Warning
TRIOMUNE IS NOT INTENDED FOR USE IN PATIENTS WHO ARE JUST
INITIATING THERAPY WITH NEVIRAPINE. TRIOMUNE SHOULD BE
ADMINISTERED ONLY TO PATIENTS WHO HAVE RECEIVED STAVUDINE
+ LAMIVUDINE (STANDARD DOSES) + NEVIRAPINE (200 MG O.D.)
FOR 2 WEEKS AND HAVE DEMONSTRATED ADEQUATE TOLERABILITY
TO NEVIRAPINE (SEE INDICATIONS, DOSAGE AND ADMINISTRATION).
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS,
INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE
OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION INCLUDING
LAMIVUDINE AND STAVUDINE (See Warnings and Precautions
SECTION). SEVERE, LIFE-THREATENING SKIN REACTIONS, INCLUDING
FATAL CASES, HAVE OCCURRED IN PATIENTS TREATED WITH NEVIRAPINE.
THESE HAVE INCLUDED CASES OF STEVENS-JOHNSON SYNDROME,
TOXIC EPIDERMAL NECROLYSIS, AND HYPERSENSITIVITY REACTIONS
CHARACTERIZED BY RASH, CONSTITUTIONAL FINDINGS AND ORGAN
DYSFUNCTION. PATIENTS DEVELOPING SIGNS OR SYMPTOMS OF
SEVERE SKIN REACTIONS OR HYPERSENSITIVITY REACTIONS MUST
DISCONTINUE NEVIRAPINE AS SOON AS POSSIBLE (SEE WARNINGS).
SEVERE AND LIFE-THREATENING HEPATOTOXICITY, INCLUDING
FATAL HEPATIC NECROSIS, HAS OCCURRED IN PATIENTS TREATED
WITH NEVIRAPINE (SEE WARNINGS). RESISTANT VIRUS EMERGES
RAPIDLY AND UNIFORMLY WHEN NEVIRAPINE IS ADMINISTERED
AS MONOTHERAPY. THEREFORE, NEVIRAPINE SHOULD ALWAYS BE
ADMINISTERED IN COMBINATION WITH ANTIRETROVIRAL AGENTS.
Composition
Triomune-30
Each uncoated tablet contains
Stavudine ............30 mg
Lamivudine ....... 150 mg
Nevirapine ...... 200 mg
Colour: Lake Quinoline Yellow WS
Triomune-40
Each uncoated tablet contains
Stavudine ................40 mg
Lamivudine ............150 mg
Nevirapine .............200 mg
Colour: Lake Sunset Yellow FCF
Description
Triomune is a combination of 3 drugs commonly used
in the management of Human Immunodeficiency Virus (HIV-1)
infection. Both stavudine and lamivudine belong to the
nucleoside analogue class of antiretroviral drugs. Both
drugs act by terminating the growth of the DNA chain and
inhibiting the reverse transcriptase of HIV. Nevirapine
is a non-nucleoside reverse transcriptase inhibitor. It
acts by directly inhibiting reverse transcriptase.
Studies using the combination of stavudine + lamivudine
+ nevirapine have demonstrated its efficacy in patients
with HIV infection. In the study presented by Kaspar et
al at the 5th Conference on Retroviruses and Opportunistic
Infections, Chicago 1998, 87% of patients had undetectable
viral loads at 33-44 weeks. In the study presented by
Russell et al at the 7th European Conference on Clinical
Aspects and Treatment of HIV Infection, Lisbon 1999, CD4
counts increased by 195 cells/mm3 and 230 cells/mm3 in
patients with low (<80,000 copies/ml) and high viral
loads (>80,000 copies/ml) respectively at the end of
1 year. 72% of patients with low viral loads and 80% of
patients with high viral loads had undetectable viral
loads at the end of 1 year.
Each tablet of Triomune contains half of the commonly
prescribed daily doses of stavudine, lamivudine and nevirapine.
