Itraconazole

Class: Azoles
VA Class: AM700
Chemical Name: 4 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1H - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - l]methoxy]phenyl] - 1 - piperazinyl]phenyl] - 2,4 - dihydro - 2 - (1 - methylpropyl) - 3H - 1,2,4 - triazol - 3 - one
CAS Number: 84625-61-6
Brands: Sporanox

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  Itraconazole capsules should not be used for treatment of onychomycosis in patients with evidence of ventricular dysfunction, including CHF or history of CHF.¹

  
  


• 
  

  Discontinue itraconazole if signs or symptoms of CHF occur.¹ IV itraconazole (no longer commercially available in the US) caused negative inotropic effects in healthy individuals and in dogs.^{1 48}

  
  


• 
  

  Concomitant use with cisapride (currently commercially available in the US only under a limited-access protocol), pimozide, quinidine, dofetilide, or levomethadyl (no longer commercially available in the US) is contraindicated.^{1 48} Itraconazole is a potent inhibitor of CYP3A4 isoenzymes and may increase plasma concentrations of drugs metabolized by CYP3A4.^{1 48} Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levomethadyl, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors.^{1 48} (See Interactions.)

  
  

Introduction

Antifungal; azole (triazole derivative).^{1 3 37 48}

Uses for Itraconazole

Aspergillosis

Treatment of invasive aspergillosis.^{1 66 423} Considered an alternative, not a drug of choice.^{1 423 436}

Treatment of pulmonary and extrapulmonary aspergillosis in patients intolerant of, or whose disease is refractory to, IV amphotericin B.^{1 66}

IDSA considers voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients and IV amphotericin B the preferred alternative.⁴²³ For salvage therapy in patients refractory to or intolerant of primary antifungal therapy, IDSA recommends amphotericin B, caspofungin, micafungin, posaconazole, or itraconazole.⁴²³ For empiric or preemptive therapy of presumed aspergillosis, IDSA recommends amphotericin B, caspofungin, itraconazole, or voriconazole.⁴²³

Not considered a drug of choice or preferred alternative for treatment of invasive aspergillosis in HIV-infected individuals.^{440 441} For treatment of invasive aspergillosis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend voriconazole as the drug of choice;⁴⁴⁰ voriconazole also considered the drug of choice for treatment of invasive aspergillosis in HIV-infected children.⁴⁴¹ Because the drugs have similar mechanisms of action and cross-resistance may occur, itraconazole not recommended for treatment of aspergillosis refractory to voriconazole.⁴⁴¹

For primary prophylaxis of aspergillosis in immunocompromised individuals at high risk of invasive disease (i.e., neutropenic patients with acute myelogenous leukemia [AML] or myelodysplastic syndrome [MDS], hematopoietic stem cell transplant [HSCT] recipients with graft-versus-host disease [GVHD]), IDSA considers posaconazole the drug of choice;⁴²³ alternatives are itraconazole or micafungin.⁴²³

Blastomycosis

Treatment of pulmonary and extrapulmonary blastomycosis caused by Blastomyces dermatitidis.^{1 36 49 50 51 52 53 54 59 62 63 424 436}

Drugs of choice are oral itraconazole or IV amphotericin B.^{36 49 50 51 52 436}

IV amphotericin B is preferred for initial treatment of severe blastomycosis, especially infections involving the CNS^{51 52 55 56 50 51 52 53 54 61 424 436} and for initial treatment of presumptive blastomycosis in immunocompromised patients, including HIV-infected individuals.^{50 55 61 424}

Itraconazole is the drug of choice for treatment of nonmeningeal, non-life-threatening blastomycosis, including mild to moderate pulmonary blastomycosis or mild to moderate disseminated blastomycosis (without CNS involvement), and also is recommended for follow-up therapy in patients with more severe infections after an initial response has been obtained with IV amphotericin B.^{36 61 62 63 424 436}

Azole antifungals should not be relied on for initial treatment of CNS blastomycosis.⁴²⁴ Treatment failures have been reported when an oral antifungal (e.g., ketoconazole) was used in the treatment of cutaneous or pulmonary blastomycosis in patients who had asymptomatic or subclinical CNS involvement at the time of the initial diagnosis.^{57 58}

IDSA states that long-term suppressive or maintenance therapy (secondary prophylaxis)† with itraconazole may be required to prevent relapse or recurrence of blastomycosis in immunocompromised patients and in other patients who experience relapse despite appropriate therapy.⁴²⁴ Such prophylaxis is not addressed in current CDC, NIH, and IDSA guidelines for prevention of opportunistic infections in individuals infected with HIV.^{440 441}

Candidemia and Other Invasive Candida Infections

Not a drug of choice or preferred alternative for treatment of candidemia† or other invasive Candida infections†.^{425 436} Fluconazole or voriconazole usually are recommended when an azole antifungal is used for treatment of candidemia.^{425 436}

Has been used and is recommended as an alternative for initial empiric treatment of suspected invasive candidiasis in neutropenic patients†.⁴²⁵ IV amphotericin B, caspofungin, or voriconazole are drugs of choice in these patients;⁴²⁵ alternatives are fluconazole or itraconazole.⁴²⁵ Do not use an azole antifungal for empiric treatment in patients who previously received an azole for prophylaxis.⁴²⁵

Oropharyngeal Candidiasis

Treatment of oropharyngeal candidiasis.^{48 425}

IDSA recommends topical treatment with clotrimazole lozenges or nystatin oral suspension for mild oropharyngeal candidiasis;⁴²⁵ oral fluconazole is recommended for moderate to severe disease.⁴²⁵ For refractory oropharyngeal candidiasis, including fluconazole-refractory infections, itraconazole oral solution, oral posaconazole, or oral voriconazole is recommended.⁴²⁵ An IV echinocandin (caspofungin, micafungin, anidulafungin) or IV amphotericin B also are recommended as alternatives for refractory infections.⁴²⁵

For treatment of oropharyngeal candidiasis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend oral fluconazole as the preferred drug of choice for initial episodes;⁴⁴⁰ other drugs of choice are clotrimazole lozenges or nystatin oral suspension.⁴⁴⁰ Alternatives for initial episodes are itraconazole oral solution or oral posaconazole.⁴⁴⁰ For fluconazole-refractory infections in HIV-infected adults and adolescents, itraconazole oral solution or oral posaconazole is preferred;⁴⁴⁰ alternatives include IV amphotericin B, an IV echinocandin (caspofungin, micafungin, anidulafungin), or oral or IV voriconazole.⁴⁴⁰

Although routine long-term suppressive or maintenance therapy (secondary prophylaxis)† to prevent relapse or recurrence is not usually recommended in patients adequately treated for oropharyngeal candidiasis, patients with frequent or severe recurrences, including HIV-infected adults, adolescents, or children, may benefit from secondary prophylaxis with oral fluconazole or itraconazole oral solution; however, consider the potential for azole resistance.^{425 440 441} Patients with fluconazole-refractory oropharyngeal candidiasis who responded to treatment with an echinocandin should receive voriconazole or posaconazole for secondary prophylaxis until antiretroviral therapy produces immune reconstitution.⁴⁴⁰

