ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
VIRAMUNE 200 mg tablets
2.
Each tablet contains 200 mg of nevirapine (as anhydrous).
Excipient: each tablet contains 318 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Tablet
White, oval, biconvex tablets. One side is embossed with the code “54 193”, with a single bisect
separating the “54” and “193”. The opposite side is marked with the company symbol. The tablet
should not be divided.
4.
VIRAMUNE is indicated in combination with other anti-retroviral medicinal products for the
treatment of HIV-1 infected adults, adolescents, and children of any age (see section 4.4.).
Most of the experience with VIRAMUNE is in combination with nucleoside reverse transcriptase
inhibitors (NRTIs). The choice of a subsequent therapy after VIRAMUNE should be based on clinical
experience and resistance testing (see section 5.1).
VIRAMUNE should be administered by physicians who are experienced in the treatment of HIV
infection.
Posology
Patients 16 years and older
The recommended dose of VIRAMUNE 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.
VIRAMUNE may be taken with or without food.
If a dose is missed the patient should not double the next dose but should take the next dose as
soon as possible.
Dose management considerations
Patients experiencing rash during the 14-day lead-in period of 200 mg/day should not have their
VIRAMUNE dose increased until the rash has resolved. The isolated rash should be closely monitored
(please refer to section 4.4). The 200 mg once daily dosing regimen should not be continued beyond
2
28 days at which point in time an alternative treatment should be sought due to the possible risk of
underexposure and resistance.
Patients who interrupt VIRAMUNE dosing for more than 7 days should restart the recommended
dosing regimen using the two week lead-in period.
For toxicities that require interruption of VIRAMUNE therapy, see section 4.4.
Special populations
Renal impairment
For patients with renal dysfunction requiring dialysis an additional 200 mg dose of VIRAMUNE
following each dialysis treatment is recommended. Patients with CLcr
≥
20 ml/min do not require a
dose adjustment, see section 5.2.
Hepatic impairment
VIRAMUNE should not be used in patients with severe hepatic impairment (Child-Pugh C, see
section 4.3). No dose adjustment is necessary in patients with mild to moderate hepatic impairment
(see sections 4.4 and 5.2).
Elderly
VIRAMUNE has not been specifically investigated in patients over the age of 65.
Paediatric population
VIRAMUNE 200 mg tablets, following the dosing schedule described above, are suitable for larger
children, particularly adolescents, below the age of 16 who weigh more than 50 kg or whose body
surface area is above 1.25 m
2
according to the Mosteller formula. An oral suspension dosage form,
which can be dosed according to body weight or body surface area, is available for children in this age
group weighing less than 50 kg or whose body surface area is below 1.25 m
2
(please refer to the
Summary of Product Characteristics of VIRAMUNE oral suspension).
Method of administration
The tablets shall be taken with liquid, and should not be crushed or chewed.
Hypersensitivity to the active substance or to any of the excipients.
VIRAMUNE must not be readministered to patients who have required permanent discontinuation for
severe rash, rash accompanied by constitutional symptoms, hypersensitivity reactions, or clinical
hepatitis due to nevirapine.
VIRAMUNE must not be used in patients with severe hepatic impairment (Child-Pugh C) or pre-
treatment ASAT or ALAT > 5 ULN until baseline ASAT/ALAT are stabilised < 5 ULN.
VIRAMUNE must not be readministered in patients who previously had ASAT or ALAT > 5 ULN
during VIRAMUNE therapy and had recurrence of liver function abnormalities upon readministration
of VIRAMUNE (see section 4.4).
Herbal preparations containing St John’s wort
(Hypericum perforatum
) must not be used while taking
VIRAMUNE due to the risk of decreased plasma concentrations and reduced clinical effects of
nevirapine (see section 4.5).
3
VIRAMUNE should only be used with at least two other antiretroviral agents (see section 5.1).
VIRAMUNE should not be used as the sole active antiretroviral, as monotherapy with any
antiretroviral has shown to result in viral resistance.
The first 18 weeks of therapy with VIRAMUNE are a critical period which requires close
monitoring of patients to disclose the potential appearance of severe and life-threatening skin
reactions (including cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN)
)
and serious hepatitis/hepatic failure.
The greatest risk of hepatic events and skin
reactions occurs in the first 6 weeks of therapy. However, the risk of any hepatic event continues
past this period and monitoring should continue at frequent intervals. Female gender and higher
CD4 counts (>250/mm3 in adult females and >400/mm3 in adult males) at the initiation of
VIRAMUNE therapy are associated with a greater risk of hepatic adverse events if the patient
has detectable plasma HIV-1 RNA - i.e. a concentration ≥ 50 copies/ml - at the initiation of
VIRAMUNE. As serious and life threatening hepatotoxicity has been observed in controlled and
uncontrolled studies predominantly in patients with a plasma HIV-1 viral load of 50 copies/ml or
higher, 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, who have a
detectable plasma HIV-1 RNA unless the benefit outweighs the risk.
In some cases, hepatic injury has progressed despite discontinuation of treatment. Patients
developing signs or symptoms of hepatitis, severe skin reaction or hypersensitivity reactions
must discontinue VIRAMUNE and seek medical evaluation immediately. Viramune must
not be
restarted following severe hepatic, skin or hypersensitivity reactions (see section 4.3).
The dosage must be strictly adhered to, especially the 14-days lead-in period (see section 4.2).
Cutaneous reactions
Severe and life-threatening skin reactions, including fatal cases, have occurred in patients treated with
VIRAMUNE mainly during the first 6 weeks of therapy. These have included cases of Stevens-
Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions characterised by rash,
constitutional findings and visceral involvement. Patients should be intensively monitored during the
first 18 weeks of treatment. Patients should be closely monitored if an isolated rash occurs.
VIRAMUNE must be permanently discontinued in any patient experiencing severe rash or a rash
accompanied by constitutional symptoms (such as fever, blistering, oral lesions, conjunctivitis, facial
oedema, muscle or joint aches, or general malaise), including Stevens-Johnson syndrome, or toxic
epidermal necrolysis. VIRAMUNE must be permanently discontinued in any patient experiencing
hypersensitivity reaction (characterised by rash with constitutional symptoms, plus visceral
involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction), see
section 4.4.
VIRAMUNE administration above the recommended dose might increase the frequency and
seriousness of skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
Rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with
VIRAMUNE use.
Concomitant prednisone use (40 mg/day for the first 14 days of VIRAMUNE administration) has been
shown not to decrease the incidence of VIRAMUNE-associated rash, and may be associated with an
increase in incidence and severity of rash during the first 6 weeks of VIRAMUNE therapy.
Some risk factors for developing serious cutaneous reactions have been identified; they include failure
to follow the initial dosing of 200 mg daily during the lead-in period and a long delay between the
initial symptoms and medical consultation. Women appear to be at higher risk than men of developing
4
rash, whether receiving VIRAMUNE or non-VIRAMUNE containing therapy.
Patients should be instructed that a major toxicity of VIRAMUNE is rash. They should be advised to
promptly notify their physician of any rash and avoid delay between the initial symptoms and medical
consultation
.
The majority of rashes associated with VIRAMUNE 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. The 200 mg once daily dosing
regimen should not be continued beyond 28 days at which point in time an alternative treatment
should be sought due to the possible risk of underexposure and resistance.
Any patient experiencing severe rash or a rash accompanied by constitutional symptoms such as fever,
blistering, oral lesions, conjunctivitis, facial oedema, muscle or joint aches, or general malaise should
discontinue the medicinal product and immediately seek medical evaluation. In these patients
VIRAMUNE must not be restarted.
If patients present with a suspected VIRAMUNE-associated rash, liver function tests should be
performed. Patients with moderate to severe elevations (ASAT or ALAT > 5 ULN) should be
permanently discontinued from VIRAMUNE.
If a hypersensitivity reaction occurs, characterised by rash with constitutional symptoms such as fever,
arthralgia, myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia,
granulocytopenia, and renal dysfunction, VIRAMUNE must be permanently stopped and not be re-
introduced (see section 4.3).
Hepatic reactions
Severe and life-threatening hepatoxicity, including fatal fulminant hepatitis, has occurred in patients
treated with VIRAMUNE. The first 18 weeks of treatment is a critical period which requires close
monitoring. The risk of hepatic events is greatest in the first 6 weeks of therapy. However the risk
continues past this period and monitoring should continue at frequent intervals throughout treatment.
Rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with
VIRAMUNE use.
Increased ASAT or ALAT levels
>
2.5 ULN and/or co-infection with hepatitis B and/or C at the start
of antiretroviral therapy is associated with greater risk of hepatic adverse reactions during
antiretroviral therapy in general, including VIRAMUNE containing regimens.
Female gender and higher CD4 counts at the initiation of VIRAMUNE therapy in treatment-naïve
patients is associated with increased risk of hepatic adverse events.Women have a three fold higher
risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and
treatment-naïve patients of either gender with detectable HIV-1 RNA in plasma with higher CD4
counts at initiation of VIRAMUNE therapy are at higher risk for symptomatic hepatic events with
VIRAMUNE. In a retrospective review of predominantly patients with a plasma HIV-1 viral load of
50 copies/ml or higher, 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 detectable HIV-1 RNA in plasma and CD4
counts > 400 cells/mm3 (6.3% versus 1.2% for men with CD4 counts <400 cells/mm3). This increased
risk for toxicity based on CD4 count thresholds has not been detected
in patients with undetectable
(i.e. < 50 copies/ml) plasma viral load.
Patients should be informed that hepatic reactions are a major toxicity of VIRAMUNE requiring close
monitoring during the first 18 weeks. They should be informed that occurrence of symptoms
5
suggestive of hepatitis should lead them to discontinue VIRAMUNE and immediately seek medical
evaluation, which should include liver function tests.
Liver monitoring
Clinical chemistry tests, which include liver function tests, should be performed prior to initiating
VIRAMUNE therapy and at appropriate intervals during therapy.
Abnormal liver function tests have been reported with VIRAMUNE, some in the first few weeks of
therapy.
Asymptomatic elevations of liver enzymes are frequently described and are not necessarily a
contraindication to use VIRAMUNE. Asymptomatic GGT elevations are not a contraindication to
continue therapy.
Monitoring of hepatic tests should be done every two weeks during the first 2 months of treatment, at
the 3
rd
month and then regularly thereafter. Liver test monitoring should be performed if the patient
experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity.
If ASAT or ALAT
>
2.5 ULN before or during treatment, then liver tests should be monitored more
frequently during regular clinic visits. VIRAMUNE must not be administered to patients with pre-
treatment ASAT or ALAT > 5 ULN until baseline ASAT/ALAT are stabilised < 5 ULN (see section
4.3).
Physicians and patients should be vigilant for prodromal signs or findings of hepatitis, such as
anorexia, nausea, jaundice, bilirubinuria, acholic stools, hepatomegaly or liver tenderness. Patients
should be instructed to seek medical attention promptly if these occur.
If ASAT or ALAT increase to > 5 ULN during treatment, VIRAMUNE should be immediately
stopped. If ASAT and ALAT return to baseline values and if the patient had no clinical signs or
symptoms of hepatitis, rash, constitutional symptoms or other findings suggestive of organ
dysfunction, it may be possible to reintroduce VIRAMUNE, on a case by case basis, at the
starting dosage regimen of 200 mg/day for 14 days followed by 400 mg/day. In these cases, more
frequent liver monitoring is required. If liver function abnormalities recur, VIRAMUNE should
be permanently discontinued.
If clinical hepatitis occurs, characterised by anorexia, nausea, vomiting, icterus AND laboratory
findings (such as moderate or severe liver function test abnormalities (excluding GGT),
VIRAMUNE must be permanently stopped. VIRAMUNE must not be readministered to
patients who have required permanent discontinuation for clinical hepatitis due to nevirapine.
Liver Disease
The safety and efficacy of VIRAMUNE has not been established in patients with significant
underlying liver disorders. VIRAMUNE is contraindicated in patients with severe hepatic impairment
(Child-Pugh C, see section 4.3). Pharmacokinetic results suggest caution should be exercised when
VIRAMUNE is administered to patients with moderate hepatic dysfunction (Child-Pugh B). Patients
with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased
risk for severe and potentially fatal hepatic adverse events. In the case of concomitant antiviral therapy
for hepatitis B or C, please refer also to the relevant product information for these medicinal products.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination antiretroviral therapy and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
6
Other warnings
Post-Exposure-Prophylaxis: Serious hepatotoxicity, including liver failure requiring transplantation,
has been reported in HIV-uninfected individuals receiving multiple doses of VIRAMUNE in the
setting of post-exposure-prophylaxis (PEP), an unapproved use.
The use of VIRAMUNE has not been
evaluated within a specific study on PEP, especially in term of treatment duration and therefore, is
strongly discouraged.
Combination therapy with VIRAMUNE is not a curative treatment of patients infected with HIV-1;
patients may continue to experience illnesses associated with advanced HIV-1 infection, including
opportunistic infections.
Combination therapy with VIRAMUNE has not been shown to reduce the risk of transmission of
HIV-1 to others through sexual contact or contaminated blood.
Hormonal methods of birth control other than DMPA should not be used as the sole method of
contraception in women taking VIRAMUNE, 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 postmenopausal hormone therapy is used during
administration of VIRAMUNE, its therapeutic effect should be monitored.
Combination antiretroviral therapy has been associated with the redistribution of body fat
(lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently
unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis
and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been
associated with individual factors such as older age, and with drug related factors such as longer
duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should
include evaluation for physical signs of fat redistribution. Consideration should be given to the
measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as
clinically appropriate (see section 4.8).
In clinical studies, VIRAMUNE has been associated with an increase in HDL- cholesterol and an
overall improvement in the total to HDL-cholesterol ratio. However, in the absence of specific studies
with VIRAMUNE on modifying the cardiovascular risk in HIV infected patients, the clinical impact of
these findings is not known. The selection of antiretroviral drugs must be guided primarily by their
antiviral efficacy.
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis
have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to
combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they
experience joint aches and pain, joint stiffness or difficulty in movement.
Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time
of institution of combination antiretroviral therapy (CART), an inflammatory reaction to
asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or
aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or
months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or
focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms
should be evaluated and treatment instituted when necessary.
The available pharmacokinetic data suggest that the concomitant use of rifampicin and VIRAMUNE is
not recommended (please also refer to section 4.5).
7
Lactose: VIRAMUNE tablets contain 636 mg of lactose per maximum recommended daily dose.
Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.
Nevirapine is an inducer of CYP3A and potentially CYP2B6, with maximal induction occurring
within 2-4 weeks of initiating multiple-dose therapy.
Compounds using this metabolic pathway may have decreased plasma concentrations when co-
administered with VIRAMUNE. Careful monitoring of the therapeutic effectiveness of P450
metabolised medicinal products is recommended when taken in combination with VIRAMUNE.
The absorption of nevirapine is not affected by food, antacids or medicinal products which are
formulated with an alkaline buffering agent.
The interaction data is presented as geometric mean value with 90% confidence interval (90% CI)
whenever these data were available. ND = Not Determined, ↑ = Increased, ↓ = Decreased,
↔
= No
Effect
Medicinal products
by therapeutic areas
Interaction
Recommendations concerning co-
administration
ANTI-INFECTIVES
ANTIRETROVIRALS
NRTIs
Didanosine
100-150 mg BID
Didanosine AUC
↔
1.08 (0.92-1.27)
Didanosine and VIRAMUNE can be
co-administered without dose
adjustments.
Didanosine C
min
ND
Didanosine C
max
↔
0.98 (0.79-1.21)
Lamivudine
150 mg BID
No changes to lamivudine apparent
clearance and volume of distribution,
suggesting no induction effect of
nevirapine on lamivudine clearance.
