Summary of medicine characteristics - Zerit
1. NAME OF THE MEDICINAL PRODUCT
Zerit 15 mg hard capsules
Zerit 20 mg hard capsules
Zerit 30 mg hard capsules
Zerit 40 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Zerit 15 mg hard capsules
Each hard capsule contains 15 mg of stavudine.
Excipients with known effect
Each hard capsule contains 80.84 mg of lactose anhydrous.
Each hard capsule contains 40.42 mg of lactose monohydrate
Zerit 20 mg hard capsules
Each hard capsule contains 20 mg of stavudine.
Excipients with known effect
Each hard capsule contains 121.30 mg of lactose anhydrous.
Each hard capsule contains 60.66 mg of lactose monohydrate
Zerit 30 mg hard capsules
Each hard capsule contains 30 mg of stavudine.
Excipients with known effect
Each hard capsule contains 121.09 mg of lactose
Each hard capsule contains 60.54 mg of lactose monohydrate.
Zerit 40 mg hard capsules
Each hard capsule contains 40 mg of stavudine.
Excipients with known effect Each hard capsule contains 159 Each hard capsule contai
f lactose anhydrous. g of lactose monohydrate.
For the full list of excipi nts, see section 6.1.
3. P
TICAL FORM
Hard
Img hard capsules
d capsule is red and yellow, opaque and imprinted with “BMS” over a BMS code “1964” on side and “15” on the other side.
Zerit 20 mg hard capsules
The hard capsule is brown, opaque and imprinted with “BMS” over a BMS code “1965” on one side and “20” on the other side.
Zerit 30 mg hard capsules
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.
Zerit 40 mg hard capsules
The hard capsule is dark orange, opaque and imprinted with “BMS” over a BMS code “1967” on one side and “40” on the other side.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Zerit is indicated in combination with other antiretroviral medicinal products for the treatment of HIV infected adult patients and paediatric patients (over the age of 3 months) only when other antiretrovirals can not be used. The duration of therapy with Zerit should be limited to the shortest time possible (see section 4.2).
4.2 Posology and method of administration
The therapy should be initiated by a doctor experienced in the management of HIV section 4.4).
(see also
For patients starting therapy with Zerit, the duration should be limited to the shortest time possible followed by a switch to an alternative appropriate therapy whenever possible. Patients continuing treatment with Zerit should be assessed frequently and switched to an alternative appropriate therapy whenever possible (see section 4.4).
Posology
Adolescents, children and infa
Adults: the recommended oral dosage is
Paediatric population
Patient weight
< 60 kg
> 60 kg _____
Pati
<i
Zerit d o 30 mg
e age of 3 months: the recommended oral dosage is
kg
ily (every 12 hours)
daily (every 12 hours)
Zerit dosage _______________________
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. Adult patients that have problems swallowing capsules should ask their doctor about the possibility of changing to the powder formulation of this medicine.
to the Summary of Product Characteristics of the powder formulation.
ustments
eripheral 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. 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
| Patient weight | Zerit dosage (according to creatinine clearance) | |
| 26–50 ml/min | < 25 ml/min (including dialysis dependence*) | |
| < 60 kg | 15 mg twice daily | 15 mg every 24 hours 1 |
| > 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 clearance of stavudine may be altered in paediatric patients with renal i insufficient data to recommend a specific dosage adjustment of Zerit in t reduction in the dose and/or an increase in the interval between d adults should be considered. There are no dosage recommendati age of 3 months with renal impairment.
Method of administration
For optimal absorption, Zerit should be taken o but, if this is not possible, it may be taken with carefully opening the hard capsule and mixing t
4.3 Contraindications
Hypersensitivity to the active
Co-administration with didanosin
notably lactic acidosis, li sections 4.4 and 4.5).