Esophageal Candidiasis

Treatment of esophageal candidiasis.^{48 425}

Esophageal candidiasis requires treatment with a systemic antifungal (not a topical antifungal).^{425 440}

IDSA recommends oral fluconazole as the preferred drug of choice for treatment of esophageal candidiasis;⁴²⁵ if oral therapy is not tolerated, IV fluconazole, IV amphotericin B, or an IV echinocandin (caspofungin, micafungin, anidulafungin) is recommended.⁴²⁵ For fluconazole-refractory infections, preferred alternatives are itraconazole oral solution, oral posaconazole, or oral or IV voriconazole;⁴²⁵ other alternatives are an IV echinocandin (caspofungin, micafungin, anidulafungin) or IV amphotericin B.⁴²⁵

For treatment of esophageal candidiasis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend oral or IV fluconazole as the preferred drug of choice and itraconazole oral solution as the preferred alternative.⁴⁴⁰ Other alternatives include an IV echinocandin (caspofungin, micafungin, anidulafungin), oral or IV voriconazole, oral posaconazole, or IV amphotericin B.⁴⁴⁰ For refractory esophageal candidiasis, including fluconazole-refractory infections, in HIV-infected adults and adolescents, itraconazole oral solution or oral posaconazole is preferred;⁴⁴⁰ alternatives include IV amphotericin B, an IV echinocandin (caspofungin, micafungin, anidulafungin), or oral or IV voriconazole.⁴⁴⁰

Although routine long-term suppressive or maintenance therapy (secondary prophylaxis)† to prevent relapse or recurrence is not usually recommended in patients adequately treated for esophageal candidiasis, patients with frequent or severe recurrences, including HIV-infected adults, adolescents, or children, may benefit from secondary prophylaxis with oral fluconazole or oral posaconazole; however, consider the potential for azole resistance.^{425 440 441} Patients with fluconazole-refractory esophageal candidiasis who responded to treatment with an echinocandin should receive voriconazole or posaconazole for secondary prophylaxis until antiretroviral therapy produces immune reconstitution.⁴⁴⁰ Itraconazole is not included in current recommendations for secondary prophylaxis of esophageal candidiasis.^{425 440}

Vulvovaginal Candidiasis

Has been used for treatment of uncomplicated vulvovaginal candidiasis†.⁴³⁶

Vulvovaginal candidiasis is usually treated with an intravaginal azole antifungal (e.g., butoconazole, clotrimazole, miconazole, terconazole, tioconazole) or a single-dose oral fluconazole regimen.^{425 436 443 444} Although some clinicians suggest that oral itraconazole or oral ketoconazole can be used as alternatives for treatment of vulvovaginal candidiasis,⁴³⁶ fluconazole is the only oral antifungal included in CDC recommendations for treatment of uncomplicated or complicated vulvovaginal candidiasis.⁴⁴³

Chromomycosis

Has been used for treatment of chromomycosis† (chromoblastomycosis) caused by various dematiaceous fungi (e.g., Cladosporium, Exophiala, Fonsecaea, Phialophora).^{43 60 71 72 73}

Coccidioidomycosis

Treatment and prevention of coccidioidomycosis† caused by Coccidioides immitis or C. posadasii.^{36 56 60 426 436 440 441} A drug of choice.^{426 436 440}

Antifungal treatment may not be necessary for mild, uncomplicated coccidioidal pneumonia since such infections may resolve spontaneously;⁴²⁶ treatment is recommended for patients with more severe or rapidly progressing infections, those with chronic pulmonary or disseminated infections, and immunocompromised or debilitated individuals (e.g., HIV-infected individuals, organ transplant recipients, those receiving immunosuppressive therapy, those with diabetes or cardiopulmonary disease).^{426 440 441}

For initial treatment of symptomatic pulmonary coccidioidomycosis and chronic fibrocavitary or disseminated (extrapulmonary) coccidioidomycosis, IDSA states than an oral azole (fluconazole or itraconazole) usually is recommended.⁴²⁶ IV amphotericin B is recommended as an alternative and is preferred for initial treatment of severely ill patients who have hypoxia or rapidly progressing disease, for immunocompromised individuals, or when azole antifungals cannot be used (e.g., pregnant women).⁴²⁶

For treatment of clinically mild coccidioidomycosis (e.g., focal pneumonia or a positive coccidioidal serologic test alone) in HIV-infected adults or adolescents, CDC, NIH, and IDSA recommend oral fluconazole or oral itraconazole.⁴⁴⁰ For treatment of diffuse pulmonary coccidioidomycosis or extrathoracic disseminated (nonmeningeal) coccidioidomycosis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend initial therapy with IV amphotericin B followed by oral azole therapy.⁴⁴⁰ Alternatively, some experts recommend initial therapy with IV amphotericin B used in conjunction with an oral azole (e.g., fluconazole) followed by an oral azole alone.⁴⁴⁰

For treatment of diffuse pulmonary or disseminated coccidioidomycosis in HIV-infected infants and children, CDC, NIH, and IDSA recommend initial treatment with IV amphotericin B followed by oral fluconazole or oral itraconazole.⁴⁴¹ In those with severe disseminated disease, some experts recommend initial therapy with IV amphotericin B used in conjunction with an oral azole (e.g., fluconazole) followed by an oral azole alone.⁴⁴¹ Use of fluconazole or itraconazole alone may be sufficient for treatment of mild coccidioidomycosis in HIV-infected infants and children with only mild disease (e.g., focal pneumonia) and also can be considered an alternative for those with stable pulmonary or disseminated (nonmeningeal) coccidioidomycosis.⁴⁴¹

For treatment of coccidioidal meningitis in HIV-infected adults, adolescents, or children or for other individuals, fluconazole (with or without intrathecal amphotericin B) is the regimen of choice.^{426 440 441} Itraconazole may be an alternative to fluconazole in adults and adolescents.⁴⁴⁰ Consultation with an expert is recommended.^{440 441}

In HIV-infected adults and adolescents who live in areas where coccidioidomycosis is endemic, CDC, NIH, and IDSA recommend primary prophylaxis against coccidioidomycosis† in those who have positive IgM or IgG serologic tests and CD4⁺ T-cell counts <250/mm³ since these individuals may be at increased risk for development of active infections.⁴⁴⁰ Oral fluconazole or oral itraconazole should be used for primary prophylaxis against coccidioidomycosis in these HIV-infected adults and adolescents. ⁴⁴⁰ Primary prophylaxis against coccidioidomycosis is not recommended in HIV-infected children.⁴⁴¹