Lamivudine and VIRAMUNE can be
co-administered without dose
adjustments.
Stavudine:
30/40 mg BID
Stavudine AUC
↔
0.96 (0.89-1.03)
Stavudine and VIRAMUNE can be
co-administered without dose
adjustments.
Stavudine C
min
ND
Stavudine C
max
↔
0.94 (0.86-1.03)
Nevirapine: compared to historical
controls, levels appeared to be
unchanged.
Tenofovir
300 mg QD
Tenofovir plasma levels remain
unchanged when co-administered
with Nevirapine.
Tenofovir and VIRAMUNE
can be
co-administered without dose
adjustments.
Nevirapine plasma levels were not
altered by co-administration of
tenofovir.
Zidovudine
100-200 mg TID
0.72 (0.60-0.96)
Zidovudine C
min
ND
Zidovudine C
max
↓
Zidovudine and VIRAMUNE can be
co-administered without dose
adjustments
↓
0.70 (0.49-1.04)
Nevirapine: Zidovudine had no
8
Zidovudine AUC
effect on its pharmacokinetics.
NNRTIs
Efavirenz
600 mg QD
Efavirenz AUC
↓
0.72 (0.66-0.86)
It is not recommended to co-
administer efavirenz and
VIRAMUNE, because of additive
toxicity and no benefit in terms of
efficacy over either NNRTI alone.
Efavirenz C
min
↓
0.68 (0.65-0.81)
Efavirenz C
max
↓
0.88 (0.77-1.01)
PIs
Atazanavir/ritonavir
300/100 mg QD
400/100 mg QD
Atazanavir/r 300/100mg
:
Atazanavir/r AUC
↓
0.58 (0.48-0.71)
It is not recommended to co-
administer atazanavir/ritonavir and
VIRAMUNE.
Atazanavir/r C
min
↓
0.28 (0.20-0.40)
Atazanavir/r C
max
↓
0.72 (0.60-0.86)
Atazanavir/r 400/100mg:
Atazanavir/r AUC
↓
0.81 (0.65-1.02)
Atazanavir/r C
min
↓
0.41 (0.27-0.60)
Atazanavir/r C
max
↔
1.02 (0.85–
1.24)
(compared to 300/100mg without
nevirapine)
Nevirapine AUC
↑
1.25 (1.17-1.34)
Nevirapine C
min
↑
1.32 (1.22–1.43)
Nevirapine C
max
↑
1.17 (1.09-1.25)
Darunavir/ritonavir
400/100 mg BID
Darunavir AUC
↑
1.24 (0.97-1.57)
Darunavir and VIRAMUNE can be
co-administered without dose
adjustments.
Darunavir C
min
↔
1.02 (0.79-1.32)
Darunavir C
max
↑
1.40 (1.14-1.73)
Nevirapine AUC
↑
1.27 (1.12-1.44)
Nevirapine C
min
↑
1.47 (1.20-1.82)
Nevirapine C
max
↑
1.18 (1.02-1.37)
Fosamprenavir
1400 mg BID,
Amprenavir AUC
↓
0.67 (0.55-0.80)
It is not recommended to co-
administer fosamprenavir and
VIRAMUNE if fosamprenavir is not
co-administered with ritonavir.
Amprenavir C
min
↓
0.65 (0.49-0.85)
Amprenavir C
max
↓
0.75 (0.63-0.89)
Nevirapine AUC
↑
1.29 (1.19-1.40)
Nevirapine C
min
↑
1.34 (1.21-1.49)
Nevirapine C
max
↑
1.25 (1.14-1.37)
Fosamprenavir/ritona
vir 700/100 mg BID
Amprenavir AUC
↔
0.89 (0.77-
Fosamprenavir/ritonavir and
VIRAMUNE can be co-administered
without dose adjustments
1.03)
Amprenavir C
min
↓
0.81 (0.69-0.96)
Amprenavir C
max
↔
0.97 (0.85-1.10)
Nevirapine AUC
↑
1.14 (1.05-1.24)
Nevirapine C
min
↑
1.22 (1.10-1.35)
Nevirapine C
max
↑
1.13 (1.03-1.24)
9
Lopinavir/ritonavir
(capsules) 400/100
mg BID
patients
:
Lopinavir AUC
↓
0.73 (0.53-0.98)
An increase in the dose of
lopinavir/ritonavir to 533/133 mg (4
capsules) or 500/125 mg (5 tablets
with 100/25 mg each) twice daily
with food is recommended in
combination with VIRAMUNE. Dose
adjustment of VIRAMUNE is not
required when co-administered with
lopinavir.
Lopinavir C
min
↓
0.54 (0.28-0.74)
Lopinavir C
max
↓
0.81 (0.62-0.95)
Lopinavir/ritonavir
(oral solution) 300/75
mg/m
2
BID
Paediatric patients
:
Lopinavir AUC
↓
0.78 (0.56-1.09)
For children, increase of the dose of
lopinavir/ritonavir to 300/75 mg/m
2
twice daily with food should be
considered when used in combination
with VIRAMUNE, particularly for
patients in whom reduced
susceptibility to lopinavir/ritonavir is
suspected.
Lopinavir C
min
↓
0.45 (0.25-0.82)
Lopinavir C
max
↓
0.86 (0.64-1.16)
Nelfinavir
750 mg TID
Nelfinavir
AUC
↔
1.06 (0.78-1.14)
Nelfinavir and VIRAMUNE can be
co-administered without dose
adjustments.
C
min
↔
0.68 (0.50-1.5)
C
max
↔
1.06 (0.92-1.22)
Nelfinavir metabolite M8:
AUC
↓
0.38 (0.30–0.47)
C
min
↓
0.34 (0.26–0.45)
C
max
↓
0.41 (0.32–0.52)
Nevirapine: compared to historical
controls, levels appeared to be
unchanged.
Ritonavir
600 mg BID
Ritonavir AUC
↔
0.92 (0.79-1.07)
Ritonavir and VIRAMUNE can be
co-administered without dose
adjustments.
Ritonavir C
min
↔
0.93 (0.76-1.14)
Ritonavir C
max
↔
0.93 (0.78-1.07)
Nevirapine: Co-administration of
ritonavir does not lead to any
clinically relevant change in
nevirapine plasma levels.
Saquinavir/ritonavir
The limited data available with
saquinavir soft gel capsule boosted
with ritonavir do not suggest any
clinically relevant interaction
between saquinavir boosted with
ritonavir and Nevirapine
Saquinavir/ritonavir and
VIRAMUNE can be co-administered
without dose adjustments
.
Tipranavir/ritonavir
500/200 mg BID
No specific drug-drug interaction
study has been performed.
The limited data available from a
phase IIa study in HIV-infected
patients have shown a clinically non
significant 20% decrease of TPV
C
min
.
Tipranavir and VIRAMUNE can be
co-administered without dose
adjustments.
10
ENTRY INHIBITORS
Enfuvirtide
Due to the metabolic pathway no
clinically significant
pharmacokinetic interactions are
expected between enfuvirtide and
nevirapine.
Enfuvirtide and VIRAMUNE can be
co-administered without dose
adjustments.
Maraviroc
300 mg QD
Maraviroc AUC
↔
1.01 (0.6 -1.55)
Maraviroc and VIRAMUNE can be
co-administered without dose
adjustments.
Maraviroc C
min
ND
Maraviroc C
max
1.54 (0.94-2.52)
compared to historical controls
↔
Nevirapine concentrations not
measured, no effect is expected.
INTEGRASE INHIBITORS
Raltegravir
400 mg BID
No clinical data available. Due to the
metabolic pathway of raltegravir no
interaction is expected.
Raltegravir and VIRAMUNE can be
co-administered without dose
adjustments.
ANTIBIOTICS
Clarithromycin
500 mg BID
Clarithromycin AUC
↓
0.69 (0.62-
Clarithromycin exposure was
significantly decreased, 14-OH
metabolite exposure increased.
Because the clarithromycin active
metabolite has reduced activity
against
Mycobacterium avium-
intracellulare complex
overall
activity against the pathogen may be
altered. Alternatives to
clarithromycin, such as azithromycin
should be considered. Close
monitoring for hepatic abnormalities
is recommended
0.76)
Clarithromycin C
min
↓
0.44 (0.30-
0.64)
Clarithromycin C
max
↓
0.77 (0.69-
0.86)
1.42 (1.16-1.73)
Metabolite 14-OH clarithromycin
C
min
↑
0 (0.68-1.49)
Metabolite 14-OH clarithromycin
C
max
↑
1.47 (1.21-1.80)
Nevirapine AUC
↑
1.26
Nevirapine C
min
↑
1.28
1.24
compared to historical controls.
↑
11
Metabolite 14-OH clarithromycin
AUC
↔
Nevirapine C
max
Rifabutin
150 or 300 mg QD
Rifabutin AUC
↑
1.17 (0.98-1.40)
No significant effect on rifabutin and
VIRAMUNE mean PK parameters is
seen. Rifabutin and VIRAMUNE can
be co-administered without dose
adjustments. However, due to the
high intersubject variability 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.
Rifabutin C
min
↔
1.07 (0.84-1.37)
Rifabutin C
max
↑
1.28 (1.09-1.51)
1.24 (0.84-1.84)
Metabolite 25-O-desacetylrifabutin
C
min
↑
1.22 (0.86-1.74)
Metabolite 25-O-desacetylrifabutin
C
max
↑
↑
1.29 (0.98-1.68)
A clinically not relevant increase in
the apparent clearance of nevirapine
(by 9%) compared to historical data
was reported.
Rifampicin
600 mg QD
Rifampicin AUC
↔
1.11 (0.96-1.28)
It is not recommended to co-
administer rifampicin and
VIRAMUNE (see section 4.4).
Physicians needing to treat patients
co-infected with tuberculosis and
using a VIRAMUNE containing
regimen may consider co-
administration of rifabutin instead.
Rifampicin C
min
ND
Rifampicin C
max
↔
1.06 (0.91-1.22)
Nevirapine AUC
↓
0.42
Nevirapine C
min
↓
0.32
0.50
compared to historical controls.
↓
ANTIFUNGALS
Fluconazole
200 mg QD
Fluconazole AUC
↔
0.94 (0.88-
Because of the risk of increased
exposure to VIRAMUNE, caution
should be exercised if the medicinal
products are given concomitantly and
patients should be monitored closely.
1.01)
Fluconazole C
min
↔
0.93 (0.86-1.01)
Fluconazole C
max
↔
0.92 (0.85-0.99)
100%
compared with historical data where
nevirapine was administered alone.
↑
Itraconazole
200 mg QD
Itraconazole AUC
↓
0.39
A dose increase for itraconazole
should be considered when these two
agents are administered
concomitantly.
Itraconazole C
min
↓
0.13
Itraconazole C
max
↓
0.62
Nevirapine: there was no significant
difference in Nevirapine
pharmacokinetic parameters.
Ketoconazole
400 mg QD
Ketoconazole AUC
↓
0.28 (0.20-
It is not recommended to co-
administer ketoconazole and
VIRAMUNE.
0.40)
Ketoconazole C
min
ND
Ketoconazole C
max
↓
0.56 (0.42-
0.73)
1.15-
1.28 compared to historical controls.
↑
12
Metabolite 25-O-desacetylrifabutin
AUC
Nevirapine C
max
Nevirapine: exposure:
Nevirapine: plasma levels:
ANTACIDS
Cimetidine
Cimetidine: no significant effect on
cimetidine PK parameters is seen.
Cimetidine and VIRAMUNE can be
co-administered without dose
adjustments.
Nevirapine C
min
↑
1.07
ANTITHROMBOTICS
Warfarin
The interaction between Nevirapine
and the antithrombotic agent
warfarin is complex, with the
potential for both increases and
decreases in coagulation time when
used concomitantly.
Close monitoring of anticoagulation
levels is warranted.
CONTRACEPTIVES
Depo-
medroxyprogesterone
acetate (DMPA)
150 mg every 3
months
DMPA AUC
↔
Viramune co-administration did not
alter the ovulation suppression effects
of DMPA. DMPA and VIRAMUNE
can be co-administered without dose
adjustments.
DMPA C
min
↔
DMPA C
max
↔
Nevirapine AUC
↑
1.20
Nevirapine C
max
↑
1.20
Ethinyl estradiol (EE)
0.035 mg
0.80 (0.67 - 0.97)
EE C
min
ND
EE C
max
↓
Oral hormonal contraceptives should
not be used as the sole method of
contraception in women taking
VIRAMUNE (see section 4.4).
Appropriate doses for hormonal
contraceptives (oral or other forms of
application) other than DMPA in
combination with VIRAMUNE
have
not been established with respect to
safety and efficacy.
↔
0.94 (0.79 - 1.12)
Norethindrone (NET)
1.0 mg QD
0.81 (0.70 - 0.93)
NET C
min
ND
NET C
max
↓
↓
0.84 (0.73 - 0.97)
DRUG ABUSE
Methadone Individual
Patient Dosing
0.40 (0.31 - 0.51)
Methadone C
min
ND
Methadone C
max
↓
Methadone-maintained patients
beginning VIRAMUNE therapy
should be monitored for evidence of
withdrawal and methadone dose
should be adjusted accordingly.
↓
0.58 (0.50 - 0.67)
HERBAL PRODUCTS
St. John's Wort
Serum levels of Nevirapine can be
reduced by concomitant use of the
herbal preparation St. John's Wort
(
Hypericum perforatum
). This is due
to induction of drug metabolism
enzymes and/or transport proteins by
St. John’s Wort.
Herbal preparations containing St.
John‘s Wort and VIRAMUNE must
not be co-administered (see section
4.3). If a patient is already taking St.
John‘s Wort check nevirapine and if
possible viral levels and stop St
John‘s Wort. Nevirapine levels may
increase on stopping St John‘s Wort.
The dose of VIRAMUNE may need
adjusting. The inducing effect may
persist for at least 2 weeks after
cessation of treatment with St. John‘s
Wort.
13
EE AUC
NET AUC
Methadone AUC
Other information:
Nevirapine metabolites: Studies using human liver microsomes indicated that the formation of
nevirapine hydroxylated metabolites was not affected by the presence of dapsone, rifabutin,
rifampicin, and trimethoprim/sulfamethoxazole. Ketoconazole and erythromycin significantly
inhibited the formation of nevirapine hydroxylated metabolites.
Women of childbearing potential / Contraception in males and females
Women of childbearing potential should not use oral contraceptives as the sole method for birth
control, since nevirapine might lower the plasma concentrations of these medications (see sections 4.4
& 4.5).
Pregnancy
Currently available data on pregnant women indicate no malformative or foeto/ neonatal toxicity. To
date no other relevant epidemiological data are available. No observable teratogenicity was detected in
reproductive studies performed in pregnant rats and rabbits (see section 5.3). There are no adequate
and well-controlled studies in pregnant women. Caution should be exercised when prescribing
VIRAMUNE to pregnant women (see section 4.4). As hepatotoxicity is more frequent in women with
CD4 cell counts above 250 cells/mm3 with detectable HIV-1 RNA in plasma (50 or more copies/mL),
these conditions should be taken in consideration on therapeutic decision (see section 4.4). There is
not enough evidence to substantiate that the absence of an increased risk for toxicity seen in pre-
treated women initiating VIRAMUNE with an undetectable viral load (less than 50 copies/mL of HIV-
1 in plasma) and CD4 cell counts above 250 cells/mm3 also applies to pregnant women. All the
randomised studies addressing this issue specifically excluded pregnant women, and pregnant women
were under-represented in cohort studies as well as in meta-analyses.
