ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
TRIZIVIR 300 mg/150 mg/300 mg film-coated tablets
2.
Each film-coated tablet contains 300 mg of abacavir (as sulfate), 150 mg lamivudine and 300 mg
zidovudine.
For a full list of excipients see section 6.1.
3.
Film-coated tablet (tablet).
Blue-green capsule-shaped film-coated tablets engraved with “GX LL1” on one side.
4.
Trizivir is indicated for the treatment of Human Immunodeficiency Virus (HIV) infection in adults.
This fixed combination replaces the three components (abacavir, lamivudine and zidovudine) used
separately in similar doses. It is recommended that treatment is started with abacavir, lamivudine, and
zidovudine separately for the first 6-8 weeks (see section 4.4). The choice of this fixed combination
should be based not only on potential adherence criteria, but mainly on expected efficacy and risk
related to the three nucleoside analogues.
The demonstration of the benefit of Trizivir is mainly based on results of studies performed in
treatment naive patients or moderately antiretroviral experienced patients with non-advanced disease.
In patients with high viral load (> 100,000 copies/ml) choice of therapy needs special consideration
(see section 5.1).
Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be
performed in any HIV-infected patient, irrespective of racial origin. Screening is also recommended
prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously
tolerated abacavir (see “Management after an interruption of Trizivir therapy”). Abacavir should not
be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is
available in these patients, based on the treatment history and resistance testing (see section 4.4 and
4.8).
Therapy should be prescribed by a physician experienced in the management of HIV infection.
The recommended dose of Trizivir in adults (18 years and over) is one tablet twice daily.
Trizivir can be taken with or without food.
Where discontinuation of therapy with one of the active substances of Trizivir is indicated, or where
dose reduction is necessary separate preparations of abacavir, lamivudine and zidovudine are
available.
2
Renal impairment
:
Whilst no dose adjustment of abacavir is necessary in patients with renal
dysfunction, lamivudine and zidovudine concentrations are increased in patients with renal impairment
due to decreased clearance. Therefore, as doe adjustments of these may be necessary, it is
recommended that separate preparations of abacavir, lamivudine and zidovudine be administered to
patients with reduced renal function (creatinine clearance ≤ 50 ml/min). Physicians should refer to the
individual summary of product characteristics of these medicinal products. Trizivir should not be
administered to patients with end-stage renal disease (see sections 4.3 and 5.2).
Hepatic impairment
: Trizivir is contraindicated in patients with hepatic impairment (see sections 4.3
and 5.2).
Elderly
: No pharmacokinetic data are currently available in patients over 65 years of age. Special care
is advised in this age group due to age associated changes such as the decrease in renal function and
alteration of haematological parameters.
Paediatric population
: The safety and efficacy of Trizivir in children has not been established. No data
are available.
Dose adjustments in patients with haematological adverse reactions
:
Dose adjustment of zidovudine
may be necessary if the haemoglobin level falls below 9 g/dl or 5.59 mmol/l or the neutrophil count
falls below 1.0 x 10
9
/l (see sections 4.3 and 4.4). As dose adjustment of Trizivir is not possible,
separate preparations of abacavir, lamivudine and zidovudine should be used. Physicians should refer
to the individual summary of product characteristics of these medicinal products.
Method of administration
Trizivir can be taken with or without food.
Hypersensitivity to the active substances or to any of the excipients. See BOXED INFORMATION
ON HYPERSENSITIVITY REACTIONS in section 4.4 and section 4.8.
Patients with end-stage renal disease.
Patients with hepatic impairment.
Due to the active substance zidovudine, Trizivir is contraindicated in patients with abnormally low
neutrophil counts (< 0.75 x 10
9
/l), or abnormally low haemoglobin levels (< 7.5 g/dl or 4.65 mmol/l)
(see section 4.4).
The special warnings and precautions relevant to abacavir, lamivudine and zidovudine are included in
this section. There are no additional precautions or warnings relevant to the combination Trizivir.
Hypersensitivity Reaction
(see also section 4.8 )
:
In a clinical study, 3.4 % of subjects with a negative HLA-B*5701 status receiving abacavir
developed a hypersensitivity reaction.
Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly
increased risk of a hypersensitivity reaction to abacavir. Based on the prospective study CNA106030
(PREDICT-1), use of pre-therapy screening for the HLA-B*5701 allele and subsequently avoiding
abacavir in patients with this allele significantly reduced the incidence of abacavir hypersensitivity
reactions. In populations similar to that enrolled in the PREDICT-1 study
,
it is estimated that 48% to
61% of patients with the HLA-B*5701 allele will develop a hypersensitivity reaction during the
3
course of abacavir treatment compared with 0% to 4% of patients who do not have the HLA-B*5701
allele.
These results are consistent with those of prior retrospective studies.
As a consequence, before initiating treatment with abacavir, screening for carriage of the HLA-
B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin.
Screening is also recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701
status who have previously tolerated abacavir (see “Management after an interruption of Trizivir
therapy”). Abacavir should not be used in patients known to carry the HLA-B*5701 allele, unless no
other therapeutic option is available based on the treatment history and resistance testing (see section
4.1).
In any patient treated with abacavir, the clinical diagnosis of suspected hypersensitivity reaction must
remain the basis of clinical decision-making. It is noteworthy that among patients with a clinically
suspected hypersensitivity reaction, a proportion did not carry HLA-B*5701. Therefore, even in the
absence of HLA-B*5701 allele, it is important to permanently discontinue abacavir and not
rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to
the potential for a severe or even fatal reaction.
Skin patch testing was used as a research tool for the PREDICT-1 study but has no utility in the
clinical management of patients and therefore should not be used in the clinical setting.
•
Clinical description
Hypersensitivity reactions are characterised by the appearance of symptoms indicating multi-organ
system involvement. Almost all hypersensitivity reactions will have fever and/or rash as part of the
syndrome.
Other signs and symptoms may include respiratory signs and symptoms such as dyspnoea, sore throat,
cough, and abnormal chest x-ray findings (predominantly infiltrates, which can be localised),
gastrointestinal symptoms, such as nausea, vomiting, diarrhoea, or abdominal pain,
and may lead to
misdiagnosis of hypersensitivity as respiratory disease (pneumonia, bronchitis, pharyngitis), or
gastroenteritis.
Other frequently observed signs or symptoms of the hypersensitivity reaction may
include lethargy or malaise and musculoskeletal symptoms (myalgia, rarely myolysis, arthralgia).
The symptoms related to this hypersensitivity reaction worsen with continued therapy and can be life-
threatening. These symptoms usually resolve upon discontinuation of abacavir.
•
Clinical management
Hypersensitivity reaction symptoms usually appear within the first six weeks of initiation of treatment
with abacavir, although these reactions
may occur at any time during therapy
. Patients should be
monitored closely, especially during the first two months of treatment with Trizivir, with consultation
every two weeks.
Regardless of their HLA-B*5701 status, patients who are diagnosed with a hypersensitivity reaction
whilst on therapy
MUST discontinue Trizivir immediately.
Trizivir, or any other medicinal product containing abacavir (e.g. Kivexa, Ziagen), MUST
NEVER be restarted in patients who have stopped therapy due to a hypersensitivity reaction.
Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms
within hours. This recurrence is usually more severe than on initial presentation, and may include life-
threatening hypotension and death.
To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction,
Trizivir must be permanently discontinued if hypersensitivity cannot be ruled out, even when other
4
diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other
medications).
Special care is needed for those patients simultaneously starting treatment with Trizivir and other
medicinal products known to induce skin toxicity (such as non-nucleoside reverse transcriptase
inhibitors - NNRTIs). This is because it is currently difficult to differentiate between rashes induced
by these products and abacavir related hypersensitivity reactions.
•
Management after an interruption of Trizivir therapy
Regardless of a patient’s HLA-B*5701 status, if therapy with Trizivir has been discontinued for any
reason and restarting therapy is under consideration, the reason for discontinuation must be
established to assess whether the patient had any symptoms of a hypersensitivity reaction.
If a
hypersensitivity reaction cannot be ruled out, Trizivir or any other medicinal product
containing abacavir (i.e. Kivexa, Ziagen
)
must not be restarted.
Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred
after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity
(skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and
malaise) prior to stopping abacavir. The most common isolated symptom of a hypersensitivity
reaction
was a skin rash. Moreover, on very rare occasions hypersensitivity reactions have been
reported in patients who have restarted therapy, and who had
no preceding symptoms
of a
hypersensitivity reaction (i.e. patients previously considered to be abacavir tolerant).
In both
cases
if a decision is made to restart Trizivir this must be done in a setting where medical assistance is
readily available.
Screening for carriage of the HLA B*5701 allele is recommended prior to re-initiation of abacavir in
patients of unknown HLA-B*5701 status who have previously tolerated abacavir. Re-initiation of
abacavir in such patients who test positive for the HLA B*5701 allele is not recommended and should
be considered only under exceptional circumstances where potential benefit outweighs the risk and
with close medical supervision.
•
Essential patient information
Prescribers
must ensure
that patients are fully informed regarding the following information on the
hypersensitivity reaction:
-
Patients must be made aware of the possibility of a hypersensitivity reaction to abacavir
that may result in a life-threatening reaction or death and that the risk of a hypersensitivity
reaction is increased if they are HLA-B*5701 positive.
-
Patients must also be informed that a HLA-B*5701 negative patient can also experience an
abacavir hypersensitivity reaction. Therefore, ANY patient who develops signs or symptoms
consistent with a possible hypersensitivity reaction to abacavir
MUST CONTACT THEIR
DOCTOR IMMEDIATELY.
-
Patients who are hypersensitive to abacavir should be reminded that they must never
take Trizivir or any other medicinal product containing abacavir (i.e. Kivexa, Ziagen) again,
regardless of their HLA-B*5701 status.
-
In order to avoid restarting Trizivir, patients who have experienced a hypersensitivity reaction
should dispose of their remaining Trizivir tablets in their possession in accordance with the
local requirements, and ask their doctor or pharmacist for advice.
