Formulating New Strategies in HIV Therapy [International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

Viramune6
go neviraplne
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT: VIRAMUNE 200 mg Tablets
2. QUALITIVE 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 Pharmacodynamic properties.
4.2 Posology and method of administration
The recommended dose for 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 at
least two additional antiretroviral 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 constitutiona 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.
Nevirapine administration should be interrupted in patients experiencing moderate or severe liver function test abnormalities
(excluding GGT), until the 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 test abnormalities recur.
Patients who interrupt nevirapine dosing for more than 7 days should restart the recommended lead-in dosing using one 200
mg tablet daily for the first 14 days followed by one 200 mg 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 hblistering.
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 patiet vwith 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-1
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 lesionsr
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 Cr,-. 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 C ux.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 coadministration 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 capsuleso 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 (p<0.01) 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 differ from that of indinavir 800 mg q8h with nevirapine 200 mg b.i.d
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 C.(). 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 performed, antifungal medicinal products which are eliminated renally (e0g,
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 GYP3A: 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-administered with nevirapine. Therefore, careful monitoring of the
therapeutic effectiveness of P450 metabolised medicinal products is recommended when taken in combination with nevirapine.
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 (+210,
n=1 1) and macrolides (+12%, n=24), known inhibitors of CYP3A. Steady-state nevirapine trough concentrations were reduced
in patients who received rifabutin (-16%, n=19) and rifampicin (-37%, n=3), known inducers of CYP3A.
There are insufficient data to assess whether dose adjustments are necessary when nevirapine and rifampicin or ritabutin are
co-administered. Therefore, these medicinal products should only be used in combination if 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 dapsune, rifabutin, rifampicin, and trimethoprim/sulfamethoxazole. Ketoconazole and erythromycin significantly
inhibited the formation of nevirapine hydroxylated metabolites.

4.6 Use during pregnancy and lactation
No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. There are no
adequate and well-controlled studies in pregnant women.
Preliminary results from an ongoing pharmacokinetic study (ACTG 250) of 10 HIV 1-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 if they are receiving
revirapine.
Nevirap ine cannotI 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 effects
The most frequenty 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 16t of patients in combination
regimens in Phase 11/111 controlled studies. In these clinical trials 350 of patients treated with nevirapine experienced rash
compared with 19yo of patients treated in control groups of either zidovudine+didanosine or zidovudine alone. Severe or lifethreatening skin reactions occurred in 6.60 of nevirapine-treated patients compared with 1.3. of patients treated in the control
groups. Overal, 70 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
one patient requiring surgical intervention.
Liver function test abnormalities have occurred in 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 J05AX04.
Mechanism of Action
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse
transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the
enrzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 reverse
transcriptase and eukaryotic DNA polymerases (such as human DNA polymerases (u, 13.y or C ) 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 nevirapine or nevirapine+zidovudine over one to 12 weeks. By week 8 of nevirapine
monotherapy 1001o of the patients tested had HIV isolates with a >100-fold decrease in susceptibility to nevirapine, regardless
of dose. Nevirapine+zidovudine 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 2100 (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 susceptible to zidovudine and didanosine. Cross-resistance between nevirapine and HIV protease inhibitors is unlikely
because the enzyme targets involved are different
Pharmacodrnamic 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/mm: plasma HIV-1 RNA 4.59 log
copies ml). who had received at least 6 months of nucleoside analogue 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 tog copies/mi (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 netfinavir 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
combinatron.
5.2 Pharmacoketic properties
Nevirapine is readily absorbed (1>90) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute
bioavai abiity in 12 healthy adults following single-dose administration was 93 9yi (mean SD) for a 50mg tablet and 91 ~ 8%
for an pral solution. Peak plasma nevirapine concentrations appear to increase linearly in the dose range of 200 to 400 mg/day.
Steady state through nevirapine cocentrations of 4.5 + 1.9 mg/ml (17 ~ 7 iM ), (n= 242 ) were attained 400 mg/day.
The absorption of nevirapine is not affected by food, antacids or medicinal products which are formulated with an alkaline
buffering agent i(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 + 0.091/ikg, suggesting that nevirapine is widely distributed in humans.
Nevirapine readily crosses the placenta and is found in breast milk. Nevirapine is about 600 bound to plasma proteins in the
plasma concentration range of 1 10 mg/ml. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 450 (+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 balance/excretion 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 (81.3 ~ 11.10) representing the primary route
of excretion compared to feces (10.1 + 1.50 ). 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 (<5O) of the radioactivity in urine (representing <30 of the total dose) was made up of parent compound; therefore,
renai 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 characterired 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 mgyday. 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, pharmacologyy 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 celluFose, lactose monohydrate, polyvidone K26/28 or 8725, sodium starch glycolate. colloidal silicon dioxide
and magnesium stearate.
6.2 Incompatibilities: None reported.
6.3 Shelf-life: 2 years.
6.4 Special precautions for storage: There are no special storage precautions.
6.5 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
Boehringer Ingeiheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany
8.NUMBER IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS: EU/1/97/055/011
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION: 5th February 1998

) Boehringer Ingeyheim GmbH 1998