ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Kivexa 600 mg/300 mg film-coated tablets
2.
Each film-coated tablet contains 600 mg of abacavir (as sulfate) and 300 mg lamivudine.
Excipient
: sunset yellow (E110) 1.7 mg per tablet
For a full list of excipients see section 6.1.
3.
Film-coated tablet (tablet).
Orange, film-coated, modified capsule shaped tablets, debossed with GS FC2 on one side.
4.
Kivexa is a fixed-dose combination of two nucleoside analogues (abacavir and lamivudine). It is
indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus
(HIV) infection in adults and adolescents from 12 years of age (see sections 4.4 and 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 Kivexa 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 Kivexa in adults and adolescents is one tablet once daily.
Kivexa should not be administered to adults or adolescents who weigh less than 40 kg because it is a
fixed-dose tablet that cannot be dose reduced.
Kivexa can be taken with or without food.
Kivexa is a fixed-dose tablet and should not be prescribed for patients requiring dose adjustments.
Separate preparations of abacavir or lamivudine are available in cases where discontinuation or dose
adjustment of one of the active substances is indicated. In these cases the physician should refer to the
individual product information for these medicinal products.
Renal impairment:
Kivexa is not recommended for use in patients with a creatinine clearance
< 50 ml/min (see section 5.2).
2
Hepatic impairment:
No data are available in patients with moderate hepatic impairment, therefore the
use of Kivexa is not recommended unless judged necessary. In patients with mild and moderate hepatic
impairment close monitoring is required, and if feasible, monitoring of abacavir plasma levels is
recommended (see sections 4.4 and 5.2). Kivexa is contraindicated in patients with severe hepatic
impairment (see section 4.3).
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:
Kivexa is not recommended for the treatment of children less than 12 years of
age as the necessary dose adjustment cannot be made.
Hypersensitivity to the active substances or to any of the excipients. See BOXED INFORMATION
ON ABACAVIR HYPERSENSITIVITY REACTIONS in section 4.4 and section 4.8.
Patients with severe hepatic impairment.
The special warnings and precautions relevant to abacavir and lamivudine are included in this section.
There are no additional precautions and warnings relevant to Kivexa.
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 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 Kivexa 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
3
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 abacavir, 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 Kivexa immediately.
Kivexa, or any other medicinal product containing abacavir (e.g. Ziagen or Trizivir), 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,
Kivexa must be permanently discontinued if hypersensitivity cannot be ruled out, even when other
diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other
medicinal products).
Special care is needed for those patients simultaneously starting treatment with Kivexa 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 Kivexa therapy
Regardless of a patient’s HLA-B*5701 status, if therapy with Kivexa 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, Kivexa or any other medicinal product containing abacavir (e.g.
Ziagen or Trizivir
)
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
4
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 abacavir 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 Kivexa
or any other medicinal product containing abacavir (e.g. Ziagen or Trizivir) again, regardless of
their HLA-B*5701 status.
-
In order to avoid restarting abacavir, patients who have experienced a hypersensitivity reaction
should dispose of their remaining Kivexa tablets in their possession in accordance with the local
requirements, and ask their doctor or pharmacist for advice.
-
Patients who have stopped Kivexa for any reason, and particularly due to possible adverse
reactions or illness, must be advised to contact their doctor before restarting.
-
Patients should be advised of the importance of taking Kivexa regularly.
-
Each patient should be reminded to read the Package Leaflet included in the Kivexa package.
-
They should be reminded of the importance of removing the Alert Card included in the package,
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.
5
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.
Lipodystrophy:
combination antiretroviral therapy has been associated with the redistribution of body
fat (lipodystrophy) in HIV patients. The long-term consequences of these events 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).
Pancreatitis:
pancreatitis has been reported, but a causal relationship to lamivudine and abacavir is
uncertain.
Risk of virological failure:
- Triple nucleoside therapy: There have been reports of a high rate of virological failure, and of
emergence of resistance at an early stage when abacavir and lamivudine were combined with tenofovir
disoproxil fumarate as a once daily regimen.
- The risk of virological failure with Kivexa might be higher than with other therapeutic options (see
section 5.1).
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 can be found in
the Summary of Product Characteristics of products such as Zeffix.
The safety and efficacy of Kivexa has not been established in patients with significant underlying liver
disorders. Kivexa is contraindicated in patients with severe 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 Kivexa 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 the Summary of Product Characteristics for a product
such as Zeffix).
Patients with pre-existing liver dysfunction, including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination antiretroviral therapy, and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
6
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 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.
Immune Reactivation Syndrome
: in HIV-infected patients with severe immune deficiency at the time of
institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or
residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of
symptoms. Typically, such reactions have been observed within the first few weeks or months of
initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal
mycobacterial infections, and
Pneumocystis carinii
pneumonia. Any inflammatory symptoms should be
evaluated and treatment instituted when necessary.
Osteonecrosis:
Although the etiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have
been reported particularly in patients with advanced HIV-disease and/or long-term exposure to
combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they
experience joint aches and pain, joint stiffness or difficulty in movement.
