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Lamivudine and Zidovudine (lamivudine 150 mg zidovudine 300 mg) Dailymed



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Boxed Warning

Warning: Hematologic Toxicity, Myopathy, Lactic Acidosis And Severe Hepatomegaly With Steatosis, And Exacerbations Of Hepatitis B

Zidovudine, a component of lamivudine and zidovudine tablets, has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV-1) disease [see Warnings and Precautions (5.1)]. Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.2)]. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine and zidovudine (components of lamivudine and zidovudine tablets). Discontinue lamivudine and zidovudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.3)]. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, which is one component of lamivudine and zidovudine tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and zidovudine tablets and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.4)]. WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning.
  • Hematologic toxicity, including neutropenia and anemia, has been associated with the use of zidovudine, a component of lamivudine and zidovudine tablets. (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 lamivudine and zidovudine (components of lamivudine and zidovudine tablets). Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.3)
  • Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of lamivudine and zidovudine tablets. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. (5.4)


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Recent Major Changes Section



Boxed Warning     04/2018

Warnings and Precautions, Lactic Acidosis and Severe Hepatomegaly with Steatosis (5.3)     04/2018

Warnings and Precautions, Lipoatrophy (5.8)     04/2018

Warning: Hematologic Toxicity, Myopathy, Lactic Acidosis And Severe Hepatomegaly With Steatosis, And Exacerbations Of Hepatitis B


Zidovudine, a component of lamivudine and zidovudine tablets, has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV-1) disease [see Warnings and Precautions (5.1)].

Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.2)].

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine and zidovudine (components of lamivudine and zidovudine tablets). Discontinue lamivudine and zidovudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.3)].

Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, which is one component of lamivudine and zidovudine tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and zidovudine tablets and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.4)].


WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B

See full prescribing information for complete boxed warning.
  • Hematologic toxicity, including neutropenia and anemia, has been associated with the use of zidovudine, a component of lamivudine and zidovudine tablets. (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 lamivudine and zidovudine (components of lamivudine and zidovudine tablets). Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.3)
  • Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of lamivudine and zidovudine tablets. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. (5.4)

1 Indications And Usage


Lamivudine and zidovudine tablets, a combination of 2 nucleoside analogues, are indicated in combination with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.


Lamivudine and zidovudine tablets, a combination of 2 nucleoside analogue reverse transcriptase inhibitors, are 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. (2.1)
  • •Pediatrics weighing greater than or equal to 30 kg: 1 tablet orally twice daily. (2.2)
  • •Because lamivudine and zidovudine is a fixed-dose tablet and cannot be dose adjusted, lamivudine and zidovudine tablets are not recommended in patients requiring dosage adjustment or with hepatic impairment or experiencing dose-limiting adverse reactions. (2.3, 4)

2.1Recommended Dosage for Adults and Adolescents


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


The recommended dosage of scored lamivudine and zidovudine 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 lamivudine and zidovudine tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a lamivudine and zidovudine tablet, the liquid oral formulations should be prescribed: EPIVIR® (lamivudine) oral solution and RETROVIR® (zidovudine) syrup.


Because lamivudine and zidovudine is a fixed-dose tablet and cannot be dose adjusted, lamivudine and zidovudine tablets are not recommended for:

Liquid and solid oral formulations of the individual components of lamivudine and zidovudine tablets are available for these populations.

3 Dosage Forms And Strengths


Lamivudine and Zidovudine Tablets, USP are available containing 150 mg of lamivudine, USP and 300 mg of zidovudine, USP.
  • •The 150 mg/300 mg tablets are white to off-white, film-coated, capsule shaped, scored tablets debossed with L on the left of the score and Z on the right of the score on one side of the tablet and M on the left of the score and 1 on the right of the score on the other side.


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

4 Contraindications


Lamivudine and zidovudine tablets are contraindicated in patients with a previous hypersensitivity reaction to lamivudine or zidovudine.


Lamivudine and zidovudine tablets are contraindicated in patients with a previous hypersensitivity reaction to lamivudine 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 lamivudine and zidovudine tablets as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.5)
  • •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 lipoatrophy have been reported in patients treated with combination antiretroviral therapy. (5.7, 5.8)

5.1Hematologic Toxicity/Bone Marrow Suppression


Zidovudine, a component of lamivudine and zidovudine tablets, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Lamivudine and zidovudine tablets 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 [see Adverse Reactions (6.1)].

