Viramune (nevirapina) 200mg Tablets

FULL PRESCRIBING INFORMATION

    INDICATIONS AND USAGE

Viramune is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on one principal clinical trial (BI 1090) that demonstrated prolonged suppression of HIV-1 RNA and two smaller supportive studies, one of which (BI 1046) is described below.

Additional important information regarding the use of Viramune for the treatment of HIV-1 infection:

• Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, Viramune should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm3 or in adult males with CD4+ cell counts greater than 400 cells/mm3 unless the benefit outweighs the risk [see Boxed Warning and Warnings and Precautions (5.1)].
  
  
• The 14-day lead-in period with Viramune 200 mg daily dosing has been demonstrated to reduce the frequency of rash [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)].
  
  
• If rash persists beyond the 14-day lead-in period, do not dose escalate to 200 mg twice daily.  The 200 mg once-daily dosing regimen should not be continued beyond 28 days, at which point an alternative regimen should be sought.

  DOSAGE AND ADMINISTRATION

   Adults

The recommended dose for Viramune is one 200 mg tablet daily for the first 14 days, followed by one 200 mg tablet twice daily, in combination with other antiretroviral agents. The lead-in period has been observed to decrease the incidence of rash. For concomitantly administered antiretroviral therapy, the manufacturer’s recommended dosage and monitoring should be followed.

   Pediatric Patients

The recommended oral dose for pediatric patients 15 days and older is 150 mg/m2 once daily for 14 days followed by 150 mg/m2 twice daily thereafter. The total daily dose should not exceed 400 mg for any patient.

DOSAGE FORMS AND STRENGTHS

Tablets: 200 mg, white, oval, biconvex, tablets embossed with 54 193 on one side
Oral suspension: 50 mg/5 mL, white to off-white oral suspension

Pharmacokinetics

Absorption

Nevirapine oral absorption is more than 90%, bioavailability is 93% (tablets) and 91% (oral solution), T _max is 4 h, and C _max is approximately 2 mcg/mL.

Distribution

Nevirapine crosses the placenta and is found in breast milk. Protein binding is approximately 60% and is highly lipophilic and widely distributed. Nevirapine Vd is 1.21 L/kg (IV), and CSF approximates 45% of concentration in plasma.

Metabolism

Extensively metabolized by CYP isozymes. In vitro studies indicated that metabolism is primarily by CYP2B6 and CYP3A4.

Elimination

Nevirapine is eliminated in urine (81.3%) and feces (10.1%). Less than 3% of the parent compound is excreted in urine. Autoinduction results in a decrease of the half-life from 45 h (single dose) to approximately 25 to 30 h (multiple doses).

Special Populations

Renal Function Impairment

No change in pharmacokinetics in patients with mild, moderate, or severe renal impairment.

Elderly

Pharmacokinetics do not appear to change within the range of 18 to 68 yr of age.

Gender

Cl is 13.8% lower in women than men.

Race

Pharmacokinetics have not been fully evaluated; however, no difference in steady-state trough levels were found based on ethnicity.

Indications and Usage

In combination with other antiretroviral agents for treatment of HIV-1 infection.

Contraindications

Moderate or severe (Child-Pugh class B or C) hepatic impairment.

Dosage and Administration

Adults Initial therapy

PO 200 mg daily for 14 days. Total daily dose not to exceed 400 mg.

Maintenance therapy

PO 200 mg twice daily in combination with other antiretroviral agents.

Children 15 days of age and older

PO 150 mg/m ² once daily for 14 days followed by 150 mg/m ² twice daily thereafter (max, 400 mg daily).

Dialysis
Adults and Children 15 days of age and older

PO An additional 200 mg following each dialysis.

General Advice

• Tablets and oral suspension are interchangeable on a mg-to-mg basis at doses of up to 200 mg.
• Administer without regard to meals. Administer with food if GI upset occurs.
• Shake suspension before measuring dose. Administer dose using oral dosing syringe or dosing cup. If using dosing cup, thoroughly rinse dosing cup with water and administer rinse water to patient.
• Therapy should be discontinued in patients experiencing severe rash or any rash accompanied by constitutional findings.
• Patients experiencing mild to moderate rash without constitutional symptoms during the 14-day lead-in period should not have their dose increased until the rash resolves. The duration of the lead-in dosing period should not exceed 28 days, at which time an alternative regimen should be sought.
• Permanently discontinue nevirapine if a symptomatic hepatic event occurs. Do not restart after recovery.

Storage/Stability

Store tablets and oral suspension at 59° to 86°F.

  CONTRAINDICATIONS

Viramune is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

  WARNINGS AND PRECAUTIONS

The most serious adverse reactions associated with Viramune are hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction.