-
Patients who have stopped Trizivir for any reason, and particularly due to possible adverse
-
reactions or illness, must be advised to contact their doctor before restarting.
5
Patients should be advised of the importance of taking Trizivir regularly.
-
Each patient should be reminded to read the Package Leaflet included in the Trizivir pack.
They should be reminded of the importance of removing the Alert Card included in the pack,
and keeping it with them at all times.
Lactic acidosis:
lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been
reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia)
include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss
of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms
(including motor weakness).
Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal
failure.
Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with nucleoside analogues should be discontinued in the setting of symptomatic
hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating
aminotransferase levels.
Caution should be exercised when administering nucleoside analogues to any patient (particularly
obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic
steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and
treated with alpha interferon and ribavirin may constitute a special risk.
Patients at increased risk should be followed closely.
Mitochondrial dysfunction
: nucleoside and nucleotide analogues have been demonstrated
in vitro
and
in vivo
to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial
dysfunction in HIV-negative infants exposed
in utero
and/or post-natally to nucleoside analogues. The
main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic
disorders (hyperlactatemia, hyperlipasemia). These adverse reactions are often transitory. Some late-
onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour).
Whether the neurological disorders are transient or permanent is currently unknown. Any child
exposed
in utero
to nucleoside and nucleotide analogues, even HIV-negative children, should have
clinical and laboratory follow-up and should be fully investigated for possible mitochondrial
dysfunction in case of relevant signs or symptoms. These findings do not affect current national
recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of
HIV.
Lipodystrophy
: combination antiretroviral therapy has been associated with the redistribution of body
fat (lipodystrophy) in HIV patients. The long-term consequences of these adverse reactions are
currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral
lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase
inhibitors (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 ).
Haematological adverse reactions
:
anaemia, neutropenia and leucopenia (usually secondary to
neutropenia) can be expected to occur in patients receiving zidovudine. These occurred more
frequently at higher zidovudine doses (1200-1500 mg/day) and in patients with poor bone marrow
reserve prior to treatment, particularly with advanced HIV disease. Haematological parameters should
therefore be carefully monitored (see section 4.3) in patients receiving Trizivir. These haematological
6
effects are not usually observed before four to six week’s therapy. For patients with advanced
symptomatic HIV disease, it is generally recommended that blood tests are performed at least every
two weeks for the first three months of therapy and at least monthly thereafter.
In patients with early HIV disease haematological adverse reactions are infrequent. Depending on the
overall condition of the patient, blood tests may be performed less often, for example every one to
three months. Additionally, dose adjustment of zidovudine may be required if severe anaemia or
myelosuppression occurs during treatment with Trizivir, or in patients with pre-existing bone marrow
compromise e.g. haemoglobin < 9 g/dl (5.59 mmol/l) or neutrophil count < 1.0 x 10
9
/l (see
section 4.2). As dose adjustment of Trizivir is not possible separate preparations of zidovudine,
abacavir and lamivudine should be used. Physicians should refer to the individual prescribing
information for these medicinal products.
Pancreatitis
: cases of pancreatitis have occurred rarely in patients treated with abacavir, lamivudine
and zidovudine. However, it is not clear whether these cases were due to treatment with these
medicinal products or to the underlying HIV disease. Treatment with Trizivir
should be stopped
immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.
Liver disease
: if lamivudine is being used concomitantly for the treatment of HIV and HBV, additional
information relating to the use of lamivudine in the treatment of hepatitis B infection is available in the
Zeffix SPC.
The safety and efficacy of Trizivir has not been established in patients with significant underlying
liver disorders. Trizivir is contraindicated in patients with hepatic impairment (see section 4.3).
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an
increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral
therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal
products.
If Trizivir is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both
liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine
may result in an acute exacerbation of hepatitis (see Zeffix SPC).
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.
Patients co-infected with hepatitis C virus
:
The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of
anaemia (see section 4.5).
Children and adolescents
: because insufficient data are available, the use of Trizivir in children or
adolescents is not recommended. In this patient population, hypersensitivity reactions are particularly
difficult to identify.
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 mycobacterium infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms
should be evaluated and treatment instituted when necessary.
Osteonecrosis
: Although the aetiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis
7
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.
Opportunistic infections
: patients should be advised that Trizivir or any other antiretroviral therapy
does not cure HIV infection and that they may still develop opportunistic infections and other
complications
of HIV infection. Therefore, patients should remain under close clinical observation by
physicians experienced in the treatment of these associated HIV diseases.
Myocardial infarction
: Observational studies have shown an association between myocardial
infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data
from clinical trials showed limited numbers of myocardial infarction and could not exclude a small
increase in risk. Overall the available data from observational cohorts and from randomised trials
show some inconsistency so can neither confirm nor refute a causal relationship between abacavir
treatment and the risk of myocardial infarction. To date, there is no established biological mechanism
to explain a potential increase in risk. When prescribing Trizivir, action should be taken to try to
minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Miscellaneous
:
patients should be advised that current antiretroviral therapy, including Trizivir, has
not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood
contamination. Appropriate precautions should continue to be taken.
To date there are insufficient data on the efficacy and safety of Trizivir given concomitantly with
NNRTIs or PIs (see section 5.1).
The concomitant use of stavudine with zidovudine should be avoided (see section 4.5).
As Trizivir contains abacavir, lamivudine and zidovudine, any interactions that have been identified
with these agents individually may occur with Trizivir.
The likelihood of metabolic interactions with lamivudine is low due to limited metabolism and plasma
protein binding, and almost complete renal clearance. Zidovudine is primarily eliminated by hepatic
conjugation to an inactive glucuronidated metabolite. Medicinal products that are primarily eliminated
by hepatic metabolism especially via glucuronidation may have the potential to inhibit metabolism of
zidovudine. Based on the results of
in vitro
experiments and the known major metabolic pathways of
abacavir, the potential for P450 mediated interactions with other medicinal products involving
abacavir are low. Clinical studies have shown that there are no clinically significant interactions
between abacavir, lamivudine and zidovudine.
The interactions listed below should not be considered exhaustive but are representative of the classes
of medicinal products where caution should be exercised.
Interactions relevant to abacavir
Based on the results of
in vitro
experiments and the known major metabolic pathways of abacavir, the
potential for P450 mediated interactions with other medicinal products involving abacavir is low. P450
does not play a major role in the metabolism of abacavir, and abacavir does not inhibit metabolism
mediated by CYP 3A4. Abacavir has also been shown
in vitro
not to inhibit CYP 3A4, CYP 2C9 or
CYP 2D6 enzymes at clinically relevant concentrations
.
Therefore, there is little potential for
interactions with antiretroviral PIs and other medicinal products metabolised by major P450 enzymes.
Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on
UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir.
8
The metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of
abacavir of about 41 %. These findings are not considered clinically significant. Abacavir has no
effect on the metabolism of ethanol.
Retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible
but has not been studied.
In a pharmacokinetic study, coadministration of 600 mg abacavir twice daily with methadone showed
a 35 % reduction in abacavir C
max
and a 1 hour delay in t
max
, but the AUC was unchanged. The
changes in abacavir pharmacokinetics are not considered clinically relevant. In this study, abacavir
increased the mean methadone systemic clearance by 22 %. The induction of drug metabolizing
enzymes cannot therefore be excluded. Patients being treated with methadone and abacavir should be
monitored for evidence of withdrawal symptoms indicating under dosing, as occasionally methadone
re-titration may be required.
Interactions relevant to lamivudine
The possibility of interactions with other medicinal products administered concurrently with Trizivir
should be considered, particularly when the main route of elimination is active renal secretion
especially via the cationic transport system e.g. trimethoprim. Nucleoside analogues (e.g. zidovudine,
didanosine and zalcitabine) and other medicinal products (e.g. ranitidine, cimetidine) are eliminated
only in part by this mechanism and were shown not to interact with lamivudine.
Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase in
lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component does
not interact. However, unless the patient has renal impairment, no dose adjustment of lamivudine is
necessary (see section 4.2). Lamivudine has no effect on the pharmacokinetics of trimethoprim or
sulfamethoxazole. When concomitant administration with co-trimoxazole is warranted, patients
should be monitored clinically. Co-administration of Trizivir with high doses of co-trimoxazole for
the treatment of
Pneumocystis carinii
pneumonia (PCP) and toxoplasmosis should be avoided.
Co-administration of lamivudine with intravenous ganciclovir or foscarnet is not recommended until
further information is available.
Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal
products are used concurrently. Trizivir is therefore not recommended to be used in combination with
zalcitabine.
Lamivudine metabolism does not involve CYP 3A, making interactions with medicinal products
metabolised by this system (e.g. PIs and non-nucleosides) unlikely.
Interactions relevant to zidovudine
Limited data suggests that co-administration of zidovudine and rifampicin decreases the AUC of
zidovudine by 48 %
±
34 %. However the clinical significance of this is unknown. Dose modifications
of zidovudine in this situation have not been formally evaluated.
Limited data suggest that probenecid increases the mean half-life and area under the plasma
concentration curve of zidovudine by decreasing glucuronidation. Renal excretion of the glucuronide
(and possibly zidovudine itself) is reduced in the presence of probenecid. Patients receiving both drugs
should be closely monitored for haematological toxicity.
Phenytoin blood levels have been reported to be low in some patients receiving zidovudine, while in
one patient a high level was noted. These observations suggest that phenytoin concentrations should
be carefully monitored in patients receiving Trizivir and phenytoin.
In a pharmacokinetic study co-administration of zidovudine and atovaquone tablets showed a decrease
in zidovudine clearance after oral dosing leading to a 35 %
±
23 % increase in plasma zidovudine
9
AUC. The mode of interaction is unknown and as higher concentrations of atovaquone can be
achieved with atovaquone suspension it is possible that greater changes in the AUC values for
zidovudine might be induced when atovaquone is administered as a suspension. Given the limited data
available the clinical significance of this is unknown.