Opportunistic infections:
patients should be advised that Kivexa 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.
Transmission of HIV:
patients should be advised that current antiretroviral therapy, including Kivexa,
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.
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 Kivexa, action should be taken to try to minimize all
modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Excipients:
Kivexa contains the azo colouring agent sunset yellow, which may cause allergic reactions.
Kivexa contains abacavir and lamivudine, therefore any interactions identified for these individually
are relevant to Kivexa. Clinical studies have shown that there are no clinically significant interactions
between abacavir and lamivudine.
Abacavir and lamivudine are not significantly metabolised by cytochrome P
450
enzymes (such as CYP
3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system. Therefore, there is little
potential for interactions with antiretroviral protease inhibitors, non-nucleosides and other medicinal
products metabolised by major P
450
enzymes. The interactions listed below should not be considered
7
exhaustive but are representative of the classes of medicinal products where caution should be
exercised.
Interactions relevant to abacavir
Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on
UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir.
The metabolism of abacavir is altered by concomitant consumption of 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 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 likelihood of metabolic interactions with lamivudine is low due to limited metabolism and plasma
protein binding, and almost complete renal clearance. The possibility of interactions with other
medicinal products administered concurrently with Kivexa should be considered, particularly when the
main route of elimination is active renal secretion, especially via the cationic transport system e.g.
trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are eliminated only in part by this
mechanism and were shown not to interact with lamivudine. The nucleoside analogues (e.g. zidovudine
and didanosine) are not metabolised by this mechanism and are unlikely 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. However, unless the patient has renal
impairment, no dose adjustment of lamivudine is necessary (see section 4.2). The pharmacokinetics of
trimethoprim or sulfamethoxazole are not affected. When concomitant administration with co-
trimoxazole is warranted, patients should be monitored clinically. Co-administration of Kivexa 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.
Kivexa is not recommended during pregnancy. The safety of abacavir and lamivudine in human
pregnancy has not been established. Studies with abacavir and lamivudine in animals have shown
reproductive toxicity (see section 5.3).
It is recommended that HIV-infected women do not breast-feed their infants under any circumstances
in order to avoid transmission of HIV. Lamivudine is 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 Kivexa.
8
No studies on the effects on ability to drive and use machines have been performed. The clinical status
of the patient and the adverse reaction profile of Kivexa should be borne in mind when considering the
patient’s ability to drive or operate machinery.
The adverse reactions reported for Kivexa were consistent with the known safety profiles of abacavir
and lamivudine when given as separate medicinal products. For many of these adverse reactions it is
unclear whether they are related to the active substance, the wide range of other medicinal products
used in the management of HIV infection, or whether they are a result of the underlying disease
process.
Abacavir hypersensitivity
(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. In clinical studies with abacavir 600 mg once daily the
reported rate of hypersensitivity remained within the range recorded for abacavir 300 mg twice daily.
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 reactions have occurred without rash or
fever.
The signs and symptoms of this hypersensitivity reaction are listed below. These have been identified
either from clinical studies or post marketing surveillance. Those reported
in at least 10% of
patients
with a hypersensitivity reaction are in bold text.
Skin
Rash
(usually maculopapular or urticarial)
Gastrointestinal tract
Nausea, vomiting, diarrhoea, abdominal pain
, mouth ulceration
Respiratory tract
Dyspnoea,
cough
, sore throat, adult respiratory distress syndrome,
respiratory failure
Miscellaneous
Fever, lethargy, malaise
, oedema, lymphadenopathy, hypotension,
conjunctivitis, anaphylaxis
Neurological/Psychiatry
Headache
, paraesthesia
Haematological
Lymphopenia
Liver/pancreas
Elevated liver function tests,
hepatitis, hepatic failure
Musculoskeletal
Myalgia
, rarely myolysis, arthralgia, elevated creatine phosphokinase
Urology
Elevated creatinine, renal failure
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
9
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 Kivexa regularly.
Restarting abacavir following a hypersensitivity reaction results 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 Kivexa and
must never be rechallenged with Kivexa, or any other medicinal product containing abacavir
(Ziagen or Trizivir).
To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction,
abacavir must be permanently discontinued if hypersensitivity cannot be ruled out, even when other
diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other
medicinal products).
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.
In both cases, if a decision is made to restart abacavir this must be done in
a setting where medical assistance is readily available.
Each patient must be warned about this hypersensitivity reaction to abacavir.
Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea,
fever, 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 Kivexa 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.
The adverse reactions considered at least possibly related to abacavir or lamivudine 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 < 1/1000), very rare
(< 1/10,000).
Body system
Abacavir
Lamivudine
Blood and lymphatic systems
disorders
Uncommon:
Neutropenia and
anaemia (both occasionally
severe), thrombocytopenia
Very rare:
Pure red cell aplasia
10
Immune system disorders
Common
: hypersensitivity
Metabolism and nutrition
disorders
Common:
anorexia
Nervous system disorders
Common
: headache
Common:
Headache, insomnia.