HIV-infected adults, adolescents, or children who have been adequately treated for coccidioidomycosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis)† to prevent recurrence or relapse.^{440 441} CDC, NIH, and IDSA recommend oral fluconazole or oral itraconazole for secondary prophylaxis of coccidioidomycosis in HIV-infected individuals.^{440 441}

Long-term (life-long) suppressive or maintenance therapy (secondary prophylaxis)† with oral fluconazole or oral itraconazole also is necessary in any individual treated for coccidioidal meningitis.⁴²⁶

Cryptococcosis

Has been used for treatment of cryptococcosis†.^{36 49 68 427 436 440 441} Not a drug of choice or preferred alternative.^{427 440 441}

For treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children, CDC, NIH, and IDSA state that the preferred regimen is initial (induction) therapy with IV amphotericin B given in conjunction with oral flucytosine, then follow-up (consolidation) therapy with oral fluconazole.^{427 440 441} Although data are limited and use of the drug is discouraged, IDSA and others state that itraconazole can be considered an alternative for induction and consolidation therapy if all other alternative regimens have failed or are not available.^{427 440 441}

For treatment of mild to moderate pulmonary cryptococcosis in immunocompetent individuals, the regimen of choice is oral fluconazole.⁴²⁷ Although data are limited, IDSA states that itraconazole, voriconazole, and posaconazole are acceptable alternatives in immunocompetent individuals if fluconazole is unavailable or contraindicated.⁴²⁷

Severe pulmonary infections, cryptococcemia, and disseminated infections in immunocompetent or immunosuppressed individuals should be treated using regimens recommended for cryptococcal meningitis.⁴²⁷

HIV-infected adults, adolescents, and children who have been adequately treated for cryptococcus should receive long-term suppressive or maintenance therapy (secondary prophylaxis)† to prevent recurrence or relapse.^{427 440 441} CDC, NIH, and IDSA recommend oral fluconazole as the drug of choice for secondary prophylaxis of cryptococcosis in HIV-infected individuals;^{427 440 441} oral itraconazole is considered an alternative in those who cannot tolerate fluconazole, but may be less effective than fluconazole.^{427 440 441}

Although data are limited, IDSA states that recommendations for treatment of CNS or disseminated infections caused by Cryptococcus gattii and recommendations for secondary prophylaxis of C. gattii infections are the same as recommendations for C. neoformans infections.⁴²⁷

Histoplasmosis

Treatment of histoplasmosis caused by Histoplasma capsulatum, including chronic cavitary pulmonary disease and disseminated nonmeningeal disease.^{48 428 436 440 441}

Drugs of choice for treatment of histoplasmosis are IV amphotericin B and oral itraconazole.^{36 49 55 59 60 61 65 428 436 440 441} IV amphotericin B is preferred for initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients such as those with HIV infection.^{36 42 44 45 49 55 56 60 61 64 65 428 436 440 441} Oral itraconazole generally is used for initial treatment of less severe disease (e.g., mild to moderate acute pulmonary histoplasmosis, chronic cavitary pulmonary histoplasmosis) and as follow-up treatment of severe infections after a response has been obtained with IV amphotericin B.^{36 49 56 59 61 65 428 436 440 441}

For treatment of moderately severe to severe acute pulmonary histoplasmosis or progressive disseminated histoplasmosis in HIV-infected adults and adolescents and other adults, CDC, NIH, and IDSA recommend initial treatment with IV amphotericin B and follow-up treatment with oral itraconazole.^{428 440}

For treatment of progressive disseminated histoplasmosis in children, IDSA states that IV amphotericin B or an initial regimen of IV amphotericin B and follow-up treatment with oral itraconazole can be used.⁴²⁸ For treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected infants and children, CDC, NIH, and IDSA recommend initial treatment with IV amphotericin B and follow-up treatment with oral itraconazole.⁴⁴¹ Although oral itraconazole may be used alone for treatment of mild to moderate disseminated histoplasmosis in children, including HIV-infected infants and children, it is not recommended for more severe infections.^{428 441}

HIV-infected adults or adolescents with CD4⁺ T-cell counts <150/mm³ who are at high risk because they reside in areas where histoplasmosis is highly endemic should receive primary prophylaxis† against initial episodes of histoplasmosis.^{428 436 440} Itraconazole is the drug of choice for primary prophylaxis against histoplasmosis in these HIV-infected adults and adolescents.^{428 436 440} Primary prophylaxis against histoplasmosis is not recommended in HIV-infected children.⁴⁴¹

HIV-infected adults, adolescents, or children and other immunosuppressed individuals who have been adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis)† to prevent recurrence or relapse.^{428 440 441} Itraconazole is the drug of choice for secondary prophylaxis against histoplasmosis†.^{428 440}

Microsporidiosis

Treatment of microsporidiosis†.^{135 136 440 442}

Has been effective in a few cases of keratoconjunctivitis or sinusitis caused by Encephalitozoon.^{135 136} Regimen of choice for ocular microsporidiosis is fumagillin (not commercially available in the US) used in conjunction with albendazole.^{440 441 442}

Alternative for disseminated microsporidiosis, especially infections caused by Trachipleistophora or Anncaliia;^{440 442} used in conjunction with albendazole.^{440 442} Albendazole usually is the drug of choice for intestinal or disseminated microsporidiosis (except infections caused by Enterocytozoon bienuesi or Vittaforma corneae).^{440 441 442}

Onychomycosis

Treatment of onychomycosis of the toenails (with or without fingernail involvement) and onychomycosis of the fingernails caused by dermatophytes (tinea unguium).^{1 132 133 436}

Paracoccidioidomycosis

Treatment of paracoccidioidomycosis† (South American blastomycosis) caused by Paracoccidioides brasiliensis.^{36 43 56 436}

IV amphotericin B is the drug of choice for initial treatment of severe paracoccidioidomycosis.⁴³⁶ Oral itraconazole is the drug of choice for treatment of less severe or localized paracoccidioidomycosis and for follow-up in more severe infections after initial treatment with IV amphotericin B.^{56 60}

Penicilliosis

Treatment of penicilliosis† caused by Penicillium marneffei.^{115 116 117 119 440}

For treatment of severe or disseminated P. marneffei infections, including in HIV-infected adults or adolescents, an initial regimen of IV amphotericin B followed by oral itraconazole is recommended.^{115 116 119 440} Oral itraconazole can be used alone for treatment of mild infections.⁴⁴⁰

Chronic suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole is recommended to prevent relapse of penicilliosis† in HIV-infected adults or adolescents who respond to an initial treatment regimen of IV amphoterin B and/or oral itraconazole.^{116 117 440}

Sporotrichosis

Treatment of sporotrichosis† caused by Sporothrix schenckii.^{43 49 55 56 61 67 429 436}