Valproic acid, fluconazole or methadone when co-administered with zidovudine have been shown to
increase the AUC of zidovudine, with a corresponding decrease in its clearance. As only limited data
are available the clinical significance of this is not known. If zidovudine is used concurrently with
either valproic acid, fluconazole or methadone, patients should be monitored closely for potential
toxicity of zidovudine.
Zidovudine and stavudine in combination are antagonistic
in vitro,
therefore, the concomitant use of
stavudine with Trizivir should be avoided (see Section 4.4).
Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen
used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of
ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4).
Consideration should be given to replacing zidovudine in a combination ART regimen if this is
already established. This would be particularly important in patients with a known history of
zidovudine induced anaemia.
Concomitant treatment, especially acute therapy, with potentially nephrotoxic or myelosuppressive
medicinal products (e.g. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole,
amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also
increase the risk of adverse reactions to zidovudine. If concomitant therapy with Trizivir and any of
these medicinal products is necessary then extra care should be taken in monitoring renal function and
haematological parameters and, if required, the dose of one or more agents should be reduced.
Limited data from clinical trials do not indicate a significantly increased risk of adverse reactions to
zidovudine with co-trimoxazole (see interaction information above relating to lamivudine and
cotrimoxazole) aerosolised pentamidine, pyrimethamine and acyclovir at doses used in prophylaxis.
Co-administration of Trizivir with high doses of co-trimoxazole for the treatment of
Pneumocystis
carinii
pneumonia (PCP) and toxoplasmosis should be avoided.
Clarithromycin tablets reduce the absorption of zidovudine. This can be avoided by separating the
administration of Trizivir and clarithromycin by at least two hours.
Pregnancy
Trizivir is not recommended during pregnancy. There are no data on the use of Trizivir in pregnancy.
Placental transfer of lamivudine and zidovudine occurs in humans, and for abacavir has been
confirmed in animals. Studies with abacavir, lamivudine and zidovudine in animals have shown
reproductive toxicity (see section 5.3). As the active substances of Trizivir may inhibit DNA
replication any use, especially during the first trimester, presents a potential risk to the foetus.
Breastfeeding
Both lamivudine and zidovudine are excreted in human milk at similar concentrations to those found
in serum. It is expected that abacavir will also be secreted into human milk, although this has not been
confirmed. It is therefore recommended that mothers do not breast-feed their babies while receiving
treatment with Trizivir. Additionally, it is recommended that HIV infected women do not breast-feed
their infants under any circumstances in order to avoid transmission of HIV.
10
No studies on the effects on the ability to drive and use machines have been performed. The clinical
status of the patient and the adverse event profile of Trizivir should be borne in mind when
considering the patient’s ability to drive or operate machinery.
Summary of the safety profile
Adverse reactions have been reported with abacavir, lamivudine and zidovudine used separately or in
combination for therapy of HIV disease. Because Trizivir contains abacavir, lamivudine and
zidovudine, the adverse reactions associated with these compounds may be expected.
Hypersensitivity to abacavir
(see also section 4.4
):
In a clinical study, 3.4 % of subjects with a negative HLA-B*5701 status receiving abacavir developed
a hypersensitivity reaction.
Some hypersensitivity reactions were life-threatening and resulted in fatal outcome despite taking
precautions. This reaction is characterised by the appearance of symptoms indicating multi-
organ/body-system involvement.
Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually
maculopapular or urticarial) as part of the syndrome, however hypersensitivity reactions have occurred
without rash or fever.
The signs and symptoms associated with hypersensitivity to abacavir are summarised in Table 1.
These have been identified either from clinical studies or post marketing surveillance.
Some patients with hypersensitivity reactions were initially thought to have gastroenteritis, respiratory
disease (pneumonia, bronchitis, pharyngitis) or a flu-like illness. This delay in diagnosis of
hypersensitivity has resulted in abacavir being continued or re-introduced, leading to more severe
hypersensitivity reactions or death. Therefore, the diagnosis of hypersensitivity reaction should be
carefully considered for patients presenting with symptoms of these diseases.
Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of
treatment with abacavir, although these reactions may occur at any time during therapy. Close medical
supervision is necessary during the first two months, with consultations every two weeks.
It is likely that intermittent therapy may increase the risk of developing sensitisation and therefore
occurrence of clinically significant hypersensitivity reactions. Consequently, patients should be
advised of the importance of taking Trizivir regularly.
Restarting Trizivir, or any other medicinal product containing abacavir, following a hypersensitivity
reaction would result in a prompt return of symptoms within hours. This recurrence of the
hypersensitivity reaction is usually more severe than on initial presentation and may include life-
threatening hypotension and death.
Regardless of their HLA-B*5701 status,
patients who develop
this hypersensitivity reaction must discontinue Trizivir and must never be rechallenged with
Trizivir, or any other medicinal product containing abacavir (i.e. Kivexa, Ziagen).
To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction,
Trizivir must be permanently discontinued if hypersensitivity cannot be ruled out, even when other
diagnoses are possible (respiratory disease, flu-like illness, gastroenteritis or reactions to other
medications).
Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred
after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity
11
(skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and
malaise) prior to stopping abacavir. The most common isolated symptom of a hypersensitivity
reaction was a skin rash. Moreover, on very rare occasions hypersensitivity reactions have been
reported in patients who have restarted therapy and who had
no preceding symptoms
of a
hypersensitivity reaction.
In both cases if a decision is made to restart Trizivir this must be done in a
setting where medical assistance is readily available.
Each patient must be warned about this hypersensitivity reaction to abacavir.
Table 1:
Summary of signs and symptoms associated with hypersensitivity to abacavir
(Signs and symptoms reported in at least 10 % of patients with a hypersensitivity reaction to abacavir
are in
bold text
).
Body system
Adverse reactions
Blood and the lymphatic
system disorders
Lymphopenia, lymphadenopathy
Immune system disorders
Anaphylaxis
Nervous system disorders
Headache
, paraesthesia,
lethargy
Eye disorders
Conjunctivitis
Vascular disorders
Hypotension
Respiratory, thoracic and
mediastinal disorders
Dyspnoea,
sore throat,
cough,
adult respiratory distress syndrome, respiratory
failure
Gastrointestinal disorders
Nausea, vomiting, diarrhoea, abdominal pain
, mouth ulceration
Hepato-biliary disorders
Hepatitis, hepatic failure
Skin and subcutaneous
tissue disorders
Rash
(usually maculopapular or urticarial)
Musculoskeletal connective
tissue and bone disorders
Myalgia,
rarely myolysis, arthralgia
Renal and urinary
disorders
Renal failure
General disorders and
administration site
conditions
Fever, malaise,
oedema
Investigations
Elevated liver function tests
, elevated creatine phosphokinase, elevated
creatinine
Tabulated list of adverse reactions reported with the individual substances
The adverse reactions reported with abacavir, lamivudine and zidovudine are presented in Table 2.
They are listed by body system, organ class and absolute frequency. Frequencies are defined as very
common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to
12
< 1/1000), very rare (< 1/10,000). Care must be taken to eliminate the possibility of a hypersensitivity
reaction if any of these symptoms occur.
Table 2
: Adverse reactions reported with the individual components of Trizivir
Abacavir
Lamivudine
Zidovudine
IMPORTANT: for information on abacavir hypersensitivity, see the description above in the
boxed information and Table 1
Blood and lymphatic system disorders
Uncommon:
neutropenia,
anaemia (both occasionally
severe), thrombocytopenia
Very rare:
pure red cell aplasia
Common:
anaemia, neutropenia
and leucopenia
Uncommon:
thrombocytopenia
and pancytopenia with marrow
hypoplasia
Rare:
pure red cell aplasia
Very rare:
aplastic anaemia
Immune system disorders
Common:
hypersensitivity
Metabolism and nutrition disorders
Common:
anorexia
Rare:
anorexia, lactic acidosis
in the absence of hypoxaemia
Psychiatric disorders
Rare:
anxiety, depression
Nervous system disorders
Common:
headache
Common:
headache, insomnia
Very rare:
peripheral
neuropathy (paraesthesiae)
Very common:
headache
Common:
dizziness
Rare:
insomnia, paraesthesia,
somnolence, loss of mental
acuity, convulsions
Cardiac disorders
Rare:
cardiomyopathy
Respiratory, thoracic and mediastinal disorders
Common:
cough, nasal
symptoms
Uncommon:
dyspnoea
Rare:
cough
13
Abacavir
Lamivudine
Zidovudine
Gastrointestinal disorders
Common:
nausea, vomiting,
diarrhoea
Rare:
pancreatitis
Common:
nausea, vomiting,
abdominal pain, diarrhoea
Rare:
rises in serum amylase,
pancreatitis
Very common:
Nausea
Common:
vomiting, abdominal
pain, and diarrhoea
Uncommon:
flatulence
Rare:
oral mucosa
pigmentation, taste disturbance
dyspepsia, pancreatitis
Hepatobiliary disorders
Uncommon:
transient rises in
liver enzymes (AST, ALT)
Rare:
hepatitis
Common:
raised blood levels of
liver enzymes and bilirubin
Rare:
liver disorders such as
severe hepatomegaly with
steatosis,
Skin and subcutaneous tissue disorders
Common:
rash (without
systemic symptoms)
Very
rare:
erythema
multiforme, Stevens-Johnson
syndrome and toxic epidermal
necrolysis
Common:
rash, alopecia
Uncommon:
rash and pruritus
Rare:
nail and skin
pigmentation, urticaria and
sweating
Musculoskeletal and connective tissue disorders
Common:
arthralgia,
muscle
disorders
Rare:
rhabdomyolysis
Common:
myalgia
Uncommon:
myopathy
Renal and urinary disorders
Rare:
urinary frequency
Reproductive system and breast disorders
Rare:
gynaecomastia
General disorders and administration site conditions
Common:
fever, lethargy,
fatigue
Common:
fatigue, malaise, fever
Common:
malaise
Uncommon:
fever, generalised
pain and asthenia
Rare:
chills, chest pain, and
influenza-like syndrome
Description of selected adverse reactions
Adverse reactions associated with abacavir:
Many of the adverse reactions listed above occur commonly (nausea, vomiting, diarrhoea, fever,
14
lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these
symptoms should be carefully evaluated for the presence of this hypersensitivity reaction. If Trizivir
has been discontinued in patients due to experiencing any one of these symptoms and
a decision is
made to restart a medicinal product containing abacavir, this must be done in a setting where medical
assistance is readily available (see Section 4.4). Very rarely cases of erythema multiforme, Stevens
Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity
could not be ruled out. In such cases medicinal products containing abacavir should be permanently
discontinued.