Very rare:
Cases of peripheral
neuropathy (or paraesthesia)
have been reported
Respiratory, thoracic and
mediastinal disorders
Common:
Cough, nasal
symptoms
Gastrointestinal disorders
Common
:
nausea, vomiting,
diarrhoea
Rare:
pancreatitis has been
reported, but a causal
relationship to abacavir
treatment is uncertain
Common:
Nausea, vomiting,
abdominal pain or cramps,
diarrhoea
Rare :
Rises in serum amylase.
Cases of pancreatitis have been
reported
Hepatobiliary disorders
Uncommon:
Transient rises in
liver enzymes (AST, ALT),
Rare:
Hepatitis
Skin and subcutaneous tissue
disorders
Common
: rash (without
systemic symptoms)
Very
rare
: erythema multiforme,
Stevens-Johnson syndrome and
toxic epidermal necrolysis
Common:
Rash, alopecia
Musculoskeletal and connective
tissue disorders
Common :
Arthralgia,
muscle
disorders
Rare:
Rhabdomyolysis
General disorders and
administration site conditions
Common
: fever, lethargy,
fatigue.
Common:
fatigue, malaise,
fever.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic
steatosis, have been reported with the use of nucleoside analogues (see section 4.4).
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).
In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections
may arise (see section 4.4).
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).
The frequency of this is unknown (see section 4.4).
11
No specific symptoms or signs have been identified following acute overdose with abacavir or
lamivudine, apart from those listed as undesirable effects.
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
haemodialysis could be used in the treatment of overdose, although this has not been studied. 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: J05AR02.
Mechanism of action
:
Abacavir and lamivudine are NRTIs, and are potent selective inhibitors of HIV-1
and HIV-2. Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the
respective 5'-triphosphate (TP) which are the active moieties. Lamivudine-TP and carbovir-TP (the
active triphosphate form of abacavir) 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 and
lamivudine 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 amprenavir
,
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.
Isolates from most patients experiencing virological failure with a regimen containing abacavir in
pivotal clinical trials showed either no NRTI-related changes from baseline (45%) or only M184V or
M184I selection (45%). The overall selection frequency for M184V or M184I was high (54%), and
less common was the selection of L74V (5%), K65R (1%) and Y115F (1%) (see Table). The inclusion
of zidovudine in the regimen has been found to reduce the frequency of L74V and K65R selection in
the presence of abacavir (with zidovudine: 0/40, without zidovudine: 15/192, 8%).
Therapy
Abacavir +
Combivir
1
Abacavir +
lamivudine +
NNRTI
Abacavir +
lamivudine +
PI (or
PI/ritonavir)
Total
Number of
Subjects
282
1094
909
2285
Number of
Virological
43
90
158
306
12
Failures
Number of On-
Therapy
Genotypes
40 (100%)
51 (100%)
2
141 (100%)
232 (100%)
K65R
0
1 (2%)
2 (1%)
3 (1%)
L74V
0
9 (18%)
3 (2%)
12 (5%)
Y115F
0
2 (4%)
0
2 (1%)
M184V/I
34 (85%)
22 (43%)
70 (50%)
126 (54%)
TAMs
3
3 (8%)
2 (4%)
4 (3%)
9 (4%)
1.Combivir is a fixed dose combination of lamivudine and zidovudine
2.Includes three non-virological failures and four unconfirmed virological failures.
3. Number of subjects with ≥1 Thymidine Analogue Mutations (TAMs).
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 vivo resistance (Therapy experienced patients):
The M184V or M184I variants arise in HIV-1
infected patients treated with lamivudine-containing antiretroviral therapy and confer 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.
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 ABC 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-1RNA [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%
13
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.
Cross-resistance between abacavir or lamivudine and antiretrovirals from other classes e.g. PIs or
NNRTIs is unlikely.
Clinical experience
Therapy-naïve patients
The combination of abacavir and lamivudine as a once daily regimen is supported by a 48 weeks multi-
centre, double-blind, controlled study (CNA30021) of 770 HIV-infected, therapy-naïve adults.
These
were primarily asymptomatic HIV infected patients (CDC stage A). They were randomised to receive
either abacavir (ABC) 600 mg once daily or 300 mg twice daily, in combination with lamivudine
300 mg once daily and efavirenz 600 mg once daily. The results are summarised in the table below:
Virologic Response Based on Plasma HIV-1 RNA < 50 copies/ml at Week 48
ITT-Exposed Population TLOVR*
Treatment regimen
ABC once/day
(N = 384 )
ABC twice/day
(N = 386 )
Virological response
253/384 (66%)
261/386 (68%)
* TLOVR=Time to Loss of Virologic Response
Similar clinical success (point estimate for treatment difference: -1.7, 95% CI –8.4, 4.9) was observed
for both regimens. From these results, it can be concluded with 95% confidence that the true difference
is no greater than 8.4% in favour of the twice daily regimen. This potential difference is sufficiently
small to draw an overall conclusion of non-inferiority of abacavir once daily over abacavir twice daily.