Breastfeeding
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 breast-feeding if they are receiving
VIRAMUNE.
Fertility
In reproductive toxicology studies, evidence of impaired fertility was seen in rats.
No studies on the effects on the ability to drive and use machines have been performed.
a. Summary of the safety profile
The most frequently reported adverse reactions related to VIRAMUNE therapy, across all clinical
trials, were rash, allergic reactions, hepatitis, abnormal liver function tests, nausea, vomiting,
diarrhoea, abdominal pain, fatigue, fever, headache and myalgia.
14
The postmarketing experience has shown that the most serious adverse reactions are Stevens-Johnson
syndrome/ toxic epidermal necrolysis, serious hepatitis/hepatic failure, and drug rash with eosinophilia
and systemic symptoms, characterised by rash with constitutional symptoms such as fever, arthralgia,
myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia,
granulocytopenia, and renal dysfunction. The first 18 weeks of treatment is a critical period which
requires close monitoring (see section 4.4).
b. Tabulated summary of adverse reactions
The following adverse reactions which may be causally related to the administration of VIRAMUNE
have been reported. The frequencies estimated are based on pooled clinical trial data for events
considered related to VIRAMUNE treatment.
Frequency is defined using the following convention: very common (
≥
1/10); common (
≥
1/100 to
<1/10); uncommon (
1/1,000 to <1/100); rare (
≥
1/10,000 to <1/1,000); very rare (<1/10,000).
Blood and lymphatic system disorders
Common granulocytopenia*
Uncommon anaemia
* In study 1100.1090, from which the majority of related adverse events (n=28) were received,
patients on placebo had a higher incidence of events of granulocytopenia (3.3%) than patients on
nevirapine (2.5%).
Immune system disorders
Common hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria)
Uncommon drug rash with eosinophilia and systemic symptoms**, anaphylactic reaction**
** These adverse reactions were not observed among the 1,761 subjects exposed to nevirapine in
clinical trials.
Nervous system disorders
Common
headache
Gastrointestinal disorders
Common
nausea, vomiting, abdominal pain, diarrhoea
Hepatobiliary disorders
Common
hepatitis (including severe and life-threatening hepatotoxicity( (1.4%)
Uncommon
jaundice
Rare
hepatitis fulminant (which may be fatal)
Skin and subcutaneous tissue disorders
Very common
rash (13.6%)
Uncommon
Stevens-Johnson syndrome/ toxic epidermal necrolysis (which may be fatal)
(0.1%), angioedema, urticaria
Musculoskeletal and connective tissue disorders
Common
myalgia
Uncommon
arthralgia
General disorders and administration site conditions
Common
pyrexia, fatigue
15
≥
Investigations
Common
liver function test abnormal (alanine aminotransferase increased; transaminases
increased; aspartate aminotransferase increased; gamma-glutamyltransferase
increased; hepatic enzyme increased; hypertransaminasaemia)
c. Description of selected adverse reactions
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV infected patients including the loss of peripheral and facial subcutaneous fat, increased intra-
abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
The following events have also been reported when VIRAMUNE has been used in combination with
other anti-retroviral agents:
pancreatitis, peripheral neuropathy and thrombocytopaenia. These events
are commonly associated with other antiretroviral agents and may be expected to occur when
VIRAMUNE is used in combination with other agents; however it is unlikely that these events are due
to VIRAMUNE treatment. Hepatic-renal failure syndromes have been reported rarely.
In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
infections may arise (see section 4.4).
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).
The frequency of this is unknown (see section 4.4).
Skin and subcutaneous tissues
The most common clinical toxicity of VIRAMUNE is rash, with VIRAMUNE attributable rash
occurring in 13.6% of patients in combination regimens in controlled studies.
Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or
without pruritus, located on the trunk, face and extremities. Hypersensitivity (anaphylactic reaction,
angioedema and urticaria) have been reported
.
Rashes occur alone or in the context of
drug rash with
eosinophilia and systemic symptoms, characterised by rash with constitutional symptoms such as
fever, arthralgia, myalgia and lympadenopathy, plus visceral involvement, such as hepatitis,
eosinophilia, granulocytopenia, and renal dysfunction
.
Severe and life-threatening skin reactions have occurred in patients treated with VIRAMUNE,
including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Fatal cases of SJS
,
TEN and drug rash with eosinophilia and systemic symptoms have been reported. The majority of
severe rashes occurred within the first 6 weeks of treatment and some required hospitalisation, with
one patient requiring surgical intervention (see section 4.4).
Hepato-biliary
The most frequently observed laboratory test abnormalities are elevations in liver function tests
(LFTs), including ALAT, ASAT, GGT, total bilirubin and alkaline phosphatase. Asymptomatic
elevations of GGT levels are the most frequent. Cases of jaundice have been reported. Cases of
hepatitis (severe and life-threatening hepatoxicity, including fatal fulminant hepatitis) have been
reported in patients treated with VIRAMUNE. The best predictor of a serious hepatic event was
elevated baseline liver function tests. The first 18 weeks of treatment is a critical period which requires
close monitoring (see section 4.4).
16
d. Paediatric population
Based on clinical trial experience of 361 paediatric patients the majority of which received
combination treatment with ZDV or/and ddI, the most frequently reported adverse events related to
VIRAMUNE were similar to those observed in adults. Granulocytopenia was more frequently
observed in children. In an open-label clinical trial (ACTG 180) granulocytopenia assessed as drug-
related occurred in 5/37 (13.5%) of patients. In ACTG 245, a double-blind placebo controlled study,
the frequency of serious drug-related granulocytopenia was 5/305 (1.6%). Isolated cases of Stevens-
Johnson syndrome or Stevens-Johnson/ toxic epidermal necrolysis transition syndrome have been
reported in this population.
There is no known antidote for VIRAMUNE overdosage. Cases of VIRAMUNE overdose at doses
ranging from 800 to 6000 mg per day for up to 15 days have been reported. Patients have experienced
oedema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash,
vertigo, vomiting, increase in transaminases and weight decrease. All of these effects subsided
following discontinuation of VIRAMUNE.
Paediatric Population
One case of massive accidental overdose in a newborn was reported. The ingested dose was 40 times
the recommended dose of 2mg/kg/day. Mild isolated neutropenia and hyperlactataemia was observed,
which spontaneously disappeared within one week without any clinical complications. One year later,
the child’s development remained normal.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: NNRTI (non-nucleoside reverse transcriptase inhibitors), ATC code
J05AG01.
Mechanism of action
Nevirapine is a NNRTI of HIV-1. Nevirapine is a non-competitive inhibitor of the HIV-1 reverse
transcriptase, but it does not have a biologically significant inhibitory effect on the HIV-2 reverse
transcriptase or on eukaryotic DNA polymerases
α
,
β
,
, or
δ
.
Antiviral activity
in vitro
Nevirapine had a median EC
50
value (50% inhibitory concentration) of 63 nM against a panel of group
M HIV-1 isolates from clades A, B, C, D, F, G, and H, and circulating recombinant forms (CRF),
CRF01_AE, CRF02_AG and CRF12_BF replicating in human embryonic kidney 293 cells. In a panel
of 2,923 predominantly subtype B HIV-1 clinical isolates, the mean EC
50
value was 90nM. Similar
EC
50
values are obtained when the antiviral activity of nevirapine is measured in peripheral blood
mononuclear cells, monocyte derived macrophages or lymphoblastoid cell line. Nevirapine had no
antiviral activity in cell culture against group O HIV-1 isolates or HIV-2 isolates.
Nevirapine in combination with efavirenz exhibited a strong antagonistic anti-HIV-1 activity
in vitro
(see section 4.5) and was additive to antagonistic with the protease inhibitor ritonavir or the fusion
inhibitor enfuvirtide.Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination
with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and
tipranavir, and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and
17
γ
zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and
by the anti-HCV drug ribavirin
in vitro
.
Resistance
HIV-1 isolates with reduced susceptibility (100-250-fold) to nevirapine emerge in cell culture.
Genotypic analysis showed mutations in the HIV-1 RT gene Y181C and/or V106A depending
upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell
culture was not altered when selection included nevirapine in combination with several other
NNRTIs.
Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve patients receiving
either nevirapine (n=24) or nevirapine and ZDV (n=14) were monitored in Phase I/II trials over 1
to ≥12 weeks. After 1 week of nevirapine monotherapy, isolates from 3/3 patients had decreased
susceptibility to nevirapine in cell culture. One or more of the RT mutations resulting in amino
acid substitutions K103N, V106A, V108I, Y181C, Y188C and G190A were detected in HIV-1
isolates from some patients as early as 2 weeks after therapy initiation. By week eight of
nevirapine monotherapy, 100% of the patients tested (n=24) had HIV-1 isolates with a >100-fold
decrease in susceptibility to nevirapine in cell culture compared to baseline, and had one or more
of the nevirapine-associated RT resistance mutations. Nineteen of these patients (80%) had
isolates with Y181C substitutions regardless of dose.
Genotypic analysis of isolates from antiretroviral naïve patients experiencing virologic failure
(n=71) receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine
and stavudine for 48 weeks showed that isolates from 8/25 and 23/46 patients, respectively, contained
one or more of the following NNRTI resistance-associated substitutions:
Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.
Cross-resistance
Rapid emergence of HIV-strains which are cross-resistant to NNRTIs has been observed in vitro.
Cross resistance to delavirdine and efavirenz is expected after virologic failure with nevirapine.
Depending on resistance testing results, an etravirine-containing regimen may be used subsequently.
Cross-resistance between nevirapine and either HIV protease inhibitors, HIV integrase inhibitors or
HIV entry inhibitors is unlikely because the enzyme targets involved are different. Similarly the
potential for cross-resistance between nevirapine and NRTIs is low because the molecules have
different binding sites on the reverse transcriptase.
Clinical results
VIRAMUNE has been evaluated in both treatment-naïve and treatment-experienced patients.
Studies in treatment-naïve patients
2NN study
The double non-nucleoside study 2 NN was a randomised, open-label, multicentre prospective study
comparing the NNRTIs VIRAMUNE, efavirenz and both drugs given together.
1216 antiretroviral-therapy naïve patients with plasma HIV-1 RNA > 5000 copies/ml at baseline were
assigned to VIRAMUNE 400 mg once daily, VIRAMUNE 200 mg twice daily, efavirenz 600 mg
once daily, or VIRAMUNE (400 mg) and efavirenz (800 mg) once daily, plus stavudine and
lamivudine for 48 weeks.
The primary endpoint, treatment failure, was defined as less than 1 log
10
decline in plasma HIV-1
RNA in the first 12 weeks, or two consecutive measurements of more than 50 copies/ ml from week
24 onwards, or disease progression (new Centers for Disease Control and Prevention grade C event or
18
death), or change of allocated treatment.
Median age was 34 years and about 64% were male patients, median CD4 cell count was 170 and 190
cells per mm
3
in the VIRAMUNE twice daily and efavirenz groups, respectively. There were no
significant differences in demographic and baseline characteristics between the treatment groups.
The predetermined primary efficacy comparison was between the VIRAMUNE twice daily and the
efavirenz treatment groups. Details of the primary efficacy comparison are given in table 1.
Table 1: Number of patients with treatment failure, components of treatment failure, and
number of patients with plasma HIV-RNA concentration < 50 c/ml, at week 48 (Intention-To-
Treat (ITT) Analysis).
VIRAMUNE
200 mg twice daily
(n = 387)
Efavirenz 600 mg
once daily
(n = 400)
Treatment failure on or before week 48,
% (95% IC)
43.7% (38.7-48.8)
37.8% (33.0-42.7)
Components of failure (%)
Virological
Progression
Change of treatment
Permanent
of
NNRTI
(n)
18.9%
2.8%
22.0%
61
13
1
1
9
15.3%
2.5%
20.0%
51
8
1
1
19
Temporary discontinuation of NNRTI (n)
Additional antiretroviral drugs (n)
Non-allowable change of NNRTI (n)
Never started ART* (n)
Plasma HIV-1 RNA concentration
<50 c/mL at 48 weeks, %(95% IC)
65.4% (60.4-70.1)
70.0% (65.2-74.5)
* ART = antiretroviral therapy
Although, overall, treatment failure was numerically lower in the efavirenz group than in the
nevirapine-only groups, the findings of this study show no evidence that efavirenz is superior to
nevirapine twice daily in terms of treatment failure. However, equivalence within the 10% limits of
these treatment groups was not shown even though the study was adequately powered for such an
analysis. The nevirapine twice daily regimen and the efavirenz regimen were not significantly
different (p= 0.091) in terms of efficacy as measured by incidence of treatment failure. There was also
no significant difference between VIRAMUNE twice daily and efavirenz regarding any components
of treatment failure including virological failure.
The simultaneous use of nevirapine (400 mg) plus efavirenz (800 mg) was associated with the highest
frequency of clinical adverse events and with the highest rate of treatment failure (53.1%). As the
regimen of nevirapine plus efavirenz did not have additional efficacy and caused more adverse events
than each drug separately, this regimen is not recommended.
Twenty per cent of patients assigned to nevirapine twice daily and 18% of patients assigned to
efavirenz had at least one grade 3 or 4 clinical adverse event. Clinical hepatitis reported as clinical
adverse event occurred in 10 (2.6%) and 2 (0.5%) patients in the nevirapine twice daily and efavirenz
groups respectively. The proportion of patients with at least one grade 3 or 4 liver-associated
laboratory toxicity was 8.3% for nevirapine twice daily and 4.5% for efavirenz. Of the patients with
grade 3 or 4 liver-associated laboratory toxicity, the proportions coinfected with hepatitis B or
hepatitis C virus were 6.7% and 20.0% in the nevirapine twice daily group, 5.6% and 11.1% in the
efavirenz group.
19
change
2NN Three-year follow-up-study
This is a retrospective multicentre study comparing the 3-year antiviral efficacy of VIRAMUNE and
efavirenz in combination with stavudine and lamivudine in 2NN patients from week 49 to week 144.
Patients who participated in the 2NN study and were still under active follow-up at week 48 when the
study closed and were still being treated at the study clinic, were asked to participate in this study.
Primary study endpoints (percentage of patients with treatment failures) and secondary study
endpoints as well as backbone therapy were similar to the original 2NN study.
Table 2 shows the main efficacy results of this study.
Table 2: Number of patients with treatment failure, components of treatment failure, and
number of patients with plasma HIV-RNA concentration < 400 copies/ml, between week 49 to
144 (ITT analysis).
VIRAMUNE
200 mg twice daily
(n=224)
Efavirenz 600
mg once daily
(n=223)
Treatment failure (%)
35.7
35.0
Virologic failure (>400 c/ml) (%)
5.8
4.9
pVL <400 c/ml at week 144 (%)
87.2
87.4
CD4 increase (cells/mm3)
+135
+130
Disease progression / death (%)
5.8
6.3
A durable response to VIRAMUNE for at least three years was documented in this study. Equivalence
within a 10% range was demonstrated between VIRAMUNE 200 mg twice daily and efavirenz with
respect to treatment failure. Both, the primary (p = 0.92) and secondary endpoints showed no
statistically significant differences between efavirenz and VIRAMUNE 200 mg twice daily.
Studies in treatment-experienced patients
NEFA study
The NEFA trial is a controlled prospective randomised study which evaluated treatment options for
patients who switch from protease inhibitor (PI) based regimen with undetectable load to either
VIRAMUNE, efavirenz or abacavir.