Haematological adverse reactions with zidovudine
Anaemia, neutropenia and leucopenia occurred more frequently at higher doses (1,200-1,500 mg/day)
and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to
treatment) and particularly in patients with CD4 cell counts less than 100/mm
3
. Dose reduction or
cessation of therapy may become necessary (see section 4.4). The anaemia may necessitate
transfusions.
The incidence of neutropenia was also increased in those patients whose neutrophil counts,
haemoglobin levels and serum vitamin B
12
levels were low at the start of zidovudine therapy.
Lactic acidosis
Treatment with nucleoside analogues has been associated with cases of lactic acidosis, sometimes
fatal, usually associated with severe hepatomegaly and hepatic steatosis, (see section 4.4).
Lipodystrophy/metabolic abnormalities
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV 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).
Immune Reactivation Syndrome
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).
Osteonecrosis
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).
There is no experience of overdose with Trizivir. No specific symptoms or signs have been identified
following acute overdose with zidovudine or lamivudine apart from those listed as adverse reactions.
No fatalities occurred, and all patients recovered. Single doses up to 1,200 mg and daily doses up to
1,800 mg of abacavir have been administered to patients in clinical studies. No unexpected adverse
reactions were reported. The effects of higher doses are not known.
If overdose occurs the patient should be monitored for evidence of toxicity (see section 4.8), and
standard supportive treatment applied as necessary. Since lamivudine is dialysable, continuous
15
haemodialysis could be used in the treatment of overdose, although this has not been studied.
Haemodialysis and peritoneal dialysis appear to have a limited effect on elimination of zidovudine, but
enhance the elimination of the glucuronide metabolite. It is not known whether abacavir can be
removed by peritoneal dialysis or haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group
: Antivirals for systemic use, antivirals for treatment of HIV infections,
combinations. ATC Code: J05AR04.
Mechanism of action
:Abacavir, lamivudine and zidovudine are all NRTIs, and are potent selective
inhibitors of HIV-1 and HIV-2.All three medicinal products are metabolised sequentially by
intracellular kinases to the respective 5′-triphosphate (TP). Lamivudine-TP, carbovir-TP (the active
triphosphate form of abacavir) and zidovudine-TP are substrates for and competitive inhibitors of HIV
reverse transcriptase (RT). However, their main antiviral activity is through incorporation of the
monophosphate form into the viral DNA chain, resulting in chain termination. Abacavir, lamivudine
and zidovudine triphosphates show significantly less affinity for host cell DNA polymerases.
Lamivudine has been shown to be highly synergistic with zidovudine, inhibiting the replication of
HIV in cell culture. Abacavir shows synergy
in vitro
in combination with nevirapine and zidovudine.
It has been shown to be additive in combination with didanosine, stavudine and lamivudine.
In vitro resistance
: HIV-1 resistance to lamivudine involves the development of a M184I or, more
commonly, M184V amino acid change close to the active site of the viral RT.
Abacavir-resistant isolates of HIV-1 have been selected
in vitro
and are associated with specific
genotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115F). Viral
resistance to abacavir develops relatively slowly
in vitro,
requiring multiple mutations for a clinically
relevant increase in EC
50
over wild-type virus.
In vivo resistance (therapy naïve patients)
:
The M184V or M184I variants arise in HIV-1 infected
patients treated with lamivudine-containing antiretroviral therapy. Most patients experiencing
virological failure with a regimen containing abacavir in a pivotal clinical trial with Combivir (fixed
dose combination of lamivudine and zidovudine) showed either no NRTI-related changes from
baseline (15 %) or only M184V or M184I selection (78 %). The overall selection frequency for
M184V or M184I was high (85 %), and selection of L74V, K65R and Y115F was not observed (see
Table). Thymidine analogue mutations (TAMs) which are selected by zidovudine (ZDV) were also
found (8%).
Therapy
Abacavir + Combivir
Number of Subjects
282
Number of Virological Failures
43
Number of On-Therapy Genotypes
40 (100 %)
K65R
0
L74V
0
Y115F
0
M184V/I
34 (85 %)
TAMs
1
3 (8 %)
1.
Number of subjects with ≥1 TAM.
16
TAMs might be selected when thymidine analogs are associated with abacavir. In a meta-analysis of
six clinical trials, TAMs were not selected by regimens containing abacavir without zidovudine
(0/127), but were selected by regimens containing abacavir and the thymidine analogue zidovudine
(22/86, 26 %). In addition, the selection of L74V and K65R was reduced when co-administered with
ZDV (K65R: without ZDV: 13/127, 10 %; with ZDV: 1/86, 1 %; L74V: without ZDV: 51/127, 40 %;
with ZDV: 2/86, 2 %).
In vivo resistance (Therapy experienced patients):
The M184V or M184I variants arise in HIV-1
infected patients treated with lamivudine-containing antiretroviral therapy and confers high-level
resistance to lamivudine.
In vitro
data tend to suggest that the continuation of lamivudine in anti-
retroviral regimen despite the development of M184V might provide residual anti-retroviral activity
(likely through impaired viral fitness). The clinical relevance of these findings is not established.
Indeed, the available clinical data are very limited and preclude any reliable conclusion in the field. In
any case, initiation of susceptible NRTIs should always be preferred to maintenance of lamivudine
therapy. Therefore, maintaining lamivudine therapy despite emergence of M184V mutation should
only be considered in cases where no other active NRTIs are available. Similarly, the presence of
TAMs gives rise to resistance to ZDV.
Clinically significant reduction of susceptibility to abacavir has been demonstrated in clinical isolates
of patients with uncontrolled viral replication, who have been pre-treated with and are resistant to
other nucleoside inhibitors. In a meta-analysis of five clinical trials where abacavir was added to
intensify therapy, of 166 subjects, 123 (74 %) had M184V/I, 50 (30 %) had T215Y/F, 45 (27%) had
M41L, 30 (18 %) had K70R and 25 (15%) had D67N. K65R was absent and L74V and Y115F were
uncommon (≤3 %). Logistic regression modelling of the predictive value for genotype (adjusted for
baseline plasma HIV-1 RNA [vRNA], CD4+ cell count, number and duration of prior antiretroviral
therapies) showed that the presence of 3 or more NRTI resistance-associated mutations was associated
with reduced response at Week 4 (p=0.015) or 4 or more mutations at median Week 24 (p≤0.012). In
addition, the 69 insertion complex or the Q151M mutation, usually found in combination with A62V,
V75I, F77L and F116Y, cause a high level of resistance to abacavir.
Baseline Reverse
Transcriptase
Mutation
Week 4
(n = 166)
n
Median
Change vRNA
(log
10
c/mL)
Percent with
<400 copies/mL vRNA
None
15
-0.96
40 %
M184V alone
75
-0.74
64 %
Any one NRTI
mutation
82
-0.72
65 %
Any two NRTI-
associated mutations
22
-0.82
32 %
Any three NRTI-
associated mutations
19
-0.30
5 %
Four or more NRTI-
associated mutations
28
-0.07
11 %
Phenotypic resistance and cross-resistance:
Phenotypic resistance to abacavir requires M184V with at
least one other abacavir-selected mutation, or M184V with multiple TAMs. Phenotypic cross-
resistance to other NRTIs with M184V or M184I mutation alone is limited. Zidovudine, didanosine,
stavudine and tenofovir maintain their antiretroviral activities against such HIV-1 variants. The
presence of M184V with K65R does give rise to cross-resistance between abacavir, tenofovir,
didanosine and lamivudine, and M184V with L74V gives rise to cross-resistance between abacavir,
didanosine and lamivudine. The presence of M184V with Y115F gives rise to cross-resistance
between abacavir and lamivudine. Appropriate use of abacavir can be guided using currently
recommended resistance algorithms.
17
Cross-resistance between abacavir, lamivudine or zidovudine and antiretrovirals from other classes
e.g. PIs or NNRTIs is unlikely.
Clinical experience
One randomised, double blind, placebo controlled clinical study has compared the combination of
abacavir, lamivudine and zidovudine to the combination of indinavir, lamivudine and zidovudine in
treatment naive patients. Due to the high proportion of premature discontinuation (42 % of patients
discontinued randomised treatment by week 48), no definitive conclusion can be drawn regarding the
equivalence between the treatment regimens at week 48. Although a similar antiviral effect was
observed between the abacavir and indinavir containing regimens in terms of proportion of patients
with undetectable viral load (≤ 400 copies/ml; intention to treat analysis (ITT), 47 % versus 49 %; as
treated analysis (AT), 86 % versus 94 % for abacavir and indinavir combinations respectively), results
favoured the indinavir combination, particularly in the subset of patients with high viral load
(> 100,000 copies/ml at baseline; ITT, 46 % versus 55 %; AT, 84 % versus 93 % for abacavir and
indinavir respectively).
ACTG5095 was a randomised (1:1:1), double-blind, placebo-controlled trial performed in 1147
antiretroviral naïve HIV-1 infected adults, comparing 3 regimens: zidovudine (ZDV), lamivudine
(3TC), abacavir (ABC), efavirenz (EFV) vs ZDV/3TC/EFV vs ZDV/3TC/ABC. After a median
follow-up of 32 weeks, the tritherapy with the three nucleosides ZDV/3TC/ABC was shown to be
virologically inferior to the two other arms regardless of baseline viral load (< or > 100 000 copies/ml)
with 26 % of subjects on the ZDV/3TC/ABC arm, 16 % on the ZDV/3TC/EFV arm and 13 % on the 4
drug arm categorised as having virological failure (HIV RNA >200 copies/ml). At week 48 the
proportion of subjects with HIV RNA <50 copies/ml were 63 %, 80 % and 86 % for the
ZDV/3TC/ABC, ZDV/3TC/EFV and ZDV/3TC/ABC/EFV arms, respectively. The study Data Safety
Monitoring Board stopped the ZDV/3TC/ABC arm at this time based on the higher proportion of
patients with virologic failure. The remaining arms were continued in a blinded fashion. After a
median follow-up of 144 weeks, 25 % of subjects on the ZDV/3TC/ABC/EFV arm and 26 % on the
ZDV/3TC/EFV arm were categorised as having virological failure. There was no significant
difference in the time to first virologic failure (p=0.73, log-rank test) between the 2 arms. In this study,
addition of ABC to ZDV/3TC/EFV did not significantly improve efficacy.
