial Agents

The fact that pharmacokinetic interactions between some antimycobacterial agents (e.g., rifabutin, rifampin) and some antiretroviral agents (especially HIV protease inhibitors [PIs] and HIV nonnucleoside reverse transcriptase inhibitors [NNRTIs]) have been reported or are expected to occur must be considered when antimycobacterial therapy is indicated for treatment of active tuberculosis or latent tuberculosis infection or for the prophylaxis or treatment of Mycobacterium avium complex infection in HIV-infected patients who are receiving or are being considered for antiretroviral therapy. Because the management of these patients is complex and must be individualized, experts in the management of mycobacterial infections in HIV-infected patients should be consulted.

Zidovudine has been used concomitantly with antituberculosis agent therapy without evidence of substantially increased toxicity in patients with pulmonary tuberculosis and symptomatic HIV infection (acquired immunodeficiency syndrome [AIDS] or advanced AIDS-related complex [ARC]). In one study in a limited number of patients who received zidovudine concomitantly with an antituberculosis regimen of isoniazid and rifampin (with or without ethambutol) or a regimen of isoniazid, ethambutol, and pyrazinamide for 12 weeks, mild to moderate decreases in leukocyte counts occurred more frequently in the group that received concomitant therapy than in a control group that received zidovudine alone; however, there was no statistical difference between the groups in other reported adverse effects. In another study in adults with HIV infection and tuberculosis, zidovudine therapy administered concomitantly with an antituberculosis regimen (isoniazid, rifampin, pyrazinamide, and ethambutol initially, followed by isoniazid and rifampin) was well tolerated for up to 8 months or longer.

Rifabutin

In one study in HIV-infected adults, concomitant use of rifabutin (300 mg once daily) and oral zidovudine (200 mg every 8 hours) did not affect most pharmacokinetic parameters of zidovudine, including AUC, peak plasma concentration, and renal clearance; the plasma half-life of zidovudine was decreased from 1.5 to 1.1 hours. In another study in HIV-infected patients designed to evaluate the effect of zidovudine on rifabutin pharmacokinetics, concomitant use of zidovudine (100 or 200 mg every 4 hours) and rifabutin (300 or 450 mg once daily) did not alter the pharmacokinetics of the antimycobacterial agent or its principal metabolite, and such use was not associated with any unusual adverse effects.

Rifampin

In a multiple-dose study in HIV-infected patients, concomitant use of zidovudine (200 mg every 8 hours) and rifampin (600 mg once daily) for 14 days resulted in a 47% decrease in zidovudine AUC. The manufacturer of zidovudine states that routine dosage adjustments are not necessary if rifampin and zidovudine are used concomitantly.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

There is in vitro evidence of additive to synergistic antiretroviral effects between enfuvirtide and zidovudine.

Maraviroc

There is no in vitro evidence of antagonistic antiretroviral effects between maraviroc and zidovudine.

Maraviroc has no effect on zidovudine pharmacokinetics.

HIV Integrase Inhibitors (INSTIs)

In vitro studies indicate that additive to synergistic antiretroviral effects can occur between raltegravir and zidovudine.

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Results of in vitro cell culture studies indicate that the antiretroviral effects of zidovudine and HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., delavirdine, efavirenz, nevirapine) are additive to synergistic against HIV-1. There is no in vitro evidence of antagonistic antiretroviral effects between zidovudine and etravirine or rilpivirine.

Delavirdine

Concomitant use of delavirdine and zidovudine does not affect the pharmacokinetics of either drug.

Efavirenz

Concomitant use of efavirenz (600 mg once daily for 14 days) and zidovudine (300 mg every 12 hours for 14 days) does not affect zidovudine peak plasma concentrations or AUC. Dosage adjustments are not necessary if zidovudine and efavirenz are used concomitantly.

Nevirapine

Concomitant use of zidovudine and nevirapine results in a 28 and 30% decrease in zidovudine peak plasma concentrations and AUC, respectively.

Rilpivirine

Although not specifically studied, clinically important pharmacokinetic interactions are not expected if rilpivirine is used concomitantly with zidovudine.

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Results of in vitro studies indicate that the antiretroviral effects of zidovudine and some other HIV nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., abacavir, didanosine, emtricitabine, lamivudine, tenofovir) are additive to synergistic against HIV-1. Although some in vitro studies indicate that the antiretroviral activities of zidovudine and stavudine are additive or synergistic against HIV-1, in vitro and in vivo antagonism has been reported.

Abacavir

Clinically important pharmacokinetic interactions have not been observed when abacavir and zidovudine were used concomitantly.

Didanosine

Concomitant use of buffered didanosine (200 mg every 12 hours for 3 days) and oral zidovudine (200 mg every 8 hours for 3 days) in HIV-infected patients decreased the peak plasma concentration and AUC of zidovudine by 17 and 10%, respectively, but did not affect the peak plasma concentration or AUC of didanosine. Results of a study in HIV-infected pediatric patients 3 months of age or older indicate that concomitant use of oral zidovudine and oral didanosine does not affect the AUC of either drug.

