ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Zerit 15 mg hard capsule
2.
Each hard capsule contains 15 mg of stavudine.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
The hard capsule is red and yellow, opaque and imprinted with “BMS” over a BMS code “1964” on
one side and “15” on the other side.
4.
Zerit is indicated in combination with other antiretroviral medicinal products for the treatment of HIV
infected patients.
Posology
The therapy should be initiated by a doctor experienced in the management of HIV infection (see also
section 4.4).
For optimal absorption, Zerit should be taken on an empty stomach (i.e. at least 1 hour prior to meals)
but, if this is not possible, it may be taken with a light meal. Zerit may also be administered by
carefully opening the hard capsule and mixing the contents with food.
Adults:
the recommended oral dosage is:
Patient weight
Zerit dosage
< 60 kg
60 kg
30 mg twice daily (every 12 hours)
40 mg twice daily
Paediatric population:
Adolescents, childr
en and infants over the age of 3 months:
the recommended oral d
osage is:
Patient weight Zerit dosage
< 30 kg
30 kg
1 mg/kg twice daily (every 12 hours)
adult dosing
The powder formulation of ZERIT should be used for infants under the age of 3 months. Please refer
to the Summary of Product Characteristics of the powder formulation.
Dose adjustments
Peripheral neuropathy:
if symptoms of peripheral neuropathy develop (usually characterised by
persistent numbness, tingling, or pain in the feet and/or hands) (see section 4.4) patients should be
switched to an alternative treatment regimen, if appropriate. In the rare cases when this is
inappropriate, dose reduction of stavudine may be considered, while the symptoms of peripheral
neuropathy are under close monitoring and satisfactory virological suppression is maintained.
2
The possible benefits of a dose reduction should be balanced in each case against the risks - which
may result from this measure (lower intracellular concentrations).
Special populations
Elderly:
Zerit has not been specifically investigated in patients over the age of 65.
Hepatic impairment:
no initial dosage adjustment is necessary.
Renal impairment:
the following dosages are recommended:
Zerit dosage (according to creatinine clearance)
Patient weight
26-50 ml/min ≤ 25 ml/min
(including dialysis dependence*)
< 60 kg
15 mg twice daily
15 mg every 24 hours
≥ 60 kg
20 mg twice daily
20 mg every 24 hours
* Patients on haemodialysis should take Zerit after the completion of haemodialysis, and at the same
time on non-dialysis days.
Since urinary excretion is also a major route of elimination of stavudine in paediatric patients, the
clearance of stavudine may be altered in paediatric patients with renal impairment. Although there are
insufficient data to recommend a specific dosage adjustment of Zerit in this patient population, a
reduction in the dose and/or an increase in the interval between doses proportional to the reduction for
adults should be considered.
Hypersensitivity to stavudine or to any of the excipients.
Stavudine therapy is associated with several severe side effects, such as lactic acidosis, lipoatrophy
and polyneuropathy, for which a potential underlying mechanism is mitochondrial toxicity. Given
these potential risks, a benefit-risk assessment for each patients should be made and an alternative
antiretroviral should be carefully considered (see
Lactic acidosis, Lipodystrophy and metabolic
abnormalities,
and
Peripheral neuropathy
below and section 4.8).
Lactic acidosis:
lactic acidosis, usually associated with hepatomegaly and hepatic steatosis has been
reported with the use of nucleoside reverse transcriptase inhibitors (NRTIs). 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, renal failure, or motor paralysis.
Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with NRTIs should be discontinued if there is symptomatic hyperlactatemia and
metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.
Caution should be exercised when administering NRTIs 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 (see also section 4.6).
Liver disease:
hepatitis or liver failure, which was fatal in some cases, has been reported. The safety
and efficacy of stavudine has not been established in patients with significant underlying liver
disorders. 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 events. In case of concomitant
3
antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these
medicinal products.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination antiretroviral therapy and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
In the event of rapidly elevating transaminase levels (ALT/AST, > 5 times upper limit of normal,
ULN), discontinuation of Zerit and any potentially hepatotoxic medicinal products should be
considered.
Lipodystrophy and metabolic abnormalities
: combination antiretroviral therapy has been associated
with the redistribution of body fat (lipodystrophy) in HIV patients. Knowledge about the mechanism is
incomplete. A connection between visceral lipomatosis and Protease Inhibitors and lipoatrophy and
NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual
factors such as older age, and with drug related factors such as longer duration of antiretroviral
treatment and associated metabolic disturbances.
In randomized controlled trials of treatment-naive patients, clinical lipoatrophy developed in a higher
proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir).
Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine
treated patients compared to limb fat gain or no change in patients treated with other NRTIs (abacavir,
tenofovir or zidovudine). The incidence and severity of lipoatrophy are cumulative over time with
stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides
(tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical
lipoatrophy. Given the potential risks of using ZERIT including lipoatrophy or lipodystrophy, a
benefit-risk assessment for each patient should be made and an alternative antiretroviral carefully
considered. Patients receiving Zerit should be frequently examined and questioned for signs of
lipoatrophy. When such development is found, discontinuation of Zerit should be considered.
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).
Peripheral neuropathy: up to 20% of patients treated with Zerit will develop peripheral neuropathy,
often starting after some months of treatment. Patients with a history of neuropathy, or with other risk
factors (for example alcohol, medications such as isoniazid) are at particular risk. Patients should be
monitored for symptoms (persistent numbness, tingling or pain in feet/hands) and if present patients
should be switched to an alternate treatment regimen (see section 4.2 and Not recommended
combinations, below).
Pancreatitis:
patients with a history of pancreatitis had an incidence of approximately 5% on Zerit, as
compared to approximately 2% in patients without such a history. Patients with a high risk of
pancreatitis or those receiving products known to be associated with pancreatitis should be closely
followed for symptoms of this condition.
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
4
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.
Not recommended combinations:
pancreatitis (fatal and nonfatal) and peripheral neuropathy (severe in
some cases) have been reported in HIV infected patients receiving stavudine in association with
hydroxyurea and didanosine. Hepatotoxicity and hepatic failure resulting in death were reported
during postmarketing surveillance in HIV infected patients treated with antiretroviral agents and
hydroxyurea; fatal hepatic events were reported most often in patients treated with stavudine,
hydroxyurea and didanosine. Hence, hydroxyurea should not be used in the treatment of HIV
infection.
Lactose intolerance:
the hard capsule contains lactose (120 mg). Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption,
should not take this medicine.
Elderly:
Zerit has not been specifically investigated in patients over the age of 65.
Paediatric population
Infants under the age of 3 months:
safety data are available from clinical trials up to 6 weeks of
treatment in 179 newborns and infants < 3 months of age (see section 4.8).
Special consideration should be given to the antiretroviral treatment history and the resistance profile
of the HIV strain of the mother.
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 (see
also section 4.8). The main adverse events reported are haematological disorders (anaemia,
neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These events 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.
Since stavudine is actively secreted by the renal tubules, interactions with other actively secreted
medicinal products are possible, e.g. with trimethoprim. No clinically relevant pharmacokinetic
interaction has, however, been seen with lamivudine.
Zidovudine and stavudine are phosphorylated by the cellular enzyme (thymidine kinase), which
preferentially phosphorylates zidovudine, thereby decreasing the phosphorylation of stavudine to its
active triphosphate form. Zidovudine is therefore not recommended to be used in combination with
stavudine.
In vitro
studies indicate that the activation of stavudine is inhibited by doxorubicin and ribavirin but
not by other medicinal products used in HIV infection which are similarly phosphorylated,
(e.g. didanosine, zalcitabine, ganciclovir and foscarnet) therefore, coadministration of stavudine with
either doxorubicin or ribavirin should be undertaken with caution. Stavudine’s influence on the
phosphorylation kinetics of nucleoside analogues other than zidovudine has not been investigated.
Clinically significant interactions of stavudine or stavudine plus didanosine with nelfinavir have not
been observed.
5
Stavudine does not inhibit the major cytochrome P450 isoforms CYP1A2, CYP2C9, CYP2C19,
CYP2D6, and CYP3A4; therefore, it is unlikely that clinically significant drug interactions will occur
with drugs metabolised through these pathways.
Because stavudine is not protein-bound, it is not expected to affect the pharmacokinetics of
protein-bound drugs.
There have been no formal interaction studies with other medicinal products.
Paediatric population
Interaction studies have only been performed in adults
Pregnancy
Zerit should not be used during pregnancy unless clearly necessary.
Clinical experience in pregnant women is limited, but congenital anomalies and abortions have been
reported.
In study AI455-094, performed in South-Africa, 362 mother-infant pairs were included in a prevention
of mother-to-child-transmission study. Treatment naive pregnant women were enrolled into the study
at gestation week 34-36 and given antiretroviral treatment until delivery. Antiretroviral prophylaxis,
the same medications as given to the mother, was given to the new-born infant within 36 hours of
delivery and continued for 6 weeks. In the stavudine containing arms, the neonates were treated
for 6 weeks with stavudine 1 mg/kg BID. The follow-up time was up to 24 weeks of age.
The mother-infant pairs were randomised to receive either stavudine (N= 91), didanosine (N= 94),
stavudine + didanosine (N= 88) or zidovudine (N= 89).
95% Confidence intervals for the mother-to-child-transmission rates were 5.4-19.3%
(stavudine), 5.2-18.7% (didanosine); 1.3-11.2% (stavudine + didanosine); and 1.9-12.6% for
zidovudine.
Preliminary safety data from this study (see also section 4.8), showed an increased infant mortality in
the stavudine + didanosine (10%) treatment group compared to the stavudine (2%), didanosine (3%)
or zidovudine (6%) groups, with a higher incidence of stillbirths in the stavudine + didanosine group.
Data on lactic acid in serum were not collected in this study.
However, lactic acidosis (see section 4.4), sometimes fatal, has been reported in pregnant women who
received the combination of didanosine and stavudine with or without other anti-retroviral treatment.
Embryo-foetal toxicities were seen only at high exposure levels in animals. Preclinical studies showed
placental transfer of stavudine (see section 5.3). Until additional data become available, Zerit should
be given during pregnancy only after special consideration; there is insufficient information to
recommend Zerit for prevention of mother-to-child transmission of HIV. Furthermore, the
combination of stavudine and didanosine should be used with caution during pregnancy and is
recommended only if the potential benefit clearly outweighs the potential risk.
Breastfeeding
It is recommended that HIV infected women should not breast-feed under any circumstances in order
to avoid transmission of HIV.
The data available on stavudine excretion into human breast milk are insufficient to assess the risk to
the infant. Studies in lactating rats showed that stavudine is excreted in breast milk. Therefore,
mothers should be instructed to discontinue breast-feeding prior to receiving Zerit.
Fertility
6
No evidence of impaired fertility was seen in rats at high exposure levels (up to 216 times that
observed at the recommended clinical dose).
Based on the pharmacodynamic properties of stavudine it is unlikely that Zerit affects the ability to
drive or operate machinery.
a. Summary of the safety profile
Stavudine therapy is associated with several severe side effects, such as lactic acidosis, lipoatrophy
and polyneuropathy, for which a potential underlying mechanism is mitochondrial toxicity. Given
these potential risks, a benefit-risk assessment for each patient should be made and an alternative
antiretroviral should be carefully considered (see section 4.4 and below).
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic
steatosis, have been reported in < 1% of patients taking stavudine in combination with other
antiretrovirals (see section 4.4).
Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy
including Zerit. Most of these cases occurred in the setting of symptomatic hyperlactatemia or lactic
acidosis syndrome (see section 4.4). The evolution of motor weakness may mimic the clinical
presentation of Guillain-Barré syndrome (including respiratory failure). Symptoms may continue or
worsen following discontinuation of therapy.
Hepatitis or liver failure, which was fatal in some cases, has been reported with the use of stavudine
and with other nucleoside analogues (see section 4.4).
Lipoatrophy was commonly reported in patients treated with stavudine in combination with other
antiretrovirals (see section 4.4).
Peripheral neuropathy was seen in combination studies of Zerit with lamivudine plus efavirenz; the
frequency of peripheral neurologic symptoms was 19% (6% for moderate to severe) with a rate of
discontinuation due to neuropathy of 2%. The patients usually experienced resolution of symptoms
after dose reduction or interruption of stavudine.
Pancreatitis, occasionally fatal, has been reported in up to 2-3% of patients enrolled in monotherapy
clinical studies (see section 4.4). Pancreatitis was reported in < 1% of patients in combination therapy
studies with Zerit.
b.
Tabulated summary of adverse reactions
Adverse reactions of moderate or greater severity with at least a possible relationship to treatment
regimen (based on investigator attribution) reported from 467 patients treated with Zerit in
combination with lamivudine and efavirenz in two randomised clinical trials and along-term follow-up
study (follow-up: median 56 weeks ranging up to 119 weeks) are listed below. Also listed are adverse
reactions observed post-marketing in association with stavudine-containing antiretroviral treatment .
The frequency of adverse reactions listed below is defined using the following convention: very
common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare
(≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); or not known (cannot be estimated from the available
data). Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
7
Blood and lymphatic system
disorders:
rare: anaemia*
very rare: neutropenia *, thrombocytopenia*
Endocrine disorders:
uncommon: gynaecomastia
Metabolism and nutrition
disorders:
common: lipoatrophy**, lipodystrophy**, asymptomatic
hyperlactatemia
uncommon: lactic acidosis (in some cases involving motor
weakness), anorexia
rare: hyperglycaemia*
very rare: diabetes mellitis*
Psychiatric disorders:
common: depression
uncommon: anxiety, emotional lability
Nervous system disorders:
common: peripheral neurologic symptoms including peripheral
neuropathy, paresthesia, and peripheral neuritis;
dizziness; abnormal dreams; headache, insomnia;
abnormal thinking; somnolence
very rare: motor weakness* (most often reported in the setting of
symptomatic hyperlactatemia or lactic acidosis syndrome)
Gastrointestinal disorders:
common: diarrhoea, abdominal pain, nausea, dyspepsia
uncommon: pancreatitis, vomiting
Hepatobiliary disorders:
uncommon: hepatitis or jaundice
rare: hepatic steatosis*
very rare: liver failure*
Skin and subcutaneous tissue
disorders:
common: rash, pruritus
uncommon: urticaria
Musculoskeletal and connective
tissue disorders:
uncommon: arthralgia, myalgia
common: fatigue
uncommon: asthenia
*
adverse reactions observed post-marketing in association with stavudine-containing antiretroviral
treatment
** See Section
c. Description of selected adverse reactions
for more details.
c. Description of selected adverse reactions
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).
Lipodystrophy and 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). In randomized controlled trials of treatment-naive
patients, clinical lipoatrophy developed in a higher proportion of patients treated with stavudine
compared to other NRTIs (tenofovir or abacavir). In one study, after 2 years of treatment, about 40%
of stavudine-treated patients had lost greater than 20% of limb fat and after 3 years the amount of limb
fat was only about half of the normal amount (4.5 kg vs about 8 kg).. The incidence and severity of
lipoatrophy are cumulative over time; lipoatrophy may affect most patients with time and is often not
reversible when stavudine treatment is stopped (see section 4.4).
8
General disorders and
administration site conditions:
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (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).
Laboratory abnormalities
Laboratory abnormalities reported in these two trials and an ongoing follow-up study included
elevations of ALT (> 5 x ULN) in 3%, of AST (> 5 x ULN) in 3%, of lipase (≥ 2.1 ULN) in 3% of the
patients in the Zerit group. Neutropenia (< 750 cells/mm
3
) was reported in 5%, thrombocytopenia
(platelets < 50,000/mm
3
) in 2%, and low haemoglobin (< 8 g/dl) in < 1% of patients receiving Zerit.
Macrocytosis was not evaluated in these trials, but was found to be associated with Zerit in an earlier
trial (MCV > 112 fl occurred in 30% of patients treated with Zerit).
d. Paediatric population
Adolescents, children and infants:
undesirable effects and serious laboratory abnormalities reported to
occur in paediatric patients ranging in age from birth through adolescence who received stavudine in
clinical studies were generally similar in type and frequency to those seen in adults. However,
clinically significant peripheral neuropathy is less frequent. These studies include ACTG 240,
where 105 paediatric patients ages 3 months to 6 years received Zerit 2 mg/kg/day for a median
of 6.4 months; a controlled clinical trial where 185 newborns received Zerit 2 mg/kg/day either alone
or in combination with didanosine from birth through 6 weeks of age; and a clinical trial
where 8 newborns received Zerit 2 mg/kg/day in combination with didanosine and nelfinavir from
birth through 4 weeks of age.
In study AI455-094 (see also section 4.6), the safety follow-up period was restricted to only six
months, which may be insufficient to capture long-term data on neurological adverse events and
mitochondrial toxicity. Relevant grade 3-4 laboratory abnormalities in the 91 stavudine treated infants
were low neutrophils in 7%, low hemoglobin in 1%, ALT increase in 1% and no lipase abnormality.
Data on lactic acid in serum were not collected. No notable differences in the frequency of adverse
drug reactions were seen between treatment groups. There was, however, an increased infant mortality
in the stavudine + didanosine (10%) treatment group compared to the stavudine (2%), didanosine (3%)
or zidovudine (6%) groups, with a higher incidence of stillbirths in the stavudine + didanosine group.
Mitochondrial dysfunction:
review of the postmarketing safety database shows that adverse events
indicative of mitochondrial dysfunction have been reported in the neonate and infant population
exposed to one or more nucleoside analogues (see also section 4.4). The HIV status for the newborns
and infants ≤ 3 months of age was negative, for older infants it tended to be positive. The profile of the
adverse events for newborns and infants ≤ 3 months of age showed increases in lactic acid levels,
neutropenia, anaemia, thrombocytopenia, hepatic transaminase increases and increased lipids,
including hypertriglyceridaemia. The number of reports in older infants was too small to identify a
pattern.
Experience in adults treated with up to 12 times the recommended daily dosage revealed no acute
toxicity. Complications of chronic overdosage could include peripheral neuropathy and hepatic
dysfunction. The mean haemodialysis clearance of stavudine is 120 ml/min. The contribution of this to
the total elimination in an overdose situation is unknown. It is not known whether stavudine is
removed by peritoneal dialysis.
9
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Nucleoside reverse transcriptase inhibitor, ATC code: J05AF04
Mechanism of action:
stavudine, a thymidine analogue, is phosphorylated by cellular kinases to
stavudine triphosphate which inhibits HIV reverse transcriptase by competing with the natural
substrate, thymidine triphosphate. It also inhibits viral DNA synthesis by causing DNA chain
termination due to a lack of the 3’-hydroxyl group necessary for DNA elongation. Cellular DNA
polymerase γ is also sensitive to inhibition by stavudine triphosphate, while cellular polymerases α and
β are inhibited at concentrations 4,000-fold and 40-fold higher, respectively, than that needed to
inhibit HIV reverse transcriptase.
Resistance:
stavudine treatment can select for and/or maintain thymidine analogue mutations (TAMs)
associated with zidovudine resistance. The decrease of susceptibility
in vitro
is subtle requiring two or
more TAMs (generally M41L and T215Y) before stavudine susceptibility is decreased (> 1.5 fold).
These TAMs are seen at a similar frequency with stavudine and zidovudine in virological treatment.
The clinical relevance of these findings suggest that stavudine should be generally avoided in the
presence of TAMs, especially M41L and T215Y.
The activity of stavudine is also affected by multi-drug resistance associated mutations such as
Q151M. In addition, K65R has been reported in patients receiving stavudine/didanosine or
stavudine/lamivudine, but not in patients receiving stavudine monotherapy. V75T is selected
in vitro
by stavudine and reduces susceptibility to stavudine by 2-fold. It occurs in ~1% of patients receiving
stavudine.
Clinical efficacy
Zerit has been studied in combination with other antiretroviral agents, e.g. didanosine, lamivudine,
ritonavir, indinavir, saquinavir, efavirenz, and nelfinavir.
In antiretroviral naive patients
Study AI455-099 was a 48-week, randomised, double-blind study with Zerit (40 mg twice daily), in
combination with lamivudine (150 mg twice daily) plus efavirenz (600 mg once daily),
in 391 treatment-naive patients, with a median CD4 cell count of 272 cells/mm
3
(range 61 to 1,215 cells/mm
3
) and a median plasma HIV-1 RNA of 4.80 log
10
copies/ml
(range 2.6 to 5.9 log
10
copies/ml) at baseline. Patients were primarily males (70%) and non-white
(58%) with a median age of 33 years (range 18 to 68 years).
Study AI455-096 was a 48-week, randomised, double-blind study with Zerit (40 mg twice daily), in
combination with lamivudine (150 mg twice daily) plus efavirenz (600 mg once daily),
in 76 treatment-naive patients, with a median CD4 cell count of 261 cells/mm
3
(range 63 to 962 cells/mm
3
) and a median plasma HIV-1 RNA of 4.63 log
10
copies/ml
(range 3.0 to 5.9 log
10
copies/ml) at baseline. Patients were primarily males (76%) and white (66%)
with a median age of 34 years (range 22 to 67 years).
The results of AI455-099 and AI455-096 are presented in Table 1. Both studies were designed to
compare two formulations of Zerit, one of which was the marketed formulation dosed as currently
approved in product labelling. Only the data from the marketed formulation are presented.
Table 1: Efficacy Outcomes at Week 48 (Studies AI455-099 and AI455-096)
Parameter
AI455-099
AI455-096
10
Zerit + lamivudine +
efavirenz
n=391
Zerit + lamivudine +
efavirenz
n=76
HIV RNA < 400 copies/ml, treatment response, %
All patients
73
66
HIV RNA < 50 copies/ml, treatment response, %
All patients
55
38
HIV RNA Mean Change from Baseline, log
10
copies/ml
All patients
-2.83 (n=321
a
)
-2.64 (n=58)
CD4 Mean Change from Baseline, cells/mm
3
All patients
182 (n=314)
195 (n=55)
a
Number of patients evaluable.
Paediatric population
The use of stavudine in adolescents, children and infants is supported by pharmacokinetic and safety
data in paediatric patients (see also sections 4.8 and 5.2).
5.2 Pharmacokinetic properties
Adults
Absorption:
the absolute bioavailability is 86±18%. After multiple oral administration
of 0.5-0.67 mg/kg doses, a C
max
value of 810±175 ng/ml was obtained. C
max
and AUC increased
proportionally with dose in the dose ranges, intravenous 0.0625-0.75 mg/kg, and oral 0.033-4.0 mg/kg.