The study randomly assigned 460 adults who were taking two nucleoside reverse-transcriptase
inhibitors and at least one PI and whose plasma HIV-1 RNA levels had been less than 200 c/ml for at
least the previous six months to switch from the PI to VIRAMUNE (155 patients), efavirenz (156), or
abacavir (149).
The primary study endpoint was death, progression to the acquired immunodeficiency syndrome, or an
increase in HIV-1 RNA levels to 200 copies or more per millilitre. The main results regarding the
primary endpoint are given in table 3.
20
Table 3: Outcome of Therapy 12 months after switch from PI based therapy
VIRAMUNE
(n=155)
Efavirenz
(n=156)
Abacavir
(n=149)
Number of patients
Death
1
2
1
Progression to AIDS
0
0
2
Virologic failure
While taking study medication
After switching study medication
14
8
6
7
5
2
16
16
0
Lost to follow-up
3
6
8
Switched study medication without virologic failure
20
29
9
Response; still taking study medication at 12 months
117
112
113
At 12 months, the Kaplan–Meier estimates of the likelihood of reaching the endpoint were 10 % in the
VIRAMUNE group, 6 % in the efavirenz group, and 13 percent in the abacavir group (P=0.10
according to an intention-to-treat analysis).
The overall incidence of adverse events was significantly lower (61 patients, or 41%) in the abacavir
group than in the nevirapine group (83 patients, or 54%) or the efavirenz group (89 patients, or 57%).
Significantly fewer patients in the abacavir group (9 patients, or 6%) than in the nevirapine group (26
patients, or 17%) or the efavirenz group (27 patients, or 17%) discontinued the study medication
because of adverse events (see table below).
21
Number of patients who had one or more adverse events*
Adverse Event
Nevirapine
(N=155)
Efavirenz
(N=156)
Abacavir
(N=149)
Any
adverse
event
Grade 3
or 4
adverse
event
Adverse
event
leading
to
disconti-
nuation
Any
adverse
event
Grade 3
or 4
adverse
event
Adverse
event
leading
to
disconti-
nuation
Any
adverse
event
Grade 3
or 4
adverse
event
Adverse
event
leading
to
disconti-
nuation
Number of patients (percent)
Clinical
- Neuropsychiatric
11
6
6
48
22
19
14
1
0
- Cutaneous
20
13
12
11
3
3
7
0
0
- Gastrointestinal
6
2
0
8
4
4
12
2
1
- Systemic**
7
1
1
5
2
0
10
8
8
- Other
25
8
1
11
5
1
12
3
0
Laboratory
- Increased
aminotransferase
levels
12
6
4
4
1
0
5
1
0
- Hyperglycemia
2
2
2
2
2
0
1
1
0
Total
83
(54)***
38
26
(17)****
89
(57)***
39
27
(17)****
61
(41)***
16
9
(6)****
* A grade 3 event was defined as severe, and a grade 4 event as life-threatening
** Systemic adverse events included hypersensitivity reactions
*** P=0.02 by the chi-square test
**** P=0.01 by the chi-square test
Perinatal Transmission
The HIVNET 012 study conducted in Kampala (Uganda) evaluated the efficacy of VIRAMUNE to
prevent vertical transmission of HIV-1 infection. Mothers received only study antiretroviral therapy
during these trials. Mother-infant pairs were randomised to receive oral VIRAMUNE (mother: 200 mg
at the onset of labour; infant: 2 mg/kg within 72 hours of birth), or an ultra-short oral zidovudine
regimen (mother: 600 mg at the onset of labour and 300 mg every 3 hours until delivery; infant:
4 mg/kg twice daily for 7 days). The cumulative HIV-1 infant infection rate at 14-16 weeks was
13.1% (n = 310) in the VIRAMUNE group, versus 25.1% (n = 308 in the ultra-short zidovudine group
(p = 0.00063).
From a study in which infants of HIV infected mothers received either placebo or single dose
nevirapine, 30 HIV infected infants, 15 who have received placebo and 15 who have received
nevirapine, were subsequently treated with nevirapine combined with other anti-retroviral drugs.
Virologic failure after 6 months of treatment with nevirapine combined with other anti-retroviral drugs
occurred in significantly more infants who had previously received a single dose of nevirapine (10 of
15) than in infants who had received placebo previously (1 of 15). This indicates that in infants
previously treated with single-dose nevirapine alone for prevention of mother to child transmission of
HIV-1, the efficacy of VIRAMUNE as part of a combination therapy which they receive for their own
health may be reduced.
22
In a study in which women who had received single dose nevirapine for prevention of mother-to-child
transmission were treated with VIRAMUNE combined with other anti-retroviral drugs for their own
health, 29 of 123, or 24% experienced virologic failure, and five (38%) of 13 women with HIV-1
detected baseline resistance to VIRAMUNE experienced virologic failure. This indicates that in
women previously treated with single-dose nevirapine alone for prevention of mother to child
transmission of HIV-1, the efficacy of VIRAMUNE as part of a combination therapy which the
women receive for their own health may be reduced.
A blinded randomized clinical trial in women already taking antiretroviral therapy throughout
pregnancy (PACTG 316) demonstrated no further reduction of vertical HIV-1 transmission when the
mother and the child received a single VIRAMUNE dose during labour and after birth respectively.
HIV-1 transmission rates were similarly low in both treatment groups (1.3% in the VIRAMUNE
group, 1.4% in the placebo group). The vertical transmission decreased neither in women with HIV-1
RNA below the limit of quantification nor in women with HIV-1 RNA above the limit of
quantification prior to partus. Of the 95 women who received intrapartum VIRAMUNE, 15%
developed nevirapine resistance mutations at 6 weeks post partus.
The clinical relevance of these data in European populations has not been established. Furthermore, in
the case VIRAMUNE is used as single dose to prevent vertical transmission of HIV-1 infection, the
risk of hepatotoxicity in mother and child cannot be excluded.
Paediatric population
Results of a 48-week analysis of the South African study BI 1100.1368 confirmed that the 4/7 mg/kg
and 150 mg/m2 nevirapine dose groups were well tolerated and effective in treating antiretroviral
naive paediatric patients. A marked improvement in the CD4+ cell percent was observed through
Week 48 for both dose groups. Also, both dosing regimens were effective in reducing the viral load. In
this 48-week study no unexpected safety findings were observed in either dosing group.
5.2 Pharmacokinetic properties
VIRAMUNE tablets and oral suspension have been shown to be comparably bioavailable and
interchangeable at doses up to 200 mg.
Absorption:
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
0.4
µ
g/ml (7.5
µ
M) 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. Data reported in the literature from 20 HIV infected
patients suggest a steady state C
max
of 5.74 µg/ml (5.00-7.44) and C
min
of 3.73 µg/ml (3.20-5.08) with
an AUC of 109.0 h
*
µg/ml (96.0-143.5) in patients taking 200 mg of nevirapine bid. Other published
data support these conclusions. Long-term efficacy appears to be most likely in patients whose
nevirapine trough levels exceed 3.5 µg/ml.
±
0.09 l/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
µ
g/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.
Biotransformation and elimination:
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
23
plasma nevirapine concentrations of 2
Distribution:
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
±
±
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 radiolabelled dose was recovered, with urine (81.3
±
11.1%) representing the primary
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 characterised 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.
Special populations:
Renal dysfunction:
The single-dose pharmacokinetics of nevirapine have been compared in 23 subjects
with either mild (50
≤
CLcr
<
80 ml/min), moderate (30
≤
CLcr
<
50 ml/min) or severe renal
30 ml/min), renal impairment or end-stage renal disease (ESRD) requiring
dialysis, and 8 subjects with normal renal function (CLcr
<
80 ml/min). Renal impairment (mild,
moderate and severe) resulted in no significant change in the pharmacokinetics of nevirapine.
However, subjects with ESRD requiring dialysis exhibited a 43.5% reduction in nevirapine AUC over
a one-week exposure period. There was also accumulation of nevirapine hydroxy-metabolites in
plasma. The results suggest that supplementing VIRAMUNE therapy with an additional 200 mg dose
of VIRAMUNE following each dialysis treatment would help offset the effects of dialysis on
nevirapine clearance. Otherwise patients with CLcr
>
≥
20 ml/min do not require an adjustment in
VIRAMUNE dosing.
Hepatic dysfunction:
A steady state study comparing 46 patients with
mild (n=17: Ishak Score 1-2),
moderate (n=20; Ishak Score 3-4),
or severe (n=9; Ishak Score 5-6, Child-Pugh A in 8 pts., for 1 Child-Pugh score not applicable)
liver fibrosis as a measure of hepatic impairment was conducted.
The patients studied were receiving antiretroviral therapy containing Viramune 200 mg twice daily for
at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years. In
this study, the multiple dose pharmacokinetic disposition of nevirapine and the five oxidative
metabolites were not altered.
However, approximately 15% of these patients with hepatic fibrosis had nevirapine trough
concentrations above 9,000 ng/ml (2 fold the usual mean trough). Patients with hepatic impairment
should be monitored carefully for evidence of drug induced toxicity.
In a 200 mg nevirapine single dose pharmacokinetic study of HIV-negative patients with mild and
moderate hepatic impairment (Child-Pugh A, n=6; Child-Pugh B, n=4), a significant increase in the
AUC of nevirapine was observed in one Child-Pugh B patient with ascites suggesting that patients
with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic
circulation. Because nevirapine induces its own metabolism with multiple dosing, this single dose
study may not reflect the impact of hepatic impairment on multiple dose pharmacokinetics (see section
4.4).
24
route of excretion compared to faeces (10.1
dysfunction (CLcr
In the multinational 2NN study, a population pharmacokinetic substudy of 1077 patients was
performed that included 391 females. Female patients showed a 13.8% lower clearance of nevirapine
than did male patients. This difference is not considered clinically relevant. Since neither body weight
nor Body Mass Index (BMI) had influence on the clearance of nevirapine, the effect of gender cannot
be explained by body size. Nevirapine pharmacokinetics in HIV-1 infected adults do not appear to
change with age (range 19-68 years) or race (Black, Hispanic, or Caucasian). VIRAMUNE has not
been specifically investigated in patients over the age of 65.
Paediatric population
Data concerning the pharmacokinetics of nevirapine has been derived from two major sources: a 48
week paediatric trial in South Africa (BI 1100.1368) involving 123 HIV-1 positive, antiretroviral
naïve patients aged 3 months to 16 years; and a consolidated analysis of five Paediatric AIDS Clinical
Trials Group (PACTG) protocols comprising 495 patients aged 14 days to 19 years.
Pharmacokinetic data on 33 patients (age range 0.77 – 13.7 years) in the intensive sampling group
demonstrated that clearance of nevirapine increased with increasing age in a manner consistent with
increasing body surface area. Dosing of nevirapine at 150 mg/m
2
BID (after a two-week lead in at
150 mg/m
2
QD) produced geometric mean or mean trough nevirapine concentrations between 4-
6 µg/ml (as targeted from adult data). In addition, the observed trough nevirapine concentrations were
comparable between the two methods.
The consolidated analysis of Paediatric AIDS Clinical Trials Group (PACTG) protocols 245, 356,
366, 377, and 403 allowed for the evaluation of paediatric patients less than 3 months of age (n=17)
enrolled in these PACTG studies. The plasma nevirapine concentrations observed were within the
range observed in adults and the remainder of the paediatric population, but were more variable
between patients, particularly in the second month of age.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans other than those observed in clinical studies
based on conventional studies of safety, pharmacology, repeated dose toxicity, and genotoxicity. In
carcinogenicity studies, nevirapine induces hepatic tumours in rats and mice. These findings are most
likely related to nevirapine being a strong inducer of liver enzymes, and not due to a genotoxic mode
of action.
6.
6.1
List of excipients
Microcrystalline cellulose
Lactose monohydrate
Povidone K25
Sodium starch glycolate
Colloidal silicon dioxide
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
25
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Treatment initiation pack:
Polyvinyl chloride (PVC)/aluminium foil push-through blister units (blister card of 7 tablets).
Cartons containing 2 blister cards (14 tablets).
Maintenance packs:
Polyvinyl chloride (PVC)/aluminium foil push-through blister units (blister card of 10 tablets).
Cartons containing 6 or 12 blister cards (60 or 120 tablets).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein, Germany
8.
EU/1/97/055/001 (60 tablets)
EU/1/97/055/003 (120 tablets)
EU/1/97/055/004 (14 tablets)
9.
Date of first authorisation: 5 February 1998
Date of latest renewal: 10 January 2008
Detailed information on this product is available on the website of the European Medicines Agency
(EMA) http://www.ema.europa.eu
26
1.
VIRAMUNE 50 mg/5 ml oral suspension
2.
Each ml of oral suspension contains 10 mg of nevirapine (as hemihydrate).
Each bottle contains 2.4 g of nevirapine.
Excipient: each ml of oral suspension contains 150 mg sucrose, 162 mg sorbitol, 1.8 mg of methyl
parahydroxybenzoate and 0.24 mg of propyl parahydroxybenzoate.
For a full list of excipients, see section 6.1.
3.
Oral suspension
White to off-white homogenous suspension.
4.
VIRAMUNE is indicated in combination with other anti-retroviral medicinal products for the
treatment of HIV-1 infected adults, adolescents, and children of any age (see section 4.4).
Most of the experience with VIRAMUNE is in combination with nucleoside reverse transcriptase
inhibitors (NRTIs).
The choice of a subsequent therapy after VIRAMUNE should be based on
clinical experience and resistance testing
(see section 5.1).
VIRAMUNE should be administered by physicians who are experienced in the treatment of HIV
infection.
Posology
Patients 16 years and older
The recommended dose for VIRAMUNE is 20 ml (200 mg) oral suspension once 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 20 ml (200 mg) oral suspension twice daily, in combination with at least two additional
antiretroviral agents.
VIRAMUNE is also available as a 200 mg tablet for patients 16 years and older, or for older children,
particularly adolescents, weighing 50 kg or more or whose BSA is above 1.25 m
2
.
VIRAMUNE may be taken with or without food.
27
If a dose is missed the patient should not double the next dose but should take the next dose as
soon as possible.
Dose management considerations
Patients experiencing rash during the 14-day lead-in period of 200 mg/day (4 mg/kg/day or
150 mg/m
2
/day for paediatric patients) should not have their VIRAMUNE dose increased until the
rash has resolved. The isolated rash should be closely monitored (please refer to section 4.4).
The 200
mg once daily dosing regimen should not be continued beyond 28 days at which point in time an
alternative treatment should be sought due to the possible risk of underexposure and resistance.
Patients who interrupt VIRAMUNE dosing for more than 7 days should restart the recommended
dosing regimen using the two week lead-in period.
For toxicities that require interruption of VIRAMUNE therapy, see section 4.4.
Special populations
Renal impairment
For patients with renal dysfunction requiring dialysis an additional 200 mg dose of VIRAMUNE
following each dialysis treatment is recommended. Patients with CLcr
≥
20 ml/min do not require a
dose adjustment, see section 5.2.
Hepatic impairment
VIRAMUNE should not be used in patients with severe hepatic impairment (Child-Pugh C, see
section 4.3). No dose adjustment is necessary in patients with mild to moderate hepatic impairment
(see sections 4.4 and 5.2).
Elderly:
VIRAMUNE has not been specifically investigated in patients over the age of 65.
Paediatric population
The total daily dose should not exceed 400 mg for any patient. VIRAMUNE may be dosed in
paediatric patients either by body surface area (BSA) or by body weight as follows:
By BSA using the Mosteller formula the recommended oral dose for paediatric patients of all ages is
150 mg/m
2
once daily for two weeks followed by 150 mg/m
2
twice daily thereafter.