Emtricitabine

Although not considered clinically important, concomitant use of emtricitabine (200 mg once daily for 7 days) and zidovudine (300 mg twice daily for 7 days) increased zidovudine peak plasma concentrations and AUC by 17 and 13%, respectively, but did not affect emtricitabine peak plasma concentrations or AUC.

Lamivudine

Results of a study in asymptomatic HIV-infected patients who received a single 200-mg dose of zidovudine in conjunction with multiple doses of lamivudine (300 mg every 12 hours) indicate that concomitant use of the drugs does not have a clinically important effect on the pharmacokinetics of either drug. The AUC of zidovudine was increased 13%, but lamivudine concentrations were not affected.

Dosage adjustments are not necessary in patients receiving lamivudine and zidovudine concomitantly.

Stavudine

Zidovudine and stavudine should not be used concomitantly at any time because of in vitro and in vivo evidence of antagonistic antiretroviral effects.

Antagonism may occur because zidovudine and stavudine compete for cellular thymidine kinase that is needed for monophosphorylation of both drugs.

HIV Protease Inhibitors (PIs)

The antiretroviral effects of zidovudine and some HIV protease inhibitors (PIs) (e.g., amprenavir [commercially available as fosamprenavir], indinavir, nelfinavir, ritonavir, saquinavir, tipranavir) are additive or synergistic against HIV-1 in vitro in cell culture. There is no in vitro evidence of antagonistic antiretroviral effects between zidovudine and atazanavir or darunavir.

Atazanavir

Concomitant use of zidovudine and atazanavir may decrease trough plasma concentrations of zidovudine, but does not affect the AUC of zidovudine. The clinical importance of this pharmacokinetic interaction is unknown.

Darunavir

Pharmacokinetic interactions between zidovudine and ritonavir-boosted darunavir are not expected.

Fosamprenavir

Concomitant use of fosamprenavir (single 600-mg dose) and zidovudine (single 300-mg dose) increased zidovudine peak plasma concentrations and AUC by 40 and 31%, respectively. When amprenavir (single 600-mg dose) and zidovudine (single 300-mg dose) were used concomitantly, there was a 13% increase in the AUC of amprenavir, but no effect on amprenavir peak plasma concentrations.

Indinavir

Concomitant use of indinavir (1 g every 8 hours) and zidovudine (200 mg every 8 hours) for 1 week resulted in slightly increased indinavir peak plasma concentrations and AUC, slightly increased zidovudine AUC, and decreased zidovudine peak plasma concentrations. In a study in HIV-infected patients who received a 3-drug regimen of indinavir (800 mg every 8 hours), zidovudine (200 mg every 8 hours), and lamivudine (150 mg every 12 hours) for 7 days, peak plasma concentrations and AUC of indinavir and zidovudine were increased, but peak plasma concentrations and AUC of lamivudine were decreased.

Lopinavir

Although the clinical importance is unclear, lopinavir induces glucuronidation and has the potential to reduce zidovudine plasma concentrations.

Nelfinavir

Concomitant use of zidovudine (single 200-mg dose) and nelfinavir (750 mg every 8 hours for 7-10 days) resulted in a 35% decrease in the AUC of zidovudine and a 31% decrease in peak plasma concentrations of zidovudine; plasma concentrations of nelfinavir were not affected by concomitant zidovudine.

The AUC and peak plasma concentration of nelfinavir were unaffected in individuals who received nelfinavir (750 mg 3 times daily for 7-10 days) concomitantly with zidovudine (single 200-mg dose) and lamivudine (single 150-mg dose).

Routine zidovudine dosage modifications are not warranted in patients receiving zidovudine and nelfinavir concomitantly.

Ritonavir

Concomitant use of oral zidovudine (200 mg every 8 hours) and oral ritonavir (300 mg every 6 hours) for 4 days decreased the peak plasma concentration and AUC of zidovudine by 27 and 25%, respectively, but did not affect the pharmacokinetics of ritonavir.

Dosage adjustments are not necessary in patients receiving zidovudine and ritonavir concomitantly.

Tipranavir

Although the clinical importance is unknown, concomitant use of ritonavir-boosted tipranavir decreases the AUC of zidovudine by approximately 35% and may also decrease peak plasma concentrations and AUC of tipranavir.

Some experts state that appropriate dosages for concomitant use of zidovudine and ritonavir-boosted tipranavir have not been established.

Atovaquone

Concomitant use of zidovudine (200 mg every 8 hours) and atovaquone (750 mg every 12 hours with food) in 14 HIV-infected adults increased the AUC of zidovudine by about 31-35% and decreased zidovudine clearance by about 24%, but did not affect peak plasma concentrations of zidovudine or half-life of the drug. It was suggested that atovaquone inhibited glucuronidation of zidovudine. The pharmacokinetics of atovaquone were not affected by concomitant zidovudine.

Routine zidovudine dosage modifications are not warranted in patients receiving zidovudine concomitantly with atovaquone, but patients should be monitored for zidovudine-associated adverse effects.

Cidofovir

Cidofovir does not affect the pharmacokinetics of zidovudine. Cidofovir, however, must be given concomitantly with probenecid, a drug that can reduce zidovudine clearance. Since recommended regimens of cidofovir and probenecid are usually administered once every 1 or 2 weeks, the manufacturer of cidofovir recommends that zidovudine be temporarily discontinued or dosage reduced by 50% on the days that cidofovir and probenecid are administered.(See Drug Interactions: Probenecid.)