In eight patients receiving 40 mg twice daily in the fasted state, steady-state AUC
0-12h
was 1284±227 ngh/ml (18%) (mean ± SD [% CV]), C
max
was 536±146 ng/ml (27%), and C
min
was 9±8 ng/ml (89%). A study in asymptomatic patients demonstrated that systemic exposure is
similar while C
max
is lower and T
max
is prolonged when stavudine is administered with a standardised,
high-fat meal compared with fasting conditions. The clinical significance of this is unknown.
Distribution:
the apparent volume of distribution at steady state is 46±21 l. It was not possible to
detect stavudine in cerebrospinal fluid until at least 2 hours after oral administration. Four hours after
administration, the CSF/plasma ratio was 0.39±0.06. No significant accumulation of stavudine is
observed with repeated administration every 6, 8, or 12 hours.
Binding of stavudine to serum proteins was negligible over the concentration range
of 0.01 to 11.4 µg/ml. Stavudine distributes equally between red blood cells and plasma.
Metabolism:
Unchanged stavudine was the major drug-related component in total plasma radioactivity
circulating after an oral 80 mg dose of
14
C-stavudine in healthy subjects. The AUC(
inf
) for stavudine
was 61% of the AUC(
inf
) of the total circulating radioactivity. Metabolites include oxidised stavudine,
glucuronide conjugates of stavudine and its oxidised metabolite, and an
N
-acetylcysteine conjugate of
the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine.
Elimination:
following an oral 80-mg dose of
14
C-stavudine to healthy subjects, approximately 95%
and 3% of the total radioactivity was recovered in urine and faeces, respectively. Approximately 70%
of the orally administered stavudine dose was excreted as an unchanged drug in urine. Mean renal
clearance of the parent compound is approximately 272 mL/min, accounting for approximately 67% of
the apparent oral clearance, indicating active tubular secretion in addition to glomerular filtration.
In HIV-infected patients,total clearance of stavudine is 594±164 ml/min, and renal clearance
is 237±98 ml/min. The total clearance of stavudine appears to be higher in HIV-infected patients,
while the renal clearance is similar between healthy subjects and HIV-infected patients. The
mechanism and clinical significance of this difference are unknown. After intravenous
administration, 42% (range: 13% to 87%) of dose is excreted unchanged in the urine. The
11
corresponding values after oral single and multiple dose administration are 35% (range: 8% to 72%)
and 40% (range: 12% to 82%), respectively. The mean terminal elimination half-life of stavudine
is 1.3 to 2.3 hours following single or multiple doses, and is independent of dose.
In vitro
, stavudine
triphosphate has an intracellular half-life of 3.5 hours in CEM T-cells (a human T-lymphoblastoid cell
line) and peripheral blood mononuclear cells, supporting twice daily dosing.
The pharmacokinetics of stavudine was independent of time, since the ratio between AUC
(ss)
at steady
state and the AUC
(0-t)
after the first dose was approximately 1. Intra- and interindividual variation in
pharmacokinetic characteristics of stavudine is low, approximately 15% and 25%, respectively, after
oral administration.
Special Populations
Renal impairment:
the clearance of stavudine decreases as creatinine clearance decreases; therefore, it
is recommended that the dosage of Zerit be adjusted in patients with reduced renal function (see
section 4.2).
Hepatic impairment:
stavudine pharmacokinetics in patients with hepatic impairment were similar to
those in patients with normal hepatic function.
Paediatric population
Adolescents, children and infants:
total exposure to stavudine was comparable between adolescents,
children and infants ≥ 14 days receiving the 2 mg/kg/day dose and adults receiving 1 mg/kg/day.
Apparent oral clearance was approximately 14 ml/min/kg for infants ages 5 weeks
to 15 years, 12 ml/min/kg for infants ages 14 to 28 days, and 5 ml/min/kg for infants on the day of
birth. Two to three hours post-dose, CSF/plasma ratios of stavudine ranged from 16% to 125% (mean
of 59%±35%).
5.3 Preclinical safety data
Animal data showed embryo-foetal toxicity at very high exposure levels. An
ex vivo
study using a
term human placenta model demonstrated that stavudine reaches the foetal circulation by simple
diffusion. A rat study also showed placental transfer of stavudine, with the foetal tissue concentration
approximately 50% of the maternal plasma concentration.
Stavudine was genotoxic in
in vitro
tests in human lymphocytes possessing triphosphorylating activity
(in which no no-effect level was established), in mouse fibroblasts, and in an
in vivo
test for
chromosomal aberrations. Similar effects have been observed with other nucleoside analogues.
Stavudine was carcinogenic in mice (liver tumours) and rats (liver tumours: cholangiocellular,
hepatocellular, mixed hepatocholangiocellular, and/or vascular; and urinary bladder carcinomas) at
very high exposure levels. No carcinogenicity was noted at doses of 400 mg/kg/day in mice
and 600 mg/kg/day in rats, corresponding to exposures ~ 39 and 168 times the expected human
exposure, respectively, suggesting an insignificant carcinogenic potential of stavudine in clinical
therapy.
12
6.
6.1 List of excipients
Capsule contents:
Lactose
Magnesium stearate
Microcrystalline cellulose
Sodium starch glycolate
Capsule shell:
Gelatin
Iron oxide colorant (E172)
Silicon dioxide
Sodium laurilsulphate
Titanium dioxide (E171)
The capsule shells are marked using edible black printing ink containing:
Shellac
Propylene Glycol
Purified Water
Potassium Hydroxide
Iron Oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store below 25°C (aclar/alu blisters)
Do not store above 30°C. (HDPE bottles)
Store in the original package.
6.5 Nature and contents of container
High-density polyethylene (HDPE) bottles with child resistant screw cap (60 hard capsules per bottle),
or
aclar/aluminum blisters with 14 hard capsules per card and 4 cards (56 hard capsules) per carton.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
BRISTOL-MYERS SQUIBB PHARMA EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
13
8.
EU/1/96/009/001 - 002
9.
Date of first authorisation: 08 May 1996
Date of last renewal: 08 June 2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/.
14
1.
Zerit 20 mg hard capsule
2.
Each hard capsule contains 20 mg of stavudine.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
The hard capsule is brown, opaque and imprinted with “BMS” over a BMS code “1965” on one side
and “20” on the other side.
4.
Zerit is indicated in combination with other antiretroviral medicinal products for the treatment of HIV
infected patients.
Posology
The therapy should be initiated by a doctor experienced in the management of HIV infection (see also
section 4.4).
For optimal absorption, Zerit should be taken on an empty stomach (i.e. at least 1 hour prior to meals)
but, if this is not possible, it may be taken with a light meal. Zerit may also be administered by
carefully opening the hard capsule and mixing the contents with food.
Adults:
the recommended oral dosage is:
Patient weight
Zerit dosage
< 60 kg
60 kg
30 mg twice daily (every 12 hours)
40 mg twice daily
Paediatric population:
Adolescents, childr
en and infants over the age of 3 months:
the recommended oral d
osage is:
Patient weight Zerit dosage
< 30 kg
30 kg
1 mg/kg twice daily (every 12 hours)
adult dosing
The powder formulation of ZERIT should be used for infants under the age of 3 months. Please refer
to the Summary of Product Characteristics of the powder formulation.
Dose adjustments
Peripheral neuropathy:
if symptoms of peripheral neuropathy develop (usually characterised by
persistent numbness, tingling, or pain in the feet and/or hands) (see section 4.4) patients should be
switched to an alternative treatment regimen, if appropriate. In the rare cases when this is
inappropriate, dose reduction of stavudine may be considered, while the symptoms of peripheral
neuropathy are under close monitoring and satisfactory virological suppression is maintained.
15
The possible benefits of a dose reduction should be balanced in each case against the risks - which
may result from this measure (lower intracellular concentrations).
Special populations
Elderly:
Zerit has not been specifically investigated in patients over the age of 65.
Hepatic impairment:
no initial dosage adjustment is necessary.
Renal impairment:
the following dosages are recommended:
Zerit dosage (according to creatinine clearance)
Patient weight
26-50 ml/min ≤ 25 ml/min
(including dialysis dependence*)
< 60 kg
15 mg twice daily
15 mg every 24 hours
≥ 60 kg
20 mg twice daily
20 mg every 24 hours
* Patients on haemodialysis should take Zerit after the completion of haemodialysis, and at the same
time on non-dialysis days.
Since urinary excretion is also a major route of elimination of stavudine in paediatric patients, the
clearance of stavudine may be altered in paediatric patients with renal impairment. Although there are
insufficient data to recommend a specific dosage adjustment of Zerit in this patient population, a
reduction in the dose and/or an increase in the interval between doses proportional to the reduction for
adults should be considered.
Hypersensitivity to stavudine or to any of the excipients.
Stavudine therapy is associated with several severe side effects, such as lactic acidosis, lipoatrophy
and polyneuropathy, for which a potential underlying mechanism is mitochondrial toxicity. Given
these potential risks, a benefit-risk assessment for each patients should be made and an alternative
antiretroviral should be carefully considered (see
Lactic acidosis, Lipodystrophy and metabolic
abnormalities,
and
Peripheral neuropathy
below and section 4.8).
Lactic acidosis:
lactic acidosis, usually associated with hepatomegaly and hepatic steatosis has been
reported with the use of nucleoside reverse transcriptase inhibitors (NRTIs). 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, renal failure, or motor paralysis.
Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with NRTIs should be discontinued if there is symptomatic hyperlactatemia and
metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.
Caution should be exercised when administering NRTIs 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 (see also section 4.6).
Liver disease:
hepatitis or liver failure, which was fatal in some cases, has been reported. The safety
and efficacy of stavudine has not been established in patients with significant underlying liver
disorders. 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 events. In case of concomitant
16
antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these
medicinal products.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination antiretroviral therapy and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
In the event of rapidly elevating transaminase levels (ALT/AST, > 5 times upper limit of normal,
ULN), discontinuation of Zerit and any potentially hepatotoxic medicinal products should be
considered.
Lipodystrophy and metabolic abnormalities
: combination antiretroviral therapy has been associated
with the redistribution of body fat (lipodystrophy) in HIV patients. Knowledge about the mechanism is
incomplete. A connection between visceral lipomatosis and Protease Inhibitors and lipoatrophy and
NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual
factors such as older age, and with drug related factors such as longer duration of antiretroviral
treatment and associated metabolic disturbances.
In randomized controlled trials of treatment-naive patients, clinical lipoatrophy developed in a higher
proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir).
Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine
treated patients compared to limb fat gain or no change in patients treated with other NRTIs (abacavir,
tenofovir or zidovudine). The incidence and severity of lipoatrophy are cumulative over time with
stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides
(tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical
lipoatrophy. Given the potential risks of using ZERIT including lipoatrophy or lipodystrophy, a
benefit-risk assessment for each patient should be made and an alternative antiretroviral carefully
considered. Patients receiving Zerit should be frequently examined and questioned for signs of
lipoatrophy. When such development is found, discontinuation of Zerit should be considered.
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).
Peripheral neuropathy: up to 20% of patients treated with Zerit will develop peripheral neuropathy,
often starting after some months of treatment. Patients with a history of neuropathy, or with other risk
factors (for example alcohol, medications such as isoniazid) are at particular risk. Patients should be
monitored for symptoms (persistent numbness, tingling or pain in feet/hands) and if present patients
should be switched to an alternate treatment regimen (see section 4.2 and Not recommended
combinations, below).
