PRINCIPAL DISPLAY PANEL

NDC 49702-213-26

RETROVIR

(zidovudine)

INJECTION

200 mg/20 mL (10 mg/mL)

MUST BE DILUTED PRIOR TO INTRAVENOUS INFUSION.

Five x 20 mL Single-Dose Vials

Discard Unused Portion

Rx only

Sterile

Made in India

©2025 ViiV Healthcare group of companies or its licensor.

Trademark is owned by or licensed to the ViiV Healthcare group of companies.

62000000099203 Rev. 03/25


WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND

SEVERE HEPATOMEGALY WITH STEATOSIS

See full prescribing information for complete boxed warning.

•

**Hematologic toxicity including neutropenia and severe anemia have been associated with the use of zidovudine. (****5.1****)**

•

**Symptomatic myopathy associated with prolonged use of zidovudine. (****5.2****)**

•

**Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including RETROVIR. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. (****5.3****)**

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity/Bone Marrow Suppression

RETROVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm3 or hemoglobin less than 9.5 g per dL. Hematologic toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the most significant adverse events observed. In patients who experience hematologic toxicity, a reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks. There have been reports of pancytopenia associated with the use of RETROVIR, which was reversible in most instances after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood transfusions, has occurred during treatment with RETROVIR alone or in combination with other antiretrovirals.

Frequent blood counts are strongly recommended to detect severe anemia or neutropenia in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease who are treated with RETROVIR. For HIV-1-infected individuals and patients with asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage interruption may be needed [see Dosage and Administration (2.4)].

5.2 Myopathy

Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of RETROVIR.

5.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including zidovudine. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment with RETROVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

5.4 Use with Interferon- and Ribavirin-Based Regimens in HIV-1/HCV Co-

infected Patients

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with zidovudine in HIV-1/HCV co-infected subjects [see Clinical Pharmacology (12.3)], exacerbation of anemia due to ribavirin has been reported when zidovudine is part of the HIV regimen. Coadministration of ribavirin and zidovudine is not advised. Consideration should be given to replacing zidovudine in established combination HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia.

Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and RETROVIR should be closely monitored for treatment- associated toxicities, especially hepatic decompensation, neutropenia, and anemia.

Discontinuation of RETROVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). See the full prescribing information for interferon and ribavirin.

5.5 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RETROVIR. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain- Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.6 Lipoatrophy

Treatment with zidovudine has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to a non-zidovudine-containing regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine and other zidovudine-containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.

See boxed warning for information about the following: hematologic toxicity, myopathy, and lactic acidosis and severe hepatomegaly. (5.1, 5.2, 5.3) 

Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and zidovudine is not advised. (5.4)

Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with/without ribavirin. Discontinue RETROVIR as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.4)

Immune reconstitution syndrome (5.5) and lipoatrophy (5.6) have been reported in patients treated with combination antiretroviral therapy.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

•

Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and Precautions (5.1)].

•

Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.2)].

•

Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.3)].

•

Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.4)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults

The frequency and severity of adverse reactions associated with the use of RETROVIR are greater in patients with more advanced infection at the time of initiation of therapy.

Table 3 summarizes adverse reactions reported at a statistically significant greater incidence for subjects receiving oral RETROVIR in a monotherapy trial.

Table 3. Percentage (%) of Subjects with Adverse Reactions (Greater than or Equal to 5% Frequency) in Asymptomatic HIV-1 Infection (ACTG 019)

a Not statistically significant versus placebo.
Adverse Reaction	RETROVIR 500 mg/day (n = 453)	Placebo (n = 428)
Body as a whole
Asthenia	9%a	6%
Headache	63%	53%
Malaise	53%	45%
Gastrointestinal
Anorexia	20%	11%
Constipation	6%a	4%
Nausea	51%	30%
Vomiting	17%	10%

In addition to the adverse reactions listed in Table 3, adverse reactions observed at an incidence of greater than or equal to 5% in any treatment arm in clinical trials (NUCA3001, NUCA3002, NUCB3001, and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in these trials hyperbilirubinemia was reported at an incidence of less than or equal to 0.8%.