Co-trimoxazole

In one study in a limited number of HIV-infected patients, concomitant use of oral zidovudine (250 mg every 12 hours) and oral co-trimoxazole (160 mg of trimethoprim and 800 mg of sulfamethoxazole twice daily 3 times weekly) did not alter the pharmacokinetics of zidovudine or its glucuronide metabolite.

Dipyridamole

Although the clinical importance is unclear, in vitro studies using human monocyte/macrophage cells and T cells indicate that the antiviral activity of zidovudine against HIV-1 is enhanced by the presence of dipyridamole. Dipyridamole alone has little antiretroviral activity. Results of one study indicate that dipyridamole inhibits conversion of thymidine to thymidine triphosphate but does not interfere with conversion of zidovudine to its active triphosphate derivative. It has been suggested that dipyridamole potentiates the antiviral activity of zidovudine by decreasing cellular concentrations of thymidine triphosphate, which competes with zidovudine triphosphate for viral RNA-directed DNA polymerase and incorporation into viral DNA.

Doxorubicin

Because there is in vitro evidence that doxorubicin inhibits phosphorylation of zidovudine to the active triphosphate metabolite and therefore could antagonize the antiretroviral activity of the drug, the manufacturer of zidovudine states that concomitant use of the drugs should be avoided.

Drugs That Affect Glucuronidation

In at least one study, concomitant use of acetaminophen reportedly resulted in an increased risk of granulocytopenia in patients receiving zidovudine; this potentiation of hematologic toxicity appeared to correlate with the duration of acetaminophen use. The exact mechanism of this possible interaction has not been determined, but it has been suggested that acetaminophen may competitively inhibit glucuronidation of zidovudine. However, further analysis of these data by the manufacturer failed to support the findings of an interaction, and there were no apparent alterations in the pharmacokinetics of zidovudine in several subsequent studies that evaluated concomitant short-term (for up to 7 days) use of acetaminophen and the drug; one study actually demonstrated an increase in zidovudine clearance during concurrent acetaminophen administration. Many clinicians suggest that intermittent therapy with acetaminophen is not contraindicated, and acetaminophen (or ibuprofen) may be used for short periods of time in patients receiving zidovudine, as long as the patient is monitored closely. In one limited study in adults with HIV infection, concomitant use of oral oxazepam and oral zidovudine did not have any clinically important effects on the pharmacokinetics of either drug other than a slight increase in the calculated oral clearance of the benzodiazepine. There was, however, an increase in the incidence of headaches in patients receiving concomitant therapy. Pending further accumulation of data, drugs that may interfere with glucuronidation of zidovudine (e.g., aspirin, cimetidine, indomethacin, lorazepam, oxazepam) probably should be avoided or, if necessary, used with caution during zidovudine therapy since the toxicity of either drug may be potentiated.

Foscarnet

Although the clinical importance is unclear, results of in vitro tests indicate that the antiviral effects of foscarnet and zidovudine are additive or synergistic against HIV. In addition, in one study in a limited number of adults with symptomatic HIV infection, use of IV foscarnet (30 mg/kg every 8 hours) in conjunction with oral zidovudine (200 mg every 4 hours) apparently resulted in a transient additive effect since serum p24 antigen levels decreased during concomitant therapy and increased when foscarnet therapy was discontinued.

Ganciclovir and Valganciclovir

Although the clinical importance is unclear, results of an in vitro study using H9 cells inoculated with HIV (strain HTLV-IIIB) indicate that ganciclovir antagonizes the antiretroviral activity of zidovudine against HIV. In addition, results of in vitro studies indicate that concomitant use of ganciclovir and zidovudine results in synergistic cytotoxicity.

Both ganciclovir and zidovudine alone produce direct, dose-dependent inhibitory effects on myeloid and erythroid progenitor cells, and concomitant use of zidovudine and ganciclovir (or valganciclovir) may increase the risk of hematologic toxicity or result in additive or synergistic myelotoxic effects. In several studies in patients with AIDS and cytomegalovirus infections, profound, intolerable myelosuppression, evidenced principally as severe neutropenia, occurred in all patients receiving ganciclovir (5 mg/kg IV 1-4 times daily) concomitantly with zidovudine (200 mg orally every 4 hours); anemia also occurred in many of these patients. Severe hematologic toxicity, which required a reduction in zidovudine dosage, also occurred in more than 80% of patients receiving ganciclovir (5 mg/kg IV 1-2 times daily) concomitantly with zidovudine (100 mg orally every 4 hours). The increased risk of hematologic toxicity does not appear to be related to a pharmacokinetic interaction between zidovudine and ganciclovir since there is no evidence that concomitant use affects the pharmacokinetic parameters of either drug.