There was a low, similar overall incidence of virologic failure (viral load > 50 copies/ml) in both the
once and twice daily treatment groups (10% and 8% respectively). In the small sample size for
genotypic analysis, there was a trend toward a higher rate of NRTI-associated mutations in the once
daily versus the twice daily abacavir regimens. No firm conclusion could be drawn due to the limited
data derived from this study.
There are conflicting data in some comparative studies with Kivexa:
EPZ104057 (HEAT study) was a randomised, double-blind, placebo-matched, 96 week, multi-centre
study with the primary objective of evaluating the relative efficacy of abacavir/lamivudine (ABC/3TC,
600mg/300mg) and tenofovir /emtricitabine (TDF/FTC, 300mg/200mg), each given once-daily in
combination with lopinavir/ritonavir (LPV/r, 800mg/200mg) in HIV-infected, therapy-naive adults.
The primary efficacy analysis was performed at week 48 with study continuation to week 96 and
demonstrated non-inferiority. The results are summarised below:
Virologic Response Based on Plasma HIV-1 RNA < 50 copies/ml
ITT-Exposed Population M=F switch included
14
Virologic Response
ABC/3TC +LPV/r
(N = 343)
TDF/FTC + LPV/r
(N = 345)
Week 48
Week 96
Week 48
Week 96
Overall response (stratified by baseline
HIV-1 RNA)
231/343
(68%)
205/343
(60%)
232/345
(67%)
200/345
(58%)
Response by Baseline HIV-1 RNA
<100,000 c/ml
134/188
(71%)
118/188
(63%)
141/205
(69%)
119/205
(58%)
Response by Baseline HIV-1 RNA
≥100,000 c/ml
97/155
(63%)
87/155
(56%)
91/140
(65%)
81/140
(58%)
A similar virologic response was observed for both regimens (point estimate for treatment difference at
week 48: 0.39%, 95% CI
:
-6.63, 7.40).
ACTG 5202 study was a, multi-centre, comparative, randomised study of double-blind
abacavir/lamivudine or emtricitabine/tenofovir in combination with open-label efavirenz or
atazanavir/ritonavir in treatment-naïve HIV-1 infected patients. Patients were stratified at screening
based on plasma HIV-1 RNA levels < 100,000 and
≥
100,000 copies/mL.
An interim analysis from ACTG 5202 revealed that abacavir/lamivudine was associated with a
statistically significantly higher risk of virological failure as compared to emtricitabine/tenofovir
(defined as viral load >1000 copies/mL at or after 16 weeks and before 24 weeks or HIV-RNA level
>200 copies/mL at or after 24 weeks) in subjects with a screening viral load ≥100,000 copies/mL
(estimated hazard ratio: 2.33, 95% CI: 1.46, 3.72, p=0.0003). The Data Safety Monitoring Board
(DSMB) recommended that consideration be given
to
change in the therapeutic management of all
subjects in the high viral load stratum due to the efficacy differences observed. The subjects in the low
viral load stratum remained blinded and on-study.
Analysis of the data from subjects in the low viral load stratum showed no demonstrable difference
between the nucleoside backbones in the proportion of patients free of virological failure at week 96.
The results are presented below:
- 88.3% with ABC/3TC vs 90.3% with TDF/FTC when taken with atazanavir/ritonovir as third
drug, treatment difference -2.0% (95% CI -7.5%, 3.4%),
- 87.4% with ABC/3TC vs 89.2% with TDF/FTC, when taken with efavirenz as third drug,
treatment difference -1.8% (95% CI -7.5%, 3.9%).
CNA109586 (ASSERT study), a multi-centre, open label, randomised study of abacavir/lamivudine
(ABC/3TC, 600mg/300mg) and tenofovir/emtricitabine (TDF/FTC, 300mg/200mg), each given once
daily with efavirenz (EFV, 600mg) in ART naïve, HLA-B*5701 negative, HIV-1 infected adults.The
virologic results are summarised in the table below:
Virologic Response at Week 48 ITT-Exposed Population < 50 copies/ml TLOVR
ABC/3TC + EFV
(N =192)
TDF/FTC + EFV
(N =193)
Overall response
114/192
(59%)
137/193
(71%)
Response by Baseline
HIV-1 RNA <100,000
c/mL
61/95
(64%)
62/83
(75%)
Response by Baseline
HIV-1 RNA ≥100,000
c/mL
53/97
(55%)
75/110
(68%)
At week 48, a lower rate of virologic response was observed for ABC/3TC compared to TDF/FTC
(point estimate for the treatment difference: 11.6%, 95% CI
:
2.2, 21.1).