Selected laboratory abnormalities observed during a clinical trial of monotherapy with oral RETROVIR are shown in Table 4.

Table 4. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Subjects with Asymptomatic HIV-1 Infection (ACTG 019)

ULN = Upper limit of normal.
Test (Abnormal Level)	RETROVIR 500 mg/day (n = 453)	Placebo (n = 428)
Anemia (Hgb <8 g/dL)	1%	<1%
Granulocytopenia (<750 cells/mm3)	2%	2%
Thrombocytopenia (platelets <50,000/mm3)	0%	<1%
ALT (>5 x ULN)	3%	3%
AST (>5 x ULN)	1%	2%

The adverse reactions reported during IV administration of RETROVIR injection are similar to those reported with oral administration; neutropenia and anemia were reported most frequently. Long-term IV administration beyond 2 to 4 weeks has not been studied in adults and may enhance hematologic adverse reactions. Local reaction, pain, and slight irritation during IV administration occur infrequently.

Pediatrics

The clinical adverse reactions reported among adult recipients of RETROVIR may also occur in pediatric patients.

Trial ACTG 300: Selected clinical adverse reactions and physical findings with a greater than or equal to 5% frequency during therapy with EPIVIR (lamivudine) oral suspension 4 mg per kg twice daily plus RETROVIR 160 mg per m2 3 times daily compared with didanosine in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 5.

Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG 300

a Includes pain, discharge, erythema, or swelling of an ear.
Adverse Reaction	EPIVIR plus RETROVIR (n = 236)	Didanosine (n = 235)
Body as a whole
Fever	25%	32%
Digestive
Hepatomegaly	11%	11%
Nausea & vomiting	8%	7%
Diarrhea	8%	6%
Stomatitis	6%	12%
Splenomegaly	5%	8%
Respiratory
Cough	15%	18%
Abnormal breath sounds/wheezing	7%	9%
Ear, Nose, and Throat
Signs or symptoms of earsa	7%	6%
Nasal discharge or congestion	8%	11%
Other
Skin rashes	12%	14%
Lymphadenopathy	9%	11%

Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6.

Table 6. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric Subjects in Trial ACTG 300

ULN = Upper limit of normal. ANC = Absolute neutrophil count.
Test (Abnormal Level)	EPIVIR plus RETROVIR	Didanosine
Neutropenia (ANC <400 cells/mm3)	8%	3%
Anemia (Hgb <7.0 g/dL)	4%	2%
Thrombocytopenia (platelets <50,000/mm3)	1%	3%
ALT (>10 x ULN)	1%	3%
AST (>10 x ULN)	2%	4%
Lipase (>2.5 x ULN)	3%	3%
Total amylase (>2.5 x ULN)	3%	3%

Macrocytosis was reported in the majority of pediatric subjects receiving RETROVIR 180 mg per m2 every 6 hours in open-label trials. Additionally, adverse reactions reported at an incidence of less than 6% in these trials were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss.

Use for the Prevention of Maternal-Fetal Transmission of HIV-1

In a randomized, double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to determine the utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission, RETROVIR oral solution at 2 mg per kg was administered every 6 hours for 6 weeks to neonates beginning within 12 hours following birth. The most commonly reported adverse reactions were anemia (hemoglobin less than 9.0 g per dL) and neutropenia (less than 1,000 cells per mm3). Anemia occurred in 22% of the neonates who received RETROVIR and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less than 1.0 g per dL for neonates receiving RETROVIR compared with neonates receiving placebo. No neonates with anemia required transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after completion of therapy with RETROVIR. Neutropenia in neonates was reported with similar frequency in the group that received RETROVIR (21%) and in the group that received placebo (27%). The long-term consequences of in utero and infant exposure to RETROVIR are unknown.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of RETROVIR. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole

Back pain, chest pain, flu-like syndrome, generalized pain, redistribution/accumulation of body fat [see Warnings and Precautions (5.6)].