Because of the risk of hematologic toxicity, concomitant use of zidovudine and ganciclovir is not recommended. If combined therapy is considered necessary, the drugs must be used with extreme caution and hematologic parameters (e.g., hemoglobin, hematocrit, leukocyte count with differential) should be monitored frequently. HIV-infected patients should be counseled that concomitant use of zidovudine and ganciclovir may not be tolerated by some patients and may result in severe granulocytopenia (neutropenia). Although experience is limited to date, intravitreal ganciclovir, which does not appear to be associated with appreciable systemic toxicity, has been suggested as an alternative to IV ganciclovir therapy in patients with cytomegalovirus retinitis in whom concomitant zidovudine therapy is considered necessary and in whom hematologic toxicity is not tolerated.

HCV Antivirals

HCV Protease Inhibitors

Simeprevir

No clinically important interactions are expected if simeprevir is used concomitantly with zidovudine.

Hematopoietic Agents

Although the clinical importance is unclear, results of in vitro studies indicate that biosynthetic granulocyte-macrophage colony-stimulating factors (GM-CSFs) may potentiate the antiretroviral activity of zidovudine against HIV. In one in vitro study using monocyte/macrophage cell cultures, the presence of GM-CSF markedly enhanced the antiretroviral effect of zidovudine against a monocytotropic strain of HIV type 1 and against HIV-1 (strain HTLV-IIIB). A synergistic effect between GM-CSF and zidovudine also was evident in vitro in monocytic U-937 cells inoculated with HIV-1 (strain HTLV-IIIB). The mechanism of this synergistic effect has not been determined but may result from enhanced entry of zidovudine into infected cells and/or enhanced conversion of zidovudine monophosphate into the metabolically active triphosphate derivative. The fact that conflicting results have been obtained from studies evaluating the in vitro effects of biosynthetic GM-CSFs on replication of HIV when used alone and the fact that GM-CSFs appear to stimulate replication of some strains of HIV in vitro in certain cell cultures should be considered if sargramostim or any other biosynthetic GM-CSF is used in conjunction with zidovudine in patients with HIV infection.

Interferon Alfa and Peginterferon Alfa

In vitro studies indicate that the antiretroviral activity of zidovudine and interferon alfa may be synergistic against HIV. There also is limited in vivo evidence of enhanced antiretroviral activity with combined therapy. Interferon alfa has been used concomitantly with zidovudine in patients with AIDS-related Kaposi's sarcoma, and there is evidence of clinical response, including good tumor response in some patients. Although concomitant use of zidovudine and interferon alfa does not appear to result in any major alterations in the pharmacokinetics of either drug, there may be a trend for increased AUC and decreased clearance of zidovudine after 3 weeks of concomitant therapy.

Depending on the dosage used, concomitant use of interferon alfa and zidovudine can be relatively well tolerated; however, concomitant use of the drugs can increase the risk of hematologic (e.g., neutropenia, thrombocytopenia) and hepatic toxicity. Potentially fatal hepatic decompensation has been reported in HIV-infected patients coinfected with hepatitis C virus (HCV) who received antiretroviral therapy concomitantly with interferon alfa (or peginterferon alfa) with or without ribavirin. Patients receiving zidovudine with interferon alfa (or peginterferon alfa) with or without ribavirin should be closely monitored for toxicities, especially hepatic decompensation. Discontinuance of zidovudine should be considered as medically appropriate. Dosage reduction or discontinuance of interferon alfa (or peginterferon alfa) and/or ribavirin also should be considered if worsening clinical toxicities, including hepatic decompensation (e.g., Child-Pugh score greater than 6) occur,

For further information on concomitant use of zidovudine and interferon alfa in patients with HIV infection, .

Macrolides

Concomitant use of clarithromycin (500 mg twice daily) and zidovudine (100 mg 4 times daily for 7 days) decreased the AUC of zidovudine by 12% (range: 34% decrease to 14% increase). Routine zidovudine dosage adjustments are not warranted in patients receiving zidovudine and clarithromycin concomitantly.

Megestrol Acetate

Results of a pharmacokinetic study in HIV-infected adults indicate that concomitant use of megestrol acetate (800 mg) and oral zidovudine (100 mg) for 13 days results in a 14% decrease in the peak plasma concentration and about a 5% decrease in the AUC_0-12 of zidovudine at steady-state. These effects were not considered clinically important.

Myelosuppressive Agents

Drugs that are cytotoxic or myelosuppressive (e.g., amphotericin B, dapsone, doxorubicin, flucytosine, ganciclovir, interferon, pentamidine, vinblastine, vincristine) may increase the risk of hematologic toxicity and should be used with caution during zidovudine therapy.

Opiates and Opiate Partial Agonists

Buprenorphine

There are no clinically important pharmacokinetic interactions between buprenorphine and zidovudine; dosage adjustments are not necessary if the drugs are used concomitantly.

Methadone

In one study in IV drug abusers with HIV infection who were receiving long-term methadone treatment for opiate addiction (30-90 mg daily), initiation of zidovudine therapy (200 mg orally every 4 hours) did not appear to have any clinically important effects on the pharmacokinetics of methadone and did not result in any evidence of narcotic withdrawal. However, the AUC of zidovudine was increased about 43% in patients receiving concomitant methadone compared with those receiving zidovudine alone. In another study in HIV-infected individuals who had been receiving methadone treatment for approximately 2 months, concomitant use of oral or IV zidovudine increased the zidovudine AUC by 29 or 41%, respectively, and reduced the clearance of zidovudine by about 26%. Methadone maintenance therapy did not appear to affect zidovudine pharmacokinetics is 5 pregnant women.