15
Therapy-experienced patients
In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised and
received treatment with either Kivexa once daily or abacavir 300 mg twice daily plus lamivudine
300 mg once daily, both in combination with tenofovir and a PI or an NNRTI for 48 weeks. Results
indicate that the Kivexa group was non-inferior to the abacavir twice daily group, based on similar
reductions in HIV-1 RNA as measured by average area under the curve minus baseline (AAUCMB, -
1.65 log
10
copies/ml versus -1.83 log
10
copies/ml respectively, 95% CI -0.13, 0.38). Proportions with
HIV-1 RNA < 50 copies/ml (50% versus 47%) and < 400 copies/ml (54% versus 57%) were also
similar in each group (ITT population). However, as there were only moderately experienced patients
included in this study with an imbalance in baseline viral load between the arms, these results should be
interpreted with caution.
In study ESS30008, 260 patients with virologic suppression on a first line therapy regimen containing
abacavir 300 mg plus lamivudine 150 mg, both given twice daily and a PI or NNRTI, were randomised
to continue this regimen or switch to Kivexa plus a PI or NNRTI for 48 weeks. Results indicate that the
Kivexa group was associated with a similar virologic outcome (non-inferior) compared to the abacavir
plus lamivudine group, based on proportions of subjects with HIV-1 RNA < 50 copies/ml (90% and
85% respectively, 95% CI -2.7, 13.5).
5.2 Pharmacokinetic properties
The fixed-dose combination tablet of abacavir/lamivudine (FDC) has been shown to be bioequivalent
to lamivudine and abacavir administered separately. This was demonstrated in a single dose, 3-way
crossover bioequivalence study of FDC (fasted) versus 2 x 300 mg abacavir tablets plus 2 x 150 mg
lamivudine tablets (fasted) versus FDC administered with a high fat meal, in healthy volunteers
(n = 30). In the fasted state there was no significant difference in the extent of absorption, as measured
by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (C
max
),
of each component. There was also no clinically significant food effect observed between
administration of FDC in the fasted or fed state. These results indicate that FDC can be taken with or
without food. The pharmacokinetic properties of lamivudine and abacavir are described below.
Absorption
Abacavir and lamivudine are rapidly and well absorbed from the gastro-intestinal tract following oral
administration. The absolute bioavailability of oral abacavir and lamivudine in adults is about 83% and
80-85% respectively. The mean time to maximal serum concentrations (t
max
) is about 1.5 hours and
1.0 hour for abacavir and lamivudine, respectively. Following a single dose of 600 mg of abacavir, the
mean (CV) C
max
is 4.26 µg/ml (28%) and the mean (CV) AUC
∞
is 11.95 µg.h/ml (21%). Following
multiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV)
steady-state C
max
is 2.04 µg/ml (26%) and the mean (CV) AUC
24
is 8.87 µg.h/ml (21%).
Distribution
Intravenous studies with abacavir and lamivudine showed that the mean apparent volume of
distribution is 0.8 and 1.3 l/kg respectively. Plasma protein binding studies
in vitro
indicate that
abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited
plasma protein binding
in vitro
(< 36%). This indicates a low likelihood for interactions with other
medicinal products through plasma protein binding displacement.
Data show that abacavir and lamivudine penetrate the central nervous system (CNS) and reach the
cerebrospinal fluid (CSF). 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
.
The mean ratio of CSF/serum
lamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extent
of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.
16
Metabolism
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 administered dose. These metabolites are excreted in the urine.
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%).
Elimination
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.
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, predominantly by 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).
Intracellular pharmacokinetics
In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg
dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular
half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in
this study of 2.6 hours. In a crossover study in 27 HIV-infected patients, intracellular carbovir-TP
exposures were higher for the abacavir 600 mg once daily regimen (AUC
24,ss
+ 32 %, C
max24,ss
+ 99 %
and C
trough
+ 18 %) compared to the 300 mg twice daily regimen. For patients receiving lamivudine
300 mg once daily, the terminal intracellular half-life of lamivudine-TP was prolonged to 16-19 hours,
compared to the plasma lamivudine half-life of 5-7 hours. In a crossover study in 60 healthy
volunteers, intracellular lamivudine-TP pharmacokinetic parameters were similar (AUC
24,ss
and
C
max24,ss
) or lower (C
trough
– 24 %) for the lamivudine 300 mg once daily regimen compared to the
lamivudine 150 mg twice daily regimen. Overall, these data support the use of lamivudine 300 mg and
abacavir 600 mg once daily for the treatment of HIV-infected patients. Additionally, the efficacy and
safety of this combination given once daily has been demonstrated in a pivotal clinical study
(CNA30021- See Clinical experience).
Special populations
Hepatically impaired:
There are no data available on the use of Kivexa in hepatically impaired patients.
Pharmacokinetic data has been obtained for abacavir and lamivudine alone.
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
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.
17
Data obtained in patients with moderate to severe hepatic impairment show that lamivudine
pharmacokinetics are not significantly affected by hepatic dysfunction.
Renally impaired:
Pharmacokinetic data have been obtained for lamivudine and abacavir alone.
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. Studies with lamivudine show that plasma concentrations (AUC)
are increased in patients with renal dysfunction due to decreased clearance. Dose reduction is required
for patients with creatinine clearance of < 50 ml/min.
Elderly
: No pharmacokinetic data are available in patients over 65 years of age.