4.4 Special w
ic patients, the ment. Although there are atient population, a ional to the reduction for iatric patients under the
stomach (i.e. at least 1 hour prior to meals) meal. Zerit may also be administered by tents with food.
nce or to any of the excipients listed in section 6.1.
ue to the potential for serious and/or life-threatening events ion abnormalities, pancreatitis and peripheral neuropathy (see
d precautions for use
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
ne therapy is associated with several severe side effects, such as lactic acidosis, lipoatrophy yneuropathy, for which a potential underlying mechanism is mitochondrial toxicity. Given potential risks, a benefit-risk assessment for each patients should be made and an alternative ntiretroviral should be carefully considered (see Lactic acidosis, Lipoatrophy, 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 stavudine. 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 stavudine 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 stavudine 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 are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of c antiviral therapy for hepatitis B or C, please refer also to the relevant product information f 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.
per limit of normal, ducts should be
In the event of rapidly elevating transaminase levels (ALT/AST, > 5 ULN), discontinuation of Zerit and any potentially hepatotoxic medi considered.
een shown to cause loss of ocks.
Lipoatrophy : on the basis of mitochondrial toxicity stavu subcutaneous fat, which is most evident in the face, limbs
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 (DEX s demonstrated overall limb fat loss in stavudine treated patients compared to limb fat gai change in patients treated with other NRTIs (abacavir, tenofovir or zidovudine). The incidence erity of lipoatrophy are cumulative over time with stavudine-containing regimens. In clinic , switching from stavudine to other nucleosides
(tenofovir or abacavir) resulte lipoatrophy. Given the potent for each patient should b receiving Zerit should be
development is fo
creases in limb fat with modest to no improvements in clinical s of using Zerit including lipoatrophy, a benefit-risk assessment an alternative antiretroviral carefully considered. Patients ntly examined and questioned for signs of lipoatrophy. When such continuation of Zerit should be considered.
Weight an occurr duri style. For li no re
etabolic parameters : an increase in weight and in levels of blood lipids and glucose may tiretroviral therapy. Such changes may in part be linked to disease control and life here is in some cases evidence for a treatment effect, while for weight gain there is
idence relating this to any particular treatment. For monitoring of blood lipids and glucose s made to established HIV treatment guidelines. Lipid disorders should be managed as ppropriate.
eripheral neuropathy: up to 20% of patients treated with Zerit will develop peripheral neuropathy, ften starting after some months of treatment. Patients with a history of neuropathy, or with other risk
factors (for example alcohol, medicines 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. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Osteonecrosis: although the etiology is considered to be multifactorial (including corticoste e, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Lactose intolerance: the hard capsule contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.
Not recommended combinations: pancreatitis (fatal and n some cases) have been reported in HIV infected patients hydroxyurea and didanosine (see section 4.3). Hepatotox were reported during postmarketing surveillance in HIV i
agents and hydroxyurea; fatal hepatic events were stavudine, hydroxyurea and didanosine. Hence, hy HIV infection.
nd peripheral neuropathy (severe in stavudine in association with
icity and hepatic failure resulting in death infected patients treated with antiretroviral ed most often in patients treated with
urea should not be used in the treatment of
Elderly: Zerit has not been specifically investigated in patients over the age of 65.
Infants under the age of 3 treatment in 179 newb Special consideration of the HIV strain of t
Paediatric population
afety data are available from clinical trials up to 6 weeks of and infants < 3 months of age (see section 4.8).
e given to the antiretroviral treatment history and the resistance profile ther.
Mitochondrial dysfunction following exposure in utero: nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. 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); these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, that present with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
4.5 Interaction with other medicinal products and other forms of interaction
The combination of stavudine with didanosine is contraindicated given that both drugs exhibits high risk of mitochondrial toxicity (see sections 4.3 and 4.4).
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 ribavir not by other medicinal products used in HIV infection which are similarly phosphorylat (e.g. didanosine, zalcitabine, ganciclovir and foscarnet) therefore, coadministration either doxorubicin or ribavirin should be undertaken with caution. Stavudine’s influe phosphorylation kinetics of nucleoside analogues other than zidovudine has not been investigated.
ut
ine with
Clinically significant interactions of stavudine or stavudine plus didanosi been observed.
not
Stavudine does not inhibit the major cytochrome P450 isoforms CYP2D6, and CYP3A4; therefore, it is unlikely that clinical with medicines metabolised through these pathways.
icant drug interactions will occur
P2C9, CYP2C19,
Because stavudine is not protein-bound, it is not ex protein-bound medicines.
to affect the pharmacokinetics of
-
4.6 Fertility, pregnan
Pregnancy
There have been no formal interaction s
Paediatric population
Interaction studies have only
ed in adults.
ith other medicinal products.
tation
Zerit shoul Clinical ex reported.
during pregnancy unless clearly necessary.