While the mechanism of this interaction requires further study, limited data indicate that methadone inhibits zidovudine glucuronidation, and also reduces renal clearance of zidovudine. Based on the results of the pharmacokinetic studies, it appears that the maintenance dose of methadone probably does not need to be adjusted when zidovudine therapy is initiated in patients receiving long-term methadone treatment.

Routine zidovudine dosage adjustments are not warranted in patients receiving zidovudine and methadone concomitantly, but patients should be monitored for zidovudine toxicity. In addition, the fact that IV drug abusers receiving methadone treatment also may be illicitly using other drugs (e.g., cannabis, cocaine, benzodiazepines, other opiate agonists) that have the potential to affect the pharmacokinetics of zidovudine should be considered when therapy with the antiretroviral agent is initiated in these patients.

Phenytoin

Decreased plasma phenytoin concentrations have been reported in some patients receiving concomitant zidovudine and, in at least one patient, an increased phenytoin concentration was reported. In one study in adults with HIV infection receiving oral zidovudine therapy (200 mg every 4 hours), administration of a single 300-mg dose of phenytoin resulted in a 30% decrease in clearance of the antiretroviral agent; pharmacokinetics of phenytoin apparently was not affected.

Probenecid

Concomitant use of probenecid may produce substantially higher and prolonged serum concentrations of zidovudine. In one study, concomitant use of probenecid (500 mg every 6 hours for 2 days) and zidovudine (2 mg/kg every 8 hours for 3 days) increased the AUC of zidovudine by 106%. Although limited information suggests that probenecid may inhibit glucuronidation and/or reduce renal excretion of zidovudine, evidence from one study suggests that probenecid may principally inhibit metabolism rather than renal excretion of zidovudine, although renal excretion of its glucuronide metabolite appears to be inhibited.

In one study in patients with HIV infection who were receiving zidovudine, initiation of concomitant probenecid therapy (500 mg orally 3 times daily) resulted in flu-like symptoms, including myalgia, malaise, and/or fever and rash with maculopapular erythematous eruptions. These adverse effects generally developed during the first or second week of concomitant therapy and were severe enough to require discontinuance of probenecid therapy in some patients. It is unclear whether these adverse effects were the result of a drug interaction between zidovudine and probenecid or whether they reflect an increased potential for hypersensitivity reactions to probenecid in patients with HIV infection. Although some clinicians have suggested that probenecid's effect on the pharmacokinetics of zidovudine could be used to therapeutic advantage to decrease the dose and/or frequency of administration of zidovudine, other clinicians state that probenecid should be used with caution in patients receiving zidovudine. The manufacturer of zidovudine states that routine zidovudine dosage modifications are not warranted if probenecid and zidovudine are used concomitantly.

For information on zidovudine therapy in patients receiving probenecid concomitantly with cidofovir, see Drug Interactions: Cidofovir.

Pyrimethamine

Results of one study indicate that zidovudine can antagonize the toxoplasmacidal action of pyrimethamine against Toxoplasma gondii in vitro and in vivo in mice and can interfere with the in vitro synergism of pyrimethamine and sulfadiazine against the organism. Although the clinical importance of this effect is unclear, it has been suggested that patients with HIV infection being treated for toxoplasmic encephalitis who also are receiving zidovudine should be monitored carefully for evidence of poor response to pyrimethamine. In vitro, trimethoprim and zidovudine have exhibited synergistic antibacterial activity in vitro against some gram-negative bacteria (i.e., Citrobacter, Enterobacter, Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Shigella).

Ribavirin

The manufacturer of zidovudine and some experts state that concomitant use of zidovudine and ribavirin should be avoided, if possible. The manufacturer of ribavirin states that concomitant use of ribavirin and nucleoside analogs should be undertaken with caution and only if the potential benefits outweigh the potential risks. If zidovudine and ribavirin are used concomitantly, patients should be closely monitored for virologic response and hematologic toxicities.

In vitro, ribavirin antagonizes the antiviral activity of zidovudine against HIV. This antagonism appears to result from inhibition of zidovudine phosphorylation by ribavirin and/or phosphorylated ribavirin, possibly secondary to a ribavirin-induced increase in deoxythymidine triphosphate (dTTP) concentrations and a subsequent feedback inhibition of thymidine kinase. Increased dTTP concentrations might also interfere with the interaction of zidovudine triphosphate with HIV RNA-directed DNA polymerase (reverse transcriptase). Despite this in vitro antagonism, zidovudine has been used concomitantly with ribavirin (with or without interferon alfa) in some HIV-infected patients coinfected with HCV without evidence of an increase in HIV viral load. No changes in zidovudine pharmacokinetics were observed in HIV-infected patients coinfected with hepatitis B virus (HBV) receiving ribavirin and zidovudine as part of a multiple-drug regimen.

