Duovir

Duovir uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Duovir reviews

1 INDICATIONS AND USAGE

Duovir, a combination of 2 nucleoside analogues, is indicated in combination with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection.

Duovir, a combination of 2 nucleoside analogue reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV‑1 infection. (1)

2 DOSAGE AND ADMINISTRATION

• Adults and Adolescents weighing greater than or equal to 30 kg: 1 tablet orally twice daily.
• Pediatrics weighing greater than or equal to 30 kg: 1 tablet orally twice daily. (2.2)
• Because Duovir is a fixed‑dose tablet and cannot be dose adjusted, Duovir is not recommended in patients requiring dosage adjustment or with hepatic impairment or experiencing dose‑limiting adverse reactions. (2.3, 4)

2.1 Recommended Dosage for Adults and Adolescents

The recommended dosage of Duovir in HIV‑1‑infected adults and adolescents weighing greater than or equal to 30 kg is 1 tablet (containing 150 mg of Duovir and 300 mg of zidovudine) taken orally twice daily.

2.2 Recommended Dosage for Pediatric Patients

The recommended dosage of scored Duovir tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is 1 tablet administered orally twice daily.

Before prescribing Duovir tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a Duovir tablet, the liquid oral formulations should be prescribed: EPIVIR^® oral solution and RETROVIR^® (zidovudine) syrup.

2.3 Not Recommended Due to Lack of Dosage Adjustment

Because Duovir is a fixed‑dose tablet and cannot be dose adjusted, Duovir is not recommended for:

• pediatric patients weighing less than 30 kg .
• patients with creatinine clearance less than 50 mL per minute .
• patients with hepatic impairment .
• patients experiencing dose‑limiting adverse reactions.

Liquid and solid oral formulations of the individual components of Duovir are available for these populations.

3 DOSAGE FORMS AND STRENGTHS

Duovir tablets contain 150 mg of Duovir and 300 mg of zidovudine. The tablets are white, scored, film-coated, modified capsule-shaped tablets, debossed on both tablet faces, such that when broken in half, the full “GX FC3” code is present on both halves of the tablet (“GX” on one face and “FC3” on the opposite face of the tablet).

Tablets: Scored 150 mg Duovir and 300 mg zidovudine (3)

4 CONTRAINDICATIONS

Duovir is contraindicated in patients with a previous hypersensitivity reaction to Duovir or zidovudine.

Duovir is contraindicated in patients with a previous hypersensitivity reaction to Duovir or zidovudine. (4)

5 WARNINGS AND PRECAUTIONS

• Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with/without ribavirin. Discontinue Duovir as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both.
• 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. (5.5)
• Pancreatitis: Use with caution in patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.6)
• Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy (5.7, 5.8).

5.1 Hematologic Toxicity/Bone Marrow Suppression

Zidovudine, a component of Duovir, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Duovir 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 grams per dL .

Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with Duovir. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed.

5.2 Myopathy

Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with Duovir.

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 and other antiretrovirals. See full prescribing information for EPIVIR and RETROVIR (zidovudine). Treatment with Duovir 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 Patients with Hepatitis B Virus Co-infection

Posttreatment Exacerbations of Hepatitis

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of Duovir. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Emergence of Lamivudine-Resistant HBV

Safety and efficacy of Duovir have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV‑1 and HBV. Emergence of hepatitis B virus variants associated with resistance to Duovir has been reported in HIV-1‑infected subjects who have received lamivudine‑containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine).

5.5 Use with Interferon- and Ribavirin-Based Regimens

Patients receiving interferon alfa with or without ribavirin and Duovir should be closely monitored for treatment‑associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for EPIVIR and RETROVIR (zidovudine). Discontinuation of Duovir 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).

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

5.6 Pancreatitis

Duovir should be used with caution in patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with Duovir should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur .

5.7 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Duovir. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections, 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.

5.8 Fat Redistribution

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

6 ADVERSE REACTIONS

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

• Hematologic toxicity, including neutropenia and anemia .
• Symptomatic myopathy .
• Lactic acidosis and severe hepatomegaly with steatosis .
• Exacerbations of hepatitis B .
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C .
• Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine .
• Pancreatitis .
• Immune reconstitution syndrome .
• Fat redistribution .

• Most commonly reported adverse reactions (incidence greater than or equal to 15%) in clinical trials of combination Duovir and zidovudine were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 clinical practice.

Duovir plus Zidovudine Administered as Separate Formulations

In 4 randomized, controlled trials of EPIVIR 300 mg per day plus RETROVIR 600 mg per day, the following selected adverse reactions and laboratory abnormalities were observed (Tables 1 and 2).