The first 18 weeks of therapy with Viramune are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events and skin reactions. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests at baseline, prior to dose escalation and at two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout Viramune treatment. In addition, the 14-day lead-in period with Viramune 200 mg daily dosing has been demonstrated to reduce the frequency of rash [see Dosage and Administration (2.1)].

   Hepatotoxicity and Hepatic Impairment

Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with Viramune. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11.0%) of patients who received Viramune and 1.2% of patients in control groups.

The risk of symptomatic hepatic events regardless of severity was greatest in the first 6 weeks of therapy. The risk continued to be greater in the Viramune groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, patients presented with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was observed in approximately half of the patients with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with Viramune use. Patients with signs or symptoms of hepatitis must be advised to discontinue Viramune and immediately seek medical evaluation, which should include liver enzyme tests.

Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible [see Boxed Warning, Dosage and Administration (2.3), and Patient Counseling Information (17.1)].

If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, Viramune should be permanently discontinued. Do not restart Viramune after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment.

The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4+ cell counts. In general, during the first 6 weeks of treatment, women have a three-fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and patients with higher CD4+ cell counts at initiation of Viramune therapy are at higher risk for symptomatic hepatic events with Viramune. In a retrospective review, women with CD4+ cell counts >250 cells/mm3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4+ cell counts <250 cells/mm3 (11.0% versus 0.9%). An increased risk was observed in men with CD4+ cell counts >400 cells/mm3 (6.3% versus 1.2% for men with CD4+ cell counts <400 cells/mm3). However, all patients, regardless of gender, CD4+ cell count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4+ cell counts. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with Viramune are associated with a greater risk of later symptomatic events (6 weeks or more after starting Viramune) and asymptomatic increases in AST or ALT.

In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-1 uninfected individuals receiving multiple doses of Viramune in the setting of post-exposure prophylaxis, an unapproved use.

Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, patients with either hepatic fibrosis or cirrhosis should be monitored carefully for evidence of drug-induced toxicity. Nevirapine should not be administered to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

   Skin Reactions

Severe and life-threatening skin reactions, including fatal cases, have been reported, occurring most frequently during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with Viramune use. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 1.5% of Viramune recipients compared to 0.1% of placebo subjects.

Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue Viramune and seek medical evaluation immediately [see Boxed Warning and Patient Counseling Information (17.1)]. Do not restart Viramune following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction.

If patients present with a suspected Viramune-associated rash, transaminases should be measured immediately. Patients with rash-associated transaminase elevations should be permanently discontinued from Viramune [see Warnings and Precautions (5.1)].

Therapy with Viramune must be initiated with a 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients), which has been shown to reduce the frequency of rash. Viramune should be discontinued if a patient experiences severe rash or any rash accompanied by constitutional findings. A patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) should not have their Viramune dose increased until the rash has resolved. The total duration of the once-daily lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought [see Dosage and Administration (2.4)]. Patients should be monitored closely if isolated rash of any severity occurs. Delay in stopping Viramune treatment after the onset of rash may result in a more serious reaction.

Women appear to be at higher risk than men of developing rash with Viramune.

In a clinical trial, concomitant prednisone use (40 mg/day for the first 14 days of Viramune administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of Viramune therapy. Therefore, use of prednisone to prevent Viramune-associated rash is not recommended.

   Resistance

Viramune must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance. When discontinuing an antiretroviral regimen containing Viramune, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than Viramune are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop [see Clinical Pharmacology (12.4)].

   Drug Interactions

See Table 4 for listings of established and potential drug interactions [see Drug Interactions (7)].

  Concomitant use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products and Viramune is not recommended. Co-administration of St. John’s wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including Viramune, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of Viramune and lead to loss of virologic response and possible resistance to Viramune or to the class of NNRTIs. Co-administration of Viramune and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy.

   Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Viramune. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci 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

   Clinical Trials in Adults

The most serious adverse reactions associated with Viramune are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see Boxed Warning and Warnings and Precautions (5.1, 5.2)].

Hepatic Reaction

In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4.0% (range 0% to 11.0%) of patients who received Viramune and 1.2% of patients in control groups. Female gender and higher CD4+ cell counts (>250 cells/mm3 in women and >400 cells/mm3 in men) place patients at increased risk of these events [see Boxed Warning and Warnings and Precautions (5.1)].

Asymptomatic transaminase elevations (AST or ALT >5X ULN) were observed in 5.8% (range 0% to 9.2%) of patients who received Viramune and 5.5% of patients in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with Viramune are associated with a greater risk of later symptomatic events (6 weeks or more after starting Viramune) and asymptomatic increases in AST or ALT.

Liver enzyme abnormalities (AST, ALT, GGT) were observed more frequently in patients receiving Viramune than in controls (see Table 3).