IV amphotericin B is the drug of choice for initial treatment of severe, life-threatening sporotrichosis and sporotrichosis that is disseminated or has CNS involvement.^{56 60 61 67 429 436} Oral itraconazole is the drug of choice for treatment of cutaneous, lymphocutaneous, or mild pulmonary or osteoarticular sporotrichosis and for follow-up treatment of severe infections after a response has been obtained with IV amphotericin B.^{43 56 60 61 67 429 436}

Zygomycosis

Treatment of GI basidiobolomycosis†, a zygomycosis caused by Basidiobolus ranarum.^{38 104 105 106 107}

Has been effective in a few patients for the treatment of subcutaneous basidiobolomycosis.^{124 125}

GI basidiobolomycosis has been successfully treated with oral itraconazole after partial surgical resection of the GI tract; unclear whether a clinical response would have been obtained if itraconazole had been used alone without surgical intervention.^{38 105}

Empiric Therapy in Febrile Neutropenic Patients

Has been used for empiric therapy of presumed fungal infections in febrile neutropenic patients.^{48 93 425}

Itraconazole Dosage and Administration

Administration

Administer orally.^{1 3 30 36 37 38 48}

Has been administered by IV infusion,⁷⁶ but an IV preparation is no longer commercially available in the US.

Oral Administration

Oral bioavailability varies depending on whether the drug is administered as capsules or the oral solution; these preparations should not be used interchangeably.^{1 48}

The possibility that GI absorption may be decreased in patients with hypochlorhydria (e.g., HIV-infected individuals) should be considered.^{1 10} (See Absorption under Pharmacokinetics.)

Capsules

The capsules should be administered with a full meal to ensure maximal absorption of the drug.¹

Capsules should not be used for treatment of oropharyngeal or esophageal candidiasis;^{425 440 441} efficacy not established,¹ may be less effective than oral solution for these infections.^{425 440 441}

If capsules are given in a dosage >200 mg daily, daily dosage should be divided into 2 doses.¹

Oral Solution

The oral solution should be administered without food to ensure maximal absorption of the drug.⁴⁸

For treatment of oropharyngeal or esophageal candidiasis, the recommended dosage of itraconazole oral solution should be vigorously swished in the mouth (10 mL at a time) for several seconds and then swallowed.⁴⁸

Manufacturer states that data are limited to date regarding the safety of long-term use of itraconazole oral solution (i.e., >6 months).⁴⁸

Dosage

Because of differences in oral bioavailability, itraconazole capsules and oral solution should not be used interchangeably.^{1 48}

Only the oral solution (not capsules) is indicated for treatment of oropharyngeal or esophageal candidiasis.⁴⁸

To ensure adequate plasma concentrations of itraconazole (especially in patients with life-threatening fungal infections), IDSA and others recommend that itraconazole plasma concentrations be determined, usually after 2 weeks of therapy.^{423 424 425 428 429}

Pediatric Patients

Blastomycosis†

Treatment of Blastomycosis†

Oral

Mild to moderate blastomycosis: IDSA recommends 10 mg/kg daily (up to 400 mg daily) for 6–12 months.⁴²⁴

Moderately severe to severe blastomycosis: IDSA recommends an initial regimen of IV amphotericin B given for 1–2 weeks, followed by itraconazole 10 mg/kg daily (up to 400 mg daily) for a total treatment duration of 12 months.⁴²⁴

Candida Infections†

Treatment of Oropharyngeal Candidiasis†

Oral

HIV-infected infants and children (oral solution): 2.5 mg/kg twice daily (up to 200 mg daily) for 7–14 days.⁴⁴¹

HIV-infected infants and children with fluconazole-refractory infections (oral solution): 2.5 mg/kg twice daily (up to 200–400 mg daily) for 7–14 days.⁴⁴¹

HIV-infected adolescents (oral solution): 200 mg daily for 7–14 days.⁴⁴⁰ Same dosage can be used for fluconazole-refractory infections.⁴⁴⁰

Prevention of Recurrence (Secondary Prophylaxis) of Oropharyngeal Candidiasis†

Oral

HIV-infected adolescents (oral solution): 200 mg daily.⁴⁴⁰

Secondary prophylaxis not usually recommended; use only if patient has frequent or severe recurrences.⁴⁴⁰ Consider discontinuing secondary prophylaxis if CD4⁺ T-cell count increases to ≥200/mm³ in response to antiretroviral therapy.⁴⁴⁰

Treatment of Esophageal Candidiasis†

Oral

HIV-infected infants and children (oral solution): 2.5 mg/kg twice daily or 5 mg/kg once daily for 14–21 days.⁴⁴¹

HIV-infected adolescents (oral solution): 200 mg daily for 14–21 days.⁴⁴⁰

Treatment of Vulvovaginal Candidiasis†

Oral

HIV-infected adolescents (oral solution): 200 mg daily for 3–7 days.⁴⁴⁰

Coccidioidomycosis†

Treatment of Coccidioidomycosis (Nonmeningeal)†

Oral

HIV-infected infants and children with mild coccidioidomycosis (e.g., focal pneumonia): 5–10 mg/kg twice daily for 3 days, then 2–5 mg/kg twice daily.⁴⁴¹

HIV-infected infants and children with diffuse pulmonary or disseminated coccidioidomycosis: Initial regimen of IV amphotericin B given until a response is obtained, followed by itraconazole 5–10 mg/kg twice daily for 3 days, then 2–5 mg/kg twice daily (up to 400 mg daily).⁴⁴¹

HIV-infected adolescents with mild coccidioidomycosis (e.g., focal pneumonia or positive coccidioidal serologic test alone): 200 mg 3 times daily for 3 days, then 200 mg twice daily.⁴⁴⁰

Treatment of Coccidioidal Meningitis†

Oral

HIV-infected adolescents with meningeal coccidioidomycosis: 200 mg 3 times daily for 3 days, then 200 mg twice daily.⁴⁴⁰

Consultation with an expert experienced in treating coccidioidal meningitis is recommended.⁴⁴¹

Primary Prophylaxis to Prevent First Episode of Coccidioidomycosis†

Oral

HIV-infected adolescents living in areas endemic for coccidioidomycosis who have positive IgM or IgG serologic test and CD4⁺ T-cell count <250/mm³: 200 mg twice daily.⁴⁴⁰

Consider discontinuing primary prophylaxis if CD4⁺ T-cell count is >250/mm³ for 6 months.⁴⁴⁰ Reinitiate primary prophylaxis against coccidioidomycosis if CD4⁺ T-cell count decreases to <250/mm³.⁴⁴⁰

Prevention of Recurrence (Secondary Prophylaxis) of Coccidioidomycosis†

Oral

HIV-infected infants and children: 2–5 mg/kg (up to 200 mg) twice daily.⁴⁴¹

HIV-infected adolescents: 200 mg twice daily.⁴⁴⁰

Initiate secondary prophylaxis after primary infection has been adequately treated.^{440 441}

HIV-infected infants and children: Continue life-long, secondary prophylaxis against coccidioidomycosis, regardless of antiretroviral therapy or immune reconstitution.⁴⁴¹