Pancreatitis:
patients with a history of pancreatitis had an incidence of approximately 5% on Zerit, as
compared to approximately 2% in patients without such a history. Patients with a high risk of
pancreatitis or those receiving products known to be associated with pancreatitis should be closely
followed for symptoms of this condition.
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
17
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.
Not recommended combinations:
pancreatitis (fatal and nonfatal) and peripheral neuropathy (severe in
some cases) have been reported in HIV infected patients receiving stavudine in association with
hydroxyurea and didanosine. Hepatotoxicity and hepatic failure resulting in death were reported
during postmarketing surveillance in HIV infected patients treated with antiretroviral agents and
hydroxyurea; fatal hepatic events were reported most often in patients treated with stavudine,
hydroxyurea and didanosine. Hence, hydroxyurea should not be used in the treatment of HIV
infection.
Lactose intolerance:
the hard capsule contains lactose (180 mg). Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption,
should not take this medicine.
Elderly:
Zerit has not been specifically investigated in patients over the age of 65.
Paediatric population
Infants under the age of 3 months:
safety data are available from clinical trials up to 6 weeks of
treatment in 179 newborns and infants < 3 months of age (see section 4.8).
Special consideration should be given to the antiretroviral treatment history and the resistance profile
of the HIV strain of the mother.
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 (see
also section 4.8). The main adverse events reported are haematological disorders (anaemia,
neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These events 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.
Since stavudine is actively secreted by the renal tubules, interactions with other actively secreted
medicinal products are possible, e.g. with trimethoprim. No clinically relevant pharmacokinetic
interaction has, however, been seen with lamivudine.
Zidovudine and stavudine are phosphorylated by the cellular enzyme (thymidine kinase), which
preferentially phosphorylates zidovudine, thereby decreasing the phosphorylation of stavudine to its
active triphosphate form. Zidovudine is therefore not recommended to be used in combination with
stavudine.
In vitro
studies indicate that the activation of stavudine is inhibited by doxorubicin and ribavirin but
not by other medicinal products used in HIV infection which are similarly phosphorylated,
(e.g. didanosine, zalcitabine, ganciclovir and foscarnet) therefore, coadministration of stavudine with
either doxorubicin or ribavirin should be undertaken with caution. Stavudine’s influence on the
phosphorylation kinetics of nucleoside analogues other than zidovudine has not been investigated.
Clinically significant interactions of stavudine or stavudine plus didanosine with nelfinavir have not
been observed.
18
Stavudine does not inhibit the major cytochrome P450 isoforms CYP1A2, CYP2C9, CYP2C19,
CYP2D6, and CYP3A4; therefore, it is unlikely that clinically significant drug interactions will occur
with drugs metabolised through these pathways.
Because stavudine is not protein-bound, it is not expected to affect the pharmacokinetics of
protein-bound drugs.
There have been no formal interaction studies with other medicinal products.
Paediatric population
Interaction studies have only been performed in adults
Pregnancy
Zerit should not be used during pregnancy unless clearly necessary.
Clinical experience in pregnant women is limited, but congenital anomalies and abortions have been
reported.
In study AI455-094, performed in South-Africa, 362 mother-infant pairs were included in a prevention
of mother-to-child-transmission study. Treatment naive pregnant women were enrolled into the study
at gestation week 34-36 and given antiretroviral treatment until delivery. Antiretroviral prophylaxis,
the same medications as given to the mother, was given to the new-born infant within 36 hours of
delivery and continued for 6 weeks. In the stavudine containing arms, the neonates were treated
for 6 weeks with stavudine 1 mg/kg BID. The follow-up time was up to 24 weeks of age.
The mother-infant pairs were randomised to receive either stavudine (N= 91), didanosine (N= 94),
stavudine + didanosine (N= 88) or zidovudine (N= 89).
95% Confidence intervals for the mother-to-child-transmission rates were 5.4-19.3%
(stavudine), 5.2-18.7% (didanosine); 1.3-11.2% (stavudine + didanosine); and 1.9-12.6% for
zidovudine.
Preliminary safety data from this study (see also section 4.8), showed an increased infant mortality in
the stavudine + didanosine (10%) treatment group compared to the stavudine (2%), didanosine (3%)
or zidovudine (6%) groups, with a higher incidence of stillbirths in the stavudine + didanosine group.
Data on lactic acid in serum were not collected in this study.
However, lactic acidosis (see section 4.4), sometimes fatal, has been reported in pregnant women who
received the combination of didanosine and stavudine with or without other anti-retroviral treatment.
Embryo-foetal toxicities were seen only at high exposure levels in animals. Preclinical studies showed
placental transfer of stavudine (see section 5.3). Until additional data become available, Zerit should
be given during pregnancy only after special consideration; there is insufficient information to
recommend Zerit for prevention of mother-to-child transmission of HIV. Furthermore, the
combination of stavudine and didanosine should be used with caution during pregnancy and is
recommended only if the potential benefit clearly outweighs the potential risk.
Breastfeeding
It is recommended that HIV infected women should not breast-feed under any circumstances in order
to avoid transmission of HIV.
The data available on stavudine excretion into human breast milk are insufficient to assess the risk to
the infant. Studies in lactating rats showed that stavudine is excreted in breast milk. Therefore,
mothers should be instructed to discontinue breast-feeding prior to receiving Zerit.
Fertility
19
No evidence of impaired fertility was seen in rats at high exposure levels (up to 216 times that
observed at the recommended clinical dose).
Based on the pharmacodynamic properties of stavudine it is unlikely that Zerit affects the ability to
drive or operate machinery.
a. Summary of the safety profile
Stavudine therapy is associated with several severe side effects, such as lactic acidosis, lipoatrophy
and polyneuropathy, for which a potential underlying mechanism is mitochondrial toxicity. Given
these potential risks, a benefit-risk assessment for each patient should be made and an alternative
antiretroviral should be carefully considered (see section 4.4 and below).
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic
steatosis, have been reported in < 1% of patients taking stavudine in combination with other
antiretrovirals (see section 4.4).
Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy
including Zerit. Most of these cases occurred in the setting of symptomatic hyperlactatemia or lactic
acidosis syndrome (see section 4.4). The evolution of motor weakness may mimic the clinical
presentation of Guillain-Barré syndrome (including respiratory failure). Symptoms may continue or
worsen following discontinuation of therapy.
Hepatitis or liver failure, which was fatal in some cases, has been reported with the use of stavudine
and with other nucleoside analogues (see section 4.4).
Lipoatrophy was commonly reported in patients treated with stavudine in combination with other
antiretrovirals (see section 4.4).
Peripheral neuropathy was seen in combination studies of Zerit with lamivudine plus efavirenz; the
frequency of peripheral neurologic symptoms was 19% (6% for moderate to severe) with a rate of
discontinuation due to neuropathy of 2%. The patients usually experienced resolution of symptoms
after dose reduction or interruption of stavudine.
Pancreatitis, occasionally fatal, has been reported in up to 2-3% of patients enrolled in monotherapy
clinical studies (see section 4.4). Pancreatitis was reported in < 1% of patients in combination therapy
studies with Zerit.
b.
Tabulated summary of adverse reactions
Adverse reactions of moderate or greater severity with at least a possible relationship to treatment
regimen (based on investigator attribution) reported from 467 patients treated with Zerit in
combination with lamivudine and efavirenz in two randomised clinical trials and along-term follow-up
study (follow-up: median 56 weeks ranging up to 119 weeks) are listed below. Also listed are adverse
reactions observed post-marketing in association with stavudine-containing antiretroviral treatment .
The frequency of adverse reactions listed below is defined using the following convention: very
common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare
(≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); or not known (cannot be estimated from the available
data). Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
20
Blood and lymphatic system
disorders:
rare: anaemia*
very rare: neutropenia *, thrombocytopenia*
Endocrine disorders:
uncommon: gynaecomastia
Metabolism and nutrition
disorders:
common: lipoatrophy**, lipodystrophy**, asymptomatic
hyperlactatemia
uncommon: lactic acidosis (in some cases involving motor
weakness), anorexia
rare: hyperglycaemia*
very rare: diabetes mellitis*
Psychiatric disorders:
common: depression
uncommon: anxiety, emotional lability
Nervous system disorders:
common: peripheral neurologic symptoms including peripheral
neuropathy, paresthesia, and peripheral neuritis;
dizziness; abnormal dreams; headache, insomnia;
abnormal thinking; somnolence
very rare: motor weakness* (most often reported in the setting of
symptomatic hyperlactatemia or lactic acidosis syndrome)
Gastrointestinal disorders:
common: diarrhoea, abdominal pain, nausea, dyspepsia
uncommon: pancreatitis, vomiting
Hepatobiliary disorders:
uncommon: hepatitis or jaundice
rare: hepatic steatosis*
very rare: liver failure*
Skin and subcutaneous tissue
disorders:
common: rash, pruritus
uncommon: urticaria
Musculoskeletal and connective
tissue disorders:
uncommon: arthralgia, myalgia
common: fatigue
uncommon: asthenia
*
adverse reactions observed post-marketing in association with stavudine-containing antiretroviral
treatment
** See Section
c. Description of selected adverse reactions
for more details.
c. Description of selected adverse reactions
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).
Lipodystrophy and 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). In randomized controlled trials of treatment-naive
patients, clinical lipoatrophy developed in a higher proportion of patients treated with stavudine
compared to other NRTIs (tenofovir or abacavir). In one study, after 2 years of treatment, about 40%
of stavudine-treated patients had lost greater than 20% of limb fat and after 3 years the amount of limb
fat was only about half of the normal amount (4.5 kg vs about 8 kg).. The incidence and severity of
lipoatrophy are cumulative over time; lipoatrophy may affect most patients with time and is often not
reversible when stavudine treatment is stopped (see section 4.4).
21
General disorders and
administration site conditions:
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (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).
Laboratory abnormalities
Laboratory abnormalities reported in these two trials and an ongoing follow-up study included
elevations of ALT (> 5 x ULN) in 3%, of AST (> 5 x ULN) in 3%, of lipase (≥ 2.1 ULN) in 3% of the
patients in the Zerit group. Neutropenia (< 750 cells/mm
3
) was reported in 5%, thrombocytopenia
(platelets < 50,000/mm
3
) in 2%, and low haemoglobin (< 8 g/dl) in < 1% of patients receiving Zerit.
Macrocytosis was not evaluated in these trials, but was found to be associated with Zerit in an earlier
trial (MCV > 112 fl occurred in 30% of patients treated with Zerit).
d. Paediatric population
Adolescents, children and infants:
undesirable effects and serious laboratory abnormalities reported to
occur in paediatric patients ranging in age from birth through adolescence who received stavudine in
clinical studies were generally similar in type and frequency to those seen in adults. However,
clinically significant peripheral neuropathy is less frequent. These studies include ACTG 240,
where 105 paediatric patients ages 3 months to 6 years received Zerit 2 mg/kg/day for a median
of 6.4 months; a controlled clinical trial where 185 newborns received Zerit 2 mg/kg/day either alone
or in combination with didanosine from birth through 6 weeks of age; and a clinical trial
where 8 newborns received Zerit 2 mg/kg/day in combination with didanosine and nelfinavir from
birth through 4 weeks of age.
In study AI455-094 (see also section 4.6), the safety follow-up period was restricted to only six
months, which may be insufficient to capture long-term data on neurological adverse events and
mitochondrial toxicity. Relevant grade 3-4 laboratory abnormalities in the 91 stavudine treated infants
were low neutrophils in 7%, low hemoglobin in 1%, ALT increase in 1% and no lipase abnormality.