Pancreatitis was observed in 9 of the 2,613 adult subjects (0.3%) who received EPIVIR in controlled clinical trials .

Selected laboratory abnormalities observed during therapy are listed in Table 2.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use. 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

Redistribution/accumulation of body fat .

Cardiovascular

Cardiomyopathy.

Endocrine and Metabolic

Gynecomastia, hyperglycemia.

Gastrointestinal

Oral mucosal pigmentation, stomatitis.

General

Vasculitis, weakness.

Hemic and Lymphatic

Anemia, (including pure red cell aplasia and anemias progressing on therapy), lymphadenopathy, splenomegaly.

Hepatic and Pancreatic

Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbations of hepatitis B .

Hypersensitivity

Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal

Muscle weakness, CPK elevation, rhabdomyolysis.

Nervous

Paresthesia, peripheral neuropathy, seizures.

Respiratory

Abnormal breath sounds/wheezing.

Skin

Alopecia, erythema multiforme, Stevens-Johnson syndrome.

7 DRUG INTERACTIONS

• Agents antagonistic with zidovudine: Concomitant use should be avoided )
• Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. (7.1)

7.1 Zidovudine

Agents Antagonistic with Zidovudine

Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro:

• Stavudine
• Doxorubicine
• Nucleoside analogues, e.g., ribavirin

Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

Coadministration with the following drugs may increase the hematologic toxicity of zidovudine:

• Ganciclovir
• Interferon alfa
• Ribavirin
• Other bone marrow suppressive or cytotoxic agents

8 USE IN SPECIFIC POPULATIONS

• Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Duovir 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 Duovir or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population . 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.

In animal reproduction studies, oral administration of Duovir to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of Duovir to pregnant rats during organogenesis at plasma concentrations (C_max) 35 times the recommended clinical dose. 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.

Data

Human Data: Duovir: Based on prospective reports to the APR of over 11,000 exposures to Duovir during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for Duovir 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 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.

Duovir pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trial assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg Duovir twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg Duovir twice daily with zidovudine, and 10 women at 38 weeks gestation using Duovir 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Duovir concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that Duovir crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of Duovir were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8).

Zidovudine: 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 zidovudine for the prevention of maternal-fetal HIV-1 transmission. 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 zidovudine 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 trial 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 .

Animal Data: Duovir: Duovir was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation Days 7 through 16 and 8 through 20, respectively). No evidence of fetal malformations due to Duovir was observed in rats and rabbits at doses producing plasma concentrations (C_max) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (C_max) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that Duovir is transferred to the fetus through the placenta. In the pre-and postnatal development study in rats, Duovir was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from gestation Day 6 through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of Duovir.

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

8.4 Pediatric Use

Duovir is not recommended for use in pediatric patients who weigh less than 30 kg because it is a fixed‑dose combination tablet that cannot be adjusted for this patient population .

8.5 Geriatric Use

Clinical trials of Duovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of Duovir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy .

8.6 Patients with Impaired Renal Function

Duovir is not recommended for patients with creatinine clearance less than 50 mL per min because Duovir is a fixed‑dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of the Duovir or zidovudine components of Duovir is required for patients with renal impairment then the individual components should be used .

8.7 Patients with Impaired Hepatic Function

Duovir is a fixed‑dose combination and the dosage of the individual components cannot be adjusted. Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.

10 OVERDOSAGE

There is no known specific treatment for overdose with Duovir. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

Duovir

Because a negligible amount of Duovir was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a Duovir overdose event.

Zidovudine

Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.

11 DESCRIPTION

Duovir tablets are combination tablets containing Duovir and zidovudine. Duovir (EPIVIR) and zidovudine (RETROVIR, azidothymidine, AZT, or ZDV) are synthetic nucleoside analogues with activity against HIV-1.

Duovir tablets are for oral administration. Each film-coated tablet contains 150 mg of Duovir, 300 mg of zidovudine, and the inactive ingredients colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

Duovir

The chemical name of Duovir is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Duovir is the (-)enantiomer of a dideoxy analogue of cytidine. Duovir has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C₈H₁₁N₃O₃S and a molecular weight of 229.3 g per mol. It has the following structural formula:

Duovir is a white to off-white crystalline solid and is soluble in water.

Zidovudine

The chemical name of zidovudine is 3′-azido-3′-deoxythymidine. It has a molecular formula of C₁₀H₁₃N₅O₄ and a molecular weight of 267.24 g per mol. It has the following structural formula:

Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg per mL in water at 25°C.