HIV-infected adolescents with history of focal coccidioidal pneumonia who responded to antifungal treatment, are receiving antiretroviral therapy, and have CD4⁺ T-cell counts >250/mm³: Consider discontinuing secondary prophylaxis against coccidioidomycosis after 12 months, but continue monitoring for recurrence (e.g., serial chest radiographs, coccidioidal serology).⁴⁴⁰

HIV-infected adolescents with history of diffuse pulmonary or disseminated coccidioidomycosis or history of coccidioidal meningitis: Continue life-long secondary prophylaxis against coccidioidomycosis, regardless of antiretroviral therapy or immune reconstitution.⁴⁴⁰

Cryptococcosis†

Treatment of Cryptococcosis†

Oral

HIV-infected infants and children with CNS cryptococcosis: Initial (induction) regimen of IV amphotericin B given for at least 2 weeks, then follow-up (consolidation) regimen of itraconazole 200 mg 3 times daily for 3 days, then 5–10 mg/kg (maximum 200 mg) once or twice daily for at least 8 weeks.⁴⁴¹

HIV-infected adolescents with CNS cryptococcosis: Initial (induction) regimen of IV amphotericin B given for at least 2 weeks, then follow-up (consolidation) regimen of itraconazole 200 mg twice daily for 8 weeks or until CD4⁺ T-cell count is ≥200/mm³ for at least 6 months as the result of antiretroviral therapy.⁴⁴⁰

Some clinicians suggest the oral solution may be preferred (instead of capsules) for treatment of cryptococcosis.⁴²⁷

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis†

Oral

HIV-infected infants and children (oral solution): 5 mg/kg (up to 200 mg) daily.⁴⁴¹

HIV-infected adolescents: 200 mg daily.⁴⁴⁰

Initiate secondary prophylaxis after primary infection has been adequately treated.^{440 441}

HIV-infected infants and children with a history of cryptococcosis usually should receive life-long suppressive therapy to prevent recurrence.⁴⁴¹ Consideration can be given to discontinuing secondary prophylaxis in HIV-infected children ≥6 years of age who are asymptomatic for cryptococcosis, have received secondary prophylaxis for ≥6 months, have been receiving antiretroviral therapy for ≥6 months, and have CD4⁺ T-cell counts ≥200/mm³ for ≥6 months.⁴⁴¹ Reinitiate secondary prophylaxis against cryptococcosis if CD4⁺ T-cell count decreases to <200/mm³.⁴⁴¹

HIV-infected adolescents with a history of cryptococcosis usually should receive life-long secondary prophylaxis to prevent recurrence.⁴⁴⁰ Some experts state that consideration can be given to discontinuing secondary prophylaxis in HIV-infected adolescents who are asymptomatic for cryptococcosis, are receiving antiretroviral therapy, and have CD4⁺ T-cell counts ≥200/mm³ for >6 months.⁴⁴⁰ Reinitiate secondary prophylaxis against cryptococcosis if CD4⁺ T-cell count decreases to <200/mm³.⁴⁴⁰

Histoplasmosis†

Treatment of Histoplasmosis†

Oral

Acute pulmonary histoplasmosis: IDSA recommends 5–10 mg/kg daily (up to 400 mg daily) given in 2 divided doses.⁴²⁸

Progressive disseminated histoplasmosis: IDSA recommends initial regimen of IV amphotericin B given for 2–4 weeks, followed by itraconazole 5–10 mg/kg daily (up to 400 mg daily) given in 2 divided doses for a total duration of 3 months.⁴²⁸ A longer duration may be necessary in children with severe disease or with immunosuppression or primary immunodeficiency syndromes.⁴²⁸

HIV-infected infants and children with mild disseminated histoplasmosis (oral solution): 2–5 mg/kg (up to 200 mg) 3 times daily for 3 days, then 2–5 mg/kg (up to 200 mg) twice daily for 12 months.⁴⁴¹

HIV-infected infants and children with moderately severe to severe disseminated histoplasmosis: Initial regimen of IV amphotericin B given for at least 1–2 weeks, followed by itraconazole (oral solution) 2–5 mg/kg (up to 200 mg) 3 times daily for 3 days, then 2–5 mg/kg (up to 200 mg) twice daily for 12 months.⁴⁴¹

HIV-infected infants and children with CNS histoplasmosis: Initial regimen of IV amphotericin B given for 4–6 weeks, followed by itraconazole (oral solution) 2–5 mg/kg (up to 200 mg) 3 times daily for 3 days, then 2–5 mg/kg (up to 200 mg) twice daily for at least 12 months and until CSF abnormalities resolve and histoplasmal antigen is undetectable.⁴⁴¹

HIV-infected adolescents with less severe disseminated histoplasmosis: 200 mg 3 times daily for 3 days, then 200 mg twice daily for at least 12 months.⁴⁴⁰

HIV-infected adolescents with moderately severe to severe disseminated histoplasmosis: Initial regimen of IV amphotericin B given for at least 2 weeks or until a response is obtained, followed by itraconazole 200 mg 3 times daily for 3 days, then 200 mg twice daily for a total duration of at least 12 months and until histoplasmal antigen is undetectable.⁴⁴¹

HIV-infected adolescents with CNS histoplasmosis: Initial regimen of IV amphotericin B given for 4–6 weeks or until a response is obtained, followed by itraconazole 200 mg 2 or 3 times daily for at least 12 months and until CSF abnormalities resolve and histoplasmal antigen is undetectable.⁴⁴¹

Some clinicians suggest the oral solution may be preferred (instead of capsules) f

Genexa LA

Generic Name: guaifenesin and phenylephrine (gwye FEN e sin and FEN il EFF rin)

Brand Names: Aldex G, Aquatab D, Crantex, D-Phen 1000, D-Tab, Deconex, Deconsal II, Deconsal Pediatric, Despec, Donatussin Drops, Duomax, Duraphen 1000, Duraphen II, Duratuss, Dynex LA, ExeTuss, Extendryl G, Fenesin PE IR, Genexa LA, Gentex LA, Gilphex TR, Guaiphen-D 1200, Guaiphen-D 600, Guaiphen-PD, Guiadex PD, Guiatex PE, J-Max, Liquibid D-R, Liquibid-D, Liquibid-PD, Lusonex, Maxiphen, Medent-PE, MontePhen, Mucinex Children's Cold, Mucus Relief Sinus, Mydex, Nariz, Nasex, Nescon-PD, Nexphen PD, Norel EX, PE-Guai, Pendex, Prolex D, Refenesen PE, Reluri, Rescon-GG, Respa-PE, Robitussin Head & Chest Congestion, Simuc, Simuc-GP, Sina-12X, Sinupan, SINUvent PE, Sitrex PD, Sudafed PE Non-Drying Sinus, Sudex, Triaminic Chest & Nasal Congestion, Visonex, Wellbid-D, Xedec, Xedec II, Xpect-PE, Zotex GPX

What is Genexa LA (guaifenesin and phenylephrine)?