Cardiovascular

Cardiomyopathy, syncope.

Eye

Macular edema.

Gastrointestinal

Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.

General

Sensitization reactions including anaphylaxis and angioedema, vasculitis.

Hematologic

Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.

Hepatobiliary

Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.

Musculoskeletal

Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis, tremor.

Nervous

Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.

Reproductive System and Breast

Gynecomastia.

Respiratory

Dyspnea, rhinitis, sinusitis.

Skin and Subcutaneous Tissue

Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweating, urticaria.

Special Senses

Amblyopia, hearing loss, photophobia, taste perversion.

Renal and Urinary

Urinary frequency, urinary hesitancy.

Most commonly reported adverse reactions (incidence greater than or equal to 15%) in adult HIV-1 clinical trials were headache, malaise, nausea, anorexia, and vomiting. (6.1)

Most commonly reported adverse reactions (incidence greater than or equal to 15%) in pediatric HIV-1 clinical trials were fever and cough. (6.1)

Most commonly reported adverse reactions in neonates (incidence greater than or equal to 15%) in the prevention of maternal-fetal transmission of HIV-1 clinical trial were anemia and neutropenia. (6.1)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RETROVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Available data from the APR show no difference in the overall risk of birth defects for zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.

Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see Data).

In an animal reproduction study, administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see Data).

Data

Human Data: Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens.

A randomized, double‑blind, placebo‑controlled trial was conducted in HIV‑1–infected pregnant women to determine the utility of RETROVIR for the prevention of maternal‑fetal HIV‑1‑transmission [see Clinical Studies (14.3)]. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received RETROVIR and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.

Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)]. There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established. The clinical relevance of transient elevations in serum lactate is unknown.

Animal Data: A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on Gestation Days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on Gestation Day 6 through 18) showed increased fetal resorptions at the 500-mg-per-kg-per-day dose, which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days 6 through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommends that HIV‑1‑infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV‑1 infection. Zidovudine is present in human milk. There is no information on the effects of zidovudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV‑1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant instruct mothers not to breastfeed if they are receiving RETROVIR.

8.4 Pediatric Use

RETROVIR has been studied in HIV-1-infected pediatric subjects aged at least 6 weeks who had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-1-related immunosuppression. RETROVIR has also been studied in neonates perinatally exposed to HIV-1 [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2, 14.3)].

8.5 Geriatric Use

Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

Unchanged zidovudine and its glucuronide metabolite (formed in the liver) are primarily eliminated from the body by renal excretion. In patients with severely impaired renal function (CrCl less than 15 mL per min), dosage reduction is recommended [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

RETROVIR is primarily eliminated by hepatic metabolism and zidovudine concentrations appear to be increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised. There are insufficient data to recommend dose adjustment of RETROVIR in patients with impaired hepatic function or liver cirrhosis [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].

Lactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. (8.2)

17 PATIENT COUNSELING INFORMATION

Hypersensitivity Reactions

Inform patients that potentially life‑threatening hypersensitivity reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) can occur while receiving RETROVIR. Instruct patients to immediately contact their healthcare provider if they develop rash, as it may be a sign of a more serious reaction. Advise patients that it is very important that they remain under a healthcare provider’s care during treatment with RETROVIR [see Contraindications (4)].

Neutropenia and Anemia

Inform patients that the major toxicities of RETROVIR are neutropenia and/or anemia. 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. Advise patients that if toxicity develops, they may require transfusions or drug discontinuation. Advise patients of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced symptomatic HIV-1 disease [see Boxed Warning, Warnings and Precautions (5.1)].

Myopathy

Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of RETROVIR [see Boxed Warning, Warnings and Precautions (5.2)].

Lactic Acidosis/Hepatomegaly with Steatosis

Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking RETROVIR if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.3)].

HIV-1/HCV Co-infection

Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.4)].

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when RETROVIR is started [see Warnings and Precautions (5.5)].