In s
at
regnant women is limited, but congenital anomalies and abortions have been 455–094, performed in South-Africa, 362 mother-infant pairs were included in a prevention o-child-transmission study. Treatment naive pregnant women were enrolled into the study station week 34–36 and given antiretroviral treatment until delivery. Antiretroviral prophylaxis, ame medications as given to the mother, was given to the new-born infant within 36 hours of elivery 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, sometimes fatal, has been reported in pregnant women who received the combination of didanosine and stavudine with or without other anti-retroviral treatment (see sections 4.3 and 4.4). 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.
Breast-feeding
It is recommended that HIV infected women should not breast-feed under any circumstanc to avoid transmission of HIV.
The data available on stavudine excretion into human breast milk are insufficient to the infant. Studies in lactating rats showed that stavudine is excreted in breast milk. mothers should be instructed to discontinue breast-feeding prior to receiving Zerit.
he risk to re,
Fertility
No evidence of impaired fertility was seen in rats at high exposur observed at the recommended clinical dose).
to 216 times that
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and cause dizziness and/or somnolence. Patients should symptoms they should avoid potentially hazardous
machines have been performed. Stavudine may instructed that if they experience these s such as driving or operating machinery.
4.8 Undesirable effects
Summary of the safety profile
Stavudine therapy is associat lipoatrophy and polyneur toxicity. Given these p alternative antiretrovir
tia
everal severe adverse reactions, such as lactic acidosis, r which a potential underlying mechanism is mitochondrial isks, a benefit-risk assessment for each patient should be made and an d be carefully considered (see section 4.4 and below).
Cases of lactic ac steatosis, ha antiretro
Mo
osis, sometimes fatal, usually associated with severe hepatomegaly and hepatic reported in < 1% of patients taking stavudine in combination with other
section 4.4).
ess has been reported rarely in patients receiving combination antiretroviral therapy
Zerit. Most of these cases occurred in the setting of symptomatic hyperlactatemia or lactic s syndrome (see section 4.4). The evolution of motor weakness may mimic the clinical ^Sentation of Guillain-Barre syndrome (including respiratory failure). Symptoms may continue or orsen following discontinuation of therapy.
a
Hepatitis or liver failure, which was fatal in some cases, has been reported with the use of stavudine (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.
p
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.
Tabulated summary of adverse reactions
eatment.
very 1/10,000 to
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-ter study (follow-up: median 56 weeks ranging up to 119 weeks) are listed below. Also listed reactions observed post-marketing in association with stavudine-containing antiretroviral t The frequency of adverse reactions listed below is defined using the following convention: common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rO^^J^ < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders:
rare: anaemia*
very rare: neutropenia , thrombocytopenia
Endocrine disorders:
uncommon: gynaecomastia
Metabolism and nutrition disorders:
common: lipoatrophy**, 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 peri neuropathy, paresthesia, and peripheral neuritis dizziness; abnormal dreams; headach abnormal thinking; somnolence
very rare: motor weakness* (most often reported in the setting of symptomatic hyperlactatemia or lactic acidosis syndrome)
Gastrointestinal disorders:
Hepatobiliary disorders:
usea, dyspepsia
common: diarrhoea, abdominal pain, uncommon: pancreatitis, vomiti
uncommon: hepatitis or rare: hepatic steatosis* very rare: liver failure*
General disorders and administration site conditions:
Skin and subcutaneous tissue disorders:
Musculoskeletal and connective tissue disorders:
s
: fatigue mon: asthenia
common: ra uncommo unco
ralgia, myalgia
-
* Adverse reactions o treatment
-
* * See Section DeScri
ost-marketing in association with stavudine-containing antiretroviral
selected adverse reactions for more details.
Description ofselected adverse reactions
Imm initiation
eactivation syndrome: in HIV-infected patients with severe immune deficiency at the time of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or pportunistic infections may arise. Autoimmune disorders (such as Graves' disease and mune hepatitis) have also been reported; however, the reported time to onset is more variable ese events can occur many months after initiation of treatment (see section 4.4).