5.3 Preclinical safety data
With the exception of a negative
in vivo
rat micronucleus test, there are no data available on the effects
of the combination of abacavir and lamivudine in animals.
Mutagenicity and carcinogenicity
Neither abacavir nor lamivudine were 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. The results of an
in vivo
rat
micronucleus test with abacavir and lamivudine in combination were negative.
Lamivudine has not shown any genotoxic activity in the
in vivo
studies at doses that gave plasma
concentrations up to 30-40 times higher than clinical plasma concentrations. Abacavir has a weak
potential to cause chromosomal damage both
in vitro
and
in vivo
at high tested concentrations.
The carcinogenic potential of a combination of abacavir and lamivudine has not been tested. In long-
term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential.
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
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
18
In reproductive toxicity studies in animals, lamivudine and abacavir were shown to cross the placenta.
Lamivudine was not teratogenic in animal studies but there were indications of an increase in early
embryonic deaths in rabbits 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.
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 rats has shown that abacavir and lamivudine had no effect on male or female
fertility.
6.
6.1 List of excipients
Core:
magnesium stearate
microcrystalline cellulose
sodium starch glycollate.
Coating:
Opadry Orange YS-1-13065-A containing:
hypromellose
titanium dioxide (E171)
macrogol 400, polysorbate 80
sunset yellow aluminium lake (E110).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30ºC.
6.5 Nature and contents of container
30 tablets in opaque white (PVC/PVDC/Aluminium) blister packs and white (high density
polyethylene) bottles with child-resistant closure.
Multipacks continuing 90 (3 packs of 30) tablets in opaque white (PVC/PVDC/Aluminium) blister
packs.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
19
7.
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
8.
EU/1/04/298/001-002
EU/1/04/298/003
9.
Date of first authorization:
17 December 2004
Date of latest renewal:
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu
20
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE
FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
21
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 SG12 0DJ
United Kingdom
Or
Glaxo Wellcome S.A.,
Avenida de Extremadura 3,
09400 Aranda de Duero Burgos,
Spain
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch
B
CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The Marketing Authorisation Holder will continue to submit Periodic Safety Update Reports and other
safety information annually, unless otherwise specified by the CHMP.
22
ANNEX III
LABELLING AND PACKAGE LEAFLET
23
A. LABELLING
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON BLISTER PACK
1.
Kivexa 600 mg/300 mg film-coated tablets
abacavir/lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains abacavir 600 mg (as sulfate) and lamivudine 300 mg
3.
LIST OF EXCIPIENTS
Contains sunset yellow (E110), see leaflet for further information
4.
30 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
”
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
25
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/1/04/298/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
kivexa
26
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer label of 90 (3 packs of 30 film-coated tablets) (with Blue Box) wrapped in clear plastic foil
1.
Kivexa 600 mg/300 mg film-coated tablets
abacavir/lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains abacavir 600 mg (as sulfate) and lamivudine 300 mg
3.
LIST OF EXCIPIENTS
Contains sunset yellow (E110), see package leaflet for further information
4.
Multipack containing 3 packs each containing 30 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
WARNING! In case of any symptoms suggesting hypersensitivity reactions, contact your doctor
IMMEDIATELY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C
27
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/1/04/298/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
28
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Multipacks of 90 (3 packs of 30 film-coated tablets) – without blue box –
OUTER CARTON BLISTER PACK
30 TABLETS
1.
Kivexa 600 mg/300 mg film-coated tablets
abacavir/lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains abacavir 600 mg (as sulfate) and lamivudine 300 mg
3.
LIST OF EXCIPIENTS
Contains sunset yellow (E110), see package leaflet for further information
4.
30 film-coated tablets
Component of a multipack comprising 3 packs each containing 30 film-coated tablets, not to be sold
separately
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
”
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
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
kivexa
30
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Kivexa 600 mg/300 mg tablets.
abacavir/lamivudine
2.
ViiV Healthcare UK Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5. OTHER
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
OUTER CARTON BOTTLE AND LABEL
1.
Kivexa 600 mg/300 mg film-coated tablets
abacavir/lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains abacavir 600 mg (as sulfate) and lamivudine 300 mg
3.
LIST OF EXCIPIENTS
Contains sunset yellow (E110), see package leaflet for further information
4.
30 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral 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
The Alert Card enclosed contains important safety information
WARNING! In case of any symptoms suggesting hypersensitivity reactions, contact your doctor
IMMEDIATELY
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/1/04/298/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Kivexa [only for the carton label]
33
KIVEXA TABLETS ALERT CARD (blister and bottle pack)
SIDE 1
IMPORTANT - ALERT CARD
Kivexa (abacavir / lamivudine) tablets
Carry this card with you at all times
Since Kivexa contains abacavir some patients taking Kivexa may develop a hypersensitivity reaction
(serious allergic reaction)
which
can be life-threatening
if treatment with Kivexa is continued.