It has been suggested that concomitant use of ribavirin and NRTIs may increase the risk of mitochondrial dysfunction and associated toxicities (e.g., pancreatitis, lactic acidosis) reported with this group of antiretroviral agents. There have been several reports of lactic acidosis or pancreatitis occurring in HIV-infected patients coinfected with HCV who received antiretroviral therapy concomitantly with ribavirin and interferon alfa. These patients had been receiving long-term therapy with multiple-drug antiretroviral regimens that included one or more NRTIs (abacavir, didanosine, stavudine, zidovudine) and were clinically stable until lactic acidosis or pancreatitis developed 4-6 months after a regimen of ribavirin and interferon alfa was initiated for treatment of chronic HCV infection. Because ribavirin also is a nucleoside analog, it has been suggested that concomitant use of ribavirin and NRTIs may result in an adverse additive effect on mitochondrial function; however, other clinicians suggest that ribavirin may have potentiated the effects of the NRTIs through some other mechanism or that the viral diseases themselves may have been partly responsible for mitochondrial dysfunction in these patients.

Valproic Acid

Concomitant use of valproic acid (250 or 500 mg every 8 hours) and oral zidovudine (100 mg every 8 hours) for 4 days in a limited number of HIV-infected adults resulted in an 80% increase in the AUC of zidovudine. The effect of concomitant zidovudine on the pharmacokinetics of valproic acid was not evaluated. Although the clinical importance of this interaction between zidovudine and valproic acid is not known, patients receiving both drugs should be monitored more closely for zidovudine-related adverse effects. Severe anemia has been reported following initiation of valproic acid therapy (500 mg twice daily) in an HIV-infected adult who was receiving an antiretroviral regimen that contained zidovudine, lamivudine, and abacavir; the patient had stable hematologic status at the time valproic acid was started.

Routine zidovudine dosage modifications are not warranted in patients receiving zidovudine and valproic acid concomitantly; however, a reduction in zidovudine dosage may be considered if a patient experiences substantial anemia or other severe zidovudine-associated adverse effect while receiving the drugs concomitantly.

Pharmacokinetics

Pharmacokinetics of zidovudine have been studied in adults with human immunodeficiency virus (HIV) infection, HIV-infected neonates, infants, and children up to 12 years of age, pregnant women, and adults with renal impairment. Pharmacokinetics of the drug have not been specifically studied in geriatric adults older than 65 years of age.

Pharmacokinetics of zidovudine in pediatric patients older than 3 months of age are similar to that reported in adults. However, zidovudine pharmacokinetics in neonates younger than 2 weeks of age, particularly premature neonates, are substantially different than those in adults. Results of a limited single-dose study indicate that gender does not affect the pharmacokinetics of zidovudine.

Pharmacokinetics of zidovudine in pregnant women are similar to that reported in nonpregnant adults. Results of studies evaluating use of oral zidovudine in women during the second and third trimesters of pregnancy indicate that, although the volume of distribution and clearance of the drug may be increased slightly in some patients during pregnancy, peak plasma concentrations and half-life of the drug generally are the same as those reported for other adults.

A concentration of 1 nmol/L of zidovudine is approximately equivalent to 0.27 ng/mL.

Absorption

Following oral administration, zidovudine is well absorbed, but absorption shows considerable interindividual variation (range: 42-95%) and the drug appears to undergo first-pass metabolism. In adults, children, and neonates, about 65% (range: 50-89%) of an oral dose reaches systemic circulation as unchanged drug.

Results of some studies indicate that the rate of absorption and peak plasma concentrations of zidovudine may be increased substantially if the drug is taken with a meal. However, the manufacturer states that the extent of absorption of zidovudine as determined by the AUC is not affected by food.

The fixed-combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine (Combivir) is bioequivalent to one 150-mg tablet of lamivudine and one 300-mg tablet of zidovudine given simultaneously. The fixed-combination tablet containing 300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine (Trizivir) is bioequivalent to one 300-mg abacavir tablet, one 150-mg lamivudine tablet, and one 300-mg zidovudine tablet given simultaneously.

Adult

Zidovudine is rapidly absorbed from the GI tract, with peak serum concentrations generally occurring within 0.4-1.5 hours after an oral dose of the drug. In fasting adults, about 64% of an oral dose reaches systemic circulation as unchanged drug. Results of a multiple-dose study in a limited number of HIV-infected adults receiving 100- or 200-mg doses of zidovudine every 4 hours indicate that the commercially available zidovudine oral solution is bioequivalent to commercially available capsules of the drug with respect to area under the plasma-concentration time curve (AUC). In addition, the AUC of zidovudine following administration of zidovudine tablets is equivalent to that following administration of the capsules or oral solution.

Following IV infusion over 1 hour of a single 2.5- or 5-mg/kg dose of zidovudine in adults with HIV infection, peak plasma concentrations of the drug immediately following completion of the infusion ranged from 1.07-1.6 or 1.6-2.7 mcg/mL, respectively. Following IV administration of zidovudine in a dosage of 2.5 mg/kg every 4 hours, mean steady-state peak plasma concentrations are 1.06 mcg/mL and trough concentrations are 0.12 mcg/mL.