Calculation of the volume of Viramune® oral suspension (50 mg/5 ml) required for paediatric dosing
on a body surface basis of 150 mg/m
2
:
BSA range (m
2
)
Volume (ml)
0.08 – 0.25
2.5
0.25 – 0.42
5
0.42 – 0.58
7.5
0.58 – 0.75
10
0.75 – 0.92
12.5
0.92 – 1.08
15
1.08 – 1.25
17.5
1.25+
20
Mosteller Formula: BSA (m
2
) =
Height
(cm)
x Wt
(kg)
3600
28
By weight the recommended oral dose for paediatric patients up to 8 years of age is 4 mg/kg once
daily for two weeks 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.
Calculation of the volume of Viramune® oral suspension (50 mg/5 ml) required for paediatric dosing
after the two weeks lead-in period.
Weight Range (kg) for
patients < 8 yrs of age on
a body weight basis
receiving 7 mg/kg.
Weight Range (kg) for
patients
Volume (ml)
8 years of age
on a body weight basis
receiving 4 mg/kg.
≥
1.79 – 5.36
3.13 – 9.38
2.5
5.36 – 8.93
9.38 – 15.63
5
8.93 – 12.50
15.63 – 21.88
7.5
12.50 – 16.07
21.88 – 28.12
10
16.07 – 19.64
28.12 – 34.37
12.5
19.64 – 23.21
34.37 – 40.62
15
23.21 – 26.79
40.62– 46.88
17.5
26.79+
46.88+
20
All patients less than 16 years of age receiving VIRAMUNE oral suspension should have their weight
or BSA checked frequently to assess if dose adjustments are necessary.
Method of administration
It is important that the entire measured dose of VIRAMUNE oral suspension is administered. This is
assisted by the use of the supplied dispensing syringe. If an alternative measuring device is used (e.g. a
dispensing cup or teaspoon for larger doses) it is important that the device is rinsed to ensure complete
removal of residual oral suspension.
Hypersensitivity to the active substance or to any of the excipients.
VIRAMUNE must not be readministered to patients who have required permanent discontinuation for
severe rash, rash accompanied by constitutional symptoms, hypersensitivity reactions, or clinical
hepatitis due to nevirapine.
VIRAMUNE must not be used in patients with severe hepatic impairment (Child-Pugh C) or pre-
treatment ASAT or ALAT > 5 ULN until baseline ASAT/ALAT are stabilised < 5 ULN.
VIRAMUNE must not be readministered in patients who previously had ASAT or ALAT > 5 ULN
during VIRAMUNE therapy and had recurrence of liver function abnormalities upon readministration
of VIRAMUNE (see section 4.4).
Herbal preparations containing St John’s wort
(Hypericum perforatum)
must not be used while taking
VIRAMUNE due to the risk of decreased plasma concentrations and reduced clinical effects of
nevirapine (see section 4.5).
VIRAMUNE should only be used with at least two other antiretroviral agents (see section 5.1).
VIRAMUNE should not be used as the sole active antiretroviral, as monotherapy with any
antiretroviral has shown to result in viral resistance.
29
The first 18 weeks of therapy with VIRAMUNE are a critical period which requires close
monitoring of patients to disclose the potential appearance of severe and life-threatening skin
reactions (including cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN)) and serious hepatitis/hepatic failure.
The greatest risk of hepatic events and skin
reactions occurs in the first 6 weeks of therapy. However, the risk of any hepatic event continues
past this period and monitoring should continue at frequent intervals. Female gender and higher
CD4 counts (>250/mm3 in adult females and >400/mm3 in adult males) at the initiation of
VIRAMUNE therapy are associated with a greater risk of hepatic adverse events if the patient
has detectable plasma HIV-1 RNA - i.e. a concentration ≥ 50 copies/ml - at the initiation of
VIRAMUNE. As serious and life threatening hepatotoxicity has been observed in controlled and
uncontrolled studies predominantly in patients with a plasma HIV-1 viral load of 50 copies/ml or
higher, 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, who have a
detectable plasma HIV-1 RNA unless the benefit outweighs the risk.
In some cases, hepatic injury has progressed despite discontinuation of treatment. Patients
developing signs or symptoms of hepatitis, severe skin reaction or hypersensitivity reactions
must discontinue VIRAMUNE and seek medical evaluation immediately. Viramune must not be
restarted following severe hepatic, skin or hypersensitivity reactions (see section 4.3).
The dosage must be strictly adhered to, especially the 14-days lead-in period (see section 4.2).
Cutaneous reactions
Severe and life-threatening skin reactions, including fatal cases, have occurred in patients treated with
VIRAMUNE
mainly during the first 6 weeks of therapy
.
These have included cases of Stevens-
Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions characterised by rash,
constitutional findings and visceral involvement. Patients should be intensively monitored during the
first 18 weeks of treatment. Patients should be closely monitored if an isolated rash occurs.
VIRAMUNE must be permanently discontinued in any patient experiencing severe rash or a rash
accompanied by constitutional symptoms (such as fever, blistering, oral lesions, conjunctivitis, facial
oedema, muscle or joint aches, or general malaise), including Stevens-Johnson syndrome, or toxic
epidermal necrolysis. VIRAMUNE must be permanently discontinued in any patient experiencing
hypersensitivity reaction (characterised by rash with constitutional symptoms, plus visceral
involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction) see section 4.4.
VIRAMUNE administration above the recommended dose might increase the frequency and
seriousness of skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
Rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with
VIRAMUNE use.
Concomitant prednisone use (40 mg/day for the first 14 days of VIRAMUNE administration) has been
shown not to decrease the incidence of VIRAMUNE-associated rash, and may be associated with an
increase in incidence and severity of rash during the first 6 weeks of VIRAMUNE therapy.
Some risk factors for developing serious cutaneous reactions have been identified, they include failure
to follow the initial dosing of 200 mg daily (4 mg/kg or 150 mg/m
2
for paediatric patients) during the
lead-in period and a long delay between the initial symptoms and medical consultation. Women
appear to be at higher risk than men of developing rash, whether receiving VIRAMUNE or non-
VIRAMUNE containing therapy.
Patients should be instructed that a major toxicity of VIRAMUNE is rash. They should be advised to
promptly notify their physician of any rash and avoid delay between the initial symptoms and medical
30
consultation. The majority of rashes associated with VIRAMUNE 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. The 200 mg once daily dosing
regimen should not be continued beyond 28 days at which point in time an alternative treatment
should be sought due to the possible risk of underexposure and resistance. Careful monitoring of
paediatric patients is especially warranted, particularly in the first 18 weeks of treatment, since these
patients may be less likely than adults to notice, or report, skin reactions.
Any patient experiencing severe rash or a rash accompanied by constitutional symptoms such as fever,
blistering, oral lesions, conjunctivitis, facial oedema, muscle or joint aches, or general malaise should
discontinue the medicinal product and immediately seek medical evaluation. In these patients
VIRAMUNE must not be restarted.
If patients present with a suspected VIRAMUNE-associated rash, liver function tests should be
performed. Patients with moderate to severe elevations (ASAT or ALAT > 5 ULN) should be
permanently discontinued from VIRAMUNE.
If a hypersensitivity reaction occurs, characterised by rash with constitutional symptoms such as fever,
arthralgia, myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia,
granulocytopenia, and renal dysfunction, VIRAMUNE must be permanently stopped and not be re-
introduced (see section 4.3).
Hepatic reactions
Severe and life-threatening hepatoxicity, including fatal fulminant hepatitis, has occurred in patients
treated with VIRAMUNE. The first 18 weeks of treatment is a critical period which requires close
monitoring. The risk of hepatic events is greatest in the first 6 weeks of therapy. However the risk
continues past this period and monitoring should continue at frequent intervals throughout treatment.
Rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with
VIRAMUNE use.
Increased ASAT or ALAT levels
>
2.5 ULN and/or co-infection with hepatitis B and/or C at the start
of antiretroviral therapy is associated with greater risk of hepatic adverse reactions during
antiretroviral therapy in general, including VIRAMUNE containing regimens.
Female gender and higher CD4 counts at the initiation of VIRAMUNE therapy in treatment-naïve
patients is associated with increased risk of hepatic adverse events. Women have a three fold higher
risk than men for symptomatic, often rash-associated
,
hepatic events (5.8% versus 2.2%), and
treatment-naïve patients of either gender with detectable HIV-1 RNA in plasma with higher CD4
counts at initiation of VIRAMUNE
therapy are at higher risk for symptomatic hepatic events with
VIRAMUNE. In a retrospective review of predominantly patients with a plasma HIV-1 viral load of
50 copies/ml or higher, women with CD4 counts >250 cells/mm
3
had a 12 fold higher risk of
symptomatic hepatic adverse events compared to women with CD4 counts <250 cells/mm
3
(11.0%
versus 0.9%). An increased risk was observed in men with detectable HIV-1 RNA in plasma and CD4
counts > 400 cells/mm
3
(6.3% versus 1.2% for men with CD4 counts <400 cells/mm
3
). This increased
risk for toxicity based on CD4 count thresholds has not been detected in patients with undetectable
(i.e. < 50 copies/ml) plasma viral load.
Patients should be informed that hepatic reactions are a major toxicity of VIRAMUNE requiring a
close monitoring during the first 18 weeks. They should be informed that occurrence of symptoms
suggestive of hepatitis should lead them to discontinue VIRAMUNE and immediately seek medical
evaluation, which should include liver function tests.
31
Liver monitoring
Clinical chemistry tests, which include liver function tests, should be performed prior to initiating
VIRAMUNE therapy and at appropriate intervals during therapy.
Abnormal liver function tests have been reported with VIRAMUNE, some in the first few weeks of
therapy.
Asymptomatic elevations of liver enzymes are frequently described and are not necessarily a
contraindication to use VIRAMUNE. Asymptomatic GGT elevations are not a contraindication to
continue therapy.
Monitoring of hepatic tests should be done every two weeks during the first 2 months of treatment, at
the 3
rd
month and then regularly thereafter. Liver test monitoring should be performed if the patient
experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity.
If ASAT or ALAT
>
2.5 ULN before or during treatment, then liver tests should be monitored more
frequently during regular clinic visits. VIRAMUNE must not be administered to patients with pre-
treatment ASAT or ALAT > 5 ULN until baseline ASAT/ALAT are stabilised < 5 ULN (see section
4.3).
Physicians and patients should be vigilant for prodromal signs or findings of hepatitis, such as
anorexia, nausea, jaundice, bilirubinuria, acholic stools, hepatomegaly or liver tenderness. Patients
should be instructed to seek medical attention promptly if these occur.
If ASAT or ALAT increase to > 5 ULN during treatment, VIRAMUNE should be immediately
stopped. If ASAT and ALAT return to baseline values and if the patient had no clinical signs or
symptoms of hepatitis, rash, constitutional symptoms or other findings suggestive of organ
dysfunction, it may be possible to reintroduce VIRAMUNE, on a case by case basis, at the
starting dosage regimen of 200 mg/day for 14 days followed by 400 mg/day. In these cases, more
frequent liver monitoring is required. If liver function abnormalities recur, VIRAMUNE should
be permanently discontinued.
If clinical hepatitis occurs, characterised by anorexia, nausea, vomiting, icterus AND laboratory
findings (such as moderate or severe liver function test abnormalities (excluding GGT),
VIRAMUNE must be permanently stopped. VIRAMUNE must not be readministered to
patients who have required permanent discontinuation for clinical hepatitis due to nevirapine.
Liver Disease
The safety and efficacy of VIRAMUNE has not been established in patients with significant
underlying liver disorders. VIRAMUNE is contraindicated in patients with severe hepatic impairment
(Child-Pugh C, see section 4.3). Pharmacokinetic results suggest caution should be exercised when
VIRAMUNE is administered to patients with moderate hepatic dysfunction (Child-Pugh B). Patients
with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased
risk for severe and potentially fatal hepatic adverse events. In the case of concomitant antiviral therapy
for hepatitis B or C, please refer also to the relevant product information for these medicinal products.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination antiretroviral therapy and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
32
Other warnings
Post-Exposure-Prophylaxis: Serious hepatotoxicity, including liver failure requiring transplantation,
has been reported in HIV-uninfected individuals receiving multiple doses of VIRAMUNE in the
setting of post-exposure-prophylaxis (PEP), an unapproved use. The use of VIRAMUNE has not been
evaluated within a specific study on PEP, especially in term of treatment duration and therefore, is
strongly discouraged.
Combination therapy with VIRAMUNE is not a curative treatment of patients infected with HIV-1;
patients may continue to experience illnesses associated with advanced HIV-1 infection, including
opportunistic infections.
Combination therapy with VIRAMUNE has not been shown to reduce the risk of transmission of
HIV-1 to others through sexual contact or contaminated blood.
Hormonal methods of birth control other than DMPA should not be used as the sole method of
contraception in women taking VIRAMUNE, 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 postmenopausal hormone therapy is used during
administration of VIRAMUNE, its therapeutic effect should be monitored.
Combination antiretroviral therapy has been associated with the redistribution of body fat
(lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently
unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis
and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been
associated with individual factors such as older age, and with drug related factors such as longer
duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should
include evaluation for physical signs of fat redistribution. Consideration should be given to the
measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as
clinically appropriate (see section 4.8).
In clinical studies, VIRAMUNE has been associated with an increase in HDL- cholesterol and an
overall improvement in the total to HDL-cholesterol ratio. However, in the absence of specific studies
with VIRAMUNE on modifying the cardiovascular risk in HIV infected patients, the clinical impact of
these findings is not known. The selection of antiretroviral drugs must be guided primarily by their
antiviral efficacy.
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis
have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to
combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they
experience joint aches and pain, joint stiffness or difficulty in movement.
Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time
of institution of combination antiretroviral therapy (CART), an inflammatory reaction to
asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or
aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or
months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or
focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms
should be evaluated and treatment instituted when necessary.
The available pharmacokinetic data suggest that the concomitant use of rifampicin and VIRAMUNE is
not recommended (please also refer to section 4.5).
33
Sucrose: VIRAMUNE oral suspension contains 150 mg of sucrose per ml. Patients with rare
hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase
insufficiency should not take this medicine.
Sorbitol: VIRAMUNE oral suspension contains 162 mg of sorbitol per ml. Patients with rare
hereditary problems of fructose intolerance should not take this medicine.
Methyl and propyl parahydroxybenzoates: VIRAMUNE oral suspension contains methyl
parahydroxybenzoate and propyl parahydroxybenzoate, which may cause allergic reaction (possibly
delayed).
Nevirapine is an inducer of CYP3A and potentially CYP2B6, with maximal induction occurring
within 2-4 weeks of initiating multiple-dose therapy.
Compounds using this metabolic pathway may have decreased plasma concentrations when co-
administered with VIRAMUNE. Careful monitoring of the therapeutic effectiveness of P450
metabolised medicinal products is recommended when taken in combination with VIRAMUNE.
The absorption of nevirapine is not affected by food, antacids or medicinal products which are
formulated with an alkaline buffering agent.
The interaction data is presented as geometric mean value with 90% confidence interval (90% CI)
whenever these data were available. ND = Not Determined, ↑ = Increased, ↓ = Decreased,
↔
= No
Effect
Medicinal products
by therapeutic areas
Interaction
Recommendations concerning co-
administration
ANTI-INFECTIVES
ANTIRETROVIRALS
NRTIs
Didanosine
100-150 mg BID
Didanosine AUC
↔
1.08 (0.92-1.27)
Didanosine and VIRAMUNE can be
co-administered without dose
adjustments.