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

5.2Myopathy


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 lamivudine and zidovudine tablets.

5.3Lactic 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 lamivudine and zidovudine (components of lamivudine and zidovudine tablets). 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. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Treatment with lamivudine and zidovudine tablets 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.

5.4Patients with Hepatitis B Virus Co-infection



Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. 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.


Safety and efficacy of lamivudine 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 lamivudine 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).

5.5Use with Interferon- and Ribavirin-Based Regimens


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

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

5.6Pancreatitis


Lamivudine and zidovudine tablets should be used with caution in patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with lamivudine and zidovudine tablets should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)].

5.7Immune Reconstitution Syndrome


Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine and zidovudine tablets. 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.

5.8Lipoatrophy


Treatment with zidovudine, a component of lamivudine and zidovudine tablets, 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-containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.

6 Adverse Reactions


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

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

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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.


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).
Table 1. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in 4 Controlled Clinical Trials with EPIVIR 300 mg per day and RETROVIR 600 mg per day

Adverse Reactions

EPIVIR Plus RETROVIR

(n = 251)

Body as a whole

     Headache

35%

     Malaise and fatigue

27%

     Fever or chills

10%

Digestive

     Nausea

33%

     Diarrhea

18%

     Nausea and vomiting

13%

     Anorexia and/or decreased appetite

10%

     Abdominal pain

9%

     Abdominal cramps

6%

     Dyspepsia

5%

Nervous System

     Neuropathy

12%

     Insomnia and other sleep disorders

11%

     Dizziness

10%

     Depressive disorders

9%

Respiratory

     Nasal signs and symptoms

20%

     Cough

18%

Skin

     Skin rashes

9%

Musculoskeletal

     Musculoskeletal pain

12%

     Myalgia

8%

     Arthralgia

5%

Pancreatitis was observed in 9 of the 2,613 adult subjects (0.3%) who received EPIVIR in controlled clinical trials [see Warnings and Precautions (5.6)].

Selected laboratory abnormalities observed during therapy are uled in Table 2.
Table 2. Frequencies of Selected Laboratory Abnormalities Among Adults in 4 Controlled Clinical Trials of EPIVIR 300 mg per day Plus RETROVIR 600 mg per dayFrequencies of these laboratory abnormalities were higher in subjects with mild laboratory abnormalities at baseline.
ULN = Upper limit of normal.ANC = Absolute neutrophil count.n = Number of subjects assessed.

Test

(Abnormal Level)

EPIVIR Plus RETROVIR

% (n)

Neutropenia (ANC < 750/mm3)

7.2% (237)

Anemia (Hgb < 8.0 g/dL)

2.9% (241)

Thrombocytopenia (platelets < 50,000/mm3)

0.4% (240)

ALT (> 5.0 x ULN)

3.7% (241)

AST (> 5.0 x ULN)

1.7% (241)

Bilirubin (> 2.5 x ULN)

0.8% (241)

Amylase (> 2.0 x ULN)

4.2% (72)

6.2Postmarketing 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 [see Warnings and Precautions (5.8)].

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 [see Boxed Warning, Warnings and Precautions (5.3), (5.4), (5.6)].

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. (7.1)
  • •Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. (7.1)
  • •Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration. (7.2)

7.1Zidovudine


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


Coadministration with the following drugs may increase the hematologic toxicity of zidovudine:
  • •Ganciclovir
  • •Interferon alfa
  • •Ribavirin
  • •Other bone marrow suppressive or cytotoxic agents

7.2Lamivudine



Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see Clinical Pharmacology (12.3)].

8 Use In Specific Populations


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

8.1 Pregnancy


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


Available data from the APR show no difference in the overall risk of birth defects for lamivudine or 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.

In animal reproduction studies, oral administration of lamivudine 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 lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 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 (see Data).


Human Data
Animal Data

8.2 Lactation


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. Lamivudine and zidovudine are present in human milk. There is no information on the effects of lamivudine or zidovudine on the breastfed infant or the effects of the drugs 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 lamivudine and zidovudine tablets.

8.4 Pediatric Use


Lamivudine and zidovudine tablets are 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 [see Dosage and Administration (2.2)].

