Keratitis in Children as Seen in a Tertiary Hospital in Africa

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Keratitis in Children as Seen in a Tertiary Hospital in Africa Adeyinka Ashaye, MBBS, MSc, FWACS and Ayeni Aimola, MBBS

Background: Blindness studies have shown that keratitis complicated by the use of traditional eye medications is a major factor of childhood blindness in developing countries. Most cases of such keratitis were presumably due to nutritional causes or bacterial infection. The patterns of outcome that are seen in hospitals may be different. Objective: To determine the clinical types of keratitis seen in children at a tertiary hospital and compare with other reports. Method: A retrospective analysis was conducted using the records of children who presented with keratitis to the eye unit of the University College Hospital, Ibadan, Nigeria, over a three-year period from January 2003 to December 2005. Information obtained were the demographic data, the etiological type of keratitis and visual outcome of management. Result: Ninety-five patients with keratitis seen during this three-year period were children. Of these, 47 (49.5%) patients had presumed herpes simplex keratitis; 78.9% of children with herpes simplex keratitis presented with combined epithelial and stromal disease; 21 (22.1%) had keratitis that was associated with a recent measles infection and protein calorie malnutrition. Fifteen (15.8%) had keratitis associated with phlyctenular keratoconjunctivitis, eight (8.4%) patients had bacterial/fungal keratitis, while four (4.2%) had vernal ulcers. Both the right and left eyes were affected in 47.6% and 52.4% of cases, respectively. Bilateral keratitis occurred in eight of the children with measles, and six patients with herpes simplex keratitis. Fifty-nine eyes had visual acuity recorded after the keratitis healed. Of these, the visual outcome was very poor in six (20.0%) eyes with herpes simplex keratitis and eight (100%) eyes with bacterial/fungal keratitis. All eyes with suppurative keratitis associated with measles developed dense corneal scars or were perforated. Conclusion: Herpes simplex keratitis was the leading cause of keratitis in children seen at this tertiary hospital, and clinical presentations do not differ from those reported in other populations. Very poor visual outcome was associated with all types of keratitis except those with herpes keratitis. Blindness studies may underrepresent the burden of herpes simplex keratitis in the location of this study. Key words: ophthalmic n children/adolescents n Africans

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© 2008. From the Department of Ophthalmology, University College Hospital, Ibadan, Nigeria (Ashaye, senior lecturer/consultant ophthalmologist; Ayeni, senior registrar). Send correspondence and reprint requests for J Natl Med Assoc. 2008;100:386–393 to: Dr. Adeyinka Ashaye, Department of Ophthalmology, College of Medicine, University of Ibadan, Nigeria; phone: 2348023512002; e-mail: [email protected]

Introduction

K

eratitis or corneal ulceration is an important cause of ocular morbidity worldwide and a major cause of uniocular blindness or visual impairment in developing countries.1-4 All age groups are affected, including children. Several etiological factors predispose to keratitis. Infective and noninfective causes when severe lead to corneal scarring or perforation, resulting in visual loss. The effect of uniocular/binocular vision loss from keratitis is more severe in children.2,3 Morbidity in terms of visual loss and/or several hospital visits and admission is severe because of late presentation and lack of corneal transplant services to manage corneal scarring. Prevention of risk factors for keratitis in children could reduce this morbidity. Prevalence and types of corneal blindness vary from one population to another and are influenced by many factors such as availability of eyecare services.5-7 In the eye unit of the University College Hospital (UCH), Ibadan, almost 20% of new patients seen in a previous study had corneal scar resulting mostly from keratitis.8 Although several studies have described the variation of etiological types of keratitis worldwide3-7,9 few have emanated from this part of West Africa, and fewer have been on children. In some of those articles, data were obtained from blindness studies. Nonblinding keratitis might have been underreported. This study was undertaken to determine the types of all keratitis seen in children <16 years of age seen at a tertiary hospital (UCH). Visual outcome of management is reported.

Patients and Methods

All cases of keratitis seen between January 2003 and December 2005 at UCH, Ibadan, were identified using ward and outpatient records. These records had been carefully kept. Records of these patients were reviewed to obtain VOL. 100, NO. 4, APRIL 2008

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demographic data, type of keratitis, duration of presenting symptoms and laterality of disease. Relevant data that focus on risk factors for keratitis, such as previous ocular trauma, surgery, ocular surface disease and presence of systemic diseases, were extracted from records. The usual practice in the eye department was to send scrapings of the ulcers for laboratory diagnosis in cases of suspected bacterial/fungal keratitis in addition to clinical appearance. The presence of a positive Gram stain, Giemsa or KOH preparations, and/or growth of organism on blood agar and Sabouraud’s agar was diagnostic of infective keratitis. Sensitivity results were used to choose the antibiotics or antifungal for treatment in such cases. The clinical diagnosis of herpes simplex keratitis, vernal ulcers and phlyctenular ulcers was based on clinical characteristics and the presence of risk factors. The visual outcome after management was obtained at the patient’s last visit to the hospital after the keratitis healed. Patients were considered to have a good clinical outcome when visual acuity (VA) in the affected eye was ≥6/18, poor outcome if visual acuity was <6/18 but >6/60, very poor outcome if visual acuity was ≤6/60 or if the eye was eviscerated.