There are many brands and forms of guaifenesin and phenylephrine available and not all brands are listed on this leaflet.

Guaifenesin is an expectorant. It helps loosen congestion in your chest and throat, making it easier to cough out through your mouth.

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of guaifenesin and phenylephrine is used to treat stuffy nose and sinus congestion, and to reduce chest congestion caused by the common cold or flu.

Guaifenesin and phenylephrine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Genexa LA (guaifenesin and phenylephrine)?

There are many brands and forms of guaifenesin and phenylephrine available and not all brands are listed on this leaflet.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Ask a doctor or pharmacist before using any other cough, cold, or allergy medicine. Guaifenesin and phenylephrine are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains guaifenesin or phenylephrine.

What should I discuss with my healthcare provider before taking Genexa LA (guaifenesin and phenylephrine)?

You should not use this medication if you are allergic to guaifenesin or phenylephrine, or to other decongestants, diet pills, stimulants, or ADHD medications. Do not use guaifenesin and phenylephrine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. Serious, life threatening side effects can occur if you use guaifenesin and phenylephrine before the MAO inhibitor has cleared from your body.

Ask a doctor or pharmacist if it is safe for you to take this medication if you have:

• 
  

  heart disease or high blood pressure;

  
  


• 
  

  diabetes;

  
  


• 
  

  circulation problems;

  
  


• 
  

  glaucoma;

  
  


• 
  

  overactive thyroid; or

  
  


• 
  

  enlarged prostate or problems with urination.

  
  

It is not known if this medication may be harmful to an unborn baby. Do not use this medication without your doctor's advice if you are pregnant. This medication passes into breast milk and could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Artificially-sweetened liquid forms of cold medicine may contain phenylalanine. This would be important to know if you have phenylketonuria (PKU). Check the ingredients and warnings on the medication label if you are concerned about phenylalanine.

How should I take Genexa LA (guaifenesin and phenylephrine)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Cold medicine is usually taken only for a short time until your symptoms clear up.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving cough or cold medicine to a child. Death can occur from the misuse of cough or cold medicine in very young children.

Measure the liquid form of this medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Do not crush, chew, break, or open an extended-release tablet or capsule. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time. Take guaifenesin and phenylephrine with food if it upsets your stomach. Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache, cough, or skin rash. Drink extra fluids to help loosen the congestion and lubricate your throat while you are taking this medication. Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Since cough or cold medicine is taken as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, vomiting, numbness or tingly feeling, dizziness, and feeling restless or nervous.

What should I avoid while taking Genexa LA (guaifenesin and phenylephrine)?

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Drinking alcohol can increase certain side effects of guaifenesin and phenylephrine. Ask a doctor or pharmacist before using any other cough, cold, or allergy medicine. Guaifenesin and phenylephrine are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains guaifenesin or phenylephrine.

Avoid taking this medication with diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.

Genexa LA (guaifenesin and phenylephrine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have any of these serious side effects:

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  fast, pounding, or uneven heartbeat;

  
  


• 
  

  severe dizziness, anxiety, restless feeling, or nervousness;

  
  


• 
  

  easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms;

  
  


• 
  

  dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, uneven heartbeats, seizure); or

  
  


• 
  

  nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

  
  

Less serious side effects may include:

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  vomiting, upset stomach;

  
  


• 
  

  warmth, tingling, or redness under your skin;

  
  


• 
  

  feeling excited or restless (especially in children);

  
  


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  sleep problems (insomnia);

  
  


• 
  

  skin rash or itching;

  
  


• 
  

  headache; or

  
  


• 
  

  dizziness.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Genexa LA (guaifenesin and phenylephrine)?

Ask a doctor or pharmacist if it is safe for you to take guaifenesin and phenylephrine if you are also using any of the following drugs:

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  medicines to treat high blood pressure;

  
  


• 
  

  a beta-blocker such as atenolol (Tenormin, Tenoretic), carvedilol (Coreg), labetalol (Normodyne, Trandate), metoprolol (Dutoprol, Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), sotalol (Betapace), and others; or

  
  


• 
  

  an antidepressant such as amitriptyline (Elavil, Vanatrip, Limbitrol), doxepin (Sinequan, Silenor), desipramine (Norpramin), imipramine (Janimine, Tofranil), nortriptyline (Pamelor), and others.

  
  

This list is not complete and other drugs may interact with guaifenesin and phenylephrine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Genexa LA resources

• Genexa LA Side Effects (in more detail)
• Genexa LA Use in Pregnancy & Breastfeeding
• Drug Images
• Genexa LA Drug Interactions
• Genexa LA Support Group
• 0 Reviews for Genexa LA - Add your own review/rating

• Crantex Prescribing Information (FDA)


• Despec Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Entex LA Sustained-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)


• Gentex LA Sustained-Release Tablets (12 Hour) MedFacts Consumer Leaflet (Wolters Kluwer)


• Guiatex PE Prescribing Information (FDA)


• Lusonex Controlled-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Rescon-GG Liquid MedFacts Consumer Leaflet (Wolters Kluwer)


• Sina-12X Suspension MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Genexa LA with other medications

• Cough and Nasal Congestion
• Sinus Symptoms

Where can I get more information?

• Your pharmacist can provide more information about guaifenesin and phenylephrine.

See also: Genexa LA side effects (in more detail)

Lamivudine and Zidovudine Tablets

FULL PRESCRIBING INFORMATION

WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B

Zidovudine, one of the 2 active ingredients in Lamivudine and Zidovudine Tablets, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patientswith advanced 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 hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine, zidovudine, and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.3)].

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)].

Indications and Usage for Lamivudine and Zidovudine Tablets

Lamivudine and Zidovudine Tablets, a combination of two nucleoside analogues, are indicated in combination with other antiretrovirals for the treatment of HIV-1 infection.

Lamivudine and Zidovudine Tablets Dosage and Administration

Adults and Adolescents Weighing ≥ 30 kg

The recommended oral dose of Lamivudine and Zidovudine Tablets USP 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) twice daily.

Pediatric Patients

The recommended oral dosage of scored Lamivudine and Zidovudine Tablets USP 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 twice daily.

Before prescribing Lamivudine and Zidovudine Tablets USP, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a lamivudine and zidovudine tablet USP, the liquid oral formulations should be prescribed: EPIVIR® (lamivudine) Oral Solution and RETROVIR® (zidovudine) Syrup.

Patients Requiring Dosage Adjustment

Because Lamivudine and Zidovudine Tablets USP are a fixed-dose combination tablet, they should not be prescribed for pediatric patients weighing less than 30 kg or patients requiring dosage adjustment, such as those with reduced renal function (creatinine clearance less than 50 mL/min), patients with hepatic impairment, or patients experiencing dose-limiting adverse reactions. Liquid and solid oral formulations of the individual components of Lamivudine and Zidovudine Tablets USP are available for these populations.