8.5 Geriatric Use


Clinical trials of lamivudine and zidovudine tablets 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 lamivudine and zidovudine tablets in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

8.6Patients with Impaired Renal Function


Lamivudine and zidovudine tablets are not recommended for patients with creatinine clearance less than 50 mL per min because lamivudine and zidovudine tablets are a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of the lamivudine or zidovudine components of lamividuine and zidovudine tablets is required for patients with renal impairment then the individual components should be used [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

8.7Patients with Impaired Hepatic Function


Lamivudine and zidovudine tablets are 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 lamivudine and zidovudine tablets. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

Lamivudine: Because a negligible amount of lamivudine 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 lamivudine 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 uled 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


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

Lamivudine and zidovudine tablets are for oral administration. Each film-coated tablet contains 150 mg of lamivudine, 300 mg of zidovudine, and the inactive ingredients colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium starch glycolate (potato) and titanium dioxide.

Lamivudine: The chemical name of lamivudine is (–)-1-[(2R,5S)-2-(Hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.26 g per mol. It has the following structural formula:

Lamivudine, USP is a white to off-white crystalline powder 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, USP is a white to yellowish powder with a solubility of 20.1 mg per mL in water at 25°C.

Meets USP Dissolution Test 2.

12 Clinical Pharmacology


12.1 Mechanism of Action


Lamivudine and zidovudine tablets are an antiretroviral agent [see Microbiology (12.4)].

12.3 Pharmacokinetics



One lamivudine and zidovudine 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).

Lamivudine

Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine 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, lamivudine and zidovudine are not significantly metabolized by cytochrome P450 enzymes.

The pharmacokinetic properties of lamivudine and zidovudine in fasting subjects are summarized in Table 3.
Table 3. Pharmacokinetic ParametersData presented as mean ± standard deviation except where noted.for Lamivudine and Zidovudine in Adults

Parameter

Lamivudine

Zidovudine

Oral bioavailability (%)

86 ± 16

n = 12

64 ± 10

n = 5

Apparent volume of distribution (L/kg)

1.3 ± 0.4

n = 20

1.6 ± 0.6

n = 8

Plasma protein binding (%)

< 36

< 38

CSF:plasma ratioMedian [range].

0.12 [0.04 to 0.47]

n = 38Children.

0.60 [0.04 to 2.62]

n = 39Adults.

Systemic clearance (L/h/kg)

0.33 ± 0.06

n = 20

1.6 ± 0.6

n = 6

Renal clearance (L/h/kg)

0.22 ± 0.06

n = 20

0.34 ± 0.05

n = 9

Elimination half-life (h)Approximate range.

5 to 7

0.5 to 3

 

Effect of Food on Absorption of Lamivudine and Zidovudine Tablets

Lamivudine and zidovudine tablets may be administered with or without food. The lamivudine and zidovudine AUC following administration of lamivudine and zidovudine tablets with food was similar when compared with fasting healthy subjects (n = 24).


Patients with Renal Impairment
Patients with Hepatic Impairment
Pregnant Women
Geriatric Patients

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

Male and Female Patients

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.

Racial Groups


No drug interaction trials have been conducted using lamivudine and zidovudine tablets.

Lamivudine and Zidovudine

No clinically significant alterations in lamivudine 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 lamivudine (300 mg every 12 hours).

Interferon Alfa

There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.

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.

Sorbitol (Excipient)

Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(∞); and 28%, 52%, and 55% in the Cmax: of lamivudine, respectively.

Table 4 presents drug interaction information for the individual components of lamivudine and zidovudine tablets.
Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUCThis table is not all inclusive.
↑ = Increase; ↓= Decrease; ↔ = No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval.

Coadministered Drug and Dose

Drug and Dose

n

Concentrations of Lamivudine or Zidovudine

Concentration of Coadministered Drug

AUC

Variability

Nelfinavir

     750 mg every 8 h x 7 to 10 days

Lamivudine single 150 mg

11

↑ 10%

95% CI:

1% to 20%



Trimethoprim 160 mg/Sulfamethoxazole

800 mg daily x 5 days

Lamivudine single 300 mg

14

↑ 43%

90% CI:

32% to 55%



Atovaquone

     750 mg every 12 h with food

Zidovudine 200 mg every 8 h

14

↑ 31%

Range:

23% to 78%Estimated range of percent difference.