Lipoatrophy : stavudine has been shown to cause loss of subcutaneous fat, which is most evident in the face, limbs and buttocks. The incidence and severity of lipoatrophy are related to cumulative exposure, and is often not reversible when stavudine treatment is stopped. Patients receiving Zerit should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with Zerit should not be continued (see section 4.4).
Metabolic parameters : weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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/mm3) was reported in 5%, thrombocytopenia (platelets < 50,000/mm3) 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).
Paediatric population
Adolescents, children and infants: adverse reactions 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 incl where 105 paediatric patients ages 3 months to 6 years received Zerit 2 m
of 6.4 months; a controlled clinical trial where 185 newborns received or in combination with didanosine from birth through 6 weeks of age; where 8 newborns received Zerit 2 mg/kg/day in combination wit birth through 4 weeks of age.
e ACTG 240, or a median /kg/day either alone
clinical trial
and nelfinavir from
In study AI455–094 (see also section 4.6), the safety follow- od 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 laborato were low neutrophils in 7%, low hemoglobin in 1% Data on lactic acid in serum were not collected. No
drug reactions were seen between treatmen in the stavudine + didanosine (10%) treatm or zidovudine (6%) groups, with a higher i
gr nt
abnormalities in the 91 stavudine treated infants LT increase in 1% and no lipase abnormality. table differences in the frequency of adverse here was, however, an increased infant mortality
oup compared to the stavudine (2%), didanosine (3%)
idence of stillbirths in the stavudine + didanosine group.
Mitochondrial dysfunction: revi indicative of mitochondrial d
exposed to one or more n and infants < 3 month adverse events for ne
ge
e postmarketing safety database shows that adverse reactions have been reported in the neonate and infant population
neutropenia, including pattern.
ide analogues (see also section 4.4). The HIV status for the newborns as negative, for older infants it tended to be positive. The profile of the d infants < 3 months of age showed increases in lactic acid levels,
Report’
spected adverse reactions
rombocytopenia, hepatic transaminase increases and increased lipids, idaemia. The number of reports in older infants was too small to identify a
g suspected adverse reactions after authorisation of the medicinal product is important. It nl continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9 Overdose
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.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF04
Stavudine, a thymidine analogue, is phosphorylated by cellular kinases to stavudine triphosphate
Mechanism of action 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 the 3’-hydroxyl group necessary for DNA elongation. Cellular DNA polymerase y is also inhibition by stavudine triphosphate, while cellular polymerases a and P are inhibited at concentrations 4,000-fold and 40-fold higher, respectively, than that needed to inhi transcriptase.
verse
Resistance
a
Stavudine treatment can select for and/or maintain thymidine analo with zidovudine resistance. The decrease of susceptibility in vitro i TAMs (generally M41L and T215Y) before stavudine susceptibi These TAMs are seen at a similar frequency with stavudine The clinical relevance of these findings suggest that stavudi
ions (TAMs) associated uiring two or more ased (> 1.5 fold). dine in virological treatment. ld 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 t dine by 2-fold. It occurs in ~1% of patients receiving stavudine.
Clinical efficacy and safety
In antiretroviral naiv
Zerit has been studied in combinati
ritonavir, indinavir, saqui
with other antiretroviral agents, e.g. didanosine, lamivudine, irenz, and nelfinavir.
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/mm3 (range 61 to 1,215 cells/mm3) and a median plasma HIV-1 RNA of 4.80 log10 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).
tudy AI455–096 was a 48-week, randomised, double-blind study with Zerit (40 mg twice daily), in ombination 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/mm3
(range 63 to 962 cells/mm3) and a median plasma HIV-1 RNA of 4.63 log10 copies/ml
(range 3.0 to 5.9 log10 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)
AI455–099
Parameter
Zerit + lamivudine + efavirenz n=391
Zerit + lamivudine + efavirenz n=76
HIV RNA < 400 copies/ml, treatment response, %
All patients
73
HIV RNA < 50 copies/ml, treatment response, %
All patients
55
HIV RNA Mean Change from Baseline, log io copies/ml
All patients
CD4 Mean Change from Baseline, cells/mm3
-2.83 (n=321a)
AI455–096
66
38
–2.64 (n=5
All patients _________________
a Number of patients evaluable.