Dosage Forms and Strengths

Lamivudine and Zidovudine Tablets USP are white, scored, film-coated, convex, oval tablets, debossed on both tablet faces, such that when broken in half, the full "TVL2" code is present on both halves of the tablet ("TV" on one face and "L2" on the opposite face of the tablet).

Contraindications

Lamivudine and Zidovudine Tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the product.

Warnings and Precautions

Hemotologic 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/mm3 or hemoglobin less than 9.5 g/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.

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 Lamivudine and Zidovudine Tablets.

Lactic Acidosis/Hepatomegaly With Steatosis

Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine, zidovudine, and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering Lamivudine and Zidovudine Tablets to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. 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).

Patients With HIV-1 and Hepatitis B Virus Co-Infection

Posttreatment Exacerbations of Hepatitis: In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic HBV, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of hepatitis B viral DNA (HBV DNA). Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.

Important Differences Among Lamivudine-Containing Products: Lamivudine and Zidovudine Tablets contain a higher dose of the same active ingredient (lamivudine) than EPIVIR-HBV® (lamivudine) Tablets and Oral Solution. EPIVIR-HBV® was developed for treating chronic hepatitis B. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV.

Emergence of Lamivudine-Resistant HBV: In non-HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see full prescribing information for EPIVIR-HBV® for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

Use With Other, Lamivudine-, Zidovudine-, and/or Emtricitabine-Containing Products

Lamivudine and Zidovudine Tablets are a fixed-dose combination of lamivudine and zidovudine. Lamivudine and Zidovudine Tablets should not be administered concomitantly with other lamivudine- or zidovudine-containing products including EPIVIR® (lamivudine) Tablets and Oral Solution, EPIVIR-HBV® Tablets and Oral Solution, RETROVIR® (zidovudine) Tablets, Capsules, Syrup, and IV Infusion, EPZICOM® (abacavir sulfate and lamivudine) Tablets, or TRIZIVIR® (abacavir sulfate, lamivudine, and zidovudine) Tablets; or emtricitabine-containing products, including ATRIPLA® (efavirenz, emtricitabine, and tenofovir), EMTRIVA® (emtricitabine), or TRUVADA® (emtricitabine and tenofovir).

Use With Interferon- and Ribavirin-Based Regimens

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine and zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine or zidovudine in HIV-1/HCV co-infected patients [see Clinical Pharmacology (12.3)], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and Lamivudine and Zidovudine Tablets should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. 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 the complete 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 zidovudine is not advised.

Pancreatitis

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)].

Immune 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.

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.

Adverse Reactions

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

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


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


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


• Acute exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.4)].


• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.6)].


• Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions (5.6)].


• Pancreatitis [see Warnings and Precautions (5.7)].

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Lamivudine Plus Zidovudine Administered As Separate Formulations: In 4 randomized, controlled trials of EPIVIR® (lamivudine) 300 mg per day plus RETROVIR® (zidovudine) 600 mg per day, the following selected adverse reactions and laboratory abnormalities were observed (see Tables 1 and 2).

Table 1. Selected Clinical Adverse Reactions (≥ 5% Frequency) in 4 Controlled Clinical Trials With EPIVIR® (Lamivudine) 300 mg/day and RETROVIR® (Zidovudine) 600 mg/day

Adverse Reaction	EPIVIR® (Lamivudine) plus RETROVIR® (Zidovudine) (n = 251)
Body as a whole
Headache	35%
Malaise & fatigue	27%
Fever or chills	10%
Digestive
Nausea	33%
Diarrhea	18%
Nausea & vomiting	13%
Anorexia and/or decreased appetite	10%
Abdominal pain	9%
Abdominal cramps	6%
Dyspepsia	5%
Nervous system
Neuropathy	12%
Insomnia & other sleep disorders	11%
Dizziness	10%
Depressive disorders	9%
Respiratory
Nasal signs & 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 patients (0.3%) who received EPIVIR® (lamivudine) in controlled clinical trials [see Warnings and Precautions (5.7)].

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

Table 2. Frequencies of Selected Laboratory Abnormalities Among Adults in 4 Controlled Clinical Trials of EPIVIR® (Lamivudine) 300 mg/day Plus RETROVIR® (Zidovudine) 600 mg/day*

* Frequencies of these laboratory abnormalities were higher in patients with mild laboratory abnormalities at baseline.
Test (Abnormal Level)	EPIVIR® (Lamivudine) plus RETROVIR® (Zidovudine) % (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)

ULN = Upper limit of normal.

ANC = Absolute neutrophil count.

n = Number of patients assessed.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-approval use of EPIVIR® (lamivudine), RETROVIR® (zidovudine), and/or Lamivudine and Zidovudine Tablets. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to EPIVIR® (lamivudine), RETROVIR® (zidovudine), and/or Lamivudine and Zidovudine Tablets.

Body as a Whole: Redistribution/accumulation of body fat [see Warnings and Precautions (5.9)].

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 exacerbation of hepatitis B [see Boxed Warning, Warnings and Precautions (5.3), (5.4), (5.7)].

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.

Drug Interactions

No drug interaction studies have been conducted using Lamivudine and Zidovudine Tablets [see Clinical Pharmacology (12.3)].

Antiretroviral Agents

Lamivudine:  Zalcitabine: Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of Lamivudine and Zidovudine Tablets in combination with zalcitabine is not recommended.

Zidovudine:  Stavudine: Concomitant use of Lamivudine and Zidovudine Tablets with stavudine should be avoided since an antagonistic relationship with zidovudine has been demonstrated invitro.

Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV-1; concomitant use of such drugs should be avoided.

Doxorubicin

Zidovudine: Concomitant use of Lamivudine and Zidovudine Tablets with doxorubicin should be avoided since an antagonistic relationship with zidovudine has been demonstrated in vitro.

Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

Zidovudine: Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.

Interferon- and Ribavirin-Based Regimens

Lamivudine: Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients, 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), Clinical Pharmacology (12.3)].

Trimethoprim/Sulfamethoxazole (TMP/SMX)

Lamivudine: No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects

Pregnancy category C

Fetal Risk Summary: There are no adequate and well-controlled studies of lamivudine and zidovudine in pregnant women. Clinical trial data demonstrate that maternal zidovudine treatment during pregnancy reduces vertical transmission of HIV-1 infection to the fetus. Animal reproduction studies performed with lamivudine and zidovudine showed increased embryotoxicity and fetal malformations (zidovudine), and increased embryolethality (lamivudine). Lamivudine and Zidovudine Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine and zidovudine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Clinical Considerations: Treatment of HIV during pregnancy optimizes the health of both mother and fetus. Clinical trial data reviewed by FDA demonstrate that maternal zidovudine treatment significantly reduces vertical transmission of HIV-1 infection to the fetus [see Clinical Studies (14.2)]. Published data suggest that combination antiretroviral regimens may reduce the rate of vertical transmission even further.