Children

In children 3 months to 12 years of age, zidovudine appears to have dose dependent increases in plasma concentrations after administration of an oral solution over the dosage range of 90-240 mg/m every 6 hours.

In one limited study in neonates and infants younger than 3 months of age born to HIV-infected mothers, zidovudine was well absorbed when administered orally; however, bioavailability decreased after 14 days of age. Following oral doses of 2-4 mg/kg, bioavailability of the drug averaged 89% in those 14 days of age or younger and 61% in those older than 14 days of age. In neonates 14 days of age or younger who received single 2-mg/kg oral doses of the drug or infants older than 14 days of age who received single 3-mg/kg oral doses, plasma zidovudine concentrations were greater than 0.267 mcg/mL for 4.12 or 2.25 hours, respectively, after the dose.

In children 14 months to 12 years of age with symptomatic HIV infection who received a single 80-mg/m dose of zidovudine given by IV infusion over 1 hour, peak plasma concentrations of the drug averaged 1.58 mcg/mL; plasma concentrations were less than 0.27 mcg/mL within an hour following completion of the infusion. When these children received continuous IV infusion of zidovudine in a dosage of 0.5, 0.9, 1.4, or 1.8 mg/kg per hour, steady-state plasma concentrations of the drug averaged 0.51, 0.75, 0.83, or 1.2 mcg/mL, respectively.

Distribution

There is limited information on the distribution of zidovudine into body tissue or fluids, but the drug appears to be widely distributed. The apparent volume of distribution of the drug in adults with HIV infection is 1.4-1.6 L/kg. In children 1-13 years of age with symptomatic HIV infection, the volume of distribution of zidovudine at steady state ranges from 22-64 L/m.

Zidovudine is distributed into CSF following oral or IV administration. The ratio of CSF/plasma concentrations of zidovudine reported in various studies in adults or children with HIV infection who received oral or IV therapy with the drug has ranged from 0.15-2.1. In one study in HIV-infected adults who received a single IV dose of zidovudine of 2.5 mg/kg by IV infusion over 1 hour, peak CSF concentrations averaged 0.35 mcg/mL (range: 0.11-0.96 mcg/mL) 1 hour after completion of the infusion and the ratio of peak CSF/plasma concentration was 0.17. In an adult who received an oral zidovudine dosage of 2 mg/kg every 8 hours, the CSF concentration of the drug 1.8 hours after a dose was about 0.04 mcg/mL and the CSF/plasma ratio was 0.15. Following IV dosages of 2.5 or 5 mg/kg every 4 hours, CSF concentrations 2-4 hours after dosing were about 0.1-0.13 or 0.23-0.37 mcg/mL, respectively, and the CSF/plasma ratio was 0.2-0.5 or 0.64-0.73, respectively. In children receiving both intermittent oral and IV zidovudine in phase 1 and 2 studies, the mean ratio of CSF/plasma concentrations of the drug was 0.52 in samples obtained at an average of 2.2 hours after an oral dose of 120-240 mg/m. At 3.2 hours after the start of an IV infusion of 80-160 mg/m given over 1 hour, the ratio was 0.87; during continuous IV infusion of the drug, the mean steady-state CSF/plasma ratio was 0.26. However, CSF concentrations may not be good indicators of distribution of the drug into brain parenchyma. Studies in rats indicate that, although zidovudine readily distributes into CSF, distribution of the drug into brain interstitial fluid may be minimal.

Zidovudine is distributed into semen following oral administration; however, there is no evidence to date that presence of the drug in semen reduces the risk of transmission of HIV. In a limited number of HIV-infected men receiving oral zidovudine (200 mg every 4-6 hours), the ratio of semen/serum concentrations of the drug ranged from 1.3-20.4 in samples obtained 0.75-4.5 hours after dosing. In another study in antiretroviral-naive, HIV-infected men who received oral zidovudine (300 mg twice daily or 200 mg 3 times daily) and oral lamivudine (150 mg twice daily), the median ratio of semen/plasma concentrations of zidovudine was 5.9.

Zidovudine is less than 38% bound to plasma proteins.

Zidovudine and its glucuronide metabolite cross the human placenta and are distributed into cord blood and amniotic fluid as well as fetal liver, muscle, and CNS tissue. Concentrations of the drug and its metabolite in cord blood, fetal plasma, amniotic fluid, and fetal muscle tissue are similar to or exceed those in maternal plasma; only very low concentrations are distributed into fetal CNS tissue. The ratio of the glucuronide metabolite to zidovudine is higher in maternal blood than in fetal blood.

Zidovudine is distributed into milk. In a study in HIV-infected women who received a single 200-mg dose of zidovudine, concentrations of the drug in milk were similar to concurrent serum concentrations.

Elimination

The plasma half-life of zidovudine in adults averages approximately 0.5-3 hours following oral or IV administration. Following IV administration of zidovudine in adults or children, plasma concentrations of the drug appear to decline in a biphasic manner. Half-life in adults is less than 10 minutes in the initial phase and 1 hour in the terminal phase.