All three drugs are to be administered twice daily, permitting
a fixed-dose combination to be formulated. With the availability
of this combination formulation, patients may be better
able to adhere to triple drug regimens, thereby enhancing
compliance.
Indications
Triomune is indicated for the treatment of HIV-1 infection
in adults, once patients have been stabilized on the maintenance
regimen of nevirapine 200 mg b.d., and have demonstrated
adequate tolerability to nevirapine.
Dosage and Administration
Adults
Triomune-30
1 tablet twice daily for patients weighing < 60 kg
Triomune-40
1 tablet twice daily for patients weighing > 60 kg
Triomune should not be administered to patients
who have just initiated therapy with nevirapine. This
is because an initial lead-in dosing of 200 mg nevirapine
once daily for 2 weeks is recommended. Following this
lead-in dose, a dose escalation (maintenance dose) to
200 mg nevirapine b.d. may be carried out in the absence
of any hypersensitivity reactions (e.g. rash, liver function
test abnormalities; See Warnings and Precautions).
Monitoring of patients
Clinical chemistry tests, which include liver function
tests, should be performed prior to initiating lead-in
nevirapine therapy and at appropriate intervals during
therapy (See Warnings and Precautions).
Dosage Adjustment
Lamivudine
Because it is a fixed-dose combination, Triomune
should not be prescribed for patients requiring dosage
adjustment, such as those with low body weight (<50
kg).
Nevirapine
Triomune should be discontinued if patients experience
severe rash or a rash accompanied by constitutional findings
(See Warnings and Precautions). Patients experiencing
mild to moderate rash during the 14-day lead-in period
of 200 mg/day should not have their nevirapine dose increased
or start therapy with Triomune until the rash has
resolved (see Warnings and Precautions).
Triomune administration should be interrupted in
patients experiencing moderate or severe liver function
tests abnormalities (excluding GGT), until the liver function
test elevations have returned to baseline. Nevirapine
(using Nevimune Tablets) may then be restarted
at 200 mg per day. Increasing the daily dose to 200 mg
twice daily (using Triomune) should be done with
caution, after extended observation. Nevirapine should
be permanently discontinued if moderate or severe liver
function test abnormalities recur (See Warnings and Precautions).
Patients who interrupt nevirapine dosing for more than
7 days should restart the recommended dosing, using one
200 mg Nevimune tablet daily for the first 14 days (lead-in)
in combination with the other antiretrovirals, followed
by 200 mg twice daily using Triomune in the absence
of any signs of hypersensitivity.
No data are available to recommend a dosage of nevirapine
in patients with hepatic dysfunction, renal insufficiency
or under-
going dialysis.
Contraindications
Triomune is contraindicated in patients with clinically
significant hypersensitivity to any of the components
contained in the formulation.
Triomune is also contraindicated for patients who are
just initiating therapy with nevirapine. These patients
require a lead-in dose of nevirapine 200 mg o.d., whereas
this formulation contains the maintenance dose of nevirapine
200 mg b.d. (See Indications).
Warnings and Precautions
Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis/severe hepatomegaly with steatosis, including
fatal cases, have been reported with the use of antiretroviral
nucleoside analogues alone or in combination, including
stavudine and lamivudine. A majority of these cases have
been in women. Obesity and prolonged nucleoside exposure
may be risk factors. Caution should be exercised when
administering stavudine to any patient, and particularly
to those with known risk factors for liver disease. Cases
have also been reported in patients with no known risk
factors. Treatment should be discontinued in any patient
who develops clinical or laboratory findings suggestive
of lactic acidosis or hepatotoxicity (which may include
hepatomegaly and steatosis) even in the absence of marked
aminotransferase elevations.
Peripheral neuropathy
Stavudine therapy can be associated with severe peripheral
neuropathy, which is dose-related and occurs more frequently
in patients with advanced HIV infection or who have previously
experienced peripheral neuropathy.
Patients should be monitored for the development of neuropathy
that is usually characterized by numbness, tingling or
pain in the feet or hands. Stavudine-related peripheral
neuropathy may resolve if therapy is withdrawn promptly.