Pharmacokinetics of lamivudine and zidovudine in pregnant women are similar to the pharmacokinetics in nonpregnant women. No dose adjustments are needed during pregnancy.

In a clinical trial, adverse events among HIV-1-infected women were not different among untreated women and women treated with zidovudine. It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients (see Human data below).

Data:  Human Data:Lamivudine: Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical studies conducted in South Africa. The study assessed pharmacokinetics in: 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. Lamivudine pharmacokinetics in pregnant women were similar to those seen in nonpregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

Zidovudine: 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. 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 study drug [see Clinical Studies (14.2)].

Zidovudine pharmacokinetics were studied in a Phase 1 study of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine were similar to that of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.

Animal Data: Lamivudine: Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus [see Nonclinical Toxicology (13.2)].

Zidovudine: Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100 mg dose of zidovudine. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one fifth the lethal dose [see Nonclinical Toxicology (13.2)].

Nursing Mothers

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. Because of both the potential for HIV-1 transmission and serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Lamivudine and Zidovudine Tablets.

Although no studies of lamivudine and zidovudine excretion in breast milk have been performed, lactation studies performed with lamivudine and zidovudine show that both drugs are excreted in human breast milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine. In another study, after administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women, the mean concentration of zidovudine was similar in human milk and serum.

Pediatric Use

Lamivudine and Zidovudine Tablets should not be administered to pediatric patients weighing less than 30 kg, because they are a fixed-dose combination that cannot be adjusted for this patient population.

Geriatric Use

Clinical studies of lamivudine and zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Lamivudine and Zidovudine Tablets are not recommended for patients with impaired renal function (i.e., creatinine clearance less than 50 mL/min) because they are a fixed-dose combination that cannot be adjusted.

Renal Impairment

Reduction of the dosages of lamivudine and zidovudine is recommended for patients with impaired renal function. Patients with creatinine clearance less than 50 mL/min should not receive Lamivudine and Zidovudine Tablets because they are a fixed-dose combination that cannot be adjusted.

Hepatic Impairment

A reduction in the daily dose of zidovudine may be necessary in patients with mild to moderate impaired hepatic function or liver cirrhosis. Lamivudine and Zidovudine Tablets are not recommended for patients with impaired hepatic function because they are a fixed-dose combination that cannot be adjusted.

Overdosage

Lamivudine and Zidovudine Tablets: There is no known antidote for Lamivudine and Zidovudine Tablets.

Lamivudine: One case of an adult ingesting 6 grams of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. 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. The only consistent findings were nausea and vomiting. Other reported occurrences included headache, dizziness, drowsiness, lethargy, confusion, and 1 report of a grand mal seizure. Hematologic changes were transient. All patients recovered. 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-ß-D-glucopyranuronosylthymidine (GZDV), is enhanced.

Lamivudine and Zidovudine Tablets 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 USP are for oral administration. Each film-coated tablet contains 150 mg of lamivudine, 300 mg of zidovudine, and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, 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 the following structural formula:

C8H11N3O3S M.W. 229.26

Lamivudine is a white to off-white solid with a solubility of approximately 70 mg/mL in water at 20°C.

Zidovudine:

The chemical name of zidovudine is 3′-azido-3′-deoxy-thymidine. It has the following structural formula:

C10H13N5O4 M.W. 267.24

Zidovudine is a white to yellowish powder sparingly soluble in water and freely soluble in alcohol.

Lamivudine and Zidovudine Tablets - Clinical Pharmacology

Mechanism of Action

Lamivudine and Zidovudine Tablets are an antiviral agent [see Clinical Pharmacology (12.4)].

Pharmacokinetics

Pharmacokinetics in Adults:  Lamivudine and Zidovudine Tablets: One lamivudine and zidovudine tablet was bioequivalent to 1 EPIVIR® (lamivudine) Tablet (150 mg) plus 1 RETROVIR® (zidovudine) Tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).

Lamivudine: The pharmacokinetic properties of lamivudine in fasting patients are summarized in Table 3. 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. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

Zidovudine: The pharmacokinetic properties of zidovudine in fasting patients are summarized in Table 3. 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.

Table 3. Pharmacokinetic Parameters* for Lamivudine and Zidovudine in Adults

* Data presented as mean ± standard deviation except where noted. † Median [range]. ‡ Children. § Adults. ¶ Approximate range.
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 ratio†	0.12 [0.04 to 0.47]	n = 38‡	0.60 [0.04 to 2.62]	n = 39§
Systemic clearance (L/hr/kg)	0.33 ± 0.06	n = 20	1.6 ± 0.6	n = 6
Renal clearance (L/hr/kg)	0.22 ± 0.06	n = 20	0.34 ± 0.05	n = 9
Elimination half-life (hr)¶	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 to fasting healthy subjects (n = 24).

Special Populations:

Pregnancy: See Use in Specific Populations (8.1).

Lamivudine and Zidovudine Tablets: No data are available.

Zidovudine: Zidovudine pharmacokinetics has been studied in a Phase 1 study of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine was similar to that of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics. In a nonpregnant adult population, a potential for interaction has been identified.

Nursing Mothers: See Use in Specific Populations (8.3).

Pediatric Patients: Lamivudine and Zidovudine Tablets should not be administered to pediatric patients weighing less than 30 kg.

Geriatric Patients: The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age.

Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in zidovudine AUC∞ or lamivudine AUC∞ normalized for body weight.

Race:  Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics.

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

Drug Interactions:  See Drug Interactions (7).

No drug interaction studies have been conducted using Lamivudine and Zidovudine Tablets. However, Table 4 presents drug interaction information for the individual components of Lamivudine and Zidovudine Tablets.

Lamivudine Plus Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr).

Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUC*

* This table is not all inclusive. † Estimated range of percent difference.
Note: ROUTINE DOSE MODIFICATION OF LAMIVUDINE AND ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Drugs That May Alter Lamivudine Blood Concentrations
Coadministered Drug and Dose	Lamivudine Dose	n	Lamivudine Concentrations		Concentration of Coadministered Drug
			AUC	Variability
Nelfinavir 750 mg q 8 hr x 7 to 10 days	single 150 mg	11	↑AUC 10%	95% CI: 1% to 20%	↔
Trimethoprim 160 mg/Sulfamethoxazole 800 mg daily x 5 days	single 300 mg	14	↑AUC 43%	90% CI: 32% to 55%	↔
Drugs That May Alter Zidovudine Blood Concentrations
Coadministered Drug and Dose	Zidovudine Dose	n	Zidovudine Concentrations		Concentration of Coadministered Drug
			AUC	Variability
Atovaquone 750 mg q 12 hr with food	200 mg q 8 hr	14	↑AUC 31%	Range 23% to 78%†