Didanosine C
min
ND
Didanosine C
max
↔
0.98 (0.79-1.21)
Lamivudine
150 mg BID
No changes to lamivudine apparent
clearance and volume of distribution,
suggesting no induction effect of
nevirapine on lamivudine clearance.
Lamivudine and VIRAMUNE can be
co-administered without dose
adjustments.
Stavudine:
30/40 mg BID
Stavudine AUC
↔
0.96 (0.89-1.03)
Stavudine and VIRAMUNE can be
co-administered without dose
adjustments.
Stavudine C
min
ND
Stavudine C
max
↔
0.94 (0.86-1.03)
Nevirapine: compared to historical
controls, levels appeared to be
unchanged.
34
Tenofovir
300 mg QD
Tenofovir plasma levels remain
unchanged when co-administered
with Nevirapine.
Tenofovir and VIRAMUNE
can be
co-administered without dose
adjustments.
Nevirapine plasma levels were not
altered by co-administration of
tenofovir.
Zidovudine
100-200 mg TID
0.72 (0.60-0.96)
Zidovudine C
min
ND
Zidovudine C
max
↓
Zidovudine and VIRAMUNE can be
co-administered without dose
adjustments
↓
0.70 (0.49-1.04)
Nevirapine: Zidovudine had no
effect on its pharmacokinetics.
NNRTIs
Efavirenz
600 mg QD
Efavirenz AUC
↓
0.72 (0.66-0.86)
It is not recommended to co-
administer efavirenz and
VIRAMUNE, because of additive
toxicity and no benefit in terms of
efficacy over either NNRTI alone.
Efavirenz C
min
↓
0.68 (0.65-0.81)
Efavirenz C
max
↓
0.88 (0.77-1.01)
PIs
Atazanavir/ritonavir
300/100 mg QD
400/100 mg QD
Atazanavir/r 300/100mg
:
Atazanavir/r AUC
↓
0.58 (0.48-0.71)
It is not recommended to co-
administer atazanavir/ritonavir and
VIRAMUNE.
Atazanavir/r C
min
↓
0.28 (0.20-0.40)
Atazanavir/r C
max
↓
0.72 (0.60-0.86)
Atazanavir/r 400/100mg:
Atazanavir/r AUC
↓
0.81 (0.65-1.02)
Atazanavir/r C
min
↓
0.41 (0.27-0.60)
Atazanavir/r C
max
↔
1.02 (0.85–
1.24)
(compared to 300/100mg without
nevirapine)
Nevirapine AUC
↑
1.25 (1.17-1.34)
Nevirapine C
min
↑
1.32 (1.22–1.43)
Nevirapine C
max
↑
1.17 (1.09-1.25)
Darunavir/ritonavir
400/100 mg BID
Darunavir AUC
↑
1.24 (0.97-1.57)
Darunavir and VIRAMUNE can be
co-administered without dose
adjustments.
Darunavir C
min
↔
1.02 (0.79-1.32)
Darunavir C
max
↑
1.40 (1.14-1.73)
Nevirapine AUC
↑
1.27 (1.12-1.44)
Nevirapine C
min
↑
1.47 (1.20-1.82)
Nevirapine C
max
↑
1.18 (1.02-1.37)
35
Zidovudine AUC
Fosamprenavir
1400 mg BID,
Amprenavir AUC
↓
0.67 (0.55-0.80)
It is not recommended to co-
administer fosamprenavir and
VIRAMUNE if fosamprenavir is not
co-administered with ritonavir.
Amprenavir C
min
↓
0.65 (0.49-0.85)
Amprenavir C
max
↓
0.75 (0.63-0.89)
Nevirapine AUC
↑
1.29 (1.19-1.40)
Nevirapine C
min
↑
1.34 (1.21-1.49)
Nevirapine C
max
↑
1.25 (1.14-1.37)
Fosamprenavir/ritona
vir 700/100 mg BID
Amprenavir AUC
↔
0.89 (0.77-
Fosamprenavir/ritonavir and
VIRAMUNE can be co-administered
without dose adjustments
1.03)
Amprenavir C
min
↓
0.81 (0.69-0.96)
Amprenavir C
max
↔
0.97 (0.85-1.10)
Nevirapine AUC
↑
1.14 (1.05-1.24)
Nevirapine C
min
↑
1.22 (1.10-1.35)
Nevirapine C
max
↑
1.13 (1.03-1.24)
Lopinavir/ritonavir
(capsules) 400/100
mg BID
patients
:
Lopinavir AUC
↓
0.73 (0.53-0.98)
An increase in the dose of
lopinavir/ritonavir to 533/133 mg (4
capsules) or 500/125 mg (5 tablets
with 100/25 mg each) twice daily
with food is recommended in
combination with VIRAMUNE. Dose
adjustment of VIRAMUNE is not
required when co-administered with
lopinavir.
Lopinavir C
min
↓
0.54 (0.28-0.74)
Lopinavir C
max
↓
0.81 (0.62-0.95)
Lopinavir/ritonavir
(oral solution) 300/75
mg/m
2
BID
Paediatric patients
:
Lopinavir AUC
↓
0.78 (0.56-1.09)
For children, increase of the dose of
lopinavir/ritonavir to 300/75 mg/m
2
twice daily with food should be
considered when used in combination
with VIRAMUNE, particularly for
patients in whom reduced
susceptibility to lopinavir/ritonavir is
suspected.
Lopinavir C
min
↓
0.45 (0.25-0.82)
Lopinavir C
max
↓
0.86 (0.64-1.16)
Nelfinavir
750 mg TID
Nelfinavir
AUC
↔
1.06 (0.78-1.14)
Nelfinavir and VIRAMUNE can be
co-administered without dose
adjustments.
C
min
↔
0.68 (0.50-1.5)
C
max
↔
1.06 (0.92-1.22)
Nelfinavir metabolite M8:
AUC
↓
0.38 (0.30–0.47)
C
min
↓
0.34 (0.26–0.45)
C
max
↓
0.41 (0.32–0.52)
Nevirapine: compared to historical
controls, levels appeared to be
unchanged.
36
Ritonavir
600 mg BID
Ritonavir AUC
↔
0.92 (0.79-1.07)
Ritonavir and VIRAMUNE can be
co-administered without dose
adjustments.
Ritonavir C
min
↔
0.93 (0.76-1.14)
Ritonavir C
max
↔
0.93 (0.78-1.07)
Nevirapine: Co-administration of
ritonavir does not lead to any
clinically relevant change in
nevirapine plasma levels.
Saquinavir/ritonavir
The limited data available with
saquinavir soft gel capsule boosted
with ritonavir do not suggest any
clinically relevant interaction
between saquinavir boosted with
ritonavir and Nevirapine
Saquinavir/ritonavir and
VIRAMUNE can be co-administered
without dose adjustments
.
Tipranavir/ritonavir
500/200 mg BID
No specific drug-drug interaction
study has been performed.
The limited data available from a
phase IIa study in HIV-infected
patients have shown a clinically non
significant 20% decrease of TPV
C
min
.
Tipranavir and VIRAMUNE can be
co-administered without dose
adjustments.
ENTRY INHIBITORS
Enfuvirtide
Due to the metabolic pathway no
clinically significant
pharmacokinetic interactions are
expected between enfuvirtide and
nevirapine.
Enfuvirtide and VIRAMUNE can be
co-administered without dose
adjustments.
Maraviroc
300 mg QD
Maraviroc AUC
↔
1.01 (0.6 -1.55)
Maraviroc and VIRAMUNE can be
co-administered without dose
adjustments.
Maraviroc C
min
ND
Maraviroc C
max
1.54 (0.94-2.52)
compared to historical controls
↔
Nevirapine concentrations not
measured, no effect is expected.
INTEGRASE INHIBITORS
Raltegravir
400 mg BID
No clinical data available. Due to the
metabolic pathway of raltegravir no
interaction is expected.
Raltegravir and VIRAMUNE can be
co-administered without dose
adjustments.
37
ANTIBIOTICS
Clarithromycin
500 mg BID
Clarithromycin AUC
↓
0.69 (0.62-
Clarithromycin exposure was
significantly decreased, 14-OH
metabolite exposure increased.
Because the clarithromycin active
metabolite has reduced activity
against
Mycobacterium avium-
intracellulare complex
overall
activity against the pathogen may be
altered. Alternatives to
clarithromycin, such as azithromycin
should be considered. Close
monitoring for hepatic abnormalities
is recommended
0.76)
Clarithromycin C
min
↓
0.44 (0.30-
0.64)
Clarithromycin C
max
↓
0.77 (0.69-
0.86)
1.42 (1.16-1.73)
Metabolite 14-OH clarithromycin
C
min
↑
0 (0.68-1.49)
Metabolite 14-OH clarithromycin
C
max
↑
1.47 (1.21-1.80)
Nevirapine AUC
↑
1.26
Nevirapine C
min
↑
1.28
1.24
compared to historical controls.
↑
Rifabutin
150 or 300 mg QD
Rifabutin AUC
↑
1.17 (0.98-1.40)
No significant effect on rifabutin and
VIRAMUNE mean PK parameters is
seen. Rifabutin and VIRAMUNE can
be co-administered without dose
adjustments. However, due to the
high intersubject variability 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.
Rifabutin C
min
↔
1.07 (0.84-1.37)
Rifabutin C
max
↑
1.28 (1.09-1.51)
1.24 (0.84-1.84)
Metabolite 25-O-desacetylrifabutin
C
min
↑
1.22 (0.86-1.74)
Metabolite 25-O-desacetylrifabutin
C
max
↑
↑
1.29 (0.98-1.68)
A clinically not relevant increase in
the apparent clearance of nevirapine
(by 9%) compared to historical data
was reported.
Rifampicin
600 mg QD
Rifampicin AUC
↔
1.11 (0.96-1.28)
It is not recommended to co-
administer rifampicin and
VIRAMUNE (see section 4.4).
Physicians needing to treat patients
co-infected with tuberculosis and
using a VIRAMUNE containing
regimen may consider co-
administration of rifabutin instead.
Rifampicin C
min
ND
Rifampicin C
max
↔
1.06 (0.91-1.22)
Nevirapine AUC
↓
0.42
Nevirapine C
min
↓
0.32
0.50
compared to historical controls.
↓
38
Metabolite 14-OH clarithromycin
AUC
↔
Nevirapine C
max
Metabolite 25-O-desacetylrifabutin
AUC
Nevirapine C
max
ANTIFUNGALS
Fluconazole
200 mg QD
Fluconazole AUC
↔
0.94 (0.88-
Because of the risk of increased
exposure to VIRAMUNE, caution
should be exercised if the medicinal
products are given concomitantly and
patients should be monitored closely.
1.01)
Fluconazole C
min
↔
0.93 (0.86-1.01)
Fluconazole C
max
↔
0.92 (0.85-0.99)
100%
compared with historical data where
nevirapine was administered alone.
↑
Itraconazole
200 mg QD
Itraconazole AUC
↓
0.39
A dose increase for itraconazole
should be considered when these two
agents are administered
concomitantly.
Itraconazole C
min
↓
0.13
Itraconazole C
max
↓
0.62
Nevirapine: there was no significant
difference in Nevirapine
pharmacokinetic parameters.
Ketoconazole
400 mg QD
Ketoconazole AUC
↓
0.28 (0.20-
It is not recommended to co-
administer ketoconazole and
VIRAMUNE.
0.40)
Ketoconazole C
min
ND
Ketoconazole C
max
↓
0.56 (0.42-
0.73)
1.15-
1.28 compared to historical controls.
↑
ANTACIDS
Cimetidine
Cimetidine: no significant effect on
cimetidine PK parameters is seen.
Cimetidine and VIRAMUNE can be
co-administered without dose
adjustments.
Nevirapine C
min
↑
1.07
ANTITHROMBOTICS
Warfarin
The interaction between Nevirapine
and the antithrombotic agent
warfarin is complex, with the
potential for both increases and
decreases in coagulation time when
used concomitantly.
Close monitoring of anticoagulation
levels is warranted.
CONTRACEPTIVES
Depo-
medroxyprogesterone
acetate (DMPA)
150 mg every 3
months
DMPA AUC
↔
Viramune co-administration did not
alter the ovulation suppression effects
of DMPA. DMPA and VIRAMUNE
can be co-administered without dose
adjustments.
DMPA C
min
↔
DMPA C
max
↔
Nevirapine AUC
↑
1.20
Nevirapine C
max
↑
1.20
39
Nevirapine: exposure:
Nevirapine: plasma levels:
Ethinyl estradiol (EE)
0.035 mg
0.80 (0.67 - 0.97)
EE C
min
ND
EE C
max
↓
Oral hormonal contraceptives should
not be used as the sole method of
contraception in women taking
VIRAMUNE (see section 4.4).
Appropriate doses for hormonal
contraceptives (oral or other forms of
application) other than DMPA in
combination with VIRAMUNE
have
not been established with respect to
safety and efficacy.
↔
0.94 (0.79 - 1.12)
Norethindrone (NET)
1.0 mg QD
0.81 (0.70 - 0.93)
NET C
min
ND
NET C
max
↓
↓
0.84 (0.73 - 0.97)
DRUG ABUSE
Methadone Individual
Patient Dosing
0.40 (0.31 - 0.51)
Methadone C
min
ND
Methadone C
max
↓
Methadone-maintained patients
beginning VIRAMUNE therapy
should be monitored for evidence of
withdrawal and methadone dose
should be adjusted accordingly.
↓
0.58 (0.50 - 0.67)
HERBAL PRODUCTS
St. John's Wort
Serum levels of Nevirapine can be
reduced by concomitant use of the
herbal preparation St. John's Wort
(
Hypericum perforatum
). This is due
to induction of drug metabolism
enzymes and/or transport proteins by
St. John’s Wort.
Herbal preparations containing St.
John‘s Wort and VIRAMUNE must
not be co-administered (see section
4.3). If a patient is already taking St.
John‘s Wort check nevirapine and if
possible viral levels and stop St
John‘s Wort. Nevirapine levels may
increase on stopping St John‘s Wort.
The dose of VIRAMUNE may need
adjusting. The inducing effect may
persist for at least 2 weeks after
cessation of treatment with St. John‘s
Wort.
Other information:
Nevirapine metabolites
:
Studies using human liver microsomes indicated that the formation of
nevirapine hydroxylated metabolites was not affected by the presence of dapsone, rifabutin,
rifampicin, and trimethoprim/sulfamethoxazole. Ketoconazole and erythromycin significantly
inhibited the formation of nevirapine hydroxylated metabolites.
Women of childbearing potential / Contraception in males and females
Women of childbearing potential should not use oral contraceptives as the sole method for birth
control, since nevirapine might lower the plasma concentrations of these medications (see sections 4.4
& 4.5).
Pregnancy
Currently available data on pregnant women indicate no malformative or foeto/ neonatal toxicity. To
date no other relevant epidemiological data are available. No observable teratogenicity was detected in
reproductive studies performed in pregnant rats and rabbits (see section 5.3). There are no adequate
and well-controlled studies in pregnant women. Caution should be exercised when prescribing
VIRAMUNE to pregnant women (see section 4.4). As hepatotoxicity is more frequent in women with
CD4 cell counts above 250 cells/mm
3
with detectable HIV-1 RNA in plasma (50 or more copies/mL),
40
EE AUC
NET AUC
Methadone AUC
these conditions should be taken in consideration on therapeutic decision (see section 4.4). There is
not enough evidence to substantiate that the absence of an increased risk for toxicity seen in pre-
treated women initiating VIRAMUNE with an undetectable viral load (less than 50 copies/mL of HIV-
1 in plasma) and CD4 cell counts above 250 cells/mm3 also applies to pregnant women. All the
randomised studies addressing this issue specifically excluded pregnant women, and pregnant women
were under-represented in cohort studies as well as in meta-analyses.