ZDV/3TC/ABC ZDV/3TC/EFV
ZDV/3TC/ABC/EFV
Virologic failure (HIV
RNA >200 copies/ml)
32 weeks
26 %
16 %
13 %
144 weeks -
26 %
25 %
Virologic success (48
weeks HIV RNA < 50
copies/ml)
63 %
80 %
86 %
In an ongoing clinical study over 16 weeks in treatment-naive patients, the combination of abacavir,
lamivudine and zidovudine showed a similar antiviral effect to the combination with nelfinavir,
lamivudine and zidovudine.
In antiretroviral-naïve patients the triple combination of abacavir, lamivudine and zidovudine was
superior in terms of durability of viral load response over 48 weeks to lamivudine and zidovudine. In a
similar patient population durability of antiviral response over 120 weeks was demonstrated in
approximately 70 % of subjects.
In antiretroviral-naive patients treated with a combination of abacavir, lamivudine, zidovudine and
efavirenz in a small, ongoing, open label pilot study, the proportion of patients with undetectable viral
load (< 400 copies/ml) was approximately 90 % with 80 % having < 50 copies/ml after 24 weeks of
treatment.
18
In patients with a low baseline viral load (< 5,000 copies/ml) and moderate exposure to antiretroviral
therapy, addition of abacavir to previous treatment including lamivudine and zidovudine, produced a
moderate impact on viral load at 48 weeks.
Currently there are no data on the use of Trizivir in heavily pre-treated patients, patients failing on
other therapies or patients with advanced disease (CD4 cells < 50 cells/mm
3
).
The degree of benefit of this nucleoside combination in heavily pre-treated patients will depend on the
nature and duration of prior therapy that may have selected for HIV-1 variants with cross-resistance to
abacavir, lamivudine or zidovudine.
To date there are insufficient data on the efficacy and safety of Trizivir given concomitantly with
NNRTIs or PIs.
5.2 Pharmacokinetic properties
Absorption
Abacavir, lamivudine and zidovudine are rapidly and well absorbed from the gastro-intestinal tract
following oral administration. The absolute bioavailability of oral abacavir, lamivudine and
zidovudine in adults is about 83 %, 80 - 85 % and 60 - 70 % respectively.
In a pharmacokinetic study in HIV-1 infected patients, the steady state pharmacokinetic parameters of
abacavir, lamivudine and zidovudine were similar when either Trizivir alone or the combination tablet
lamivudine/zidovudine and abacavir in combination were administered, and also similar to the values
obtained in the bioequivalence study of Trizivir in healthy volunteers.
A bioequivalence study compared Trizivir with abacavir 300 mg, lamivudine 150 mg and zidovudine
300 mg taken together. The effect of food on the rate and extent of absorption was also studied.
Trizivir was shown to be bioequivalent to abacavir 300 mg, lamivudine 150 mg and zidovudine
300 mg given as separate tablets for AUC
0-∞
and C
max
. Food decreased the rate of absorption of
Trizivir (slight decrease C
max
(mean 18 - 32 %) and increase t
max
(approximately 1 hour), but not the
extent of absorption (AUC
0-∞
). These changes are not considered clinically relevant and no food
restrictions are recommended for administration of Trizivir.
At a therapeutic dose (one Trizivir tablet twice daily) in patients, the mean (CV) steady-state C
max
of
abacavir, lamivudine and zidovudine in plasma are 3.49 µg/ml (45 %), 1.33 µg/ml (33 %) and
1.56 µg/ml (83 %), respectively. Corresponding values for C
min
could not be established for abacavir
and are 0.14 µg/ml (70 %) for lamivudine and 0.01 µg/ml (64 %) for zidovudine. The mean (CV)
AUCs for abacavir, lamivudine and zidovudine over a dosing interval of 12 hours are 6.39 µg.h/ml
(31 %), 5.73 µg.h/ml (31 %) and 1.50 µg.h/ml (47 %), respectively.
A modest increase in C
max
(28 %) was observed for zidovudine when administered with lamivudine,
however overall exposure (AUC) was not significantly altered. Zidovudine has no effect on the
pharmacokinetics of lamivudine. An effect of abacavir is observed on zidovudine (C
max
reduced with
20 %) and on lamivudine (C
max
reduced with 35 %).
Distribution
Intravenous studies with abacavir, lamivudine and zidovudine showed that the mean apparent volume
of distribution is 0.8, 1.3 and 1.6 l/kg respectively. Lamivudine exhibits linear pharmacokinetics over
the therapeutic dose range and displays limited binding to the major plasma protein albumin (< 36 %
serum albumin
in vitro
). Zidovudine plasma protein binding is 34 % to 38 %. Plasma protein binding
studies
in vitro
indicate that abacavir binds only low to moderately (~ 49 %) to human plasma proteins
at therapeutic concentrations. This indicates a low likelihood for interactions with other medicinal
products through plasma protein binding displacement.
19
Interactions involving binding site displacement are not anticipated with Trizivir.
Data show that abacavir, lamivudine and zidovudine penetrate the central nervous system (CNS) and
reach the cerebrospinal fluid (CSF). The mean ratios of CSF/serum lamivudine and zidovudine
concentrations 2 - 4 hours after oral administration were approximately 0.12 and 0.5 respectively. The
true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is
unknown.
Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44 %. The observed
values of the peak concentrations are 9 fold greater than the IC
50
of abacavir of 0.08 µg/ml or 0.26 µM
when abacavir is given at 600 mg twice daily
.
Biotransformation
Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared by
renal excretion of unchanged lamivudine. The likelihood of metabolic drug interactions with
lamivudine is low due to the small extent of hepatic metabolism (5 - 10 %) and low plasma binding.
The 5’-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for
approximately 50 - 80 % of the administered dose eliminated by renal excretion. 3’-amino-3’-
deoxythymidine (AMT) has been identified as a metabolite of zidovudine following intravenous
dosing.
Abacavir is primarily metabolised by the liver with approximately 2 % of the administered dose being
renally excreted, as unchanged compound. The primary pathways of metabolism in man are by alcohol
dehydrogenase and by glucuronidation to produce the 5’-carboxylic acid and 5’-glucuronide which
account for about 66 % of the dose excreted in the urine.
Elimination
The observed lamivudine half-life of elimination is 5 to 7 hours. The mean systemic clearance of
lamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (> 70 %) via the organic
cationic transport system. Studies in patients with renal impairment show lamivudine elimination is
affected by renal dysfunction. Dose reduction is required for patients with creatinine clearance
≤ 50 ml/min (see section 4.2).
From studies with intravenous zidovudine, the mean terminal plasma half-life was 1.1 hours and the
mean systemic clearance was 1.6 l/h/kg. Renal clearance of zidovudine is estimated to be 0.34 l/h/kg,
indicating glomerular filtration and active tubular secretion by the kidneys. Zidovudine concentrations
are increased in patients with advanced renal failure.
The mean half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mg
twice a day there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic
metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and
unchanged abacavir account for about 83 % of the administered abacavir dose in the urine the
remainder is eliminated in the faeces.
Special populations
Hepatically impaired:
There are no data available on the use of Trizivir in hepatically impaired
patients. Limited data in patients with cirrhosis suggest that accumulation of zidovudine may occur in
patients with hepatic impairment because of decreased glucuronidation. Data obtained in patients with
moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly
affected by hepatic dysfunction.
Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in
patients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose. The
20
results showed that there was a mean increase of 1.89 fold [1.32; 2.70] in the abacavir AUC, and 1.58
[1.22; 2.04] fold in the elimination half-life. No recommendation on dose reduction is possible in
patients with mild hepatic impairment due to substantial variability of abacavir exposure in this patient
population. The pharmacokinetics of abacavir have not been studied in patients with moderate or
severe hepatic impairment. Plasma concentrations of abacavir are expected to be variable and
substantially increased in these patients (see section 4.3).
Renally impaired:
The observed lamivudine half-life of elimination is 5 to 7 hours. The mean systemic
clearance of lamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (> 70 %) via
the organic cationic transport system. Studies in patients with renal impairment show lamivudine
elimination is affected by renal dysfunction.
From studies with intravenous zidovudine, the mean terminal plasma half-life was 1.1 hours and the
mean systemic clearance was 1.6 l/h/kg. Renal clearance of zidovudine is estimated to be 0.34 l/h/kg,
indicating glomerular filtration and active tubular secretion by the kidneys. Zidovudine concentrations
are increased in patients with advanced renal failure.
Abacavir is primarily metabolised by the liver with approximately 2 % of abacavir excreted
unchanged in the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is
similar to patients with normal renal function, and, therefore, no dose reduction is required in patients
with renal impairment.
As dose adjustments of lamivudine and zidovudine may be necessary it is recommended that separate
preparations of abacavir, lamivudine and zidovudine be administered to patients with reduced renal
function (creatinine clearance ≤ 50 ml/min). Trizivir is contraindicated in patients with end-stage renal
disease (see section 4.3).
Elderly
: No pharmacokinetic data are available in patients over 65 years of age.
5.3 Preclinical safety data
There are no data available on treatment with the combination of abacavir, lamivudine and zidovudine
in animals. The clinically relevant toxicological effects of these three medicinal products are anaemia,
neutropenia and leucopenia.