Results

A total of 102 cases of keratitis were seen in children <16 years of age, constituting 32% of all keratitis seen during this period. Out of these, seven patients with incomplete follow-up were excluded from this analysis. The age of the patients ranged from 4 months to 15 years (mean 7.1 years ± 4.2 years). The ratio of males: females was 1:1.2. Forty-seven (49.5%) of the patients had presumed herpes simplex keratitis, 15 (15.8%) had phlyctenular keratitis and 21 (22.1%) were due to suppurative keratitis following measles and protein calorie

malnutrition. Other causes were bacterial/fungal keratitis unassociated with measles in eight (8.4%) patients, and four (4.2%) patients had vernal ulcers (Table 1). There was a statistically significant difference in the mean ages of patients with different etiogical types of ulcers (F=4.92, P=0.002). Younger children had measles with suppurative keratitis, and older children presented with bacterial/fungal keratitis (Table 2). There were 44 (52.4%) left and 40 (47.6%) right eyes with unilateral ulcers. Fourteen had bilateral ulcers; thus, 95 patients with 109 eyes with keratitis presented to the eye clinic during the study period. Thirty-seven (78.9%) who had presumed herpetic keratitis had a combined stromal and epithelial keratitis, while 10 (21.3%) had epithelial keratitis alone. Bilateral herpetic ulcers occurred in six (12.8%) patients who were age <5 years. Primary herpes occurred in 29 (61.8%) patients, while recurrent herpes presented in 18 (38.2%) patients. Traditional eye medication was used by three (6.4%) of these patients prior to presentation. After the herpetic keratitis healed, records of visual acuity measurement were available in 30 (63.8%) patients. Of these, 12 (40%) achieved visual acuity of ≥6/18. Twelve eyes (40.0%) had poor outcome, i.e., visual acuity <6/18 and >6/60, six (20.0%) had very poor visual outcome (visual acuity ≤6/60). The latter were subjects with recurrent keratitis. Twenty-one (22.1%) patients presented with suppurative keratitis associated with measles infection during the study period. Laboratory studies were negative in all the 22 cases. The mean age of these patients was 2.9 years ± SD 1.8 years. Keratitis was bilateral in eight (36.1%) patients. The male:female ratio in subjects with keratitis associated with measles was 1:1.6. Visual acuity was not available in all these patients, but all devel-

Table 1. Clinical types of keratitis in African children seen at a tertiary hospital Types of Keratitis Herpes simplex Measles with suppurative keratitis Phlyclenular Bacterial/fungal Vernal ulcer Total

Number 47 21 15 8 4 95

Percent 49.5 22.1 15.8 8.4 4.2 100

Table 2. Mean age of patients with different types of keratitis Types of Keratitis Measles with suppurative keratitis Phlyclenular Bacterial/fungal Viral keratitis

Mean Age 2.9 years SD ± 1.8 4.9 years SD ± 3.5 8.2 years SD ± 3.9 8.5 years SD

F=4.92; P=0.002

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oped dense corneal leucoma or perforation. In all eight cases of suspected bacterial/fungal keratitis not associated with measles, laboratory studies were requested. The Gram stain was positive for bacteria organisms in four cases, but the culture was positive only in one case. The positive culture yielded a growth of Streptococcus pneumonae. Other cultures yielded no growth of organisms. The patients ranged in age from 3–15 years (mean 8.2 ± 3.9 years). The male:female ratio was 1.5:1. There was a preceding history of ocular trauma prior to presentation in all eight patients. Such injuries were whiplash injuries with broomsticks in six cases and injuries on the farm with vegetable matter in two cases. Traditional eye medications were admittedly used prior to presentation to the hospital in 50% of patients with bacterial/fungal keratitis. Visual outcome after treatment was very poor in all eight eyes. Five eyes were eviscerated in this group of patients. Fifteen (15.8%) patients presented with features of phlyctenular keratitis. The male:female ratio was 1:1. Mean age was 4.9 ± 3.5 years. Patients with phlyctenular keratitis had clinical features of protein calorie malnultrition and/or systemic tuberculosis in 10 of the 15 patients. The ocular lesions healed with good outcome, visual acuity ≥6/18 in the affected eyes of all the patients. The four subjects with vernal ulcers had clinical features of severe vernal keratoconjunctivitis. Visual outcome was good in all four affected eyes. Generally, all patients presented late (Table 3). There was, however, slight variation in the time of delay before presentation to the tertiary hospital (range 4–28 days), which seems to depend on the type of ulcer. Twenty percent of all subjects studied admitted to having been previously treated with traditional eye medications or drugs bought from chemists (Table 4).

Discussion

In this hospital series, clinical types of keratitis seen in children were examined, and it was found that herpes simplex keratitis was the commonest etiological type. Herpes keratitis was seen in various forms in Nigerian children just as in developed countries. Epithelial herpetic ulcers were associated with stromal keratitis in these African children as found in children from developed countries and other parts of Africa.10-13 The number presenting to this hospital may be a small fraction of the actual disease in the children population served by the hospital because of the self-limiting nature of the disease coupled with the poor access to hospital for the affected group. Herpetic keratitis is often considered an unimportant ophthalmic problem in the developing countries where the prevalence of other corneal diseases is high. Many articles in the literature report on the importance of microbial keratitis, measles and vitamin-A deficiency as major causes of corneal scarring. The ocular morbidity caused by herpes keratitis is often underreported, presumably because few of the children go blind from the disease. In this series, 20% of the subjects with herpes keratitis were blind in ≥1 eye, a much higher blindness rate than that reported in children in Dublin.10 This could be the result of late presentation in our patients or a selection bias for severe cases. Higher prevalence of visual loss was reported by Yorston in Tanzania14 and Colin after a five-year follow-up.11 A higher prevalence of blindness might have been found in our series if patients had been followed up for a longer period of time, since recurrent disease is more likely to lead to blindness.11,12 The diagnosis of herpes keratitis was presumptive, and no attempt was made to isolate the virus because of

Table 3. Days before presentation for treatment Types of Keratitis Viral Bacterial/fungal—not associated with measles Phlyclenular keratoconjunctivitis Vernal keratitis Measles with suppurative keratitis Mean day

Mean (Days) 50.0 9.3 31.1 21.2 4.7 32.3

Table 4. Use of traditional eye medications before presentation to hospital Type of Ulcer Uses of TEM Yes No

Viral n 13 34

% 27.7 72.3

Bacterial/Fungal n % 4 50.0 4 20.0

Phlyctenular n % 2 13.3 13 54.5

Vernal n 0 4

Others % 0 100

TEM: traditional eye medication

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the extra cost to the patients; however, the clinical presentation and response to treatment with antiviral topical agents were typically as described by other authors.10-13 Keratitis associated with measles was the second commonest presentation to this tertiary hospital. Measles have remained a major problem in developing countries where millions of children are affected; several, especially females, die in the first year.15 Few of these children get to hospitals. Particularly affected are children from low-income groups,6,7 who may have poor access to a hospital. These children are often malnourished. The associated high mortality may have caused an underrepresentation of keratitis associated with measles in this series. The visual outcome is generally very poor. This may reflect the severity of the disease or an indication of late presentation. In West Africa, previous eye trauma and use of traditional eye medications have been significantly associated with bacteria or fungal keratitis form of keratitis in adults.16-18 In this series, all eight patients with bacterial and/or fungal keratitis had a history of trauma. A broomstick used by older persons giving out corporal punishment to children was the agent of injury in six cases. Some other children in this category had trauma sustained on the farm from vegetable matter. The low number of positive cultures from specimens taken from the keratitis in cases of suspected bacterial/ fungal keratitis was probably the result of previous use of medications brought from chemists and traditional eye medication use. The poor outcome of these cases also reflects the severity of the disease, the presence of mixed infection and late presentation. Diagnostic problems and lack of clear choice of antibiotics and nonavailability of antifungal agents could be part of the problem. Vernal ulcer is rarely reported in the African ophthalmic literature. In the Indian literature, 76 patients with vernal conjunctivitis and corneal involvement referred to the corneal service were found to have various corneal involvement. Vernal ulcers were found more in patients with the palpebral form of vernal conjunctivitis in their series.19 Similarly, all the patients with vernal ulcer studied had palpebral vernal conjunctivitis. Prajna et al. reported the use of traditional eye medication in 47.7% of their patients.20 In this series, 20% of children with keratitis had used traditional eye medication or drugs bought from chemists prior to presentation. This may be an underestimation of the number who used traditional eye medication. In this series, no subject was seen with ulceration from ophthalmia neonatorum. Perhaps ocular prophylaxis in this region from birth is responsible for this or that mildto-moderate cases were treated in maternity ward. Most of the causes of keratitis seen in this series are avoidable, yet the clinical presentation was severe. Predisposing factors include measles, malnutrition and trauma complicated by the use of traditional eye medJOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

ication. Pathogens as contaminants of traditional eye medication may worsen the prognosis of keratitis in patients who have used traditional eye medication prior to presentation. The use of traditional eye medication is a serious health problem throughout developing countries. Cooperation with and education of traditional healers are a good approach to the prevention of problems arising from their use. The outcome of keratitis found among these patients was reduced vision from corneal scar or loss of the globe. The treatment of corneal scar resulting from keratitis in developing countries is currently not widely available; therefore, eyes blind from corneal ulcer remain blind throughout life for now. Amblyopia in children and its treatment are another big challenge; therefore, a decrease in corneal blindness in the long term with effective health promotion strategies seem to be the need among the population served by the UCH. Rehabilitation of the blind child must be an active program. The observations found among these patients presenting to this tertiary clinic may not be applicable to the population in general, but the preliminary information has to be considered prior to planning a corneal subspecialty clinic. A population-based survey soon to be undertaken should provide more information on corneal blindness in children.

Conclusion

This study has provided information on the types of keratitis and visual outcome in children presenting to the eye unit of the UCH. Herpes simplex keratitis and vernal keratoconjunctivitis were not uncommon clinical presentations to this tertiary institution. The observed very poor visual outcome of patients seen with keratitis associated with measles and bacterial/fungal keratitis poses a big challenge for prevention and promotive intervention. The cornea service program of this hospital should be proceeded by community awareness of causes of corneal blindness. Early identification, improved laboratory diagnosis and prompt management of these cases are recommended. Effective health strategies must be put in place to include all the etiological types of keratitis.

References

1. Gilbert CE, Anderton L, Dandonna L, et al. Prevalence of visual impairment in children: a review of available data. Ophthalmic Epidemiol. 1999;6:73-82. 2. Schwab L, Kagame K. Blindness in Africa: Zimbabwe schools for the blind survey. Br J Ophthalmol. 1993;77:410-412. 3. Gilbert C, Canovas R, Hagan M, et al. Causes of childhood blindness: results from West Africa, South India and Chile. Eye. 1993;7:184-188. 4. Whitcher JP, Svimvasan: Corneal ulceration in the developing world—a silent epidemic. Br J Ophthalmol. 1997;81:622-623. 5. Foster A, Gilbert C. Epidemiology of childhood blindness. Eye. 1992;6:172-176. 6. Whitcher PM, Svinivasan M, Upadbyay MP. Corneal blindness: a global perspective. Bull World Organ. 2001;79(3):1-17.

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Patients are sharing their experiences with VIRAMUNE Ask them why VIRAMUNE combination therapy: > provides rapid (<2 weeks) and sustained (48-week) virological suppression1,2 > achieved undetectable VL of <50 copies/mL in a majority of treatment-naive patients in the 2NN Study2 > provides improved immunologic response (CD4 count)3 INDICATION AND IMPORTANT SAFETY INFORMATION 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 that demonstrated prolonged suppression of HIVRNA and two smaller supportive studies. Life-threatening and fatal hepatotoxicity has occurred in patients receiving VIRAMUNE. Any patient can experience hepatic events; however, female gender and higher CD4 counts at initiation of therapy place patients at greater risk. Women, including pregnant women, with CD4+ cell counts >250 cells/mm3 are at the greatest risk. 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. Hepatic events are often associated with rash. Life-threatening and fatal skin reactions have also occurred, including Stevens-Johnson Syndrome, toxic epidermal necrolysis and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients should be intensively monitored for hepatic and skin reactions for the first 18 weeks of therapy with extra vigilance during the first 6 weeks, which is the period of greatest risk. Frequent monitoring should be performed throughout therapy with VIRAMUNE.

VIRAMUNE should be discontinued and not restarted in patients who develop signs or symptoms of hepatitis, hypersensitivity or severe skin reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment. Other common side effects include nausea, fatigue, fever, headache, vomiting, diarrhea, abdominal pain, and myalgia. Immune reconstitution syndrome has been reported in patients treated with combination ARV therapy. Please see Brief Summary of Prescribing Information for VIRAMUNE on following pages, including boxed WARNING. The dose of VIRAMUNE for adults is one 200-mg tablet daily for the first 14 days (this has been shown to reduce the frequency of rash), followed by one 200-mg tablet twice daily.

REDISCOVER

References: 1. van Leth F, Kappelhof B, Hall DB, Beijnen J, Lange JMA; for the 2NN Study Group. Regional differences in treatment failure in the 2NN study. Presented at the 7th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 14-18, 2004. Poster. 2. van Leth F, Phanuphak P, Ruxrungtham K, et al; for the 2NN Study Team. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet. 2004;363:1253-1263. 3. Viramune ® (nevirapine) Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc. June 2007.

Copyright © 2007, Boehringer Ingelheim Pharmaceuticals, Inc.

(nevirapine) tablets / oral suspension

All rights reserved.

(10/07)

VR47615

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Viramune® (nevirapine) Tablets Viramune® (nevirapine) Oral Suspension Brief Summary of Prescribing Information: see full Prescribing Information for complete product information. WARNING Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with VIRAMUNE®. In some cases, patients presented with non-specific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. These events are often associated with rash. Female gender and higher CD4 counts at initiation of therapy place patients at increased risk; women with CD4 counts >250 cells/mm3, including pregnant women receiving VIRAMUNE in combination with other antiretrovirals for the treatment of HIV infection, are at the greatest risk. However, hepatotoxicity associated with VIRAMUNE use can occur in both genders, all CD4 counts and at any time during treatment. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue VIRAMUNE and seek medical evaluation immediately (see WARNINGS). Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with VIRAMUNE. These have included cases of StevensJohnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue VIRAMUNE and seek medical evaluation immediately (see WARNINGS). It is essential that patients be monitored intensively during the first 18 weeks of therapy with VIRAMUNE to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of these events. Do not restart VIRAMUNE following severe hepatic, skin or hypersensitivity reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment. In addition, the 14-day lead-in period with VIRAMUNE 200 mg daily dosing must be strictly followed (see WARNINGS). CONTRAINDICATIONS VIRAMUNE (nevirapine) is contraindicated in patients with clinically significant hypersensitivity to any of the components contained in the tablet or the oral suspension. WARNINGS General The most serious adverse reactions associated with VIRAMUNE (nevirapine) 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 function 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. Hepatic Events 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 function tests. Liver function tests should be performed immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Liver function tests should also be obtained 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 liver function tests are initially normal or alternative diagnoses are possible (see PRECAUTIONS, Information for Patients and DOSAGE AND ADMINISTRATION). 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 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 counts at initiation of VIRAMUNE therapy are at higher risk for symptomatic hepatic events with VIRAMUNE. In a retrospective review, women with CD4 counts >250 cells/mm3 had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4 counts <250 cells/mm3 (11.0% versus 0.9%). An increased risk was observed in men with CD4 counts >400 cells/mm3 (6.3% versus 1.2% for men with CD4 counts <400 cells/mm3). However, all patients, regardless of gender, CD4 count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 counts. Co-infection with hepatitis B or C and/or increased liver function tests 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-uninfected individuals receiving multiple doses of VIRAMUNE in the setting of post-exposure prophylaxis, an unapproved use. Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, VIRAMUNE should not be administered to patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations: Hepatic Impairment; PRECAUTIONS, General). 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 PRECAUTIONS, Information for Patients). 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, liver function tests should be performed. Patients with rash-associated AST or ALT elevations should be permanently discontinued from VIRAMUNE. Therapy with VIRAMUNE must be initiated with a 14-day lead-in period of 200 mg/day (4 mg/kg/day in pediatric patients), which has been shown to reduce the frequency of rash. If rash is observed during this lead-in period, dose escalation should not occur until the rash has resolved (see DOSAGE AND ADMINISTRATION). 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 or added on as a sole agent to a failing regimen. As with all other non-nucleoside reverse transcriptase inhibitors, 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. St. John’s wort Concomitant use of St. John's wort (Hypericum perforatum) or St. John's wort containing products and VIRAMUNE is not recommended. Co-administration of non-nucleoside reverse transcriptase inhibitors (NNRTIs), including VIRAMUNE, with St. John's wort 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. PRECAUTIONS General The most serious adverse reactions associated with VIRAMUNE (nevirapine) 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 WARNINGS). Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. No adjustment in nevirapine dosing is required in patients with CrCL ≥ 20 mL/min. In patients undergoing chronic hemodialysis, an additional 200 mg dose following each dialysis treatment is indicated. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations: Renal Impairment; DOSAGE AND ADMINISTRATION, Dosage Adjustment). It is not clear whether a dosing adjustment is needed for patients with mild to moderate hepatic impairment, because multiple dose pharmacokinetic data are not available for this population. However, patients with moderate hepatic impairment and ascites may be at risk of accumulating nevirapine in the systemic circulation. Caution should be exercised when nevirapine is administered to patients with moderate hepatic impairment. Nevirapine should not be administered to patients with severe hepatic impairment (see WARNINGS; CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations: Hepatic Impairment). The duration of clinical benefit from antiretroviral therapy may be limited. Patients receiving VIRAMUNE or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases. When administering VIRAMUNE as part of an antiretroviral regimen, the complete product information for each therapeutic component should be consulted before initiation of treatment. Drug Interactions Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A4 and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when co-administered with nevirapine. The specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in CLINICAL PHARMACOLOGY, Table 1. Clinical comments about possible dosage modifications based on these pharmacokinetic changes are listed in Table 3. The data in Tables 1 and 3 are based on the results of drug interaction studies conducted in HIV-1 seropositive subjects unless otherwise indicated. In addition to established drug interactions, there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are listed in Table 4. Although specific drug interaction studies in HIV-1 seropositive subjects have not been conducted for the classes of drugs listed in Table 4, additional clinical monitoring may be warranted when co-administering these drugs. The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex. As a result, when giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation time. When warfarin is co-administered with nevirapine, anticoagulation levels should be monitored frequently.

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. Table 3 Established Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies (See CLINICAL PHARMACOLOGY,Table 1 for Magnitude of Interaction) Drug Name

Effect on Concentration of Nevirapine or Concomitant Drug

Clarithromycin ↓ Clarithromycin ↑ 14-OH clarithromycin

Efavirenz

↓ Efavirenz

Clinical Comment Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium aviumintracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Appropriate doses for this combination are not established.

Ethinyl ↓ Ethinyl estradiol estradiol and Norethindrone ↓ Norethindrone

Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

Fluconazole

↑ Nevirapine

Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.

Indinavir

↓ Indinavir

Ketoconazole

↓ Ketoconazole

Lopinavir/ Ritonavir

↓ Lopinavir

Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. KALETRA 400/100 mg tablets can be used twice-daily in combination with nevirapine with no dose adjustment in antiretroviral-naïve patients. A dose increase of KALETRA tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with nevirapine in treatment experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to < 15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/133 mg for those > 45 kg twice daily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected.

Methadone

↓ Methadone

Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.

Nelfinavir

↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C min

The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.

Rifabutin

↑ Rifabutin

Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.

Rifampin

↓ Nevirapine

Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.

Saquinavir

↓ Saquinavir

Appropriate doses for this combination are not established, but an increase in the dosage of saquinavir may be required.

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 jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Information for Patients Patients should be informed of the possibility of severe liver disease or skin reactions associated with VIRAMUNE that may result in death. Patients developing signs or symptoms of liver disease or severe skin reactions should be instructed to discontinue VIRAMUNE and seek medical attention immediately, including performance of laboratory monitoring. Symptoms of liver disease include fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness or hepatomegaly. Symptoms of severe skin or hypersensitivity reactions include rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema and/or hepatitis.

Table 4 Potential Drug Interactions: Use With Caution, Dose Adjustment of Co-administered Drug May Be Needed Due to Possible Decrease in Clinical Effect Examples of Drugs in Which Plasma Concentrations May Be Decreased By Co-administration With Nevirapine Drug Class

Examples of Drugs

Antiarrhythmics

Amiodarone, disopyramide, lidocaine

Anticonvulsants

Carbamazepine, clonazepam, ethosuximide

Antifungals

Itraconazole

Calcium channel blockers Diltiazem, nifedipine, verapamil Cancer chemotherapy

Cyclophosphamide

Ergot alkaloids

Ergotamine

Immunosuppressants

Cyclosporin, tacrolimus, sirolimus

Motility agents

Cisapride

Opiate agonists

Fentanyl

Examples of Drugs in Which Plasma Concentrations May Be Increased By Co-administration With Nevirapine Antithrombotics

Warfarin Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

Intensive clinical and laboratory monitoring, including liver function tests, is essential during the first 18 weeks of therapy with VIRAMUNE to detect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period, therefore monitoring should continue at frequent intervals throughout VIRAMUNE treatment. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of hepatic events and skin reactions. Patients with signs and symptoms of hepatitis should discontinue VIRAMUNE and seek medical evaluation immediately. If VIRAMUNE is discontinued due to hepatotoxicity, do not restart it. Patients, particularly women, with increased CD4+ cell count at initiation of VIRAMUNE therapy (>250 cells/mm3 in women and >400 cells/mm3 in men) are at substantially higher risk for development of symptomatic hepatic events, often associated with rash. Patients should be advised that co-infection with hepatitis B or C and/or increased liver function tests 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 (see WARNINGS, Hepatic Events). The majority of rashes associated with VIRAMUNE occur within the first 6 weeks of initiation of therapy. Patients should be instructed that if any rash occurs during the two-week lead-in period, the VIRAMUNE dose should not be escalated until the rash resolves. Any patient experiencing a rash should have their liver function evaluated immediately. Patients with severe rash or hypersensitivity reactions should discontinue VIRAMUNE immediately and consult a physician. VIRAMUNE should not be restarted following severe skin rash or hypersensitivity reaction. Women tend to be at higher risk for development of VIRAMUNE associated rash. Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking VIRAMUNE, since VIRAMUNE may lower the plasma levels of these medications. Additionally, when oral contraceptives are used for hormonal regulation during VIRAMUNE therapy, the therapeutic effect of the hormonal therapy should be monitored (see PRECAUTIONS, Drug Interactions). VIRAMUNE may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with VIRAMUNE and methadone concomitantly. Methadonemaintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. VIRAMUNE may interact with some drugs, therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort. Patients should be informed that VIRAMUNE therapy has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination. The long-term effects of VIRAMUNE are unknown at this time. VIRAMUNE is not a cure for HIV-1 infection; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using VIRAMUNE. Patients should be informed to take VIRAMUNE every day as prescribed. Patients should not alter the dose without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose. Patients should be advised to report to their doctor the use of any other medications. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time. The Medication Guide provides written information for the patient, and should be dispensed with each new prescription and refill. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies in mice and rats were carried out with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day for two years. Hepatocellular adenomas and carcinomas were increased at all doses in males and at the two high doses in females. In studies in which rats were administered nevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for two years, an increase in hepatocellular adenomas was seen in males at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal studies were lower than that measured in humans at the 200 mg BID dose. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assays for gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine treated mice and rats is not known. In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with the recommended clinical dose of VIRAMUNE. Pregnancy: Pregnancy Category B No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. The maternal and developmental no-observableeffect level dosages produced systemic exposures approximately equivalent to or approximately 50% higher in rats and rabbits, respectively, than those seen at the recommended daily human dose (based on AUC). In rats, decreased fetal body weights were observed due to administration of a maternally toxic dose (exposures approximately 50% higher than that seen at the recommended human clinical dose). There are no adequate and well-controlled studies of VIRAMUNE in pregnant women. The Antiretroviral Pregnancy Registry, which has been surveying pregnancy outcomes since January 1989, has not found an increased risk of birth defects following first trimester exposures to nevirapine. The prevalence of birth defects after any trimester exposure to nevirapine is comparable to the prevalence observed in the general population. Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic VIRAMUNE therapy as part of combination treatment of HIV infection. Regardless of pregnancy status women with CD4 counts >250 cells/mm3

should not initiate VIRAMUNE unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women (see Boxed WARNING). VIRAMUNE 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 VIRAMUNE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Nevirapine is excreted in breast milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIRAMUNE. Pediatric Use The pharmacokinetics of nevirapine have been studied in two open-label studies in children with HIV-1 infection (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations). For dose recommendations for pediatric patients see DOSAGE AND ADMINISTRATION. The most frequently reported adverse events related to VIRAMUNE in pediatric patients were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and VIRAMUNE (see ADVERSE REACTIONS, Pediatric Patients). The evaluation of the antiviral activity of VIRAMUNE in pediatric patients is ongoing. Geriatric Use Clinical studies of VIRAMUNE did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects 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. ADVERSE REACTIONS The most serious adverse reactions associated with VIRAMUNE (nevirapine) 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 WARNINGS). Adults The most common clinical toxicity of VIRAMUNE is rash, which can be severe or life-threatening (see WARNINGS). 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, 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. 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 counts (>250 cells/mm3 in women and >400 cells/mm3 in men) place patients at increased risk of these events (see WARNINGS). 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 liver function tests 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. Treatment related, adverse experiences of moderate or severe intensity observed in >2% of patients receiving VIRAMUNE in placebo-controlled trials are shown in Table 5. Table 5: Percentage of Patients with Moderate or Severe Drug Related Events in Adult Placebo Controlled Trials Trial 10901

Median exposure (weeks) Any adverse events Rash Nausea Granulocytopenia Headache Fatigue Diarrhea Abdominal pain Myalgia

Trials 1037, 1038, 10462

VIRAMUNE

Placebo

VIRAMUNE

Placebo

(n=1121)

(n=1128)

(n=253)

(n=203)

58

52

28

28

14.5% 5.1 0.5 1.8 0.7 0.2 0.2 0.1 0.2

11.1% 1.8 1.1 2.8 0.4 0.3 0.8 0.4 0

31.6% 6.7 8.7 0.4 3.6 4.7 2.0 2.0 1.2

13.3% 1.5 3.9 0 0.5 3.9 0.5 0 2.0

Background therapy included 3TC for all patients and combinations of NRTIs and PIs. Patients had CD4+ cell counts <200 cells/mm3. Background therapy included ZDV and ZDV+ddI; VIRAMUNE monotherapy was administered in some patients. Patients had CD4+ cell count ≥200 cells/mm3.

1

2

Laboratory Abnormalities: Liver function test abnormalities (AST, ALT) were observed more frequently in patients receiving VIRAMUNE than in controls (Table 6). Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue VIRAMUNE therapy in the absence of elevations in other liver function tests. Other laboratory abnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) were observed with similar frequencies in clinical trials comparing VIRAMUNE and control regimens (see Table 6). Post Marketing Surveillance: In addition to the adverse events identified during clinical trials, the following events have been reported with the use of VIRAMUNE in clinical practice: Body as a Whole: fever, somnolence, drug withdrawal (see PRECAUTIONS: Drug Interactions), redistribution/accumulation of body fat (see PRECAUTIONS, Fat Redistribution) Gastrointestinal: vomiting Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure Hematology: anemia, eosinophilia, neutropenia Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions Neurologic: paraesthesia Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue or significant hepatic abnormalities (see WARNINGS) plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy and/or renal dysfunction have been reported with the use of VIRAMUNE.

Table 6: Percentage of Adult Patients with Laboratory Abnormalities Trial 10901 Laboratory Abnormality

Trials 1037, 1038, 10462

VIRAMUNE

Placebo

VIRAMUNE

Placebo

(n=1121)

(n=1128)

(n=253)

(n=203)

14.0%

4.0%

Blood Chemistry SGPT (ALT) >250 U/L

5.3%

4.4%

SGOT (AST) >250 U/L

3.7

2.5

7.6

1.5

Bilirubin >2.5 mg/dL

1.7

2.2

1.7

1.5

Hematology Hemoglobin <8.0 g/dL

3.2

4.1

0

0

Platelets <50,000/mm3

1.3

1.0

0.4

1.5

Neutrophils <750/mm3

13.3

13.5

3.6

1.0

Background therapy included 3TC for all patients and combinations of NRTIs and PIs. Patients had CD4+ cell counts <200 cells/mm3. 2 Background therapy included ZDV and ZDV+ddI; VIRAMUNE monotherapy was administered in some patients. Patients had CD4+ cell count ≥200 cells/mm3. 1

Pediatric Patients Safety was assessed in trial BI 882 in which patients were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up in 29 of these patients in trial BI 892). The most frequently reported adverse events related to VIRAMUNE in pediatric patients were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and VIRAMUNE. Serious adverse events were assessed in ACTG 245, a double-blind, placebocontrolled trial of VIRAMUNE (n = 305) in which pediatric patients received combination treatment with VIRAMUNE. In this trial two patients were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Cases of allergic reaction, including one case of anaphylaxis, were also reported. In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out. OVERDOSAGE There is no known antidote for VIRAMUNE (nevirapine) overdosage. Cases of VIRAMUNE overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease. All events subsided following discontinuation of VIRAMUNE. DOSAGE AND ADMINISTRATION Adults The recommended dose for VIRAMUNE (nevirapine) is one 200 mg tablet daily for the first 14 days (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 200 mg tablet twice daily, in combination with other antiretroviral agents. For concomitantly administered antiretroviral therapy, the manufacturer’s recommended dosage and monitoring should be followed. Pediatric Patients The recommended oral dose of VIRAMUNE for pediatric patients 2 months up to 8 years of age is 4 mg/kg once daily for the first 14 days followed by 7 mg/kg twice daily thereafter. For patients 8 years and older the recommended dose is 4 mg/kg once daily for two weeks followed by 4 mg/kg twice daily thereafter. The total daily dose should not exceed 400 mg for any patient. VIRAMUNE suspension should be shaken gently prior to administration. It is important to administer the entire measured dose of suspension by using an oral dosing syringe or dosing cup. An oral dosing syringe is recommended, particularly for volumes of 5 mL or less. If a dosing cup is used, it should be thoroughly rinsed with water and the rinse should also be administered to the patient. Monitoring of Patients Intensive clinical and laboratory monitoring, including liver function tests, is essential at baseline and during the first 18 weeks of treatment with VIRAMUNE. The optimal frequency of monitoring during this 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 function 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 (see WARNINGS). In some cases, hepatic injury has progressed despite discontinuation of treatment. Dosage Adjustment VIRAMUNE should be discontinued if patients experience severe rash or a rash accompanied by constitutional findings (see WARNINGS). Patients experiencing rash during the 14-day lead-in period of 200 mg/day (4 mg/kg/day in pediatric patients) should not have their VIRAMUNE dose increased until the rash has resolved (see PRECAUTIONS, Information for Patients). If a clinical (symptomatic) hepatic event occurs, VIRAMUNE should be permanently discontinued. Do not restart VIRAMUNE after recovery (see WARNINGS). Patients who interrupt VIRAMUNE dosing for more than 7 days should restart the recommended dosing, using one 200 mg tablet daily (4 mg/kg/day in pediatric patients) for the first 14 days (lead-in) followed by one 200 mg tablet twice daily (4 or 7 mg/kg twice daily, according to age, for pediatric patients). An additional 200 mg dose of VIRAMUNE following each dialysis treatment is indicated in patients requiring dialysis. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations: Renal Impairment). Patients with CrCL ≥20 mL/min do not require an adjustment in VIRAMUNE dosing. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA

© Copyright Boehringer Ingelheim Pharmaceuticals, Inc., 2007, ALL RIGHTS RESERVED Rev: June 2007 10003354/US/2 10003354/02 OT1801DF2507 VR-BS (06/07) VR48001