In some cases, symptoms may worsen temporarily following
discontinuation of therapy.
If symptoms resolve completely, resumption of treatment
may be considered using the following dosage schedule
for adults:
20 mg twice daily for patients > 60 kg
15 mg twice daily for patients < 60 kg
In this case, therapy with Triomune is no longer
appropriate.
Patients with HIV and hepatitis B virus coinfection:
In clinical trials, some patients with HIV infection who
have chronic liver disease due to hepatitis B virus infection
experienced clinical or laboratory evidence of recurrent
hepatitis upon discontinuation of lamivudine. Consequences
may be more severe in patients with decompensated liver
disease.
Hypersensitivity reactions
Severe, life-threatening skin reactions, including fatal
cases, have occurred in patients treated with nevirapine.
These have included cases of Stevens-Johnson syndrome,
toxic epidermal necrolysis, and hypersensitivity reactions
characterized by rash, constitutional findings, and organ
dysfunction. Patients developing signs or symptoms of
severe skin reactions or hypersensitivity reactions (including,
but not limited to, severe rash or rash accompanied by
fever, blisters, oral lesions, conjunctivitis, facial
edema, muscle or joint aches, general malaise and/or significant
hepatic abnormalities must discontinue nevirapine as soon
as possible. Nevirapine therapy must be initiated with
a 14-day lead - in period of 200 mg/day which has been
shown to reduce the frequency of rash. If rash is observed
during this lead-in period, dose escalation and administration
of Triomune should not occur until the rash has resolved
(See Dosage and Administration).
Severe or life-threatening hepatotoxicity, including fatal
fulminant hepatitis (transaminase elevations, with or
without hyperbilirubinemia, prolonged partial thromboplastin
time, or eosinophilia), has occurred in patients treated
with nevirapine. Some of these cases began in the first
few weeks of therapy, and some were accompanied by rash.
Nevirapine administration should be interrupted in patients
experiencing moderate or severe ALT or AST abnormalities
until these return to baseline values. Nevirapine should
be permanently discontinued if liver function abnormalities
recur upon readministration. Monitoring of ALT and AST
is strongly recommended, especially during the first six
months of nevirapine treatment (See Side Effects, Dosage
and Administration).
Drug Interactions
Lamivudine
Trimethoprim 160 mg/sulphamethoxazole 800 mg once daily
has been shown to increase lamivudine exposure (AUC).
Nevirapine
The induction of CYP3A by nevirapine may result in lower
plasma concentrations of other concomitantly administered
drugs that are extensively metabolized by CYP3A. Thus,
if a patient has been stabilized on a dosage regimen for
a drug metabolized by CYP3A, and begins treatment with
nevirapine, dose adjustments may be necessary.
Rifampin/Rifabutin
There are insufficient data to assess whether dose adjustments
are necessary when nevirapine and rifampin or rifabutin
are coadministered. Therefore, these drugs should only
be used in combination if clearly indicated and with careful
monitoring.
Ketoconazole
Nevirapine and ketoconazole should not be administered
concomitantly. Coadminis-tration of nevirapine and ketoconazole
results in a significant reduction in ketoconazole plasma
concentrations.
Oral Contraceptives
There are no clinical data on the effects of nevirapine
on the pharmacokinetics of oral contraceptives. Nevirapine
may decrease plasma concentrations of oral contraceptives
(also other hormonal contraceptives); therefore, these
drugs should not be administered concomitantly with nevirapine.
Methadone
Based on the known metabolism of methadone, nevirapine
may decrease plasma concentrations of methadone by increasing
its hepatic metabolism. Narcotic withdrawal syndrome has
been reported in patients treated with nevirapine and
methadone concomitantly. Methadone-maintained patients
beginning nevirapine therapy should be monitored for evidence
of withdrawal and methadone dose should be adjusted accordingly.
Impaired renal function
Reduction of the dosage of both stavudine and lamivudine
is required in patients with a creatinine clearance of
50 ml/min or less. Hence, Triomune cannot be used in this
patient population. There are no data available on dosage
in patients with renal insufficiency or undergoing dialysis.