Mutagenicity and carcinogenicity
Neither abacavir, lamivudine nor zidovudine is mutagenic in bacterial tests, but like many nucleoside
analogues they show activity in the
in vitro
mammalian tests such as the mouse lymphoma assay. This
is consistent with the known activity of other nucleoside analogues.
Lamivudine has not shown any genotoxic activity in the
in vivo
studies at doses that gave plasma
concentrations up to 40 - 50 times higher than clinical plasma levels. Zidovudine showed clastogenic
effects in oral repeated dose micronucleus tests in mice and rats. Peripheral blood lymphocytes from
AIDS patients receiving zidovudine treatment have also been observed to contain higher numbers of
chromosome breakages.
A pilot study has demonstrated that zidovudine is incorporated into leukocyte nuclear DNA of adults,
including pregnant women, taking zidovudine as treatment for HIV-1 infection, or for the prevention
of mother to child viral transmission. Zidovudine was also incorporated into DNA from cord blood
leukocytes of infants from zidovudine-treated mothers. A transplacental genotoxicity study conducted
in monkeys compared zidovudine alone with the combination of zidovudine and lamivudine at human-
equivalent exposures. The study demonstrated that foetuses exposed
in utero
to the combination
sustained a higher level of nucleoside analogue-DNA incorporation into multiple foetal organs, and
showed evidence of more telomere shortening than in those exposed to zidovudine alone. The clinical
significance of these findings is unknown.
21
Abacavir has a weak potential to cause chromosomal damage both
in vitro
and
in vivo
at high test
concentrations and therefore any potential risk to man must be balanced against the expected benefits
of treatment.
The carcinogenic potential of a combination of abacavir, lamivudine and zidovudine has not been
tested. In long-term oral carcinogenicity studies in rats and mice, lamivudine did not show any
carcinogenic potential. In oral carcinogenicity studies with zidovudine in mice and rats, late appearing
vaginal epithelial tumours were observed. A subsequent intravaginal carcinogenicity study confirmed
the hypothesis that the vaginal tumours were the result of long term local exposure of the rodent
vaginal epithelium to high concentrations of unmetabolised zidovudine in urine. There were no other
zidovudine-related tumours observed in either sex of either species.
In addition, two transplacental carcinogenicity studies have been conducted in mice. In one study, by
the US National Cancer Institute, zidovudine was administered at maximum tolerated doses to
pregnant mice from day 12 to 18 of gestation. One year postnatally, there was an increase in the
incidence of tumours in the lung, liver and female reproductive tract of offspring exposed to the
highest dose level (420 mg/kg term body weight).
In a second study, mice were administered zidovudine at doses up to 40 mg/kg for 24 months, with
exposure beginning prenatally on gestation day 10. Treatment related findings were limited to late-
occurring vaginal epithelial tumours, which were seen with a similar incidence and time of onset as in
the standard oral carcinogenicity study. The second study thus provided no evidence that zidovudine
acts as a transplacental carcinogen.
It is concluded that as the increase in incidence of tumours in the first transplacental carcinogenicity
study represents a hypothetical risk, this should be balanced against the proven therapeutic benefit.
Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the
incidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial gland
of males and the clitoral gland of females of both species, and in rats in the thyroid gland of males and
and in the liver, urinary bladder, lymph nodes and the subcutis of females.
The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and
600 mg/kg/day in rats. The exception was the preputial gland tumour which occurred at a dose of
110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3
and 7 times the human systemic exposure during therapy. While the carcinogenic potential in humans
is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential
clinical benefit.
Repeat-dose toxicity
In toxicology studies abacavir was shown to increase liver weights in rats and monkeys. The clinical
relevance of this is unknown. There is no evidence from clinical studies that abacavir is hepatotoxic.
Additionally, autoinduction of abacavir metabolism or induction of the metabolism of other medicinal
products hepatically metabolised has not been observed in man.
Mild myocardial degeneration in the heart of mice and rats was observed following administration of
abacavir for two years. The systemic exposures were equivalent to 7 to 24 times the expected systemic
exposure in humans. The clinical relevance of this finding has not been determined.
Reproductive toxicology
Lamivudine was not teratogenic in animal studies but there were indications of an increase in early
embryonic deaths in the rabbit at relatively low systemic exposures, comparable to those achieved in
humans. A similar effect was not seen in rats even at very high systemic exposure.
22
Zidovudine had a similar effect in both species, but only at very high systemic exposures. At
maternally toxic doses, zidovudine given to rats during organogenesis resulted in an increased
incidence of malformations, but no evidence of foetal abnormalities was observed at lower doses.
Abacavir demonstrated toxicity to the developing embryo and foetus in rats, but not in rabbits. These
findings included decreased foetal body weight, foetal oedema, and an increase in skeletal
variations/malformations, early intra-uterine deaths and still births. No conclusion can be drawn with
regard to the teratogenic potential of abacavir because of this embryo-foetal toxicity.
A fertility study in the rat has shown that abacavir had no effect on male or female fertility. Likewise,
neither lamivudine nor zidovudine had any effect on fertility. Zidovudine has not been shown to affect
the number of sperm, sperm morphology and motility in man.
6.
6.1 List of excipients
Core
:
microcrystalline cellulose,
sodium starch glycollate (type A),
magnesium stearate.
Coating
:
Opadry Green 03B11434 containing: hypromellose, titanium dioxide, polyethylene glycol, indigo
carmine aluminium lake, iron oxide yellow.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 30°C
6.5 Nature and contents of container
Trizivir tablets are available in opaque PVC/PCTFE or PVC/ PCTFE /PVC blister packs containing 60
tablets or child-resistant HDPE bottles containing 60 tablets.
6.6 Special precautions for disposal
Any unused product should be disposed of in accordance with local requirements.
7.
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
23
8.
EU/1/00/156/002 – PVC/Aclar Blister pack (60 Tablets)
EU/1/00/156/003 -Bottle pack (60 Tablets)
EU/1/00/156/004 - PVC/Aclar/PVC Blister pack (60 Tablets)
9.
Date of first authorisation: 28 December 2000
Date of latest renewal:
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.ema.europa.eu
24
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
25
A.
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations),
Priory Street,
Ware,
Hertfordshire, SG 12 0DJ, UK
Or
GlaxoSmithKline Pharmaceuticals S.A.
ul. Grunwaldzka 189
60-322 Poznan
Poland
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, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
PSURs
PSURs will have to be submitted yearly, until otherwise specified by the
CHMP.
26
ANNEX III
LABELLING AND PACKAGE LEAFLET
27
A. LABELLING
28
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BLISTER CARTON x 60 FILM-COATED TABLETS
1.
Trizivir 300 mg/150 mg/300 mg film-coated tablets
abacavir/lamivudine/zidovudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains:
abacavir 300 mg (as sulfate)
lamivudine 150 mg
zidovudine 300 mg
3.
LIST OF EXCIPIENTS
4.
60 film-coated 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
Detach enclosed Alert Card, it contains important safety information
WARNING! In case of any symptoms suggesting hypersensitivity reactions, contact your doctor
IMMEDIATELY.
“
Pull here
” (with Alert card attached)
8.
EXPIRY DATE
EXP
29
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/00/156/002 PVC/Aclar
EU/1/00/156/004 PVC/Aclar/PVC
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Trizivir
30
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER x 60 FILM-COATED TABLETS
1.
Trizivir 300 mg/150 mg/300 mg tablets
abacavir/lamivudine/zidovudine
2.
ViiV Healthcare UK Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BOTTLE CARTON x 60 FILM COATED TABLETS
1.
Trizivir 300 mg/150 mg/300 mg film-coated tablets
abacavir/lamivudine/zidovudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains:
abacavir 300 mg (as sulfate)
lamivudine 150 mg
zidovudine 300 mg
3.
LIST OF EXCIPIENTS
4.
60 film-coated 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
Detach enclosed Alert Card, it contains important safety information
WARNING! In case of any symptoms suggesting hypersensitivity reactions, contact your doctor
IMMEDIATELY.
“
Pull here
” (with Alert card attached)
8.
EXPIRY DATE
EXP
32
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/00/156/003
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Trizivir
33
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE LABEL x 60 FILM-COATED TABLETS
1.
Trizivir 300 mg/150 mg/300 mg film-coated tablets
abacavir/lamivudine/zidovudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains:
abacavir 300 mg (as sulfate)
lamivudine 150 mg
zidovudine 300 mg
3.
LIST OF EXCIPIENTS
4.
60 film-coated 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
Do not store above 30°C
34
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/00/156/003
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
35
TRIZIVIR TABLETS ALERT CARD (blister and bottle pack)
SIDE 1
IMPORTANT - ALERT CARD
TRIZIVIR (abacavir sulfate / lamivudine / zidovudine) Tablets
Carry this card with you at all times
Since Trizivir contains abacavir (Ziagen) some patients taking Trizivir may develop a hypersensitivity
reaction (serious allergic reaction)
which
can be life-threatening
if treatment with Trizivir is
continued.
CONTACT YOUR DOCTOR IMMEDIATELY for advice on whether you should
stop taking Trizivir if:
1) you get a skin rash OR
2) you get one or more symptoms from at least TWO of the following groups
- fever
- shortness of breath, sore throat or cough
- nausea or vomiting or diarrhoea or abdominal pain
- severe tiredness or achiness or generally feeling ill
If you have discontinued Trizivir due to this reaction,
YOU MUST NEVER
TAKE
Trizivir, or any
medicine containing abacavir (
Kivexa
,
Ziagen
) again as
within hours
you may experience a
life-threatening lowering of your blood pressure or death.
( see reverse of card)
SIDE 2
You should immediately contact your doctor if you think you are having a hypersensitivity reaction to
Trizivir. Write your doctor's details below:
Doctor:.......................……………………………………………
Tel:...................…………………………………………
If your doctor is not available, you must urgently seek alternative medical advice (e.g. the
emergency unit of the nearest hospital).
For general Trizivir information enquiries, contact (local company name and telephone number inserted
here)
36
B. PACKAGE LEAFLET
37
PACKAGE LEAFLET: INFORMATION FOR USER
Trizivir 300 mg/150 mg/300 mg Film-coated tablets
abacavir/lamivudine/zidovudine
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet, you may need to read it again.