Data on lactic acid in serum were not collected. No notable differences in the frequency of adverse
drug reactions were seen between treatment groups. There was, however, an increased infant mortality
in the stavudine + didanosine (10%) treatment group compared to the stavudine (2%), didanosine (3%)
or zidovudine (6%) groups, with a higher incidence of stillbirths in the stavudine + didanosine group.
Mitochondrial dysfunction:
review of the postmarketing safety database shows that adverse events
indicative of mitochondrial dysfunction have been reported in the neonate and infant population
exposed to one or more nucleoside analogues (see also section 4.4). The HIV status for the newborns
and infants ≤ 3 months of age was negative, for older infants it tended to be positive. The profile of the
adverse events for newborns and infants ≤ 3 months of age showed increases in lactic acid levels,
neutropenia, anaemia, thrombocytopenia, hepatic transaminase increases and increased lipids,
including hypertriglyceridaemia. The number of reports in older infants was too small to identify a
pattern.
Experience in adults treated with up to 12 times the recommended daily dosage revealed no acute
toxicity. Complications of chronic overdosage could include peripheral neuropathy and hepatic
dysfunction. The mean haemodialysis clearance of stavudine is 120 ml/min. The contribution of this to
the total elimination in an overdose situation is unknown. It is not known whether stavudine is
removed by peritoneal dialysis.
22
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Nucleoside reverse transcriptase inhibitor, ATC code: J05AF04
Mechanism of action:
stavudine, a thymidine analogue, is phosphorylated by cellular kinases to
stavudine triphosphate which inhibits HIV reverse transcriptase by competing with the natural
substrate, thymidine triphosphate. It also inhibits viral DNA synthesis by causing DNA chain
termination due to a lack of the 3’-hydroxyl group necessary for DNA elongation. Cellular DNA
polymerase γ is also sensitive to inhibition by stavudine triphosphate, while cellular polymerases α and
β are inhibited at concentrations 4,000-fold and 40-fold higher, respectively, than that needed to
inhibit HIV reverse transcriptase.
Resistance:
stavudine treatment can select for and/or maintain thymidine analogue mutations (TAMs)
associated with zidovudine resistance. The decrease of susceptibility
in vitro
is subtle requiring two or
more TAMs (generally M41L and T215Y) before stavudine susceptibility is decreased (> 1.5 fold).
These TAMs are seen at a similar frequency with stavudine and zidovudine in virological treatment.
The clinical relevance of these findings suggest that stavudine should be generally avoided in the
presence of TAMs, especially M41L and T215Y.
The activity of stavudine is also affected by multi-drug resistance associated mutations such as
Q151M. In addition, K65R has been reported in patients receiving stavudine/didanosine or
stavudine/lamivudine, but not in patients receiving stavudine monotherapy. V75T is selected
in vitro
by stavudine and reduces susceptibility to stavudine by 2-fold. It occurs in ~1% of patients receiving
stavudine.
Clinical efficacy
Zerit has been studied in combination with other antiretroviral agents, e.g. didanosine, lamivudine,
ritonavir, indinavir, saquinavir, efavirenz, and nelfinavir.
In antiretroviral naive patients
Study AI455-099 was a 48-week, randomised, double-blind study with Zerit (40 mg twice daily), in
combination with lamivudine (150 mg twice daily) plus efavirenz (600 mg once daily),
in 391 treatment-naive patients, with a median CD4 cell count of 272 cells/mm
3
(range 61 to 1,215 cells/mm
3
) and a median plasma HIV-1 RNA of 4.80 log
10
copies/ml
(range 2.6 to 5.9 log
10
copies/ml) at baseline. Patients were primarily males (70%) and non-white
(58%) with a median age of 33 years (range 18 to 68 years).
Study AI455-096 was a 48-week, randomised, double-blind study with Zerit (40 mg twice daily), in
combination with lamivudine (150 mg twice daily) plus efavirenz (600 mg once daily),
in 76 treatment-naive patients, with a median CD4 cell count of 261 cells/mm
3
(range 63 to 962 cells/mm
3
) and a median plasma HIV-1 RNA of 4.63 log
10
copies/ml
(range 3.0 to 5.9 log
10
copies/ml) at baseline. Patients were primarily males (76%) and white (66%)
with a median age of 34 years (range 22 to 67 years).
The results of AI455-099 and AI455-096 are presented in Table 1. Both studies were designed to
compare two formulations of Zerit, one of which was the marketed formulation dosed as currently
approved in product labelling. Only the data from the marketed formulation are presented.
Table 1: Efficacy Outcomes at Week 48 (Studies AI455-099 and AI455-096)
Parameter
AI455-099
AI455-096
23
Zerit + lamivudine +
efavirenz
n=391
Zerit + lamivudine +
efavirenz
n=76
HIV RNA < 400 copies/ml, treatment response, %
All patients
73
66
HIV RNA < 50 copies/ml, treatment response, %
All patients
55
38
HIV RNA Mean Change from Baseline, log
10
copies/ml
All patients
-2.83 (n=321
a
)
-2.64 (n=58)
CD4 Mean Change from Baseline, cells/mm
3
All patients
182 (n=314)
195 (n=55)
a
Number of patients evaluable.
Paediatric population
The use of stavudine in adolescents, children and infants is supported by pharmacokinetic and safety
data in paediatric patients (see also sections 4.8 and 5.2).
5.2 Pharmacokinetic properties
Adults
Absorption:
the absolute bioavailability is 86±18%. After multiple oral administration
of 0.5-0.67 mg/kg doses, a C
max
value of 810±175 ng/ml was obtained. C
max
and AUC increased
proportionally with dose in the dose ranges, intravenous 0.0625-0.75 mg/kg, and oral 0.033-4.0 mg/kg.
In eight patients receiving 40 mg twice daily in the fasted state, steady-state AUC
0-12h
was 1284±227 ngh/ml (18%) (mean ± SD [% CV]), C
max
was 536±146 ng/ml (27%), and C
min
was 9±8 ng/ml (89%). A study in asymptomatic patients demonstrated that systemic exposure is
similar while C
max
is lower and T
max
is prolonged when stavudine is administered with a standardised,
high-fat meal compared with fasting conditions. The clinical significance of this is unknown.
Distribution:
the apparent volume of distribution at steady state is 46±21 l. It was not possible to
detect stavudine in cerebrospinal fluid until at least 2 hours after oral administration. Four hours after
administration, the CSF/plasma ratio was 0.39±0.06. No significant accumulation of stavudine is
observed with repeated administration every 6, 8, or 12 hours.
Binding of stavudine to serum proteins was negligible over the concentration range
of 0.01 to 11.4 µg/ml. Stavudine distributes equally between red blood cells and plasma.
Metabolism:
Unchanged stavudine was the major drug-related component in total plasma radioactivity
circulating after an oral 80 mg dose of
14
C-stavudine in healthy subjects. The AUC(
inf
) for stavudine
was 61% of the AUC(
inf
) of the total circulating radioactivity. Metabolites include oxidised stavudine,
glucuronide conjugates of stavudine and its oxidised metabolite, and an
N
-acetylcysteine conjugate of
the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine.
Elimination:
following an oral 80-mg dose of
14
C-stavudine to healthy subjects, approximately 95%
and 3% of the total radioactivity was recovered in urine and faeces, respectively. Approximately 70%
of the orally administered stavudine dose was excreted as an unchanged drug in urine. Mean renal
clearance of the parent compound is approximately 272 mL/min, accounting for approximately 67% of
the apparent oral clearance, indicating active tubular secretion in addition to glomerular filtration.
In HIV-infected patients,total clearance of stavudine is 594±164 ml/min, and renal clearance
is 237±98 ml/min. The total clearance of stavudine appears to be higher in HIV-infected patients,
while the renal clearance is similar between healthy subjects and HIV-infected patients. The
mechanism and clinical significance of this difference are unknown. After intravenous
administration, 42% (range: 13% to 87%) of dose is excreted unchanged in the urine. The
24
corresponding values after oral single and multiple dose administration are 35% (range: 8% to 72%)
and 40% (range: 12% to 82%), respectively. The mean terminal elimination half-life of stavudine
is 1.3 to 2.3 hours following single or multiple doses, and is independent of dose.
In vitro
, stavudine
triphosphate has an intracellular half-life of 3.5 hours in CEM T-cells (a human T-lymphoblastoid cell
line) and peripheral blood mononuclear cells, supporting twice daily dosing.
The pharmacokinetics of stavudine was independent of time, since the ratio between AUC
(ss)
at steady
state and the AUC
(0-t)
after the first dose was approximately 1. Intra- and interindividual variation in
pharmacokinetic characteristics of stavudine is low, approximately 15% and 25%, respectively, after
oral administration.
Special Populations
Renal impairment:
the clearance of stavudine decreases as creatinine clearance decreases; therefore, it
is recommended that the dosage of Zerit be adjusted in patients with reduced renal function (see
section 4.2).
Hepatic impairment:
stavudine pharmacokinetics in patients with hepatic impairment were similar to
those in patients with normal hepatic function.
Paediatric population
Adolescents, children and infants:
total exposure to stavudine was comparable between adolescents,
children and infants ≥ 14 days receiving the 2 mg/kg/day dose and adults receiving 1 mg/kg/day.
Apparent oral clearance was approximately 14 ml/min/kg for infants ages 5 weeks
to 15 years, 12 ml/min/kg for infants ages 14 to 28 days, and 5 ml/min/kg for infants on the day of
birth. Two to three hours post-dose, CSF/plasma ratios of stavudine ranged from 16% to 125% (mean
of 59%±35%).
5.3 Preclinical safety data
Animal data showed embryo-foetal toxicity at very high exposure levels. An
ex vivo
study using a
term human placenta model demonstrated that stavudine reaches the foetal circulation by simple
diffusion. A rat study also showed placental transfer of stavudine, with the foetal tissue concentration
approximately 50% of the maternal plasma concentration.
Stavudine was genotoxic in
in vitro
tests in human lymphocytes possessing triphosphorylating activity
(in which no no-effect level was established), in mouse fibroblasts, and in an
in vivo
test for
chromosomal aberrations. Similar effects have been observed with other nucleoside analogues.
Stavudine was carcinogenic in mice (liver tumours) and rats (liver tumours: cholangiocellular,
hepatocellular, mixed hepatocholangiocellular, and/or vascular; and urinary bladder carcinomas) at
very high exposure levels. No carcinogenicity was noted at doses of 400 mg/kg/day in mice
and 600 mg/kg/day in rats, corresponding to exposures ~ 39 and 168 times the expected human
exposure, respectively, suggesting an insignificant carcinogenic potential of stavudine in clinical
therapy.
25
6.
6.1 List of excipients
Capsule contents:
Lactose
Magnesium stearate
Microcrystalline cellulose
Sodium starch glycolate
Capsule shell:
Gelatin
Iron oxide colorant (E172)
Silicon dioxide
Sodium laurilsulphate
Titanium dioxide (E171)
The capsule shells are marked using edible black printing ink containing:
Shellac
Propylene Glycol
Purified Water
Potassium Hydroxide
Iron Oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store below 25°C (aclar/alu blisters)
Do not store above 30°C. (HDPE bottles)
Store in the original package.
6.5 Nature and contents of container
High-density polyethylene (HDPE) bottles with child resistant screw cap (60 hard capsules per bottle),
or
aclar/aluminum blisters with 14 hard capsules per card and 4 cards (56 hard capsules) per carton.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
BRISTOL-MYERS SQUIBB PHARMA EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
26
8.