Duovir chemical structure zidovudine chemical structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Duovir is an antiretroviral agent .

12.3 Pharmacokinetics

Pharmacokinetics in Adults

One Duovir tablet was bioequivalent to 1 EPIVIR tablet (150 mg) plus 1 RETROVIR tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).

Duovir: Following oral administration, Duovir is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of Duovir is recovered as unchanged drug in the urine. Metabolism of Duovir is a minor route of elimination (approximately 5% of an oral dose after 12 hours). In humans, the only known metabolite is the trans‑sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

Zidovudine: Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one fifth of the zidovudine AUC.

In humans, Duovir and zidovudine are not significantly metabolized by cytochrome P450 enzymes.

The pharmacokinetic properties of Duovir and zidovudine in fasting subjects are summarized in Table 3.

Effect of Food on Absorption of Duovir: Duovir may be administered with or without food. The Duovir and zidovudine AUC following administration of Duovir with food was similar when compared with fasting healthy subjects (n = 24).

Specific Populations

Renal Impairment: Duovir: The effect of renal impairment on the combination of Duovir and zidovudine has not been evaluated.

Hepatic Impairment: Duovir: The effect of hepatic impairment on the combination of Duovir, and zidovudine has not been evaluated.

Pregnancy: Duovir: Duovir pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Duovir pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Duovir concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

Zidovudine: Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of non-pregnant 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.

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

Geriatric Patients

The pharmacokinetics of Duovir and zidovudine have not been studied in subjects over 65 years of age.

Gender

There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (lamivudine or zidovudine) based on the available information that was analyzed for each of the individual components.

Race

Duovir: There are no significant or clinically relevant racial differences in Duovir pharmacokinetics based on the available information that was analyzed for the individual Duovir component.

Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined.

Drug Interactions

No drug interaction trials have been conducted using Duovir tablets.

Duovir and Zidovudine: No clinically significant alterations in Duovir or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV‑1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of Duovir (300 mg every 12 hours).

Other Interactions

Interferon Alfa: There was no significant pharmacokinetic interaction between Duovir and interferon alfa in a trial of 19 healthy male subjects.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of Duovir, 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 Duovir (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.

Table 4 presents drug interaction information for the individual components of Duovir.

12.4 Microbiology

Mechanism of Action

Duovir: Duovir is a synthetic nucleoside analogue. Intracellularly, Duovir is phosphorylated to its active 5′-triphosphate metabolite, Duovir triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.

Zidovudine: 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 RT via DNA chain termination after incorporation of the nucleotide analogue.

Antiviral Activity

Duovir plus Zidovudine: In HIV-1–infected MT‑4 cells, Duovir in combination with zidovudine at various ratios was not antagonistic.

Duovir: The antiviral activity of Duovir against HIV‑1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC₅₀ values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC₅₀ values of Duovir were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV‑1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC₅₀ values against HIV‑2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV‑1 activity of Duovir by 3.5‑fold in MT‑4 cells.

Zidovudine: 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. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.

Neither Duovir nor zidovudine was antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine).

Resistance

In subjects receiving Duovir monotherapy or combination therapy with Duovir plus zidovudine, HIV‑1 isolates from most subjects became phenotypically and genotypically resistant to Duovir within 12 weeks.

HIV‑1 strains resistant to both Duovir and zidovudine have been isolated from subjects after prolonged Duovir therapy. Dual resistance required the presence of multiple amino acid substitutions, the most essential of which may be G333E. The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown.

Duovir: Lamivudine‑resistant isolates of HIV‑1 have been selected in cell culture and have also been recovered from subjects treated with Duovir or Duovir plus zidovudine. Genotypic analysis of isolates selected in cell culture and recovered from lamivudine‑treated subjects showed that the resistance was due to a specific amino acid substitution in the HIV‑1 reverse transcriptase at codon 184 changing the methionine to either valine or isoleucine (M184V/I).

Zidovudine: 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 analogue mutation (TAM) substitutions in HIV‑1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N) 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 Duovir and zidovudine.

Cross‑Resistance

Cross‑resistance has been observed among NRTIs. Cross‑resistance between Duovir and zidovudine has not been reported. In some subjects treated with Duovir alone or in combination with zidovudine, isolates have emerged with a substitution at codon 184, which confers resistance to Duovir.

TAM substitutions are selected by zidovudine and confer cross‑resistance to abacavir, didanosine, stavudine, and tenofovir.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Duovir: Long‑term carcinogenicity studies with Duovir in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.