Skin Reaction

The most common clinical toxicity of Viramune is rash, which can be severe or life-threatening [see Boxed Warning and Warnings and Precautions (5.2)]. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. In controlled clinical trials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes were reported in 13.3% of patients receiving Viramune compared to 5.8% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 1.5% of Viramune recipients compared to 0.1% of subjects receiving placebo. Women tend to be at higher risk for development of Viramune-associated rash [see Boxed Warning and Warnings and Precautions (5.2)].

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.

Precautions

Pregnancy

Category B .

Lactation

Excreted in breast milk. Ensure that HIV-infected mothers do not breast-feed their infants.

Children

For use in children 15 days of age and older.

Elderly

Select dose with caution, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Renal Function

In patients receiving chronic hemodialysis, additional dosing is needed following each dialysis treatment.

Hepatic Function

Do not administer to patients with moderate or severe hepatic impairment.

Discontinuation

Do not restart treatment following severe hepatic, skin, or hypersensitivity reactions. Hepatic injury can progress after discontinuation of treatment.

Fat redistribution

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, may occur.

Hepatotoxicity

Consider the possibility of hepatotoxicity for the appearance of signs or symptoms of hepatitis, including fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, or hepatomegaly.

Immune reconstitution syndrome

Has been reported.

Missed doses

Restart patients who interrupt maintenance dosing for more than 7 days on the recommended dosing (1 daily for 14 days followed by 1 twice daily).

Resistance

When used as monotherapy, resistant virus emerges rapidly and uniformly.

Skin reactions

Discontinue drug if skin rash accompanied by constitutional symptoms (eg, blistering, conjunctivitis, fever, general malaise, muscle or joint aches, oral lesions, swelling) occurs. If rash is mild to moderate in severity and not accompanied by constitutional symptoms, the drug can be continued with close monitoring. If rash develops during first 14 days of therapy, do not increase dosage beyond 200 mg daily until rash resolves.

Overdosage

Symptoms

Edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, weight decrease.

Patient Information

• Warn patient that this drug is not to be used by itself but is combined with other antiretroviral agents, and not to change the dose or stop taking any of the antiretroviral agents unless advised by health care provider.
• Advise patient to review patient information leaflet before starting therapy and with each refill of the medication.
• Advise patient to take prescribed dose without regard to meals, but to take with food if stomach upset occurs.
• Advise patient or caregiver using suspension to shake suspension before measuring dose and to administer prescribed dose using oral dosing syringe or dosing cup. If using dosing cup, advise patient or caregiver to thoroughly rinse the dosing cup with water and administer rinse water to patient.
• Advise patient that a 14-day lead-in period (lower dose) is used to reduce frequency of rash and not to exceed the prescribed dose during this period.
• Advise patient that if a dose is missed, to take the dose as soon as possible and then return to the normal schedule. However, if it is almost time for the next dose, advise patient to skip the dose and take the next dose at the regular time. Caution patient not to double the dose to catch up.
• Instruct patient that if therapy is stopped for longer than 7 days for any reason, not to restart therapy without discussing how to restart nevirapine with health care provider. Advise patient that therapy may have to be restarted using the 14-day lead-in dose again.
• Instruct patient to discontinue use and notify health care provider immediately if any of the following are noted: appetite loss, blisters, dark urine, decreased urination, facial swelling, fatigue, general body discomfort, mouth sores, muscle or joint aches, nausea, pale stools, red or inflamed eyelids, severe skin rash or rash accompanied by fever, swollen lymph nodes, tenderness on right side below ribs, or yellowing of skin or eyes.
• Advise patient that changes in body fat (increased fat in upper back and neck, breast, or around the trunk and loss of fat from legs, arms, or face) may occur but that the cause and long-term health effects of these changes are not known at this time. Advise patient to discuss with health care provider if noted and significant.
• Inform patient that drug does not completely eliminate HIV virus and, therefore, does not reduce risk of transmitting HIV. Inform patients that appropriate precautions must still be followed.
• Advise patient that drug is not a cure for HIV infection and that illnesses associated with HIV infection, including opportunistic infections, may still be acquired. Advise patient to remain under a health care provider's care.
• Advise women using combination oral contraceptives to use an additional nonhormonal form of contraception because nevirapine can reduce the effectiveness of combination oral contraceptives.
• Caution HIV-infected women that breast-feeding a baby could cause HIV infection in the baby.

©Copyright 2010 Boehringer Ingelheim Pharmaceuticals, Inc.
ALL RIGHTS RESERVED

OT1801JA1910
10003354/05

U.S. Patent Nos. 5,366,972 and 6,172,059

Viramune: 200 mg x 60 Tablets

NDC 0597-0046-60