Breastfeeding
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 breast-feeding if they are receiving
VIRAMUNE.
Fertility
In reproductive toxicology studies, evidence of impaired fertility was seen in rats.
No studies on the effects on the ability to drive and use machines have been performed.
a. Summary of the safety profile
The most frequently reported adverse reactions related to VIRAMUNE therapy, across all clinical
trials, were rash, allergic reactions, hepatitis, abnormal liver function tests, nausea, vomiting,
diarrhoea, abdominal pain, fatigue, fever, headache and myalgia.
The postmarketing experience has shown that the most serious adverse reactions are Stevens-Johnson
syndrome/ toxic epidermal necrolysis, serious hepatitis/hepatic failure, and drug rash with eosinophilia
and systemic symptoms, characterised by rash with constitutional symptoms such as fever, arthralgia,
myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia,
granulocytopenia, and renal dysfunction. The first 18 weeks of treatment is a critical period which
requires close monitoring (see section 4.4).
b. Tabulated summary of adverse reactions
The following adverse reactions which may be causally related to the administration of VIRAMUNE
have been reported. The frequencies estimated are based on pooled clinical trial data for events
considered related to VIRAMUNE treatment.
Frequency is defined using the following convention: very common (
≥
1/10); common (
≥
1/100 to
<1/10); uncommon (
1/1,000 to <1/100); rare (
≥
1/10,000 to <1/1,000); very rare (<1/10,000).
Blood and lymphatic system disorders
Common granulocytopenia*
Uncommon anaemia
* In study 1100.1090, from which the majority of related adverse events (n=28) were received,
patients on placebo had a higher incidence of events of granulocytopenia (3.3%) than patients on
nevirapine (2.5%).
Immune system disorders
Common hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria)
Uncommon drug rash with eosinophilia and systemic symptoms**, anaphylactic reaction**
** These adverse reactions were not observed among the 1,761 subjects exposed to nevirapine in
41
≥
clinical trials.
Nervous system disorders
Common
headache
Gastrointestinal disorders
Common
nausea, vomiting, abdominal pain, diarrhoea
Hepatobiliary disorders
Common
hepatitis (including severe and life-threatening hepatotoxicity) (1.4%)
Uncommon
jaundice
Rare
hepatitis fulminant (which may be fatal)
Skin and subcutaneous tissue disorders
Very common
rash (13.6%)
Uncommon
Stevens-Johnson syndrome/ toxic epidermal necrolysis (which may be fatal)
(0.1%), angioedema, urticaria
Musculoskeletal and connective tissue disorders
Common
myalgia
Uncommon
arthralgia
General disorders and administration site conditions
Common
pyrexia, fatigue
Investigations
Common
liver function test abnormal (alanine aminotransferase increased; transaminases
increased; aspartate aminotransferase increased; gamma-glutamyltransferase
increased; hepatic enzyme increased; hypertransaminasaemia)
c. Description of selected adverse reactions
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV infected patients including the loss of peripheral and facial subcutaneous fat, increased intra-
abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
The following events have also been reported when VIRAMUNE has been used in combination with
other anti-retroviral agents:
pancreatitis, peripheral neuropathy and thrombocytopaenia. These events
are commonly associated with other antiretroviral agents and may be expected to occur when
VIRAMUNE is used in combination with other agents; however it is unlikely that these events are due
to VIRAMUNE treatment. Hepatic-renal failure syndromes have been reported rarely.
In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
infections may arise (see section 4.4).
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).
The frequency of this is unknown (see section 4.4).
42
Skin and subcutaneous tissues
The most common clinical toxicity of VIRAMUNE is rash, with VIRAMUNE attributable rash
occurring in 13.6% of patients in combination regimens in controlled studies.
Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or
without pruritus, located on the trunk, face and extremities. Hypersensitivity (anaphylactic reaction,
angioedema and urticaria) have been reported
.
Rashes occur alone or in the context of
drug rash with
eosinophilia and systemic symptoms, characterised by rash with constitutional symptoms such as
fever, arthralgia, myalgia and lympadenopathy, plus visceral involvement, such as hepatitis,
eosinophilia, granulocytopenia, and renal dysfunction
.
Severe and life-threatening skin reactions have occurred in patients treated with VIRAMUNE,
including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Fatal cases of SJS
,
TEN and drug rash with eosinophilia and systemic symptoms have been reported. The majority of
severe rashes occurred within the first 6 weeks of treatment and some required hospitalisation, with
one patient requiring surgical intervention (see section 4.4).
Hepato-biliary
The most frequently observed laboratory test abnormalities are elevations in liver function tests
(LFTs), including ALAT, ASAT, GGT, total bilirubin and alkaline phosphatase. Asymptomatic
elevations of GGT levels are the most frequent. Cases of jaundice have been reported. Cases of
hepatitis (severe and life-threatening hepatoxicity, including fatal fulminant hepatitis) have been
reported in patients treated with VIRAMUNE. The best predictor of a serious hepatic event was
elevated baseline liver function tests. The first 18 weeks of treatment is a critical period which requires
close monitoring (see section 4.4).
d. Paediatric population
Based on clinical trial experience of 361 paediatric patients the majority of which received
combination treatment with ZDV or/and ddI, the most frequently reported adverse events related to
VIRAMUNE were similar to those observed in adults. Granulocytopenia was more frequently
observed in children. In an open-label clinical trial (ACTG 180) granulocytopenia assessed as drug-
related occurred in 5/37 (13.5%) of patients. In ACTG 245, a double-blind placebo controlled study,
the frequency of serious drug-related granulocytopenia was 5/305 (1.6%). Isolated cases of Stevens-
Johnson syndrome or Stevens-Johnson/ toxic epidermal necrolysis transition syndrome have been
reported in this population.
There is no known antidote for VIRAMUNE overdosage. Cases of VIRAMUNE overdose at doses
ranging from 800 to 6000 mg per day for up to 15 days have been reported. Patients have experienced
oedema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash,
vertigo, vomiting, increase in transaminases and weight decrease. All of these effects subsided
following discontinuation of VIRAMUNE.
Paediatric Population
One case of massive accidental overdose in a newborn was reported. The ingested dose was 40 times
the recommended dose of 2mg/kg/day. Mild isolated neutropenia and hyperlactataemia was observed,
which spontaneously disappeared within one week without any clinical complications. One year later,
the child’s development remained normal.
43
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
NNRTI (non-nucleoside reverse transcriptase inhibitors)
, ATC code
J05AG01.
Mechanism of action
Nevirapine is a NNRTI of HIV-1. Nevirapine is a non-competitive inhibitor of the HIV-1 reverse
transcriptase, but it does not have a biologically significant inhibitory effect on the HIV-2 reverse
transcriptase or on eukaryotic DNA polymerases
α
,
β
,
, or
δ
.
Antiviral activity
in vitro
Nevirapine had a median EC
50
value (50% inhibitory concentration) of 63 nM against a panel of group
M HIV-1 isolates from clades A, B, C, D, F, G, and H, and circulating recombinant forms (CRF),
CRF01_AE, CRF02_AG and CRF12_BF replicating in human embryonic kidney 293 cells. In a panel
of 2,923 predominantly subtype B HIV-1 clinical isolates, the mean EC
50
value was 90nM. Similar
EC
50
values are obtained when the antiviral activity of nevirapine is measured in peripheral blood
mononuclear cells, monocyte derived macrophages or lymphoblastoid cell line. Nevirapine had no
antiviral activity in cell culture against group O HIV-1 isolates or HIV-2 isolates.
Nevirapine in combination with efavirenz exhibited a strong antagonistic anti-HIV-1 activity
in vitro
(see section 4.5) and was additive to antagonistic with the protease inhibitor ritonavir or the fusion
inhibitor enfuvirtide.Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination
with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and
tipranavir, and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and
zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and
by the anti-HCV drug ribavirin
in vitro
.
Resistance
HIV-1 isolates with reduced susceptibility (100-250-fold) to nevirapine emerge in cell culture.
Genotypic analysis showed mutations in the HIV-1 RT gene Y181C and/or V106A depending
upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell
culture was not altered when selection included nevirapine in combination with several other
NNRTIs.
Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve patients receiving
either nevirapine (n=24) or nevirapine and ZDV (n=14) were monitored in Phase I/II trials over 1
to ≥12 weeks. After 1 week of nevirapine monotherapy, isolates from 3/3 patients had decreased
susceptibility to nevirapine in cell culture. One or more of the RT mutations resulting in amino
acid substitutions K103N, V106A, V108I, Y181C, Y188C and G190A were detected in HIV-1
isolates from some patients as early as 2 weeks after therapy initiation. By week eight of
nevirapine monotherapy, 100% of the patients tested (n=24) had HIV-1 isolates with a >100-fold
decrease in susceptibility to nevirapine in cell culture compared to baseline, and had one or more
of the nevirapine-associated RT resistance mutations. Nineteen of these patients (80%) had
isolates with Y181C substitutions regardless of dose.
Genotypic analysis of isolates from antiretroviral naïve patients experiencing virologic failure
(n=71) receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine
and stavudine for 48 weeks showed that isolates from 8/25 and 23/46 patients, respectively, contained
one or more of the following NNRTI resistance-associated substitutions:
44
γ
Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.
Cross-resistance
Rapid emergence of HIV-strains which are cross-resistant to NNRTIs has been observed in vitro.
Cross resistance to delavirdine and efavirenz is expected after virologic failure with nevirapine.
Depending on resistance testing results, an etravirine-containing regimen may be used subsequently.
Cross-resistance between nevirapine and either HIV protease inhibitors, HIV integrase inhibitors or
HIV entry inhibitors is unlikely because the enzyme targets involved are different. Similarly the
potential for cross-resistance between nevirapine and NRTIs is low because the molecules have
different binding sites on the reverse transcriptase.
Clinical results
VIRAMUNE has been evaluated in both treatment-na
ï
ve and treatment-experienced patients.
Studies in treatment-naïve patients
2NN study
The double non-nucleoside study 2 NN was a randomised, open-label, multicentre prospective study
comparing the NNRTIs VIRAMUNE, efavirenz and both drugs given together.
1216 antiretroviral-therapy naïve patients with plasma HIV-1 RNA > 5000 copies/ml at baseline were
assigned to VIRAMUNE 400 mg once daily, VIRAMUNE 200 mg twice daily, efavirenz 600 mg
once daily, or VIRAMUNE (400 mg) and efavirenz (800 mg) once daily, plus stavudine and
lamivudine for 48 weeks.
The primary endpoint, treatment failure, was defined as less than 1 log
10
decline in plasma HIV-1
RNA in the first 12 weeks, or two consecutive measurements of more than 50 copies/ ml from week
24 onwards, or disease progression (new Centers for Disease Control and Prevention grade C event or
death), or change of allocated treatment.
Median age was 34 years and about 64% were male patients, median CD4 cell count was 170 and 190
cells per mm
3
in the VIRAMUNE twice daily and efavirenz groups, respectively. There were no
significant differences in demographic and baseline characteristics between the treatment groups.
The predetermined primary efficacy comparison was between the VIRAMUNE twice daily and the
efavirenz treatment groups. Details of the primary efficacy comparison are given in table 1.
45
Table 1: Number of patients with treatment failure, components of treatment failure, and
number of patients with plasma HIV-RNA concentration < 50 c/ml, at week 48 (Intention-To-
Treat (ITT) Analysis).
VIRAMUNE
200 mg twice daily
(n = 387)
Efavirenz 600 mg
once daily
(n = 400)
Treatment failure on or before week 48,
% (95% IC)
43.7% (38.7-48.8)
37.8% (33.0-42.7)
Components of failure (%)
Virological
Progression
Change of treatment
Permanent
of
NNRTI
(n)
18.9%
2.8%
22.0%
61
13
1
1
9
15.3%
2.5%
20.0%
51
8
1
1
19
Temporary discontinuation of NNRTI (n)
Additional antiretroviral drugs (n)
Non-allowable change of NNRTI (n)
Never started ART* (n)
Plasma HIV-1 RNA concentration
<50 c/mL at 48 weeks, %(95% IC)
65.4% (60.4-70.1)
70.0% (65.2-74.5)
* ART = antiretroviral therapy
Although, overall, treatment failure was numerically lower in the efavirenz group than in the
nevirapine-only groups, the findings of this study show no evidence that efavirenz is superior to
nevirapine twice daily in terms of treatment failure. However, equivalence within the 10% limits of
these treatment groups was not shown even though the study was adequately powered for such an
analysis. The nevirapine twice daily regimen and the efavirenz regimen were not significantly
different (p= 0.091) in terms of efficacy as measured by incidence of treatment failure.There was also
no significant difference between VIRAMUNE twice daily and efavirenz regarding any components
of treatment failure including virological failure.
The simultaneous use of nevirapine (400 mg) plus efavirenz (800 mg) was associated with the highest
frequency of clinical adverse events and with the highest rate of treatment failure (53.1%). As the
regimen of nevirapine plus efavirenz did not have additional efficacy and caused more adverse events
than each drug separately, this regimen is not recommended.
Twenty per cent of patients assigned to nevirapine twice daily and 18% of patients assigned to
efavirenz had at least one grade 3 or 4 clinical adverse event. Clinical hepatitis reported as clinical
adverse event occurred in 10 (2.6%) and 2 (0.5%) patients in the nevirapine twice daily and efavirenz
groups respectively. The proportion of patients with at least one grade 3 or 4 liver-associated
laboratory toxicity was 8.3% for nevirapine twice daily and 4.5% for efavirenz. Of the patients with
grade 3 or 4 liver-associated laboratory toxicity, the proportions coinfected with hepatitis B or
hepatitis C virus were 6.7% and 20.0% in the nevirapine twice daily group, 5.6% and 11.1% in the
efavirenz group.
2NN Three-year follow-up-study
This is a retrospective multicentre study comparing the 3-year antiviral efficacy of VIRAMUNE and
efavirenz in combination with stavudine and lamivudine in 2NN patients from week 49 to week 144.
Patients who participated in the 2NN study and were still under active follow-up at week 48 when the
study closed and were still being treated at the study clinic, were asked to participate in this study.
Primary study endpoints (percentage of patients with treatment failures) and secondary study
endpoints as well as backbone therapy were similar to the original 2NN study.
Table 2 shows the main efficacy results of this study.
46
change
Table 2: Number of patients with treatment failure, components of treatment failure, and
number of patients with plasma HIV-RNA concentration < 400 copies/ml, between week 49 to
144 (ITT analysis).
VIRAMUNE
200 mg twice daily
(n=224)
Efavirenz 600
mg once daily
(n=223)
Treatment failure (%)
35.7
35.0
Virologic failure (>400 c/ml) (%)
5.8
4.9
pVL <400 c/ml at week 144 (%)
87.2
87.4
CD4 increase (cells/mm3)
+135
+130
Disease progression / death (%)
5.8
6.3
A durable response to VIRAMUNE for at least three years was documented in this study. Equivalence
within a 10% range was demonstrated between VIRAMUNE 200 mg twice daily and efavirenz with
respect to treatment failure. Both, the primary (p = 0.92) and secondary endpoints showed no
statistically significant differences between efavirenz and VIRAMUNE 200 mg twice daily.
Studies in treatment-experienced patients
NEFA study
The NEFA trial is a controlled prospective randomised study which evaluated treatment options for
patients who switch from protease inhibitor (PI) based regimen with undetectable load to either
VIRAMUNE, efavirenz or abacavir.