182(n=314)
Paediatric population
The use of stavudine in adolescents, children and infants is s data in paediatric patients (see also sections 4.8 and 5.2).
ed by pharmacokinetic and safety
Absorption
The absolute bioavailability is 86±18% Cmax value of 810±175 ng/ml was obta dose ranges, intravenous 0.0625–0.7
In eight patients receiving 40 was 1284±227 ng-h/mi (18%; was 9±8 ng/ml (89%). A stud
5.2 Pharmacokinetic properties
ed.
ultiple oral administration of 0.5–0.67 mg/kg doses, a and AUC increased proportionally with dose in the , and oral 0.033–4.0 mg/kg.
aily in the fasted state, steady-state AUC0–12h mean ± SD [% CV]), Cmax was 536±146 ng/ml (27%), and Cmin in asymptomatic patients demonstrated that systemic exposure is
similar while Cmax is lower and Tmax is prolonged when stavudine is administered with a standardised, high-fat meal compared with fasting conditions. The clinical significance of this is unknown.
Distributio
The app in cereb
me of distribution at steady state is 46±21 l. It was not possible to detect stavudine fluid until at least 2 hours after oral administration. Four hours after administration, sma ratio was 0.39±0.06. No significant accumulation of stavudine is observed with
Metabolism
ated administration every 6, 8, or 12 hours.
ding of stavudine to serum proteins was negligible over the concentration range.01 to 11.4 gg/ml. Stavudine distributes equally between red blood cells and plasma.
Unchanged stavudine was the major drug-related component in total plasma radioactivity circulating after an oral 80 mg dose of 14C-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 14C-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 corresponding values after oral single and multiple dose administration are 35% (range: 8% and 40% (range: 12% to 82%), respectively. The mean terminal elimination half-life of stav is 1.3 to 2.3 hours following single or multiple doses, and is independent of dose. In vitro , s triphosphate has an intracellular half-life of 3.5 hours in CEM T-cells (a human T-lymphobl line) and peripheral blood mononuclear cells, supporting twice daily dosing.
udine oid cell
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
e clearance decreases; therefore, it h reduced renal function (see
Renal impairment: the clearance of stavudine decreases a is recommended that the dosage of Zerit be adjusted in p section 4.2).
Hepatic impairment: stavudine those in patients with normal he
Paediatric population
tients with hepatic impairment were similar to
Adolescents, children and inf children and infants > 14 day Apparent oral clearance to 15 years, 12 ml/min/k birth. Two to three hour of 59%±35%).
tal exposure to stavudine was comparable between adolescents, iving the 2 mg/kg/day dose and adults receiving 1 mg/kg/day.
imately 14 ml/min/kg for infants ages 5 weeks
ants ages 14 to 28 days, and 5 ml/min/kg for infants on the day of -dose, CSF/plasma ratios of stavudine ranged from 16% to 125% (mean
5.3
Ani ter
owed embryo-foetal toxicity at very high exposure levels. An ex vivo study using a placenta model demonstrated that stavudine reaches the foetal circulation by simple. A rat study also showed placental transfer of stavudine, with the foetal tissue concentration imately 50% of the maternal plasma concentration.
ine 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.
6. PHARMACEUTICAL PARTICULARS6.2 Incompatibilities6.4 Special precautions for st6.1 List of excipientsNot applicable.2 years.Capsule contentsLactoseMagnesium stearate Microcrystalline cellulose Sodium starch glycolate6.5 Nature a6.3 Shelf lifettles).s of containerresistant screw cap (60 hard capsules per bottle).blisters with 14 hard capsules per card and 4 cards (56 hard capsules) per carton.k sizes may be marketed.
Capsule shell
Gelatin
Iron oxide colorant (E172)
Silicon dioxide
Sodium laurilsulphate
Titanium dioxide (E171)
Black ink containing Shellac
Propylene Glycol Purified Water Potassium Hydroxide Iron Oxide (E172)
Store below 25°C (aclar/alu Do not store above 30°C Store in the original p
HDPE bottle
Aclar
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Bristol-Myers Squibb Pharma EEIG Plaza 254
Blanchardstown Corporate Park 2
Dublin 15, D15 T867
Ireland
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/96/009/001 – 008
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 08 May 1996
Date of last renewal: 20 April 2011