Lipoatrophy

Advise patients that loss of subcutaneous fat may occur in patients receiving RETROVIR and that they will be regularly assessed during therapy [see Warnings and Precautions (5.6)].

Common Adverse Reactions

Inform patients that the most commonly reported adverse reactions in adult patients being treated with RETROVIR were headache, malaise, nausea, anorexia, and vomiting. The most commonly reported adverse reactions in pediatric patients receiving RETROVIR were fever, cough, and digestive disorders. Patients also should be encouraged to contact their physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being treated with RETROVIR [see Adverse Reactions (6)].

Drug Interactions

Advise patients that other medications may interact with RETROVIR and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of RETROVIR [see Drug Interactions (7)].

Dosage and Administration in Neonates

Due to the small volume of RETROVIR administered to neonates, advise caregivers to use an appropriate-sized syringe with 0.1-mL graduation to ensure accurate dosing of the oral solution formulation [see Dosage and Administration (2.3)].

Pregnancy

Inform pregnant women considering the use of RETROVIR during pregnancy for prevention of HIV-1 transmission to their infants that transmission may still occur in some cases despite therapy.

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RETROVIR during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].

Missed Dose

Instruct patients that if they miss a dose of RETROVIR, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)].

EPIVIR and RETROVIR are trademarks owned by or licensed to the ViiV Healthcare group of companies.

Manufactured for:

ViiV Healthcare

Durham, NC 27701

©2024 ViiV Healthcare group of companies or its licensor.

RTR:13PI

11 DESCRIPTION

RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following structural formula:


Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a solubility of 20.1 mg per mL in water at 25°C. The molecular formula is C10H13N5O4.

RETROVIR capsules are for oral administration. Each capsule contains 100 mg of zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and titanium dioxide.

Each mL of RETROVIR oral solution contains 10 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to adjust pH.

RETROVIR injection is a sterile solution for IV infusion only. Each mL contains 10 mg zidovudine in water for injection. Hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH to approximately 5.5. RETROVIR injection contains no preservatives.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Zidovudine is an antiretroviral agent [see Microbiology (12.4)].

12.3 Pharmacokinetics

Absorption and Bioavailability

Following IV dosing, dose‑independent kinetics was observed over the range of 1 to 5 mg per kg. The mean steady‑state peak and trough concentrations of zidovudine at 2.5 mg per kg every 4 hours were 1.1 and 0.1 mcg per mL, respectively.

In adults, following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was equivalent when zidovudine was administered as RETROVIR tablets or oral solution compared with RETROVIR capsules. The pharmacokinetic properties of zidovudine in fasting adult subjects are summarized in Table 7.

Table 7. Zidovudine Pharmacokinetic Parameters in Adult Subjects

a Median [range] for 50 paired samples drawn 1 to 8 hours after the last dose in subjects on chronic therapy with RETROVIR. b Approximate range.
Parameter	Mean ± SD (except where noted)
Oral bioavailability (%)	64 ± 10 (n = 5)
Apparent volume of distribution (L/kg)	1.6 ± 0.6 (n = 8)
Cerebrospinal fluid (CSF):plasma ratioa	0.6 [0.04 to 2.62] (n = 39)
Systemic clearance (L/h/kg)	1.6 ± 0.6 (n = 6)
Renal clearance (L/h/kg)	0.34 ± 0.05 (n = 9)
Elimination half-life (h)b	0.5 to 3 (n = 19)

Distribution

The apparent volume of distribution of zidovudine is 1.6 ± 0.6 L per kg (Table 7) and binding to plasma protein is low (less than 38%).

Metabolism and Elimination

Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration and 18% and 60%, respectively, following IV dosing. A second metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in the plasma following single-dose IV administration of zidovudine. The AMT AUC was one-fifth of the zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from 2 mg per kg every 8 hours to 10 mg per kg every 4 hours.

Effect of Food on Absorption

RETROVIR may be administered with or without food. The zidovudine AUC was similar when a single dose of zidovudine was administered with food.