EU/1/96/009/003 - 004
9.
Date of first authorisation: 08 May 1996
Date of last renewal: 08 June 2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/.
27
1.
Zerit 30 mg hard capsule
2.
Each hard capsule contains 30 mg of stavudine.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
The hard capsule is light and dark orange, opaque and imprinted with “BMS” over a BMS code
“1966” on one side and “30” on the other side.
4.
Zerit is indicated in combination with other antiretroviral medicinal products for the treatment of HIV
infected patients.
Posology
The therapy should be initiated by a doctor experienced in the management of HIV infection (see also
section 4.4).
For optimal absorption, Zerit should be taken on an empty stomach (i.e. at least 1 hour prior to meals)
but, if this is not possible, it may be taken with a light meal. Zerit may also be administered by
carefully opening the hard capsule and mixing the contents with food.
Adults:
the recommended oral dosage is:
Patient weight
Zerit dosage
< 60 kg
60 kg
30 mg twice daily (every 12 hours)
40 mg twice daily
Paediatric population:
Adolescents, childr
en and infants over the age of 3 months:
the recommended oral d
osage is:
Patient weight Zerit dosage
< 30 kg
30 kg
1 mg/kg twice daily (every 12 hours)
adult dosing
The powder formulation of ZERIT should be used for infants under the age of 3 months. Please refer
to the Summary of Product Characteristics of the powder formulation.
Dose adjustments
Peripheral neuropathy:
if symptoms of peripheral neuropathy develop (usually characterised by
persistent numbness, tingling, or pain in the feet and/or hands) (see section 4.4) patients should be
switched to an alternative treatment regimen, if appropriate. In the rare cases when this is
inappropriate, dose reduction of stavudine may be considered, while the symptoms of peripheral
neuropathy are under close monitoring and satisfactory virological suppression is maintained.
28
The possible benefits of a dose reduction should be balanced in each case against the risks - which
may result from this measure (lower intracellular concentrations).
Special populations
Elderly:
Zerit has not been specifically investigated in patients over the age of 65.
Hepatic impairment:
no initial dosage adjustment is necessary.
Renal impairment:
the following dosages are recommended:
Zerit dosage (according to creatinine clearance)
Patient weight
26-50 ml/min ≤ 25 ml/min
(including dialysis dependence*)
< 60 kg
15 mg twice daily
15 mg every 24 hours
≥ 60 kg
20 mg twice daily
20 mg every 24 hours
* Patients on haemodialysis should take Zerit after the completion of haemodialysis, and at the same
time on non-dialysis days.
Since urinary excretion is also a major route of elimination of stavudine in paediatric patients, the
clearance of stavudine may be altered in paediatric patients with renal impairment. Although there are
insufficient data to recommend a specific dosage adjustment of Zerit in this patient population, a
reduction in the dose and/or an increase in the interval between doses proportional to the reduction for
adults should be considered.
Hypersensitivity to stavudine or to any of the excipients.
Stavudine therapy is associated with several severe side effects, such as lactic acidosis, lipoatrophy
and polyneuropathy, for which a potential underlying mechanism is mitochondrial toxicity. Given
these potential risks, a benefit-risk assessment for each patients should be made and an alternative
antiretroviral should be carefully considered (see
Lactic acidosis, Lipodystrophy and metabolic
abnormalities,
and
Peripheral neuropathy
below and section 4.8).
Lactic acidosis:
lactic acidosis, usually associated with hepatomegaly and hepatic steatosis has been
reported with the use of nucleoside reverse transcriptase inhibitors (NRTIs). 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, renal failure, or motor paralysis.
Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with NRTIs should be discontinued if there is symptomatic hyperlactatemia and
metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.
Caution should be exercised when administering NRTIs 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 (see also section 4.6).
Liver disease:
hepatitis or liver failure, which was fatal in some cases, has been reported. The safety
and efficacy of stavudine has not been established in patients with significant underlying liver
disorders. 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 events. In case of concomitant
29
antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these
medicinal products.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination antiretroviral therapy and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
In the event of rapidly elevating transaminase levels (ALT/AST, > 5 times upper limit of normal,
ULN), discontinuation of Zerit and any potentially hepatotoxic medicinal products should be
considered.
Lipodystrophy and metabolic abnormalities
: combination antiretroviral therapy has been associated
with the redistribution of body fat (lipodystrophy) in HIV patients. Knowledge about the mechanism is
incomplete. A connection between visceral lipomatosis and Protease Inhibitors and lipoatrophy and
NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual
factors such as older age, and with drug related factors such as longer duration of antiretroviral
treatment and associated metabolic disturbances.
In randomized controlled trials of treatment-naive patients, clinical lipoatrophy developed in a higher
proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir).
Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine
treated patients compared to limb fat gain or no change in patients treated with other NRTIs (abacavir,
tenofovir or zidovudine). The incidence and severity of lipoatrophy are cumulative over time with
stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides
(tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical
lipoatrophy. Given the potential risks of using ZERIT including lipoatrophy or lipodystrophy, a
benefit-risk assessment for each patient should be made and an alternative antiretroviral carefully
considered. Patients receiving Zerit should be frequently examined and questioned for signs of
lipoatrophy. When such development is found, discontinuation of Zerit should be considered.
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).
Peripheral neuropathy: up to 20% of patients treated with Zerit will develop peripheral neuropathy,
often starting after some months of treatment. Patients with a history of neuropathy, or with other risk
factors (for example alcohol, medications such as isoniazid) are at particular risk. Patients should be
monitored for symptoms (persistent numbness, tingling or pain in feet/hands) and if present patients
should be switched to an alternate treatment regimen (see section 4.2 and Not recommended
combinations, below).
Pancreatitis:
patients with a history of pancreatitis had an incidence of approximately 5% on Zerit, as
compared to approximately 2% in patients without such a history. Patients with a high risk of
pancreatitis or those receiving products known to be associated with pancreatitis should be closely
followed for symptoms of this condition.
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
30
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.
Not recommended combinations:
pancreatitis (fatal and nonfatal) and peripheral neuropathy (severe in
some cases) have been reported in HIV infected patients receiving stavudine in association with
hydroxyurea and didanosine. Hepatotoxicity and hepatic failure resulting in death were reported
during postmarketing surveillance in HIV infected patients treated with antiretroviral agents and
hydroxyurea; fatal hepatic events were reported most often in patients treated with stavudine,
hydroxyurea and didanosine. Hence, hydroxyurea should not be used in the treatment of HIV
infection.
Lactose intolerance:
the hard capsule contains lactose (180 mg). Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption,
should not take this medicine.
Elderly:
Zerit has not been specifically investigated in patients over the age of 65.
Paediatric population
Infants under the age of 3 months:
safety data are available from clinical trials up to 6 weeks of
treatment in 179 newborns and infants < 3 months of age (see section 4.8).
Special consideration should be given to the antiretroviral treatment history and the resistance profile
of the HIV strain of the mother.
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 (see
also section 4.8). The main adverse events reported are haematological disorders (anaemia,
neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These events 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.
Since stavudine is actively secreted by the renal tubules, interactions with other actively secreted
medicinal products are possible, e.g. with trimethoprim. No clinically relevant pharmacokinetic
interaction has, however, been seen with lamivudine.
Zidovudine and stavudine are phosphorylated by the cellular enzyme (thymidine kinase), which
preferentially phosphorylates zidovudine, thereby decreasing the phosphorylation of stavudine to its
active triphosphate form. Zidovudine is therefore not recommended to be used in combination with
stavudine.
In vitro
studies indicate that the activation of stavudine is inhibited by doxorubicin and ribavirin but
not by other medicinal products used in HIV infection which are similarly phosphorylated,
(e.g. didanosine, zalcitabine, ganciclovir and foscarnet) therefore, coadministration of stavudine with
either doxorubicin or ribavirin should be undertaken with caution. Stavudine’s influence on the
phosphorylation kinetics of nucleoside analogues other than zidovudine has not been investigated.
Clinically significant interactions of stavudine or stavudine plus didanosine with nelfinavir have not
been observed.
31
Stavudine does not inhibit the major cytochrome P450 isoforms CYP1A2, CYP2C9, CYP2C19,
CYP2D6, and CYP3A4; therefore, it is unlikely that clinically significant drug interactions will occur
with drugs metabolised through these pathways.
Because stavudine is not protein-bound, it is not expected to affect the pharmacokinetics of
protein-bound drugs.
There have been no formal interaction studies with other medicinal products.
Paediatric population
Interaction studies have only been performed in adults
Pregnancy
Zerit should not be used during pregnancy unless clearly necessary.
Clinical experience in pregnant women is limited, but congenital anomalies and abortions have been
reported.
In study AI455-094, performed in South-Africa, 362 mother-infant pairs were included in a prevention
of mother-to-child-transmission study. Treatment naive pregnant women were enrolled into the study
at gestation week 34-36 and given antiretroviral treatment until delivery. Antiretroviral prophylaxis,
the same medications as given to the mother, was given to the new-born infant within 36 hours of
delivery and continued for 6 weeks. In the stavudine containing arms, the neonates were treated
for 6 weeks with stavudine 1 mg/kg BID. The follow-up time was up to 24 weeks of age.
The mother-infant pairs were randomised to receive either stavudine (N= 91), didanosine (N= 94),
stavudine + didanosine (N= 88) or zidovudine (N= 89).
95% Confidence intervals for the mother-to-child-transmission rates were 5.4-19.3%
(stavudine), 5.2-18.7% (didanosine); 1.3-11.2% (stavudine + didanosine); and 1.9-12.6% for
zidovudine.
Preliminary safety data from this study (see also section 4.8), showed an increased infant mortality in
the stavudine + didanosine (10%) treatment group compared to the stavudine (2%), didanosine (3%)
or zidovudine (6%) groups, with a higher incidence of stillbirths in the stavudine + didanosine group.
Data on lactic acid in serum were not collected in this study.
However, lactic acidosis (see section 4.4), sometimes fatal, has been reported in pregnant women who
received the combination of didanosine and stavudine with or without other anti-retroviral treatment.
Embryo-foetal toxicities were seen only at high exposure levels in animals. Preclinical studies showed
placental transfer of stavudine (see section 5.3). Until additional data become available, Zerit should
be given during pregnancy only after special consideration; there is insufficient information to
recommend Zerit for prevention of mother-to-child transmission of HIV. Furthermore, the
combination of stavudine and didanosine should be used with caution during pregnancy and is
recommended only if the potential benefit clearly outweighs the potential risk.
Breastfeeding
It is recommended that HIV infected women should not breast-feed under any circumstances in order
to avoid transmission of HIV.
The data available on stavudine excretion into human breast milk are insufficient to assess the risk to
the infant. Studies in lactating rats showed that stavudine is excreted in breast milk. Therefore,
mothers should be instructed to discontinue breast-feeding prior to receiving Zerit.
Fertility
32
No evidence of impaired fertility was seen in rats at high exposure levels (up to 216 times that
observed at the recommended clinical dose).
Based on the pharmacodynamic properties of stavudine it is unlikely that Zerit affects the ability to
drive or operate machinery.
a. Summary of the safety profile
Stavudine therapy is associated with several severe side effects, such as lactic acidosis, lipoatrophy
and polyneuropathy, for which a potential underlying mechanism is mitochondrial toxicity. Given
these potential risks, a benefit-risk assessment for each patient should be made and an alternative
antiretroviral should be carefully considered (see section 4.4 and below).