-
If you have any further questions ask your doctor or pharmacist.
-
This medicine has been prescribed for you personally. Do not pass it on to others. It may harm
them, even if their symptoms seem to be the same as yours.
-
If any of the side effects get serious or if you notice any side effects not listed in this
leaflet, please tell your doctor or pharmacist immediately
.
IMPORTANT — Hypersensitivity reactions
Trizivir contains abacavir
(which is also an active ingredient in medicines such as
Kivexa
and
Ziagen
). Some people who take abacavir may develop a
hypersensitivity reaction
(a serious allergic
reaction), which can be life-threatening if they continue to take abacavir.
You must carefully read all the information under ‘Hypersensitivity reactions’ in the panel in
Section 4
.
The Trizivir pack includes an
Alert Card
, to remind you and medical staff about abacavir
hypersensitivity.
Detach this card and keep it with you at all times
.
In this leaflet
1.
What Trizivir is and what it is used for
3.
How to take Trizivir
4.
Possible side effects
5.
How to store Trizivir
6.
Further information
1. WHAT TRIZIVIR IS AND WHAT IT IS USED FOR
Trizivir is used to treat HIV (human immunodeficiency virus) infection in adults
.
Trizivir contains three active ingredients that are used to treat HIV infection: abacavir, lamivudine and
zidovudine. All of these belong to a group of anti-retroviral medicines called
nucleoside analogue
reverse transcriptase inhibitors (NRTIs)
.
Trizivir helps to control your condition. Trizivir does not cure HIV infection; it reduces the amount of
virus in your body, and keeps it at a low level. This helps your body to increases the CD4 cell count in
your blood. CD4 cells are a type of white blood cells that are important in helping your body to fight
infection.
Not everyone responds to treatment with Trizivir in the same way. Your doctor will monitor the
effectiveness of your treatment.
38
2.
Before you take Trizivir
2.
BEFORE YOU TAKE TRIZIVIR
Don’t take Trizivir:
•
if you’re
allergic
(hypersensitive)
to abacavir (or any other medicine containing abacavir —
Kivexa
or
Ziagen
), lamivudine or zidovudine, or any of the other ingredients of Trizivir
(listed in
Section 6)
Carefully read all the information about hypersensitivity reactions in Section 4
.
•
if you
have
liver problems
•
if you
have
severe kidney problems
•
if you have
a very low red blood cell count
(anaemia)
or
a very low white blood cell count
(neutropenia)
.
Check with your doctor
if you think any of these apply to you.
Take special care with Trizivir
Hypersensitivity reactions
About 3 to 4 in every 100 patients treated with abacavir in a clinical trial who did not have a gene
called HLA-B*5701 developed a
hypersensitivity reaction
(a serious allergic reaction).
Carefully read all the information about hypersensitivity reactions in Section 4 of this leaflet.
Some people taking Trizivir are more at risk of serious side effects. You need to be aware of the extra
risks:
•
if you have ever had
liver disease,
including hepatitis B or C (if you have hepatitis B infection,
don’t stop Trizivir without your doctor’s advice, as your hepatitis may come back)
•
if you’re seriously
overweight
(especially if you’re a woman)
•
if you’re
diabetic
and using insulin.
Talk to your doctor if any of these apply to you
. You may need extra check-ups, including
blood tests, while you’re taking your medicine.
See Section 4 for more information
.
Risk of heart attack
It cannot be excluded that abacavir may increase the risk of having a heart attack.
Tell your doctor
if you have heart problems, if you smoke, or have other illnesses that may
increase your risk of heart disease such as high blood pressure, or diabetes. Don’t stop taking
Trizivir unless your doctor advises you to do so.
Look out for important symptoms
Some people taking Trizivir develop other conditions, which can be serious. You need to know about
important signs and symptoms to look out for while you’re taking Trizivir.
Read the information ‘Other possible side effects of Trizivir’ in Section 4 of this leaflet
.
Protect other people
HIV infection is spread by sexual contact with someone who has the infection, or by transfer of
infected blood (for example, by sharing injection needles). Trizivir will not stop you passing HIV
infection on to other people. To protect other people from becoming infected with HIV:
•
Use a condom
when you have oral or penetrative sex.
•
Avoid contact with other peoples’ blood
— for example, don’t share needles.
Taking other medicines
Tell your doctor or pharmacist if you’re taking any other medicines
, or if you’ve taken any
recently, including herbal medicines or other medicines you bought without a prescription.
Remember to tell your doctor or pharmacist if you begin taking a new medicine while you’re taking
Trizivir.
These medicines should not be used with Trizivir:
39
•
stavudine or zalcitabine, to treat
HIV infection
•
ribavirin, or injections of ganciclovir or foscarnet, to treat
viral infections
•
high doses of
co-trimoxazole
, an antibiotic.
Tell your doctor
if you’re being treated with any of these.
Some medicines can make it more likely that you’ll have side effects, or make side effects worse
These include:
•
sodium valproate, to treat
epilepsy
•
interferon, to treat
viral
infections
•
pyrimethamine, to treat
malaria
and other parasitic infections
•
dapsone, to prevent
pneumonia
and treat skin infections
•
fluconazole or flucytosine, to treat
fungal infections
such as
candida
•
pentamidine or atovaquone, to treat parasitic infections such as
PCP
•
amphotericin or co-trimoxazole, to treat
fungal and bacterial infections
•
probenecid, to treat
gout
and similar conditions, and given with some antibiotics to make them
more effective
•
methadone
, used as a
heroin substitute
•
vincristine, vinblastine or doxorubicin, to treat
cancer
.
Tell your doctor
if you’re taking any of these.
Some medicines interact with Trizivir
These include:
•
clarithromycin
, an antibiotic
If you’re taking clarithromycin, take your dose at least 2 hours before or after you take your
Trizivir.
•
phenytoin
, for treating
epilepsy
.
Tell your doctor
if you’re taking phenytoin. Your doctor may need to monitor you while
you’re taking Trizivir.
Methadone and Trizivir
Abacavir increases the rate at which methadone is removed from the body. If you are taking
methadone, you will be checked for any withdrawal symptoms. Your methadone dose may need to
be changed.
Pregnancy
Trizivir is not recommended for use during pregnancy
. Trizivir and similar medicines may cause
side effects in unborn babies. If you become pregnant while you’re taking Trizivir, your baby may be
given extra check-ups (including blood tests) to make sure it is developing normally.
If you are pregnant, if you become pregnant, or if you’re planning to become pregnant:
Talk to your doctor immediately
about the risks and benefits of taking Trizivir during your
pregnancy.
Children whose mothers took NRTIs (medicines like Trizivir) during pregnancy have a reduced risk of
being infected with HIV. This benefit is greater than the risk of having side effects.
Breast-feeding
Women who are HIV-positive must not breast-feed
, because HIV infection can be passed on to the
baby in breast milk.
If you’re breast-feeding, or thinking about breast-feeding:
Talk to your doctor immediately
.
Driving and using machines
Trizivir can make you dizzy
and have other side effects that make you less alert.
Don’t drive or operate machines
unless you’re feeling well.
40
3.
HOW TO TAKE TRIZIVIR
Always take Trizivir exactly as your doctor has told you to
. Check with your doctor or pharmacist
if you’re not sure.
Keep in touch with your doctor, and don’t stop taking Trizivir
without your doctor’s advice.
How much to take
The usual dose of Trizivir for adults is one tablet twice a day
.
Take the tablets at regular times, leaving approximately 12 hours between each tablet.
Swallow the tablets whole, with some water. Trizivir can be taken with or without food.
If you take too much Trizivir
If you accidentally take too much Trizivir, tell your doctor or your pharmacist, or contact your nearest
hospital emergency department for further advice.
If you forget to take Trizivir
If you forget to take a dose, take it as soon as you remember. Then continue your treatment as before.
Don’t take a double dose to make up for a missed dose.
It is important to take Trizivir regularly, because if you take it at irregular intervals it may not continue
to work against the HIV infection, and you may be more likely to have a hypersensitivity reaction.
If you have stopped taking Trizivir
If you have stopped taking Trizivir for any reason — especially because you think you are having side
effects, or because you have other illness:
Talk to your doctor before you start taking it again
. Your doctor will check whether your
symptoms were related to a hypersensitivity reaction. If the doctor thinks they may have been
related,
you will be told never again to take Trizivir, or any other medicine containing
abacavir (Kivexa or Ziagen)
. It is important that you follow this advice.
If your doctor advises that you can start taking Trizivir again, you may be asked to take your first
doses in a place where you will have ready access to medical care if you need it.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Trizivir can cause side effects, but not everyone gets them.
When you’re being treated for HIV, it can be hard to tell whether a symptom is a side effect of Trizivir
or other medicines you are taking, or an effect of the HIV infection itself.
So it is very important to
talk to your doctor about any changes in your health
.
About 3 to 4 in every 100 patients treated with abacavir in a clinical trial who did not have a
gene called HLA-B*5701 developed a hypersensitivity reaction
(a serious allergic reaction),
described on the other side of this leaflet under ‘Hypersensitivity reactions’.
It is very important that
you read and understand the information about this serious reaction
.
As well as the side effects listed below for Trizivir
, other conditions can develop during treatment.
It is important to read the information on the other side of this leaflet under ‘Other possible side
effects of Trizivir’.
Hypersensitivity reactions
41
Trizivir
contains
abacavir
(which is also an active ingredient in
Kivexa
and
Ziagen
).
Who gets these reactions?
Anyone taking Trizivir could develop a hypersensitivity reaction to abacavir, which could be life
threatening if they continue to take Trizivir.
You are more likely to develop such a reaction if you have a gene called
HLA-B*5701
(but you can
get a reaction even if you don’t have this gene). You should have been tested for this gene before
Trizivir was prescribed for you.
If you know you have this gene, tell your doctor before you take
Trizivir.
What are the symptoms?