CONTACT YOUR DOCTOR IMMEDIATELY for advice on whether you should stop taking
Kivexa 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 Kivexa due to this reaction,
YOU MUST NEVER
TAKE
Kivexa, or any
medicine containing abacavir (e.g. Ziagen or Trizivir) 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
Kivexa. 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 Kivexa information enquiries, contact ………
34
B. PACKAGE LEAFLET
35
PACKAGE LEAFLET: INFORMATION FOR THE USER
Kivexa 600 mg/300 mg Film-coated tablets
abacavir/lamivudine
-
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
.
IMPORTANT — Hypersensitivity reactions
Kivexa contains abacavir
(which is also an active ingredient in medicines such as
Trizivir
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 Kivexa 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 Kivexa is and what it is used for
2.
Before you take Kivexa
3.
How to take Kivexa
4.
Possible side effects
5.
How to store Kivexa
6.
Further information
1.
WHAT KIVEXA IS AND WHAT IT IS USED FOR
Kivexa is used to treat HIV (human immunodeficiency virus) infection in adults
.
Kivexa contains two active ingredients that are used to treat HIV infection: abacavir and lamivudine.
These belong to a group of anti-retroviral medicines called
nucleoside analogue reverse transcriptase
inhibitors (NRTIs)
.
Kivexa does not completely cure HIV infection; it reduces the amount of virus in your body, and keeps
it at a low level. It also 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 Kivexa in the same way. Your doctor will monitor the
effectiveness of your treatment.
2.
BEFORE YOU TAKE KIVEXA
36
Don’t take Kivexa:
•
if you’re
allergic
(hypersensitive)
to abacavir (or any other medicine containing abacavir — (e.g.
Trizivir
or
Ziagen
), lamivudine or any of the other ingredients of Kivexa
(listed in Section 6)
!
Carefully read the all information about hypersensitivity reactions in Section 4
.
•
if you
have
severe liver disease
•
if you
have
severe kidney disease
•
if you have
a very low red blood cell count
(anaemia)
or
a very low white blood cell count
(neutropenia)
.
Î
Check with your doctor
if you think any of these apply to you.
Don’t take Kivexa
Take special care with Kivexa
Some people taking Kivexa or other combination treatments for HIV 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 Kivexa without your doctor’s advice, as your hepatitis may come back)
•
if you’re seriously
overweight
(especially if you’re a woman)
Î
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
.
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).
Î
Carefully read all the information about hypersensitivity reactions in Section 4 of this leaflet.
Risk of heart attack
It cannot be excluded that abacavir may increase the risk of having a heart attack.
Î
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
Kivexa unless your doctor advises you to do so.
Look out for important symptoms
Some people taking medicines for HIV infection develop other conditions, which can be serious. You
need to know about important signs and symptoms to look out for while you’re taking Kivexa.
Î
Read the information ‘Other possible side effects of combination therapy for HIV’ 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). Kivexa 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.
•
Don’t risk blood transfer
— for example, don’t share needles.
Other medicines and Kivexa
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
Kivexa.
These medicines should not be used with Kivexa:
•
ribavirin, or injections of ganciclovir or foscarnet, to treat
viral infections
•
high doses of
co-trimoxazole
, an antibiotic.
Î
Tell your doctor
if you’re being treated with any of these.
37
Some medicines can make it more likely that you’ll have side effects, or make side effects worse
These include:
•
co-trimoxazole, to treat
bacterial infections
Î
Tell your doctor
if you’re taking this.
Some medicines interact with Kivexa
These include:
•
phenytoin
, for treating
epilepsy
.
Î
Tell your doctor
if you’re taking phenytoin. Your doctor may need to monitor you while you’re
taking Kivexa.
•
methadone,
used as a
heroin substitute.
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.
Î
Tell your doctor
if you’re taking methadone.
Pregnancy
Kivexa is not recommended for use during pregnancy
. Kivexa and similar medicines may cause
side effects in unborn babies. If you become pregnant while you’re taking Kivexa, 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:
Î
Talk to your doctor immediately
about the risks and benefits of taking Kivexa, or other medicines
for treating HIV infection, during your pregnancy.
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:
Î
Talk to your doctor immediately
.
Driving and using machines
Î
Don’t drive or operate machines
unless you’re feeling well.
Important information about some of the other ingredients of Kivexa tablets
Kivexa contains a colouring called sunset yellow (E110), this may cause allergic reactions in some
people.
3.
HOW TO TAKE KIVEXA
Always take Kivexa exactly as your doctor has told you to
. Check with your doctor or pharmacist if
you’re not sure.
Swallow the tablets whole, with some water. Kivexa can be taken with or without food.
Stay in regular contact with your doctor
Kivexa helps to control your condition. You need to keep taking it every day to stop your illness
getting worse. You may still develop other infections and illnesses linked to HIV infection.
Î
Keep in touch with your doctor, and don’t stop taking Kivexa
without your doctor’s advice.
How much to take
The usual dose of Kivexa for adults is one tablet once a day
.