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic
steatosis, have been reported in < 1% of patients taking stavudine in combination with other
antiretrovirals (see section 4.4).
Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy
including Zerit. Most of these cases occurred in the setting of symptomatic hyperlactatemia or lactic
acidosis syndrome (see section 4.4). The evolution of motor weakness may mimic the clinical
presentation of Guillain-Barré syndrome (including respiratory failure). Symptoms may continue or
worsen following discontinuation of therapy.
Hepatitis or liver failure, which was fatal in some cases, has been reported with the use of stavudine
and with other nucleoside analogues (see section 4.4).
Lipoatrophy was commonly reported in patients treated with stavudine in combination with other
antiretrovirals (see section 4.4).
Peripheral neuropathy was seen in combination studies of Zerit with lamivudine plus efavirenz; the
frequency of peripheral neurologic symptoms was 19% (6% for moderate to severe) with a rate of
discontinuation due to neuropathy of 2%. The patients usually experienced resolution of symptoms
after dose reduction or interruption of stavudine.
Pancreatitis, occasionally fatal, has been reported in up to 2-3% of patients enrolled in monotherapy
clinical studies (see section 4.4). Pancreatitis was reported in < 1% of patients in combination therapy
studies with Zerit.
b.
Tabulated summary of adverse reactions
Adverse reactions of moderate or greater severity with at least a possible relationship to treatment
regimen (based on investigator attribution) reported from 467 patients treated with Zerit in
combination with lamivudine and efavirenz in two randomised clinical trials and along-term follow-up
study (follow-up: median 56 weeks ranging up to 119 weeks) are listed below. Also listed are adverse
reactions observed post-marketing in association with stavudine-containing antiretroviral treatment .
The frequency of adverse reactions listed below is defined using the following convention: very
common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare
(≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); or not known (cannot be estimated from the available
data). Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
33
Blood and lymphatic system
disorders:
rare: anaemia*
very rare: neutropenia *, thrombocytopenia*
Endocrine disorders:
uncommon: gynaecomastia
Metabolism and nutrition
disorders:
common: lipoatrophy**, lipodystrophy**, asymptomatic
hyperlactatemia
uncommon: lactic acidosis (in some cases involving motor
weakness), anorexia
rare: hyperglycaemia*
very rare: diabetes mellitis*
Psychiatric disorders:
common: depression
uncommon: anxiety, emotional lability
Nervous system disorders:
common: peripheral neurologic symptoms including peripheral
neuropathy, paresthesia, and peripheral neuritis;
dizziness; abnormal dreams; headache, insomnia;
abnormal thinking; somnolence
very rare: motor weakness* (most often reported in the setting of
symptomatic hyperlactatemia or lactic acidosis syndrome)
Gastrointestinal disorders:
common: diarrhoea, abdominal pain, nausea, dyspepsia
uncommon: pancreatitis, vomiting
Hepatobiliary disorders:
uncommon: hepatitis or jaundice
rare: hepatic steatosis*
very rare: liver failure*
Skin and subcutaneous tissue
disorders:
common: rash, pruritus
uncommon: urticaria
Musculoskeletal and connective
tissue disorders:
uncommon: arthralgia, myalgia
common: fatigue
uncommon: asthenia
*
adverse reactions observed post-marketing in association with stavudine-containing antiretroviral
treatment
** See Section
c. Description of selected adverse reactions
for more details.
c. Description of selected adverse reactions
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).
Lipodystrophy and 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). In randomized controlled trials of treatment-naive
patients, clinical lipoatrophy developed in a higher proportion of patients treated with stavudine
compared to other NRTIs (tenofovir or abacavir). In one study, after 2 years of treatment, about 40%
of stavudine-treated patients had lost greater than 20% of limb fat and after 3 years the amount of limb
fat was only about half of the normal amount (4.5 kg vs about 8 kg).. The incidence and severity of
lipoatrophy are cumulative over time; lipoatrophy may affect most patients with time and is often not
reversible when stavudine treatment is stopped (see section 4.4).
34
General disorders and
administration site conditions:
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (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).
Laboratory abnormalities
Laboratory abnormalities reported in these two trials and an ongoing follow-up study included
elevations of ALT (> 5 x ULN) in 3%, of AST (> 5 x ULN) in 3%, of lipase (≥ 2.1 ULN) in 3% of the
patients in the Zerit group. Neutropenia (< 750 cells/mm
3
) was reported in 5%, thrombocytopenia
(platelets < 50,000/mm
3
) in 2%, and low haemoglobin (< 8 g/dl) in < 1% of patients receiving Zerit.
Macrocytosis was not evaluated in these trials, but was found to be associated with Zerit in an earlier
trial (MCV > 112 fl occurred in 30% of patients treated with Zerit).
d. Paediatric population
Adolescents, children and infants:
undesirable effects and serious laboratory abnormalities reported to
occur in paediatric patients ranging in age from birth through adolescence who received stavudine in
clinical studies were generally similar in type and frequency to those seen in adults. However,
clinically significant peripheral neuropathy is less frequent. These studies include ACTG 240,
where 105 paediatric patients ages 3 months to 6 years received Zerit 2 mg/kg/day for a median
of 6.4 months; a controlled clinical trial where 185 newborns received Zerit 2 mg/kg/day either alone
or in combination with didanosine from birth through 6 weeks of age; and a clinical trial
where 8 newborns received Zerit 2 mg/kg/day in combination with didanosine and nelfinavir from
birth through 4 weeks of age.
In study AI455-094 (see also section 4.6), the safety follow-up period was restricted to only six
months, which may be insufficient to capture long-term data on neurological adverse events and
mitochondrial toxicity. Relevant grade 3-4 laboratory abnormalities in the 91 stavudine treated infants
were low neutrophils in 7%, low hemoglobin in 1%, ALT increase in 1% and no lipase abnormality.
Data on lactic acid in serum were not collected. No notable differences in the frequency of adverse
drug reactions were seen between treatment groups. There was, however, an increased infant mortality
in the stavudine + didanosine (10%) treatment group compared to the stavudine (2%), didanosine (3%)
or zidovudine (6%) groups, with a higher incidence of stillbirths in the stavudine + didanosine group.
Mitochondrial dysfunction:
review of the postmarketing safety database shows that adverse events
indicative of mitochondrial dysfunction have been reported in the neonate and infant population
exposed to one or more nucleoside analogues (see also section 4.4). The HIV status for the newborns
and infants ≤ 3 months of age was negative, for older infants it tended to be positive. The profile of the
adverse events for newborns and infants ≤ 3 months of age showed increases in lactic acid levels,
neutropenia, anaemia, thrombocytopenia, hepatic transaminase increases and increased lipids,
including hypertriglyceridaemia. The number of reports in older infants was too small to identify a
pattern.
Experience in adults treated with up to 12 times the recommended daily dosage revealed no acute
toxicity. Complications of chronic overdosage could include peripheral neuropathy and hepatic
dysfunction. The mean haemodialysis clearance of stavudine is 120 ml/min. The contribution of this to
the total elimination in an overdose situation is unknown. It is not known whether stavudine is
removed by peritoneal dialysis.
35
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Nucleoside reverse transcriptase inhibitor, ATC code: J05AF04
Mechanism of action:
stavudine, a thymidine analogue, is phosphorylated by cellular kinases to
stavudine triphosphate which inhibits HIV reverse transcriptase by competing with the natural
substrate, thymidine triphosphate. It also inhibits viral DNA synthesis by causing DNA chain
termination due to a lack of the 3’-hydroxyl group necessary for DNA elongation. Cellular DNA
polymerase γ is also sensitive to inhibition by stavudine triphosphate, while cellular polymerases α and
β are inhibited at concentrations 4,000-fold and 40-fold higher, respectively, than that needed to
inhibit HIV reverse transcriptase.
Resistance:
stavudine treatment can select for and/or maintain thymidine analogue mutations (TAMs)
associated with zidovudine resistance. The decrease of susceptibility
in vitro
is subtle requiring two or
more TAMs (generally M41L and T215Y) before stavudine susceptibility is decreased (> 1.5 fold).
These TAMs are seen at a similar frequency with stavudine and zidovudine in virological treatment.
The clinical relevance of these findings suggest that stavudine should be generally avoided in the
presence of TAMs, especially M41L and T215Y.
The activity of stavudine is also affected by multi-drug resistance associated mutations such as
Q151M. In addition, K65R has been reported in patients receiving stavudine/didanosine or
stavudine/lamivudine, but not in patients receiving stavudine monotherapy. V75T is selected
in vitro
by stavudine and reduces susceptibility to stavudine by 2-fold. It occurs in ~1% of patients receiving
stavudine.
Clinical efficacy
Zerit has been studied in combination with other antiretroviral agents, e.g. didanosine, lamivudine,
ritonavir, indinavir, saquinavir, efavirenz, and nelfinavir.
In antiretroviral naive patients
Study AI455-099 was a 48-week, randomised, double-blind study with Zerit (40 mg twice daily), in
combination with lamivudine (150 mg twice daily) plus efavirenz (600 mg once daily),
in 391 treatment-naive patients, with a median CD4 cell count of 272 cells/mm
3
(range 61 to 1,215 cells/mm
3
) and a median plasma HIV-1 RNA of 4.80 log
10
copies/ml
(range 2.6 to 5.9 log
10
copies/ml) at baseline. Patients were primarily males (70%) and non-white
(58%) with a median age of 33 years (range 18 to 68 years).
Study AI455-096 was a 48-week, randomised, double-blind study with Zerit (40 mg twice daily), in
combination with lamivudine (150 mg twice daily) plus efavirenz (600 mg once daily),
in 76 treatment-naive patients, with a median CD4 cell count of 261 cells/mm
3
(range 63 to 962 cells/mm
3
) and a median plasma HIV-1 RNA of 4.63 log
10
copies/ml
(range 3.0 to 5.9 log
10
copies/ml) at baseline. Patients were primarily males (76%) and white (66%)
with a median age of 34 years (range 22 to 67 years).
The results of AI455-099 and AI455-096 are presented in Table 1. Both studies were designed to
compare two formulations of Zerit, one of which was the marketed formulation dosed as currently
approved in product labelling. Only the data from the marketed formulation are presented.
Table 1: Efficacy Outcomes at Week 48 (Studies AI455-099 and AI455-096)
Parameter
AI455-099
AI455-096
36
Zerit + lamivudine +
efavirenz
n=391
Zerit + lamivudine +
efavirenz
n=76
HIV RNA < 400 copies/ml, treatment response, %
All patients
73
66
HIV RNA < 50 copies/ml, treatment response, %
All patients
55
38
HIV RNA Mean Change from Baseline, log
10
copies/ml
All patients
-2.83 (n=321
a
)
-2.64 (n=58)
CD4 Mean Change from Baseline, cells/mm
3
All patients
182 (n=314)
195 (n=55)
a
Number of patients evaluable.
Paediatric population
The use of stavudine in adolescents, children and infants is supported by pharmacokinetic and safety
data in paediatric patients (see also sections 4.8 and 5.2).
5.2 Pharmacokinetic properties
Adults
Absorption:
the absolute bioavailability is 86±18%. After multiple oral administration
of 0.5-0.67 mg/kg doses, a C
max
value of 810±175 ng/ml was obtained. C
max
and AUC increased
proportionally with dose in the dose ranges, intravenous 0.0625-0.75 mg/kg, and oral 0.033-4.0 mg/kg.