Pregnancy
Lamivudine, stavudine and nevirapine are all classified
under category C. There are no adequate and well-controlled
studies in pregnant women. Triomune should be used during
pregnancy only if the potential benefits outweigh the
potential risk.
Lactation
It is recommended that HIV-infected mothers do not breast-feed
their infants to avoid risking postnatal transmission
of HIV infection. It is not known whether stavudine or
lamivudine is excreted in human milk. Nevirapine is present
in breast milk.
Paediatrics
Triomune is not intended for use in paediatric
patients.
Side Effects
Lamivudine
Pancreatitis has been reported with the use of lamivudine.
Lactic acidosis and hepatic steatosis, hepatitis and liver
failure have been reported with the use of antiretroviral
nucleoside analogue, alone or in combination.
Other side effects associated with the use of lamivudine
are diarrhoea, malaise and fatigue, headache, nausea and
vomiting, abdominal pain and discomfort, peripheral neuropathy,
arthralgias, myalgias, skin rash, pruritus, transient
neutropenia and thrombocytopenia and rarely, pancreatitis.
Transiently elevated levels of hepatic enzymes and bilirubin
(> 5 times the normal level) have also been observed
occasionally during treatment with the drug. Resolution
of transient neutropenia and raised hepatic and bilirubin
levels occurred without dosage modification or discontinuation
of therapy.
Stavudine
Therapy with stavudine can be associated with severe peripheral
neuropathy, which is dose related and occurs more frequently
in patients with advanced HIV infection or who have previously
experienced peripheral neuropathy.
Lactic acidosis and hepatic steatosis, hepatitis and liver
failure have been reported with the use of antiretroviral
nucleoside analogues, alone or in combination.
Rash, diarrhoea, nausea/vomiting, pancreatitis, dementia
and other peripheral neurologic symptoms have also been
associated with the use of stavudine.
Nevirapine
The most clinically important adverse events associated
with nevirapine therapy are rash and increases in liver
function tests. Cases of hypersensitivity reactions have
been observed.
The major clinical toxicity of nevirapine is rash, with
nevirapine-attributable rash occurring in 16% of patients
in combination regimens in Phase II/III controlled studies.
Thirty-five percent of patients treated with nevirapine
experienced rash compared with 19% of patients treated
in control groups of either zidovudine + didanosine or
zidovudine alone. Severe or life-threatening rash occurred
in 6.6% of nevirapine-treated patients compared with 1.3%
of patients treated in the control groups.
Rashes are usually mild to moderate, maculopapular erythematous
cutaneous eruptions; with or without pruritus, located
on the trunk, face and extremities. The majority of severe
rashes occurred within the first 28 days of treatment.
25% of the patients with severe rashes required hospitalization,
and one patient required surgical intervention. Overall,
7% of patients discontinued nevirapine due to rash.
With respect to laboratory abnormalities, asymptomatic
elevations in GGT levels are more frequent in nevirapine
recipients than in controls. Because clinical hepatitis
has been reported in nevirapine-treated patients, monitoring
of ALT (SGPT) and AST (SGOT) is strongly recommended,
especially during the first six months of nevirapine treatment
(See Warnings and Precautions). Decreased neutrophils
(< 750/mm3), platelets (< 50,000/mm3) and Hb (<
8.0 g/dL), and increased total bilirubin (> 2.5 mg/dL)
have also been reported.
Overdosage
Lamivudine
There is no known antidote for lamivudine. It is not known
whether lamivudine can be removed by peritoneal dialysis
or hemodialysis.
Stavudine
Stavudine can be removed by hemodialysis. Experience with
adults treated with 12 to 24 times the recommended daily
dosage revealed no acute toxicity. Complications of chronic
overdosage include peripheral neuropathy and hepatic toxicity.
Nevirapine
There is no known antidote for nevirapine overdosage.
Storage
Store in a cool dry place
Presentation
Triomune-30 Container pack of 30 tablets
Triomune-40 Container pack of 30 tablets |