Specific Populations

Patients with Renal Impairment: Zidovudine clearance was decreased resulting in increased zidovudine and GZDV half-life and AUC in subjects with impaired renal function (n = 14) following a single 200-mg oral dose (Table 8). Plasma concentrations of AMT were not determined. No dose adjustment is recommended for patients with CrCl greater than or equal to 15 mL per min.

Table 8. Zidovudine Pharmacokinetic Parameters in Subjects with Severe Renal Impairmenta

a Data are expressed as mean ± standard deviation.
Parameter	Control Subjects (Normal Renal Function) (n = 6)	Subjects with Renal Impairment (n = 14)
CrCl (mL/min)	120 ± 8	18 ± 2
Zidovudine AUC (ng•h/mL)	1,400 ± 200	3,100 ± 300
Zidovudine half-life (h)	1.0 ± 0.2	1.4 ± 0.1

Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose trial in subjects undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating oral doses up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in subjects with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis [see Dosage and Administration (2.5)].

Patients with Hepatic Impairment: Data describing the effect of hepatic impairment on the pharmacokinetics of zidovudine are limited. However, zidovudine is eliminated primarily by hepatic metabolism and it appears that zidovudine clearance is decreased and plasma concentrations are increased in subjects with hepatic impairment. There are insufficient data to recommend dose adjustment of RETROVIR in patients with impaired hepatic function or liver cirrhosis [see Dosage and Administration (2.6)].

Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in HIV-1-infected pediatric subjects (Table 9).

Patients Aged 3 Months to 12 Years: Overall, zidovudine pharmacokinetics in pediatric patients older than 3 months are similar to those in adult patients. Proportional increases in plasma zidovudine concentrations were observed following administration of oral solution from 90 to 240 mg per m2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable to adult values. As in adult subjects, the major route of elimination was by metabolism to GZDV. After IV dosing, about 29% of the dose was excreted in the urine unchanged, and about 45% of the dose was excreted as GZDV [see Dosage and Administration (2.2)].

Patients Aged Less than 3 Months: Zidovudine pharmacokinetics have been evaluated in pediatric subjects from birth to 3 months of life. Zidovudine elimination was determined immediately following birth in 8 neonates who were exposed to zidovudine in utero. The half-life was 13.0 ± 5.8 hours. In neonates less than or equal to 14 days old, bioavailability was greater, total body clearance was slower, and half-life was longer than in pediatric subjects older than 14 days. For dose recommendations for neonates [see Dosage and Administration (2.3)].

Table 9. Zidovudine Pharmacokinetic Parameters in Pediatric Subjectsa

a Data presented as mean ± standard deviation except where noted. b Median [range].
Parameter	Birth to 14 Days	Aged 14 Days to 3 Months	Aged 3 Months to 12 Years
Oral bioavailability (%)	89 ± 19 (n = 15)	61 ± 19 (n = 17)	65 ± 24 (n = 18)
CSF:plasma ratio	no data	no data	0.68 [0.03 to 3.25]b (n = 38)
CL (L/h/kg)	0.65 ± 0.29 (n = 18)	1.14 ± 0.24 (n = 16)	1.85 ± 0.47 (n = 20)
Elimination half-life (h)	3.1 ± 1.2 (n = 21)	1.9 ± 0.7 (n = 18)	1.5 ± 0.7 (n = 21)

Pregnant Women: Zidovudine pharmacokinetics have been studied in a Phase I trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Use in Specific Populations (8.1)].

Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.

Geriatric Patients: Zidovudine pharmacokinetics have not been studied in subjects over 65 years of age.

Male and Female Patients: A pharmacokinetic trial in healthy male (n = 12) and female (n = 12) subjects showed no differences in zidovudine AUC when a single dose of zidovudine was administered as a 300-mg RETROVIR tablet.

Drug Interaction Studies

[See Drug Interactions (7).]