In eight patients receiving 40 mg twice daily in the fasted state, steady-state AUC
0-12h
was 1284±227 ngh/ml (18%) (mean ± SD [% CV]), C
max
was 536±146 ng/ml (27%), and C
min
was 9±8 ng/ml (89%). A study in asymptomatic patients demonstrated that systemic exposure is
similar while C
max
is lower and T
max
is prolonged when stavudine is administered with a standardised,
high-fat meal compared with fasting conditions. The clinical significance of this is unknown.
Distribution:
the apparent volume of distribution at steady state is 46±21 l. It was not possible to
detect stavudine in cerebrospinal fluid until at least 2 hours after oral administration. Four hours after
administration, the CSF/plasma ratio was 0.39±0.06. No significant accumulation of stavudine is
observed with repeated administration every 6, 8, or 12 hours.
Binding of stavudine to serum proteins was negligible over the concentration range
of 0.01 to 11.4 µg/ml. Stavudine distributes equally between red blood cells and plasma.
Metabolism:
Unchanged stavudine was the major drug-related component in total plasma radioactivity
circulating after an oral 80 mg dose of
14
C-stavudine in healthy subjects. The AUC(
inf
) for stavudine
was 61% of the AUC(
inf
) of the total circulating radioactivity. Metabolites include oxidised stavudine,
glucuronide conjugates of stavudine and its oxidised metabolite, and an
N
-acetylcysteine conjugate of
the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine.
Elimination:
following an oral 80-mg dose of
14
C-stavudine to healthy subjects, approximately 95%
and 3% of the total radioactivity was recovered in urine and faeces, respectively. Approximately 70%
of the orally administered stavudine dose was excreted as an unchanged drug in urine. Mean renal
clearance of the parent compound is approximately 272 mL/min, accounting for approximately 67% of
the apparent oral clearance, indicating active tubular secretion in addition to glomerular filtration.
In HIV-infected patients,total clearance of stavudine is 594±164 ml/min, and renal clearance
is 237±98 ml/min. The total clearance of stavudine appears to be higher in HIV-infected patients,
while the renal clearance is similar between healthy subjects and HIV-infected patients. The
mechanism and clinical significance of this difference are unknown. After intravenous
administration, 42% (range: 13% to 87%) of dose is excreted unchanged in the urine. The
37
corresponding values after oral single and multiple dose administration are 35% (range: 8% to 72%)
and 40% (range: 12% to 82%), respectively. The mean terminal elimination half-life of stavudine
is 1.3 to 2.3 hours following single or multiple doses, and is independent of dose.
In vitro
, stavudine
triphosphate has an intracellular half-life of 3.5 hours in CEM T-cells (a human T-lymphoblastoid cell
line) and peripheral blood mononuclear cells, supporting twice daily dosing.
The pharmacokinetics of stavudine was independent of time, since the ratio between AUC
(ss)
at steady
state and the AUC
(0-t)
after the first dose was approximately 1. Intra- and interindividual variation in
pharmacokinetic characteristics of stavudine is low, approximately 15% and 25%, respectively, after
oral administration.
Special Populations
Renal impairment:
the clearance of stavudine decreases as creatinine clearance decreases; therefore, it
is recommended that the dosage of Zerit be adjusted in patients with reduced renal function (see
section 4.2).
Hepatic impairment:
stavudine pharmacokinetics in patients with hepatic impairment were similar to
those in patients with normal hepatic function.
Paediatric population
Adolescents, children and infants:
total exposure to stavudine was comparable between adolescents,
children and infants ≥ 14 days receiving the 2 mg/kg/day dose and adults receiving 1 mg/kg/day.
Apparent oral clearance was approximately 14 ml/min/kg for infants ages 5 weeks
to 15 years, 12 ml/min/kg for infants ages 14 to 28 days, and 5 ml/min/kg for infants on the day of
birth. Two to three hours post-dose, CSF/plasma ratios of stavudine ranged from 16% to 125% (mean
of 59%±35%).
5.3 Preclinical safety data
Animal data showed embryo-foetal toxicity at very high exposure levels. An
ex vivo
study using a
term human placenta model demonstrated that stavudine reaches the foetal circulation by simple
diffusion. A rat study also showed placental transfer of stavudine, with the foetal tissue concentration
approximately 50% of the maternal plasma concentration.
Stavudine was genotoxic in
in vitro
tests in human lymphocytes possessing triphosphorylating activity
(in which no no-effect level was established), in mouse fibroblasts, and in an
in vivo
test for
chromosomal aberrations. Similar effects have been observed with other nucleoside analogues.
Stavudine was carcinogenic in mice (liver tumours) and rats (liver tumours: cholangiocellular,
hepatocellular, mixed hepatocholangiocellular, and/or vascular; and urinary bladder carcinomas) at
very high exposure levels. No carcinogenicity was noted at doses of 400 mg/kg/day in mice
and 600 mg/kg/day in rats, corresponding to exposures ~ 39 and 168 times the expected human
exposure, respectively, suggesting an insignificant carcinogenic potential of stavudine in clinical
therapy.
38
6.
6.1 List of excipients
Capsule contents:
Lactose
Magnesium stearate
Microcrystalline cellulose
Sodium starch glycolate
Capsule shell:
Gelatin
Iron oxide colorant (E172)
Silicon dioxide
Sodium laurilsulphate
Titanium dioxide (E171)
The capsule shells are marked using edible black printing ink containing:
Shellac
Propylene Glycol
Purified Water
Potassium Hydroxide
Iron Oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store below 25°C (aclar/alu blisters)
Do not store above 30°C. (HDPE bottles)
Store in the original package.
6.5 Nature and contents of container
High-density polyethylene (HDPE) bottles with child resistant screw cap (60 hard capsules per bottle),
or
aclar/aluminum blisters with 14 hard capsules per card and 4 cards (56 hard capsules) per carton.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
BRISTOL-MYERS SQUIBB PHARMA EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
39
8.
EU/1/96/009/005 - 006
9.
Date of first authorisation: 08 May 1996
Date of last renewal: 08 June 2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/.
40
1.
FURTHER INFORMATION
What Zerit contains
-
The active substance is stavudine
-
The other ingredients of the powder are: cherry flavour, methylhydroxybenzoate (E218),
propylhydroxybenzoate (E216), silicon dioxide, simethicone, sodium carmellose, sorbic acid,
stearate emulsifiers and sucrose.
What Zerit looks like and content of the pack
The powder contains 200 mg stavudine. The reconstituted solution contains 1 mg of stavudine per ml.
Before reconstitution the Zerit powder appears as off-white to pale-pink, gritty powder. When
reconstituted with 202 ml of water, produces 210 ml of a colorless to slightly pink, hazy solution.
Zerit 200 mg powder for oral solution is supplied in a bottle containing 200 ml solution.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
BRISTOL-MYERS SQUIBB PHARMA EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
Manufacturer:
Bristol-Myers Squibb S.r.l.
Contrada Fontana del Ceraso
03012 Anagni (FR) - Italy
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
127
Belgique/België/Belgien
B
RISTOL
-M
YERS
S
QUIBB
B
ELGIUM
S.A./N.V.
Tél/Tel: + 32 2 352 76 11
Luxembourg/Luxemburg
B
RISTOL
-M
YERS
S
QUIBB
B
ELGIUM
S.A./N.V.
Tél/Tel: + 32 2 352 76 11
България
B
RISTOL
-M
YERS
S
QUIBB
G
YÓGYSZERKERESKEDELMI
K
FT
.
Teл.: + 359 800 12 400
Magyarország
B
RISTOL
-M
YERS
S
QUIBB
G
YÓGYSZERKERESKEDELMI
K
FT
.
Tel.: + 36 1 301 9700
Česká republika
B
RISTOL
-M
YERS
S
QUIBB SPOL
.
S R
.
O
.
Tel: + 420 221 016 111
Malta
B
RISTOL
-M
YERS
S
QUIBB
S.
R
.
L
.
Tel: + 39 06 50 39 61
Danmark
B
RISTOL
-M
YERS
S
QUIBB
Tlf: + 45 45 93 05 06
Nederland
B
RISTOL
-M
YERS
S
QUIBB
BV
Tel: + 31 34 857 42 22
Deutschland
B
RISTOL
-M
YERS
S
QUIBB
G
MB
H
&
C
O
.
KG
A
A
Tel: + 49 89 121 42-0
Norge
B
RISTOL
-M
YERS
S
QUIBB
N
ORWAY
L
TD
Tlf: + 47 67 55 53 50
Eesti
B
RISTOL
-M
YERS
S
QUIBB
G
YÓGYSZERKERESKEDELMI
K
FT
.
Tel: + 372 6827 400
Österreich
B
RISTOL
-M
YERS
S
QUIBB
G
ESMB
H
Tel: + 43 1 60 14 30
Ελλάδα
B
RISTOL
-M
YERS
S
QUIBB
A.E.
Τηλ: + 30 210 6074300
Polska
B
RISTOL
-M
YERS
S
QUIBB
P
OLSKA
S
P
.
Z O
.
O
.
Tel.: + 48 22 5796666
España
B
RISTOL
-M
YERS
S
QUIBB
,
S.A.
Tel: + 34 91 456 53 00
Portugal
B
RISTOL
-M
YERS
S
QUIBB
F
ARMACÊUTICA
P
ORTUGUESA
, S.A.
Tel: + 351 21 440 70 00
France
B
RISTOL
-M
YERS
S
QUIBB
S
ARL
Tél: + 33 (0)810 410 500
România
B
RISTOL
-M
YERS
S
QUIBB
G
YÓGYSZERKERESKEDELMI
K
FT
.
Tel: + 40 (0)21 272 16 00
Ireland
B
RISTOL
-M
YERS
S
QUIBB
P
HARMACEUTICALS
L
TD
Tel: + 353 (1 800) 749 749
Slovenija
B
RISTOL
-M
YERS
S
QUIBB SPOL
.
S R
.
O
.
Tel: + 386 1 236 47 00
Ísland
V
ISTOR HF
Sími: + 354 535 7000
Slovenská republika
B
RISTOL
-M
YERS
S
QUIBB SPOL
.
S R
.
O
.
Tel: + 421 2 59298411
Italia
B
RISTOL
-M
YERS
S
QUIBB
S.
R
.
L
.
Tel: + 39 06 50 39 61
Suomi/Finland
O
Y
B
RISTOL
-M
YERS
S
QUIBB
(F
INLAND
)
A
B
Puh/Tel: + 358 9 251 21 230
Κύπρος
BRISTOL-MYERS
SQUIBB
A.E
Τηλ: + 357 800 92666
Sverige
B
RISTOL
-M
YERS
S
QUIBB
AB
Tel: + 46 8 704 71 00
128
Latvija
B
RISTOL
-M
YERS
S
QUIBB
G
YÓGYSZERKERESKEDELMI
K
FT
.
Tel: + 371 67 50 21 85
United Kingdom
B
RISTOL
-M
YERS
S
QUIBB
P
HARMACEUTICALS
L
TD
Tel: + 44 (0800) 731 1736
Lietuva
B
RISTOL
-M
YERS
S
QUIBB
G
YÓGYSZERKERESKEDELMI
K
FT
.
Tel: + 370 5 2790 762
This leaflet was last approved in {month year}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.
129
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