If you take too much Kivexa
38
If you accidentally take too much Kivexa, tell your doctor or your pharmacist, or contact your nearest
hospital emergency department for further advice.
If you forget to take Kivexa
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 Kivexa regularly, because if you take it at irregular intervals, you may be more
likely to have a hypersensitivity reaction.
If you have stopped taking Kivexa
If you have stopped taking Kivexa for any reason — especially because you think you are having side
effects, or because you have other illness:
Î
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 Kivexa, or any other medicine containing abacavir
(e.g. Trizivir or Ziagen)
. It is important that you follow this advice.
If your doctor advises that you can start taking Kivexa 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, Kivexa 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 Kivexa
or other medicines you are taking, or an effect of the HIV disease 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 in this leaflet in the panel headed ‘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 Kivexa
, other conditions can develop during combination
therapy for HIV.
Î
It is important to read the information later in this section under ‘Other possible side effects of
combination therapy for HIV’.
Hypersensitivity reactions
Kivexa
contains
abacavir
(which is also an active ingredient in medicines such as
Trizivir
and
Ziagen
).
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).
Who gets these reactions?
Anyone taking Kivexa could develop a hypersensitivity reaction to abacavir, which could be life
threatening if they continue to take Kivexa.
You are more likely to develop such a reaction if 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 Kivexa
was prescribed for you.
If you know you have this gene, tell your doctor before you take Kivexa.
What are the symptoms?
The most common symptoms are:
39
•
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 Kivexa, 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 Kivexa, 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 a skin rash, OR
2 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 Kivexa
.
Always carry your Alert Card while you are taking Kivexa.
If you have stopped taking Kivexa
!
If you have stopped taking Kivexa because of a hypersensitivity reaction,
you must NEVER
AGAIN take Kivexa, or any other medicine containing abacavir (e.g. Trizivir or Ziagen)
. If
you do, within hours, your blood pressure could fall dangerously low, which could result in death.
If you have stopped taking Kivexa for any reason — especially because you think you are having side
effects, or because you have other illness:
Î
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 be told
never again to take Kivexa, or any other medicine containing abacavir (e.g. Trizivir or
Ziagen)
. It is important that you follow this advice.
If your doctor advises that you can start taking Kivexa 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 Kivexa, return all your unused Kivexa tablets for safe disposal.
Ask
your doctor or pharmacist for advice.
Common side effects
These may affect
up to 1 in 10
people:
•
hypersensitivity reaction
•
headache
40
•
being sick
(vomiting)
•
feeling sick
(nausea)
.
•
diarrhoea
•
stomach pains
•
loss of appetite
•
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.
Uncommon side effects
These may affect
up to 1 in 100
people and may show up in blood tests:
•
a low red blood cell count
(anaemia)
or low white blood cell count
(neutropenia)
•
an increase in the level of liver enzymes
•
a decrease in the number of cells involved in blood clotting (
thrombocytopenia
).
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 combination therapy for HIV’
)
•
inflammation of the pancreas
(pancreatitis)
•
breakdown of muscle tissue.
Rare side effects that may show up in blood tests are:
•
increase in an enzyme called
amylase
Very rare side effects
These may affect
up to 1 in 10,000
people:
•
numbness, tingly feelings in the skin (pins and needles)
•
sensation of weakness in the limbs
•
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
.
Very rare side effects that may show up in blood tests are:
•
a failure of the bone marrow to produce new red blood cells (
pure red cell aplasia
).
If you get side effects
Î
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 combination therapy for HIV
Combination therapy such as Kivexa may cause other conditions to develop during HIV treatment.
41
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 Kivexa:
Î
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:
Î
Tell your doctor
.
Lactic acidosis is a rare but serious side effect
Some people taking Kivexa, 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:
Î
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.
42
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:
Î
Tell your doctor
.
Other effects may show up in blood tests
Combination therapy for HIV 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 KIVEXA
Keep Kivexa out of the reach and sight of children.
Do not take Kivexa after the expiry date shown on the carton.
Do not store above 30°C.
If you have any unwanted Kivexa 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.
6.
FURTHER INFORMATION
What Kivexa contains
The active substances in each Kivexa film-coated tablet are 600 mg of abacavir (as sulphate) and 300
mg of lamivudine.
The other ingredients are microcrystalline cellulose, sodium starch glycollate and magnesium stearate
in the core of the tablet. The tablet coating contains Opadry Orange YS-1-13065-A containing
hypromellose, titanium dioxide (E171), macrogol 400, polysorbate 80 and sunset yellow aluminium
lake (E110).
What Kivexa looks like and contents of the pack
Kivexa film-coated tablets are engraved with ‘GS FC2’ on one side. They are orange and capsule-
shaped and are provided in bottles or blister packs containing 30 tablets and blister packs containing
90(3
x
30) tablets.
Marketing Authorisation Holder and Manufacturer
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
Glaxo Wellcome S.A., Avenida de Extremadura 3, 09400 Aranda de Duero Burgos, Spain.
43
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
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
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
44
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 approved in {MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
45
Source: European Medicines Agency
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