Following IV administration over 1 hour of a single 80-, 120-, or 160-mg/m dose in children 1-13 years of age with symptomatic HIV infection, the t_½α of zidovudine averaged 0.16-0.25 hours and the t_½β averaged 1-1.7 hours. Plasma half-life of zidovudine generally is longer in neonates than in older children and adults but decreases with neonatal maturity. In one limited study in neonates and infants younger than 3 months of age, plasma half-life of zidovudine averaged 3.1 hours in those 14 days of age or younger and 1.9 hours in those older than 14 days of age. In a study in premature neonates (26-32 weeks' gestation; birthweight 0.7-1.9 kg), the serum half-life of zidovudine averaged 7.3 hours at an average postnatal age of 6.3 days and averaged 4.4 hours at an average postnatal age of 17.7 days.

Zidovudine is rapidly metabolized via glucuronidation in the liver principally to 3'-azido-3'-deoxy-5'-O-β-d-glucopyranuronosylthymidine (GZDV; formerly GAZT); zidovudine is also metabolized to GZDV in renal microsomes. GZDV has an apparent elimination half-life of 1 hour (range: 0.6-1.7 hours) and does not appear to have antiviral activity against HIV. In addition, two other hepatic metabolites of zidovudine have been identified as 3'-amino-3'-deoxythymidine (AMT) and its glucuronide derivative (GAMT). Intracellularly, in both virus-infected and uninfected cells, zidovudine is converted to zidovudine monophosphate by cellular thymidine kinase; the monophosphate derivative is phosphorylated to zidovudine diphosphate via cellular dTMP kinase (thymidylate kinase) and then to zidovudine triphosphate via other cellular enzymes. Intracellular (host cell) conversion of zidovudine to the triphosphate derivative is necessary for the antiviral activity of the drug. Activation for antibacterial action, however, does not depend on phosphorylation within host cells but rather depends on conversion within bacterial cells.(See Mechanism of Action.)

Zidovudine and GZDV are eliminated principally in urine via both glomerular filtration and tubular secretion. Following oral or IV administration in adults with HIV infection, total body clearance of zidovudine averages 1.6 L/hr per kg (range: 0.8-2.7 L/hr per kg) and renal clearance of the drug averages 0.34 L/hr per kg. In children 3 months to 12 years of age, the total body clearance averaged 1.85 L/hr per kg. In one limited study in neonates and infants younger than 3 months of age, total body clearance of the drug averaged 0.65 L/hr per kg in those 14 days of age or younger and 1.14 L/hr per kg in those older than 14 days of age.

Following oral administration of zidovudine in patients with HIV infection, 63-95% of the dose is excreted in urine; approximately 14-18% of the dose is excreted as unchanged zidovudine and 72-74% is excreted as GZDV within 6 hours. Following IV administration of the drug in adults or children with HIV infection, approximately 18-29% of the dose is excreted in urine as unchanged drug and 45-60% is excreted as GZDV within 6 hours.

In patients with impaired renal function, plasma concentrations of zidovudine may be increased and the half-life prolonged. In one study in adults with impaired renal function (creatinine clearances ranging from 6-31 mL/minute) without HIV infection, t_½β of zidovudine averaged 1.4 hours and was similar to that reported for adults with HIV infection who had normal renal function. However, the t_½β of GZDV in these adults with impaired renal function averaged 8 hours and was considerably prolonged compared with that reported for adults with HIV infection who had normal renal function.

In one study in adults with hemophilia and HIV infection who had elevated serum concentrations of AST (SGOT), ALT (SGPT), alkaline phosphatase, and γ-glutamyltransferase (GGT, γ-glutamyl transpeptidase, GGTP), pharmacokinetics of zidovudine after a single 300-mg oral dose showed considerable interindividual variation In some of these patients, pharmacokinetics of the drug could be described by a biexponential equation and the t_½β of the zidovudine and GZDV averaged 1.3 and 1.2 hours, respectively. In some of these patients, pharmacokinetics of the drug was best described by a triexponential equation and the t_½βs were prolonged, averaging 48 and 5.2 hours, respectively.

In a limited number of HIV-infected patients with or without liver disease who received a single 250-mg oral dose of zidovudine, peak zidovudine plasma concentrations were attained within about an hour in both groups but averaged 8.3 mcg/mL in those with liver disease compared with 1.5 mcg/mL in those without liver disease; mean plasma half-life was 1.8 hours in those with liver disease compared with 0.5 hours in those without liver disease. In addition, peak plasma concentrations of GZDV were attained later in those with liver disease. Because zidovudine clearance may be decreased and plasma concentrations increased following administration of the usual adult dosage to patients with hepatic impairment, dosage reduction may be necessary.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Hemodialysis and peritoneal dialysis appear to have a negligible effect on removal of zidovudine, but may enhance elimination of GZDV. In anuric patients undergoing hemodialysis, the relative amount of a zidovudine dose eliminated via dialysis as unchanged drug compared with that eliminated via metabolism and dialysis of the metabolite appears to be minimal. The amount of drug removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate). In anuric adults without HIV infection undergoing 4-hour periods of hemodialysis, plasma half-life of GZDV averaged 1.7 hours during dialysis and 52 hours between dialysis sessions. The manufacturer and some clinicians recommend that zidovudine be administered in a reduced dosage in patients undergoing hemodialysis or peritoneal dialysis.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)