Zidovudine: Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatment‑related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279.

In mice, 7 late‑appearing (after 19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late‑appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.

In rats, 2 late‑appearing (after 20 months), non-metastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug‑related tumors were observed in either sex of either species.

At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.

It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Mutagenicity

Duovir: Duovir was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Duovir was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.

Zidovudine: Zidovudine was mutagenic in an L5178Y 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 after repeated doses. It was negative in a cytogenetic study in rats given a single dose.

Impairment of Fertility

Duovir: Duovir did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (C_max) in humans at the dose of 300 mg.

Zidovudine: Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is 7 times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.

14 CLINICAL STUDIES

One Duovir tablet given twice daily is an alternative regimen to EPIVIR tablets 150 mg twice daily plus RETROVIR 600 mg per day in divided doses.

14.1 Adults

The NUCB3007 trial was conducted using EPIVIR 150‑mg tablets (150 mg twice daily) and RETROVIR 100‑mg capsules (2 x 100 mg 3 times daily). CAESAR was a multi‑center, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor, randomized 1:2:1. A total of 1,816 HIV‑1‑infected adults with 25 to 250 (median 122) CD4 cells per mm³ at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy‑naive. The median duration on trial was 12 months. Results are summarized in Table 5.

14.2 Prevention of Maternal-Fetal HIV-1 Transmission

The utility of zidovudine alone for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells per mm³ (median in the treated group: 560 cells per mm³) who had little or no previous exposure to zidovudine. Oral zidovudine was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of zidovudine during labor and delivery. Following birth, neonates received oral zidovudine syrup for 6 weeks. The trial showed a statistically significant difference in the incidence of HIV‑1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving zidovudine and the group receiving placebo. Of 363 neonates evaluated in the trial, the estimated risk of HIV‑1 infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. Zidovudine was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.

16 HOW SUPPLIED/STORAGE AND HANDLING

Duovir tablets, containing 150 mg Duovir and 300 mg zidovudine, are white, scored, film-coated, modified-capsule-shaped tablets, debossed on both tablet faces, such that when broken in half, the full “GXFC3” code is present on both halves of the tablet (“GX” on one face and “FC3” on the opposite face of the tablet). They are available as follows:

60 Tablets/Bottle (NDC 49702-202-18).

Unit Dose Pack of 120 (NDC 49702-202-29).

Store between 2° and 30°C (36° and 86°F).

17 PATIENT COUNSELING INFORMATION

Neutropenia and Anemia

Inform patients that the important toxicities associated with zidovudine are neutropenia and/or anemia. Inform them of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced HIV‑1 disease .

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 zidovudine .

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 Duovir if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity .

Patients with Hepatitis B or C Co-infection

Advise patients co‑infected with HIV‑1 and HBV that worsening of liver disease has occurred in some cases when treatment with Duovir was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider .

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 .

Drug Interactions

Advise patients that other medications may interact with Duovir and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of zidovudine, a component of Duovir .

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 Duovir is started .

Redistribution/Accumulation of Body Fat

Inform patients 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 not known at this time .

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Duovir 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 .

Missed Dose

Instruct patients that if they miss a dose of Duovir, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose .

Duovir, EPIVIR, and RETROVIR are registered trademarks of the ViiV Healthcare group of companies.

The other brands listed are trademarks of their respective owners and are not trademarks of the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.

Manufactured for:

ViiV Healthcare

Research Triangle Park, NC 27709

by:

GlaxoSmithKline

Research Triangle Park, NC 27709

Duovir is manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

©2017 the ViiV Healthcare group of companies. All rights reserved.

CMB:8PI

Duovir pharmaceutical active ingredients containing related brand and generic drugs:

• Lamivudine
• Zidovudine

Duovir available forms, composition, doses:

• Tablets; Oral; Lamivudine 150 mg; Zidovudine 300 mg

Duovir destination | category:

• Human:
• Antivirals
• Nucleoside and nucleotide reverse transcriptase inhibitors

Duovir Anatomical Therapeutic Chemical codes:

• J05AR01 - Zidovudine and Lamivudine

Duovir pharmaceutical companies:

• Cipla
• Cristalia Produtos Quimicos Farmaceuticos

References

1. Dailymed."ZIDOVUDINE TABLET, FILM COATED [LANNETT COMPANY, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."LAMIVUDINE TABLET, FILM COATED [APOTEX CORP.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. Dailymed."ZIDOVUDINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Duovir after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Duovir not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology