Bridging the Gap: Conference Workbook [International Conference on AIDS (12th: 1994: Geneva, Switzerland)]

Viramune~
090 nevirapine
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT: VIRAMUNE 200 mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION: Tablets each containing 200 mg of nevirapine anhydrate (active substance).
3. PHARMACEUTICAL FORM: Tablets
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Nevirapine is indicated as part of combination therapy for the antiviral treatment of HIV-1 infected adult patients with advanced or progressive immunodeficiency.
Most of the experience with nevirapine is in combination with nucleoside reverse transcriptase inhibitors. There is at present insufficient data on the
efficacy of subsequent use of triple combination including protease inhibitors after nevirapine therapy.
Refer to Section 5.1 Pharmacodyramic properties.
4.2 Posologiy and method of administratio
Ohe recommended dose for nevirapine is one 200 mg tablet daily for the first 14 days (this lead-i n period should be used because it has been found to
lessen the frequency of rash), followed by ore 200 mg tablet twice daily, in combination with at least two additional antiretrosiral agents to which the
patient has not been previously exposed. Resistant virus emerges rapidly and uniformly when nevirapine is administered as monotherapy; therefore
nevirapine should always be administered in combination therapy. For concomitantly administered antiretroviral therapy, the recommended dosage and
monitoring should be followed.
Clinical chemistry tests, which include liver function tests, should be performed prior to initiating nevirapine therapy and at appropriate intervals during therapy.
Nevirapine should be discontinued if patients experience severe rash or a rash accompanied by constitutional findings such as fever,
blistering, oral lesions, conjunctivitis, swelling, muscle or joint aches, or general malaise. Patients experiencing rash during the 14-day lead-in period of 200 mg/day should not have their nevirapine dose increased until the rash has resolved.
Refer to Section 4.4 Special warnings and special precautions for use.
Nevirapire administration should be interrupted in patients experiencing moderate or severe liver function ntest abormaities (excluding GGT), until the liver
function tests return to baseline values. Nevirapire may then be restarted at 200 mg per day. Increasing the daily dose to 200 mg twice daily should be
done with caution, after extended observation. Nevirapine should be permanently discontinued if moderate or severe liver function test abnormalities recur.
Patients who interrupt nevirapine dosing for more than T days should restart the recommended lead-in dosing, using one 200 mg tablet daily for the
first 14 days followed by one 200 my tablet twice daily.
No data are available to recommend a dosage of nevirapine in patients with hepatic dysfunction, renal insufficiency, or undergoing dialysis.
Safety and effectiveness of nevirapine in paediatric patients under the age of 16 have not been established.
Nevirapine should be administered by physicians who are experienced in the treatment of HIV infection.
4.3 Contra-indications
Nevirapine is contraindicated in patients with clinically significant hypersensitivity to the active substance or to any of the excipients of the medicinal
product.
4.4 Special warnings and special precautions for use
On the basis of pharmacodynamic data (see section 5.1) nevirapine should only be used with at least two other antiretroviral agents.
Severe and life-threatening skin reactions have occurred in patients treated with nevirapine, including Stevens-Johnson syndrome (SJS) and rarely,
toxic epidermal necrolysis (TEN). Fatal cases of TEN have been reported. Nevirapine must be discontinued in patients developing a severe rash or a
rash accompanied by constitutional symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, muscle or joint aches, or general malaise.
While nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney, the pharmacokinetics of
nevirapine have not been evaluated in patients with either hepatic or renal dysfunction. Therefore, nevirapine should not be used in patients with hepatic or renal failure.
Abnormal liver function tests have been reported with nevirapine, some in the first few weeks of therapy, including cases of hepatitis which have resulted
in at least one fatal outcome. Nevirapine administration should be interrupted in patients experiencing moderate or severe liver function test abnormalities
(except for isolated, asymptomatic GGT elevations) until liver function tests return to baseline values. Nevirapine may then be restarted at 200 mg per day.
Increasing the daily dose to 200 mg twice daily should be done with caution, after extended observation. Nevirapine should be permanently discontinued
if moderate or severe liver function abnormalities recur. Because clinical hepatitis has occasionally been reported in nevirapine treated patients, some in
the first few weeks after initiation of therapy, monitoring of ALT (SGOT) and AST (SGOT) is strongly recommended, especially during the first 6 months of
nevirapine treatment.
Nevirapine is not a cure for HIV-1 infection; patients may continue to experience illnesses associated with advanced HIV-1i infection, including opportunistic infections.
The long-term effects of nevirapine are unknown at this time. Nevirapine therapy has not been shown to reduce the risk of transmission of HIV 1 to others through sexual contact or blood contamination.
Patients should be instructed that the major toxicity of nevirapine is rash. They should be advised to promptly notify their physician of any rash. The majority of
rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy. Therefore, patients should be monitored carefully for the appearance of
rash during this period. Patients should be instructed that dose escalation is not to occur if any rash occurs during the two-week lead-in dosing period, until the
rash resolves. Any patient experiencing severe rash or a rash accompanied by constitutional symptoms such as fever, blistering, oral lesions, conjunctivitis,
swelling, muscle or joint aches, or general malaise should discontinue medication and consult a physician.
Nevirapine may interact with some medicinal products; therefore, patients should be advised to report to their doctor the use of any other medications.
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 might lower the plasma concentrations of these medications. For this reason, and to reduce the risk of HIV transmission, barrier contraception (e.g., condoms) is recommended. Additionally, when oral contraceptives are used for hormonal regulation during administration of nevirapine therapeutic effect should be monitored.
4.5 Interaction with other medicinal products and other forms of interaction
Nucleoside Analogues: No dosage adjustments are required when nevirapine is taken in combination with zidovudine, didanosine, or
zalcitabine. When the zidovudine data were pooled from two studies (n=33) in which HIV-1-infected patients received nevirapine 400 mg/day either
alone or in combination with 200-300 mg/day didanosine or 0.375 to 0.75 mg/day zalcitabine on a background of zidovudine therapy, nevirapine produced a non-significant decline of 13% in zidovudine area under the curve (AUC) and a non-significant increase of 5.8% in zidovudine Cmax. In a
subset of patients (n=6) who were administered nevirapine 400 mg/day and didanosine on a background of zidovudine therapy, nevirapine produced a
significant decline of 32% in zidovudine AUC and a non-significant decline of 27% in zidovudine Cmax. Paired data suggest that zidovudine had no
effect on the pharmacokinetics of nevirapine. In one crossover study, nevirapine had no effect on the steady-state pharmacokinetics of either didanosine (n=18) or zalcitabine (n=6).
Protease Inhibitors: Nevirapine is a mild to moderate inducer of the hepatic enzyme CYP3A; therefore, it is possible that co-administration with protease inhibitors (also metabolised by CYP3A) may result in an alteration in the plasma concentration of either agent.
Results from a clinical trial (n=31) with HIV infected patients administered nevirapine and saquinavir (hard gelatin capsules; 600 mg t.i.d.) indicated
that their co-administration leads to a mean reduction of 27% (p=0.03) in saquinavir AUC and no significant change in nevirapine plasma levels. The
reduction in saquinavir levels due to this interaction may further reduce the marginal plasma levels of saquinavir which are achieved with the hard
gelatin capsule formulation.
Results from a clinical trial (n=25) with HIV infected patients administered nevirapine and indinavir (800 mg q8h) indicated that their co-administration leads to a
28% mean decrease (pt0.01) in indinavir AUC and no significant change in nevirapine plasma levels. No definitive clinical conclusions have been reached regarding the potential impact of co-administration of nevirapine and indinavir. A dose increase of indinavir to 1000 mg q8h should be considered when indinavir is given
with nevirapine 200 mg b.i.d.; however, there are no data currently available to establish that the short term or long term antiviral activity of indinavir 1000 mg q8h
with nevirapine 200 mg b.i.d. will differfrom that of indinavir 8000mg q8h with nevirapine 200 mg b.id.
Results from a clinical trial (n=25) with HIV infected patients administered nevirapine and ritonavir (600 mg b.i.d. [using a gradual dose escalation regimen]) indicated that their coadministration leads to no significant change in ritonavir or nevirapine plasma levels. There were no increased safety concerns noted with the coadministration of nevirapine with any of these three protease inhibitors when used in combination.
Ketoconazole: In one study, administration of nevirapine 200 mg b.i.d. with ketoconazole 400 mg q.d. resulted in a significant reduction (63% median
reduction in ketoconazole AUC and a 40% median reduction in ketoconazole Cmax). In the same study, ketoconazole administration resulted in a 15-28%
increase in the plasma levels of nevirapine compared to historical controls. Ketoconazole and nevirapine should not be given concomitantly. The effects of
nevirapine on itraconazole are not known. Although interaction studies have not been pedormed, antifungal medicinal products which are eliminated renally (e.g., fluconazole) might be substituted for ketoconazole.
Oral Contraceptives: There are no clinical data on the effects of nevirapine on the pharmacokinetics of oral contraceptives. Nevirapine might decrease
the plasma concentrations of oral contraceptives (also other hormonal contraceptives); therefore, oral contraceptives should not be used as the sole
method of birth control in patients being treated with nevirapine. For other therapeutic uses requiring hormonal regulation, the therapeutic effect in
patients being treated with nevirapine should be monitored.
Other medicinal products metabolised by CYP3A: Nevirapine is an inducer of CYP3A and potentially CYP2B6, with maximal induction occurring within 2-4 weeks of initiating multiple-dose therapy, Other compounds that are substrates of these isoforms may have decreased plasma concentrations
when co-admisiatered with nevirspire. Therefore, careful monitoring of the therapeutic effectiveness of P450 metabolised medicinal products is rec
ommerded when taken in combination with nevirapie.
Other information: Monitoring of steady-state nevirapine trough plasma concentrations in patients who received long-term nevirapine treatment revealed
that nevirapine trough concentrations were elevated in patients who received cimetidine (+21%, n=11) and macrolides (+12%, n=24), known inhibitors
of CYP3A. Steady-state nevirapine trough concentrations were reduced in patients who received rilabutin (-16%, n=19) and rifampicin (-37%, n=3),
known inducers of CYP3A.
There are insufficient data to assess whether dose adjustments are necessary when neviapine and rilampicin or rilabutin are co-administered. Therefore,
these medicinal products should only be used in combination it clearly indicated and with careful monitoring.
Studies using human liver microsomes indicated that the formation of nevirapine hydroxylated metabolites was not affected by the presence of dapsone, ritabutin, rifampicin, and trimethoprim/sulfamethoxazole. Ketoconazole and erythromycin significantly inhibited the formation of nevirapine
hydroxylated metabolites.

4.6 Use during pregnancy and lactation
No observable teratogesicity was detected is reproductive studies performed is pregnant rats and rabbits. There are so adequate and
well-controlled studies is pregnant women.
Preliminary results from an ongoing pharmacakinetic study (ACTO 250) of 10 HIV-i-infected pregnant women who were administered a single oral
dose of 100 or 200 mg nevirapine at a median of 5.8 hours before delivery, indicate that nevirapine readily crosses the placenta and is found in breast
milk. It is recommended that HIV-infected mothers do not breast-feed their infants to avoid risking postnatal transmission of HIV and that mothers
should discontinue nursing it they are receiving revirapine.
Nevirapine cannot be recommended for pregnant or lactating women at this time.
4.7 Effects on ability to drive and use machines
Somnolence has been reported in association with nevirapine therapy.
4.8 Undesirable effllects
The most frequently reported adverse events related to nevirapine therapy, across all clinical trials, were rash, nausea, fatigue, fever, headache, somnolence and abnormal liver function tests.
The major clinical toxicity of nevirapine is rash, with nevirapine attributable rash occurring in 16% of patients in combination regimens in Phase II/Itt controlled studies. In these clinical trials 35% of patients treated with nevirapine experienced rash compared with 19% of patients treated in control groups of
either zidovudine+didanosine or zidovudine alone. Severe or life-threatening skin reactions occurred in 6.6% of nevirapine-treated patients compared with
1.3% of patients treated in the control groups. Overall, 7% of patients discontinued nevirapine due to rash.
Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. Severe and life-threatening skin reactions have occurred in patients treated with nevirapine, including Stevens-Johnson syndrome (SJS) and, rarely,
toxic epidermal necrolysis (TEN). Fatal cases of TEN have been reported. The majority of severe rashes occurred within the first 28 days of treatment and
some required hospitalization, with ore patient requiring surgical intervention.
Liver function teat abnormalities have occurred is patients treated with nevirapine, some in the first few weeks of therapy, including cases of hepatitis
which have resulted in at least one fatal outcome.
4.9 Overdose
There is no known antidote for nevirapine overdosage. No acute toxicities or sequelae were reported for one patient who ingested 800 mg of nevirapine
in one day.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiviral agent, ATC code J05AXO4.
Mechanism of Action
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase and blocks the RNAdependent and DNA-dependent DNA polymerase activities by causing a disruption of the enymes catalytic site. The activity of nevirapine does not
compete with template or nucleoside toiphusphates. HIV-2 reverse transcriptase and eukaryotic DNA polymerases (such as human DNA potymerases
a, y, 3, or 8) are not inhibited by nevirapine.
Resistance
HIV isolates with reduced susceptibility (100 to 250-fold) to nevirapine emerge in vitro. Phenotypic and genotypic changes occur in HIV isolates from
patients treated with eviraopine or nevirapine+zidoudie over one to 1 2 weeks. By week 8 of neviorapine monotherapy, 100% of the patients tested had
HIV isolates with a >100-told decrease is susceptibility to revirapine, regardless of dose. Nevirapine+zidovudioe combination therapy did not alter the
emergence rate of nevirapine-resistant virus. In a trial with nevirapine+zidovudine+didanosine in previously untreated patients, after 6 months of therapy, decreased phenotypic nevirapine susceptibility emerged in 21% (5/24) patients who had plasma submitted for testing. Virus was suppressed in the
other 19 plasma specimens. The clinical relevance of phenotypic and genotypic changes associated with nevirapine therapy has not been established.
Cross-resistance
Rapid emergence of HIV strains which are cross-resistant to NNRTIs has been observed in vitro. Data on cross-resistance between the NNRTI nevirapine and
nucleoside analogue reverse transcriptase inhibitors are very limited. In four patients, zidovudine-resistant isolates tested in vitro retained susceptibility to
nevirapine and in six patients, nevirapine-resistant isolates were susceptibleto zidovudine and didanosine. Cross-resistance between nevirapine and HIV protease inhibitors is unlikely because the enzyme targets involved are differentL
Pharmacodynamic Effects
Nevirapine has been evaluated in both treatment naive and treatment experienced patients.
Results from a trial (ACTG 241) evaluated triple therapy with nevirapine, zidovudine and didanosine compared to zidovudine+didanosine, in 398 HIV-1 -infected patients (mean baseline 153 CD4+ cells/mmr; plasma HIV-1 RNA 4.59 logro copies/mi), who had received at least 6 months of nucleoside ana
logue therapy prior to enrollment (median 115 weeks). These heavily experienced patients demonstrated a significant improvement of the triple therapy
group over the double therapy group for one year in both viral RNA and CD4+ cell counts.
A durable response for at least one year was documented in a trial (INCAS) for the triple therapy arm with nevirapine, zidovudine and didanosine compared to zidovudine+didanosine or nevirapine+zidovudine in 151 HIV-1 infected, treatment naive patients with CD4+ cell counts of 200-600 cells/mm'
(mean 376 cells/mm') and a mean baseline plasma HIV-1 RNA concentration of 4.41 logio copies/ml (25,704 copies/ml). Treatment doses were nevirapine, 200 mg daily for two weeks, followed by 200 mg twice daily, or placebo; zidovudine, 200 mg three times daily; didanosine, 125 or 200 mg twice
daily (depending on the weight).
The two largest controlled trials of nevirapine described above have both evaluated nevirapine in combination with zidovudine and didanosine; there is
currently limited information on long term safety and activity with combinations of other antiretroviral medicinal products. Nevirapine has also been
studied in combination with other antiretroviral agents, e.g., zalcitabine, indinavir, ritonavir, and saquinavir. Ongoing trials are examining nevirapine in
combinations with nelfinavir, lamivudine, and stavudine. No new and overt safety problems have been reported for these combinations, but clinical
experience is still somewhat limited.
Studies are on-going to evaluate the efficacy and safety of combination therapies with nevirapine in patients failing protease inhibitor therapy. Data will
be collected on the efficacy and safety of protease inhibitor therapy following failure with nevirapine combination.
5.2 Pharmacokinetic properties
Nevirapine is readily absorbed (>90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12
healthy adults following single-dose administration was 93 ~ 9% (mean SD) for a 50 mg tablet and 91 ~ 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ~ 0.4 pg/mI (7.5 aM) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak
concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Steady state trough nevirapine concentrations of 4.5 ~ 1.9 pg/ml
(17 / 7 pM), (n = 242) were attained at 400 mg/day.
The absorption of nevirapine is not affected by food, antacids or medicinal products which are formulated with an alkaline buffering agent (e.g.,
didanosine).
Nevirapine is lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the
volume of distribution (Vdss) of nevirapine was 1.21 ~ 0.09 I/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily
crosses the placenta and is found in breast milk. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10
gg/ml. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% (~5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.
In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome
P450 (oxidative) metabolism to several hydroxylated metabolites. in vitro studies with human liver microsomes suggest that oxidative metabolism of
nevirapine is mediated primarily by cytochrome P450 isozymes from the CYP3A family, although other isozymes may have a secondary role. In a mass
balancelexcretion study in eight healthy male volunteers dosed to steady state with nevirapine 200 mg given twice daily followed by a single 50 mg
dose of 14C-nevirapine, approximately 91.4 10.5% of the radiolabeled dose was recovered, with urine (81.3t~11.1%) representing the primary route
of excretion compared to feces (10.1 x 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated
metabolites. Thus cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary
route of nevirapine biotransformation and elimination in humans. Only a small fraction (<5%) of the radioactivity in urine (representing <3% of the total
dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.
Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes. The pharmacokinetics of autoinduction are characterized
by an approximately 1.5 to 2 fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of
dosing with 200-400 mg/day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200-400 mg/day.
The pharmacokinetics of nevirapine have not been evaluated in patients with either renal or hepatic dysfunction.
Although a slightly higher weight adjusted volume of distribution of nevirapine was found in female subjects compared to males, no
significant gender differences in nevirapine plasma concentrations following single or multiple dose administrations were seen. Nevirapine pharmacokinetics in HIV-1 infected adults do not appear to change with age (range 19-68 years) or race (Black, Hispanic, or Caucasian). Nevirapine has not been
specifically investigated in patients over the age of 65.
5.3 Preclinical safety data
Preclinical data revealed no special hazard for humans other than those observed in clinical studies based on conventional studies of safety, pharmacology, repeated dose toxicity, and genotoxicity. Long-term carcinogenicity studies of nevirapine in animals are currently under progress. In reproductive toxicology studies, evidence of impaired fertility was seen in rats.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose, lactose monohydrate, polyvidone K26/28 or 1/25, sodium starch glycolate, colloidal silicon dioxide and magnesium
stearate.
6.2 Incompatibilities: None reported.
6.3 Shelf-life: 2 years.
0.4 Special precautions tor storage: There are no special storage precautions.

0.5 Nature and content of container
Polyvinyl chloride (PVC)/aluminium foil push-through blister units (blister card of 10 tablets, 6 blister cards per carton).
7. MARKETING AUTHORISATION HOLDER
Boehninger Ingelheim International GmbH
Ringer Stoasse 173
55216 Ingelheim am Rhein, Germany
U. NUMBER IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS: EU/1/97/055/001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION: Sth February 1998
@ Boehringer Ingelheim International GmbH 1998