Clarithromycin

     500 mg twice daily

Zidovudine 100 mg every 4 h x 7 days

4

↓ 12%

Range:

↓ 34% to ↑ 14%

Not Reported

Fluconazole

     400 mg daily

Zidovudine 200 mg every 8 h

12

↑ 74%

95% CI:

54% to 98%

Not Reported

Methadone

     30 to 90 mg daily

Zidovudine 200 mg every 4 h

9

↑ 43%

Range:

16% to 64%



Nelfinavir

     750 mg every 8 h x 7 to 10 days

Zidovudine single 200 mg

11

↓ 35%

Range:

28% to 41%



Probenecid

     500 mg every 6 h x 2 days

Zidovudine 2 mg/kg every 8 h x 3 days

3

↑ 106%

Range:

100% to 170%

Not Assessed

Rifampin

     600 mg daily x 14 days

Zidovudine 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

Zidovudine 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

Zidovudine 100 mg every 8 h x 4 days

6

↑ 80%

Range:

64% to 130%

Not Assessed

12.4Microbiology


Lamivudine

Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine 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.


Lamivudine Plus Zidovudine

In HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios was not antagonistic.

Lamivudine

The antiviral activity of lamivudine 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 lamivudine 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 lamivudine 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 lamivudine 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).


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

HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from subjects after prolonged lamivudine/zidovudine 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.

Lamivudine

Lamivudine-resistant isolates of HIV-1 have been selected in cell culture and have also been recovered from subjects treated with lamivudine or lamivudine 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 lamivudine and zidovudine.


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

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

Lamivudine

Long-term carcinogenicity studies with lamivudine 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.


Lamivudine

Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine 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.


Lamivudine

Lamivudine 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 (Cmax) 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 lamivudine and zidovudine tablet given twice daily is an alternative regimen to EPIVIR tablets 150 mg twice daily plus RETROVIR 600 mg per day in divided doses.

14.1Adults


The NUCB3007 (CAESAR) 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.
Table 5. Number of Subjects (%) with at Least 1 HIV-1 Disease-Progression Event or Death

Endpoint

Current Therapy

(n = 460)

EPIVIR

Plus Current Therapy (n = 896)

EPIVIR Plus a NNRTI An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.

Plus Current Therapy (n = 460)

HIV-1 progression or death

90 (19.6%)

86 (9.6%)

41 (8.9%)

Death

27 (5.9%)

23 (2.6%)

14 (3.0%)

 

14.2Prevention 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


Lamivudine and Zidovudine Tablets, USP are available containing 150 mg of lamivudine, USP and 300 mg of zidovudine, USP.

The 150 mg/300 mg tablets are white to off-white, film-coated, capsule shaped, scored tablets debossed with L on the left of the score and Z on the right of the score on one side of the tablet and M on the left of the score and 1 on the right of the score on the other side. They are available as follows:

NDC 0378-5180-91bottle of 60 tablets

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

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

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 [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 zidovudine [see 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 lamivudine and zidovudine tablets if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.3)].

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 lamivudine was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider [see Warnings and Precautions (5.4)].

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 (5.5)].

Drug Interactions:  Advise patients that other medications may interact with lamivudine and zidovudine tablets and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of zidovudine, a component of lamivudine and zidovudine tablets [see Drug Interactions (7.1)].

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 lamivudine and zidovudine tablets are started [see Warnings and Precautions (5.7)].

Lipoatrophy:  Advise patients that loss of subcutaneous fat may occur in patients receiving lamivudine and zidovudine tablets and that they will be regularly assessed during therapy [see Warnings and Precautions (5.8)].

Pregnancy Registry:  Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine and zidovudine tablets 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 lamivudine and zidovudine tablets, 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)].

The brands uled are trademarks of their respective owners.

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

Manufactured by: Mylan Laboratories Limited Hyderabad — 500 096, India

75065005

Revised: 5/2018MX:LMZT:R6

Principal Display Panel 150 Mg/300 Mg


NDC 0378-5180-91

Lamivudine and Zidovudine Tablets, USP 150 mg/300 mg

Rx only      60 Tablets

Each film-coated tablet contains:Lamivudine, USP      150 mgZidovudine, USP       300 mg

Usual Dosage: See accompanyingprescribing information.

Do not use if printed safety sealunder cap is broken or missing.

Keep this and all medication out of the reach of children.

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

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

Made in India

Mylan.com

RMX5180D3

Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.

Keep container tightly closed.

Code No.: MH/DRUGS/25/NKD/89

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