Table 10. Effect of Coadministered Drugs on Zidovudine AUCa

↑ = Increase; ↓ = Decrease; ↔ = No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval. a This table is not all inclusive. b Estimated range of percent difference.
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered Drug and Dose	Zidovudine Oral Dose	n	Zidovudine Concentrations	Concentration of Coadministered Drug
AUC	Variability
Atovaquone 750 mg every 12 h with food	200 mg every 8 h	14	↑31%	Range: 23% to 78%b	↔
Clarithromycin 500 mg twice daily	100 mg every 4 h x 7 days	4	↓12%	Range: ↓34% to ↑14%b	Not Reported
Fluconazole 400 mg daily	200 mg every 8 h	12	↑74%	95% CI: 54% to 98%	Not Reported
Lamivudine 300 mg every 12 h	single 200 mg	12	↑13%	90% CI: 2% to 27%	↔
Methadone 30 to 90 mg daily	200 mg every 4 h	9	↑43%	Range: 16% to 64%b	↔
Nelfinavir 750 mg every 8 h x 7 to 10 days	single 200 mg	11	↓35%	Range: 28% to 41%b	↔
Probenecid 500 mg every 6 h x 2 days	2 mg/kg every 8 h x 3 days	3	↑106%	Range: 100% to 170%b	Not Assessed
Rifampin 600 mg daily x 14 days	200 mg every 8 h x 14 days	8	↓47%	90% CI: 41% to 53%	Not Assessed
Ritonavir 300 mg every 6 h x 4 days	200 mg every 8 h x 4 days	9	↓25%	95% CI: 15% to 34%	↔
Valproic acid 250 mg or 500 mg every 8 h x 4 days	100 mg every 8 h x 4 days	6	↑80%	Range: 64% to 130%b	Not Assessed

Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving RETROVIR, while in one case a high level was documented. However, in a pharmacokinetic interaction trial in which 12 HIV-1-positive volunteers received a single 300-mg phenytoin dose alone and during steady- state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects [see Warnings and Precautions (5.4)].

12.4 Microbiology

Mechanism of Action

Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.

Antiviral Activity

The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine were 0.01 to 0.49 microM (1 microM = 0.27 mcg per mL) and 0.1 to 9 microM, respectively. HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.011 microM (range: 0.005 to 0.110 microM) from Virco (n = 92 baseline samples) and 0.0017 microM (range: 0.006 to 0.0340 microM) from Monogram Biosciences (n = 135 baseline samples). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 microM, and against HIV-2 isolates from 0.00049 to 0.004 microM. Zidovudine was not antagonistic to tested anti-HIV agents with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.

Resistance

HIV-1 isolates with reduced susceptibility to zidovudine have been selected in cell culture and were also recovered from subjects treated with zidovudine. Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine‑treated subjects showed thymidine analog mutation (TAMs) substitutions in the HIV‑1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N/Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of substitutions. In some subjects harboring zidovudine‑resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine.

Cross-Resistance

Cross-resistance has been observed among NRTIs. TAM substitutions are selected by zidovudine and confer cross‑resistance to abacavir, didanosine, stavudine, and tenofovir.

16 HOW SUPPLIED/STORAGE AND HANDLING

RETROVIR 100-mg capsules are supplied as white, opaque cap and body capsules containing 100 mg zidovudine per capsule. Each capsule is printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on body.

Bottles of 100 (NDC 49702-211-20).

Store at 15° to 25°C (59° to 77°F) and protect from moisture.

RETROVIR oral solution is supplied as a colorless to pale yellow, strawberry- flavored solution containing 10 mg zidovudine in each mL.

Bottle of 240 mL (NDC 49702-212-48) with child-resistant cap.

Store at 15° to 25°C (59° to 77°F).

RETROVIR injection is a clear, colorless to slightly yellow aqueous solution. The strength of the presentation is 200 mg of zidovudine in 20 mL solution (10 mg per mL).

Single-dose vial (NDC 49702-213-01), Carton of 5 (NDC 49702-213-26).

Store vials at 15° to 25°C (59° to 77°F) and protect from light.