The most common symptoms are:
•
fever
(high temperature) and
skin rash
.
Other common symptoms are:
•
nausea (feeling sick), vomiting (being sick), diarrhoea, abdominal (stomach) pain, severe
tiredness.
Other symptoms include:
•
pains in the joints or muscles, swelling of the neck, shortness of breath, sore throat, cough,
headache
•
occasionally, inflammation of the eye
(conjunctivitis)
, mouth ulcers, low blood pressure.
If you continue to take Trizivir, the symptoms will get worse, and may be life-threatening.
When do these reactions happen?
Hypersensitivity reactions can start at any time during treatment with Trizivir, but are more likely
during the first 6 weeks of treatment.
Occasionally, reactions have developed in people who start taking abacavir again, and had only one
symptom on the Alert Card before they stopped taking it.
Very rarely, reactions have developed in people who start taking abacavir again, but who had no
symptoms before they stopped taking it.
Contact your doctor immediately:
1
if you get symptoms from at least 2 of the following groups:
- fever
- shortness of breath, sore throat or cough
- nausea or vomiting, diarrhoea or abdominal pain
- severe tiredness or achiness, or generally feeling ill.
Your doctor may advise you to stop taking Trizivir
.
Always carry your Alert Card while you are taking Trizivir.
If you have stopped taking Trizivir
If you have stopped taking Trizivir because of a hypersensitivity reaction,
you must NEVER
AGAIN take Trizivir, or any other medicine containing abacavir (Kivexa or Ziagen)
. If you
do, within hours, your blood pressure could fall dangerously low, which could result in death.
If you have stopped taking Trizivir for any reason — especially because you think you are having side
effects, or because you have other illness:
Talk to your doctor before you start again
. Your doctor will check whether your symptoms
were related to a hypersensitivity reaction. If the doctor thinks they may have been,
you will then
42
2
if you get a skin rash, OR
be told never again to take Trizivir, or any other medicine containing abacavir (Kivexa or
Ziagen)
. It is important that you follow this advice.
If your doctor advises that you can start taking Trizivir again, you may be asked to take your first
doses in a place where you will have ready access to medical care if you need it.
If you are hypersensitive to Trizivir, return all your unused Trizivir tablets for safe disposal.
Ask your doctor or pharmacist for advice.
Very common side effects
These may affect
more than 1 in 10
people:
•
headache
•
feeling sick
(nausea)
.
Common side effects
These may affect
up to 1 in 10
people:
•
hypersensitivity reaction
•
being sick
(vomiting)
•
diarrhoea
•
stomach pains
•
loss of appetite
•
feeling dizzy
•
tiredness, lack of energy
•
fever (high temperature)
•
general feeling of being unwell
•
difficulty in sleeping
(insomnia)
•
muscle pain and discomfort
•
joint pain
•
cough
•
irritated or runny nose
•
skin rash
•
hair loss.
Common side effects that may show up in blood tests are:
•
a low red blood cell count
(anaemia)
or low white blood cell count
(neutropenia or leucopenia)
•
an increase in the level of liver enzymes
•
an increased amount in the blood of
bilirubin
(a substance produced in the liver) which may make
your skin appear yellow.
Uncommon side effects
These may affect
up to 1 in 100
people:
•
feeling breathless
•
wind
(flatulence)
•
itching
•
muscle weakness.
An uncommon side effect that may show up in blood tests is:
•
a decrease in the number of cells involved in blood clotting (thrombocytopenia), or in all kinds of
blood cells
(pancytopenia)
.
Rare side effects
These may affect
up to 1 in 1000
people:
•
liver disorders, such as jaundice, enlarged liver or fatty liver, inflammation
(hepatitis)
•
lactic acidosis (
see the next section, ‘Other possible side effects of Trizivir’
)
•
inflammation of the pancreas
(pancreatitis)
•
chest pain; disease of the heart muscle
(cardiomyopathy)
43
•
fits (convulsions)
•
feeling depressed or anxious, not being able to concentrate, feeling drowsy
•
indigestion, taste disturbance
•
changes in the colour of your nails, your skin, or the skin inside your mouth
•
a flu-like feeling — chills and sweating
•
tingly feelings in the skin (pins and needles)
•
sensation of weakness in the limbs
•
breakdown of muscle tissue
•
numbness
•
passing urine more often
•
enlarged breasts in men.
Rare side effects that may show up in blood tests are:
•
increase in an enzyme called amylase
•
a failure of the bone marrow to produce new red blood cells
(pure red cell aplasia)
.
Very rare side effects
These may affect
up to 1 in 10,000
people:
•
skin rash, which may form blisters and looks like small targets (central dark spots surrounded by
a paler area, with a dark ring around the edge)
(erythema multiforme)
•
a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and
genitals
(Stevens–Johnson syndrome)
, and a more severe form causing skin peeling in more than
30% of the body surface
(toxic epidermal necrolysis)
.
If you notice any of these symptoms contact a doctor urgently
.
A very rare side effect that may show up in blood tests is:
y
a failure of the bone marrow to produce new red or white blood cells (
aplastic anaemia
).
If you get side effects
Tell your doctor or pharmacist
if any of the side effects gets severe or troublesome, or if you
notice any side effects not listed in this leaflet.
Other possible side effects of Trizivir
Trizivir may cause other conditions to develop during HIV treatment.
Old infections may flare up
People with advanced HIV infection (AIDS) have weak immune systems, and are more likely to
develop serious infections (opportunistic infections). When these people start treatment, they may find
that old, hidden infections flare up, causing signs and symptoms of inflammation. These symptoms are
probably caused by the body’s immune system becoming stronger, so that the body starts to fight these
infections.
If you get any symptoms of infection while you’re taking Trizivir:
Tell your doctor immediately
. Don’t take other medicines for the infection without your doctor’s
advice.
Your body shape may change
People taking combination therapy for HIV may find that their body shape changes, because of
changes in fat distribution:
•
Fat may be lost from the legs, arms or face.
•
Extra fat may build up around the tummy (abdomen), or on the breasts or internal organs.
•
Fatty lumps (sometimes called buffalo hump) may appear on the back of the neck.
It is not yet known what causes these changes, or whether they have any long-term effects on your
health. If you notice changes in your body shape:
Tell your doctor
.
44
Lactic acidosis is a rare but serious side effect
Some people taking Trizivir, or other medicines like it (NRTIs), develop a condition called lactic
acidosis, together with an enlarged liver.
Lactic acidosis is caused by a build-up of lactic acid in the body. It is rare; if it happens, it usually
develops after a few months of treatment. It can be life-threatening, causing failure of internal organs.
Lactic acidosis is more likely to develop in people who have liver disease, or in obese (very
overweight) people, especially women.
Signs of lactic acidosis include:
•
deep, rapid, difficult breathing
•
drowsiness
•
numbness
or
weakness
in the limbs
•
feeling sick
(nausea),
being sick
(vomiting)
•
stomach pain
.
During your treatment, your doctor will monitor you for signs of lactic acidosis. If you have any of the
symptoms listed above or any other symptoms that worry you:
See your doctor as soon as possible
.
You may have problems with your bones
Some people taking combination therapy for HIV develop a condition called osteonecrosis. With this
condition, parts of the bone tissue die because of reduced blood supply to the bone. People may be
more likely to get this condition:
•
if they have been taking combination therapy for a long time
•
if they are also taking anti-inflammatory medicines called corticosteroids
•
if they drink alcohol
•
if their immune systems are very weak
•
if they are overweight.
Signs of osteonecrosis include:
•
stiffness in the joints
•
aches and pains
(especially in the hip, knee or shoulder)
•
difficulty moving
.
If you notice any of these symptoms:
Tell your doctor
.
Other effects may show up in blood tests
Trizivir can also cause:
•
increased levels of lactic acid
in the blood, which on rare occasions can lead to lactic acidosis
•
increased levels of sugar and fats
(triglycerides and cholesterol) in the blood
•
resistance to insulin
(so if you’re diabetic, you may have to change your insulin dose to control
your blood sugar).
5.
HOW TO STORE TRIZIVIR
Keep Trizivir out of the reach and sight of children.
Do not take Trizivir after the expiry date shown on the carton.
Do not store above 30°C.
If you have any unwanted Trizivir tablets, don’t dispose of them in your waste water or your
household rubbish. Ask your pharmacist how to dispose of medicines no longer required. These
measures will help to protect the environment.
45
6.
FURTHER INFORMATION
What Trizivir contains
The active substances in each Trizivir film-coated tablet are 300 mg of abacavir (as sulphate), 150 mg
lamivudine and 300 mg zidovudine.
The other ingredients are microcrystalline cellulose, sodium starch glycollate and magnesium stearate
in the core of the tablet. The tablet coating contains hypromellose, titanium dioxide, polyethylene
glycol, indigo carmine aluminium lake, iron oxide yellow.
What Trizivir looks like and contents of the pack
Trizivir film-coated tablets are engraved with ‘GX LL1’ on one side. They are blue/green and capsule-
shaped and are provided in blister packs containing 60 tablets or bottles containing 60 tablets with
child-resistant tops.
Marketing Authorisation Holder
ViiV Healthcare UK Limited, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United
Kingdom
Manufacturer:
Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations), Priory Street,
Ware, Hertfordshire, SG 12 0DJ, United Kingdom.
or
GlaxoSmithKline Pharmaceuticals S.A., ul. Grunwaldzka 189 , 60-322 Poznan, Poland
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
ViiV Healthcare sprl/bvba
Tél/Tel: + 32 (0)2 656 25 11
Luxembourg/Luxemburg
ViiV Healthcare sprl/bvba
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 25 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
46
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
Ísland
GlaxoSmithKline ehf.
Sími:+ 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
Italia
ViiV Healthcare S.r.l
Tel: + 39 (0)45 9212611
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline Cyprus Ltd
Τηλ: + 357 22 39 70 00
Sverige
GlaxoSmithKline AB
Tel: + 46 (0)8 638 93 00
info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
ViiV Healthcare UK Limited
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site:
http://www.ema.europa.eu
47
Source: European Medicines Agency
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