The study randomly assigned 460 adults who were taking two nucleoside reverse-transcriptase
inhibitors and at least one PI and whose plasma HIV-1 RNA levels had been less than 200 c/ml for at
least the previous six months to switch from the PI to VIRAMUNE (155 patients), efavirenz (156), or
abacavir (149).
The primary study endpoint was death, progression to the acquired immunodeficiency syndrome, or an
increase in HIV-1 RNA levels to 200 copies or more per millilitre. The main results regarding the
primary endpoint are given in table 3.
Table 3: Outcome of Therapy 12 months after switch from PI based therapy
VIRAMUNE
(n=155)
Efavirenz
(n=156)
Abacavir
(n=149)
Number of patients
Death
1
2
1
Progression to AIDS
0
0
2
Virologic failure
While taking study medication
After switching study medication
14
8
6
7
5
2
16
16
0
Lost to follow-up
3
6
8
Switched study medication without virologic failure
20
29
9
Response; still taking study medication at 12 months
117
112
113
At 12 months, the Kaplan–Meier estimates of the likelihood of reaching the endpoint were 10 % in the
VIRAMUNE group, 6 % in the efavirenz group, and 13 percent in the abacavir group (P=0.10
according to an intention-to-treat analysis).
47
The overall incidence of adverse events was significantly lower (61 patients, or 41%) in the abacavir
group than in the nevirapine group (83 patients, or 54%) or the efavirenz group (89 patients, or 57%).
Significantly fewer patients in the abacavir group (9 patients, or 6%) than in the nevirapine group (26
patients, or 17%) or the efavirenz group (27 patients, or 17%) discontinued the study medication
because of adverse events (see table below).
Number of patients who had one or more adverse events*
Adverse Event
Nevirapine
(N=155)
Efavirenz
(N=156)
Abacavir
(N=149)
Any
adverse
event
Grade 3
or 4
adverse
event
Adverse
event
leading
to
disconti-
nuation
Any
adverse
event
Grade 3
or 4
adverse
event
Adverse
event
leading
to
disconti-
nuation
Any
adverse
event
Grade 3
or 4
adverse
event
Adverse
event
leading
to
disconti-
nuation
Number of patients (percent)
Clinical
- Neuropsychiatric
11
6
6
48
22
19
14
1
0
- Cutaneous
20
13
12
11
3
3
7
0
0
- Gastrointestinal
6
2
0
8
4
4
12
2
1
- Systemic**
7
1
1
5
2
0
10
8
8
- Other
25
8
1
11
5
1
12
3
0
Laboratory
- Increased
aminotransferase
levels
12
6
4
4
1
0
5
1
0
- Hyperglycemia
2
2
2
2
2
0
1
1
0
Total
83
(54)***
38
26
(17)****
89
(57)***
39
27
(17)****
61
(41)***
16
9
(6)****
* A grade 3 event was defined as severe, and a grade 4 event as life-threatening
** Systemic adverse events included hypersensitivity reactions
*** P=0.02 by the chi-square test
**** P=0.01 by the chi-square test
Perinatal Transmission
The HIVNET 012 study conducted in Kampala (Uganda) evaluated the efficacy of VIRAMUNE to
prevent vertical transmission of HIV-1 infection. Mothers received only study antiretroviral therapy
during these trials. Mother-infant pairs were randomised to receive oral VIRAMUNE (mother: 200 mg
at the onset of labour; infant: 2 mg/kg within 72 hours of birth), or an ultra-short oral zidovudine
regimen (mother: 600 mg at the onset of labour and 300 mg every 3 hours until delivery; infant
4 mg/kg twice daily for 7 days). The cumulative HIV-1 infant infection rate at 14-16 weeks was
13.1% (n = 310) in the VIRAMUNE group, versus 25.1% (n = 308 in the ultra-short zidovudine group
(p = 0.00063).
48
From a study in which infants of HIV infected mothers received either placebo or single dose
nevirapine, 30 HIV infected infants, 15 who have received placebo and 15 who have received
nevirapine, were subsequently treated with nevirapine combined with other anti-retroviral drugs.
Virologic failure after 6 months of treatment with nevirapine combined with other anti-retroviral drugs
occurred in significantly more infants who had previously received a single dose of nevirapine (10 of
15) than in infants who had received placebo previously (1 of 15). This indicates that in infants
previously treated with single-dose nevirapine alone for prevention of mother to child transmission of
HIV-1, the efficacy of VIRAMUNE as part of a combination therapy which they receive for their own
health may be reduced.
In a study in which women who had received single dose nevirapine for prevention of mother-to-child
transmission were treated with VIRAMUNE combined with other anti-retroviral drugs for their own
health, 29 of 123, or 24% experienced virologic failure, and five (38%) of 13 women with HIV-1
detected baseline resistance to VIRAMUNE experienced virologic failure. This indicates that in
women previously treated with single-dose nevirapine alone for prevention of mother to child
transmission of HIV-1, the efficacy of VIRAMUNE as part of a combination therapy which the
women receive for their own health may be reduced.
A blinded randomized clinical trial in women already taking antiretroviral therapy throughout
pregnancy (PACTG 316) demonstrated no further reduction of vertical HIV-1 transmission when the
mother and the child received a single VIRAMUNE dose during labour and after birth respectively.
HIV-1 transmission rates were similarly low in both treatment groups (1.3% in the VIRAMUNE
group, 1.4% in the placebo group). The vertical transmission decreased neither in women with HIV-1
RNA below the limit of quantification nor in women with HIV-1 RNA above the limit of
quantification prior to partus. Of the 95 women who received intrapartum VIRAMUNE, 15%
developed nevirapine resistance mutations at 6 weeks post partus.
The clinical relevance of these data in European populations has not been established. Furthermore, in
the case VIRAMUNE is used as single dose to prevent vertical transmission of HIV-1 infection, the
risk of hepatotoxicity in mother and child cannot be excluded.
Paediatric population
Results of a 48-week analysis of the South African study BI 1100.1368 confirmed that the 4/7 mg/kg
and 150 mg/m2 nevirapine dose groups were well tolerated and effective in treating antiretroviral
naive paediatric patients. A marked improvement in the CD4+ cell percent was observed through
Week 48 for both dose groups. Also, both dosing regimens were effective in reducing the viral load. In
this 48-week study no unexpected safety findings were observed in either dosing group.
5.2 Pharmacokinetic properties
VIRAMUNE tablets and oral suspension have been shown to be comparably bioavailable and
interchangeable at doses up to 200 mg.
Absorption: 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
0.4
µ
g/ml (7.5
µ
M) 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. Data reported in the literature from 20 HIV infected
patients suggest a steady state C
max
of 5.74 µg/ml (5.00-7.44) and C
min
of 3.73 µg/ml (3.20-5.08) with
an AUC of 109.0 h
*
µg/ml (96.0-143.5) in patients taking 200 mg of nevirapine bid. Other published
data support these conclusions. Long-term efficacy appears to be most likely in patients whose
nevirapine trough levels exceed 3.5 µg/ml.
±
49
±
plasma nevirapine concentrations of 2
0.09 l/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
µ
g/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.
Biotransformation and elimination:
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 radiolabelled dose was recovered, with urine (81.3
±
11.1%) representing the primary
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.
Special populations:
Renal dysfunction:
The single-dose pharmacokinetics of nevirapine have been compared in 23 subjects
with either mild (50
≤
CLcr
<
80 ml/min), moderate (30
≤
CLcr
<
50 ml/min) or severe renal
30 ml/min), renal impairment or end-stage renal disease (ESRD) requiring
dialysis, and 8 subjects with normal renal function (CLcr
<
80 ml/min). Renal impairment (mild,
moderate and severe) resulted in no significant change in the pharmacokinetics of nevirapine.
However, subjects with ESRD requiring dialysis exhibited a 43.5% reduction in nevirapine AUC over
a one-week exposure period. There was also accumulation of nevirapine hydroxy-metabolites in
plasma. The results suggest that supplementing VIRAMUNE therapy with an additional 200 mg dose
of VIRAMUNE following each dialysis treatment would help offset the effects of dialysis on
nevirapine clearance. Otherwise patients with CLcr
>
≥
20 ml/min do not require an adjustment in
VIRAMUNE dosing.
Hepatic dysfunction:
A steady state study comparing 46 patients with
mild (n=17: Ishak Score 1-2),
moderate (n=20; Ishak Score 3-4),
or severe (n=9; Ishak Score 5-6, Child-Pugh A in 8 pts., for 1 Child-Pugh score not applicable)
liver fibrosis as a measure of hepatic impairment was conducted.
The patients studied were receiving antiretroviral therapy containing Viramune 200 mg twice daily for
at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years. In
this study, the multiple dose pharmacokinetic disposition of nevirapine and the five oxidative
metabolites were not altered.
50
Distribution:
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
±
±
route of excretion compared to faeces (10.1
dysfunction (CLcr
However, approximately 15% of these patients with hepatic fibrosis had nevirapine trough
concentrations above 9,000 ng/ml (2 fold the usual mean trough). Patients with hepatic impairment
should be monitored carefully for evidence of drug induced toxicity.
In a 200 mg nevirapine single dose pharmacokinetic study of HIV-negative patients with mild and
moderate hepatic impairment (Child-Pugh A, n=6; Child-Pugh B, n=4), a significant increase in the
AUC of nevirapine was observed in one Child-Pugh B patient with ascites suggesting that patients
with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic
circulation. Because nevirapine induces its own metabolism with multiple dosing, this single dose
study may not reflect the impact of hepatic impairment on multiple dose pharmacokinetics (see section
4.4).
In the multinational 2NN study, a population pharmacokinetic substudy of 1077 patients was
performed that included 391 females. Female patients showed a 13.8% lower clearance of nevirapine
than did male patients. This difference is not considered clinically relevant. Since neither body weight
nor Body Mass Index (BMI) had influence on the clearance of nevirapine, the effect of gender cannot
be explained by body size. Nevirapine pharmacokinetics in HIV-1 infected adults do not appear to
change with age (range 19-68 years) or race (Black, Hispanic, or Caucasian). VIRAMUNE has not
been specifically investigated in patients over the age of 65.
Paediatric population
Data concerning the pharmacokinetics of nevirapine has been derived from two major sources: a 48
week paediatric trial in South Africa (BI 1100.1368) involving 123 HIV-1 positive, antiretroviral
naïve patients aged 3 months to 16 years; and a consolidated analysis of five Paediatric AIDS Clinical
Trials Group (PACTG) protocols comprising 495 patients aged 14 days to 19 years.
Pharmacokinetic data on 33 patients (age range 0.77 – 13.7 years) in the intensive sampling group
demonstrated that clearance of nevirapine increased with increasing age in a manner consistent with
increasing body surface area. Dosing of nevirapine at 150 mg/m
2
BID (after a two-week lead in at
150 mg/m
2
QD) produced geometric mean or mean trough nevirapine concentrations between 4-
6 µg/ml (as targeted from adult data). In addition, the observed trough nevirapine concentrations were
comparable between the two methods.
The consolidated analysis of Paediatric AIDS Clinical Trials Group (PACTG) protocols 245, 356,
366, 377, and 403 allowed for the evaluation of paediatric patients less than 3 months of age (n=17)
enrolled in these PACTG studies. The plasma nevirapine concentrations observed were within the
range observed in adults and the remainder of the paediatric population, but were more variable
between patients, particularly in the second month of age.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans other than those observed in clinical studies
based on conventional studies of safety, pharmacology, repeated dose toxicity, and genotoxicity. In
carcinogenicity studies, nevirapine induces hepatic tumours in rats and mice. These findings are most
likely related to nevirapine being a strong inducer of liver enzymes, and not due to a genotoxic mode
of action.
51
6.
6.1 List of excipients
Carbomer
Methyl parahydroxybenzoate (E218)
Propyl parahydroxybenzoate (E216)
Sorbitol
Sucrose
Polysorbate 80
Sodium hydroxide (for pH-adjustment)
Purified water
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
The product should be used within 6 months of opening.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
White high density polyethylene (HDPE) bottle with two piece child-resistant closure (outer shell
white high density polyethylene, inner shell natural polypropylene) with a low density polyethylene
(LDPE) foam liner. Each bottle contains 240 ml of oral suspension.
Clear polypropylene 5 ml dispensing syringe with silicone rubber piston seal.
Clear low density polyethylene bottle-syringe adapter.
6.6 Special precautions for disposal and other handling
Instructions for administration:
The required dosage volumes should be measured employing the enclosed dispensing syringe and
adapter, as described in steps 1-5 below. The maximum volume which can be measured with the
dispensing syringe is 5 ml and therefore steps 3-5 must be repeated for dosage volumes greater than
5 ml.
1. Shake the bottle gently
2. Fit (by first pressing and then screwing) the adapter onto the open bottle neck
3. Insert the syringe into the adapter
4. Invert the bottle
5. Withdraw the required dosage volume
52
The bottle can be kept sealed with the flexible lid of the adapter. VIRAMUNE oral suspension should
be used within 6 months after first opening of the bottle.
Disposal:
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein,
Germany
8.
EU/1/97/055/002
9.
Date of first authorisation: 18 June 1999
Date of latest renewal: 10 January 2008
Detailed information on this product is available on the website of the European Medicines Agency
(EMA) http://www.ema.europa.eu
53
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
54
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Viramune 200 mg Tablets
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173 - 55216 Ingelheim am Rhein
Germany
Boehringer Ingelheim Ellas A.E.
5th km Paiania-Markopoulo
194 00 Koropi
Greece
Viramune 50 mg/5 ml Oral suspension
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173 – 55216 Ingelheim am Rhein
Germany
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
PSUR: The Marketing Authorisation Holder will continue to submit the PSUR on a yearly basis.
55
ANNEX III
LABELLING AND PACKAGE LEAFLET
56
A. LABELLING
57
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BLISTER CARTON LABEL
1.
Viramune 200 mg tablets
nevirapine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 200 mg of nevirapine (as anhydrous)
3.
LIST OF EXCIPIENTS
Excipients: includes lactose (see leaflet for further information)
4.
60 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
58
Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany
EU/1/97/055/001
13. MANUFACTURER’S BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Viramune 200 mg
59
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BLISTER CARTON LABEL
1.
FURTHER INFORMATION
What VIRAMUNE contains
-
The active substance is nevirapine. Each ml contains 10 mg of the active substance nevirapine
(as nevirapine hemihydrate).
-
The other ingredients are:
-
carbomer
-
methyl parahydroxybenzoate
-
propyl parahydroxybenzoate
-
sorbitol
-
sucrose
-
polysorbate 80
-
sodium hydroxide
-
water
What VIRAMUNE looks like and contents of pack
VIRAMUNE oral suspension is a white to off-white homogenous suspension.
VIRAMUNE oral suspension is supplied in plastic bottles of suspension for oral use, with 240 ml
suspension per bottle. A plastic measuring syringe is included for measuring the correct dose.
VIRAMUNE is also supplied as 200 mg tablets for older children and adults.
Marketing Authorisation Holder
Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany
88
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
Luxembourg/Luxemburg
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98
Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel.: +36 1 299 8900
Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111
Malta
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88
Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900
Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00
Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 60 80 940
Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-0
Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Polska
Boehringer Ingelheim Sp.zo.o.
Tel.: +48 22 699 0 699
España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 58 00
Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00
France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33
România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +4 021 330 99 63
Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Vistor hf.
Tel: +354 535 7000
Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211
89
Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1
Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800
Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00
Latvija
Boehringer Ingelheim Pharma GmbH
Pārstāvniecība Latvijā
Tel: +371 67 240 068
United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel.: +370 37 473922
This leaflet was last approved in {MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu
90
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/viramune.html
Copyright © 1995-2021 ITA all rights reserved.