ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Ketek 400 mg film-coated tablets.
2.
Each film
-
coated tablet contains 400 mg of telithromycin.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Light orange, oblong, biconvex tablet, imprinted with H3647 on one side and 400 on the other.
4.
When prescribing Ketek, consideration should be given to official guidance on the appropriate use of
antibacterial agents and the local prevalence of resistance (see also sections 4.4 and 5.1).
Ketek is indicated for the treatment of the following infections:
In patients of 18 years and older:
• Community-acquired pneumonia, mild or moderate (see section 4.4).
• When treating infections caused by known or suspected beta-lactam and/or macrolide resistant
strains (according to history of patients or national and/or regional resistance data) covered by
the antibacterial spectrum of telithromycin (see sections 4.4 and 5.1):
-
Acute exacerbation of chronic bronchitis,
-
Acute sinusitis
In patients of 12 years and older:
•Tonsillitis/pharyngitis caused by S
treptococcus pyogenes
, as an alternative when beta lactam
antibiotics are not appropriate in countries/regions with a significant prevalence of macrolide
resistant
S. pyogenes
, when mediated by ermTR or mefA (see sections 4.4 and 5.1).
Posology
The recommended dose is 800 mg once a day i.e. two 400 mg tablets once a day. The tablets should be
swallowed whole with a sufficient amount of water. The tablets may be taken with or without food.
Consideration may be given to taking Ketek at bedtime, to reduce the potential impact of visual
disturbances and loss of consciousness (see section 4.4).
In patients of 18 years and older, according to the indication, the treatment regimen will be:
-
Community-acquired pneumonia: 800 mg once a day for 7 to 10 days,
-
Acute exacerbation of chronic bronchitis: 800 mg once a day for 5 days,
-
Tonsillitis/pharyngitis caused by
Streptococcus pyogenes:
800 mg once a day for 5 days.
In patients of 12 to 18 years old, the treatment regimen will be:
-
Tonsillitis/pharyngitis caused by S
treptococcus pyogenes:
800 mg once a day for 5 days.
2
-
Acute sinusitis: 800 mg once a day for 5 days,
In the elderly:
No dosage adjustment is required in elderly patients based on age alone
.
Paediatric population:
Ketek is not recommended for use in children below 12 years of age due to limited data on safety and
efficacy (see section 5.2).
Impaired renal function:
No dosage adjustment is necessary in patients with mild or moderate renal impairment. Ketek is not
recommended as first choice in patients with severe renal impairment (creatinine clearance
<30 ml/min) or patients with both severe renal impairment and co-existing hepatic impairment, as an
optimal dosage format (600 mg) is not available. If telithromycin treatment is deemed necessary, these
patients may be treated with alternating daily doses of 800 mg and 400 mg, starting with the 800 mg
dose.
In haemodialysed patients, the posology should be adjusted so that Ketek 800 mg is given after the
dialysis session (see also section 5.2).
Impaired hepatic function:
No dosage adjustment is necessary in patients with mild, moderate, or severe hepatic impairment,
unless renal function is severely impaired, however the experience in patients with impaired hepatic
function is limited. Hence, Ketek should be used with caution (see also sections 4.4 and 5.2).
Ketek is contraindicated in patients with myasthenia gravis (see section 4.4).
Hypersensitivity to the active substance, to any of the macrolide antibacterial agents, or to any of the
excipients.
Ketek must not be used in patients with previous history of hepatitis and/or jaundice associated with
the use of telithromycin.
Concomitant administration of Ketek
and any of the following substances is contraindicated:
cisapride, ergot alkaloid derivatives (such as ergotamine and dihydroergotamine), pimozide,
astemizole and terfenadine (see section 4.5).
Ketek should not be used concomitantly with simvastatin, atorvastatin, and lovastastin. Treatment with
these agents should be interrupted during Ketek treatment (see section 4.5).
Ketek is contraindicated in patients with a history of congenital or a family history of long QT
syndrome (if not excluded by ECG) and in patients with known acquired QT interval prolongation.
In patients with severely impaired renal and/or hepatic function, concomitant administration of Ketek
and strong CYP3A4 inhibitors, such as protease inhibitors or ketoconazole, is contraindicated.
As with macrolides, due to a potential to increase QT interval, Ketek should be used with care in
patients with coronary heart disease, a history of ventricular arrhythmias, uncorrected hypokalaemia
and or hypomagnesaemia, bradycardia (<50 bpm), or during concomitant administration of Ketek with
QT interval prolonging agents or potent CYP 3A4 inhibitors such as protease inhibitors and
ketoconazole.
As with nearly all antibacterial agents, diarrhoea, particularly if severe, persistent and /or bloody,
during or after treatment with Ketek
may be caused by
pseudomembranous colitis
. If
3
pseudomembranous colitis
is suspected, the treatment must be stopped immediately and patients
should be treated with supportive measures and/or specific therapy.
Exacerbations of myasthenia gravis have been reported in patients treated with telithromycin and
sometimes occurred within a few hours of the first dose. Reports have included death and life
threatening acute respiratory failure with rapid onset (see section 4.8).
Alterations in hepatic enzymes have been commonly observed in clinical studies with telithromycin.
Post-marketing cases of severe hepatitis and liver failure, including fatal cases (which have generally
been associated with serious underlying diseases or concomitant medications), have been reported (see
section 4.8). These hepatic reactions were observed during or immediately after treatment, and in most
cases were reversible after discontinuation of telithromycin.
Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic
disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.
Due to limited experience, Ketek should be used with caution in patients with liver impairment (see
section 5.2).
Ketek may cause visual disturbances particularly in slowing the ability to accommodate and the ability
to release accommodation. Visual disturbances included blurred vision, difficulty focusing, and
diplopia. Most events were mild to moderate; however, severe cases have been reported (see sections
4.7 and 4.8).
There have been post-marketing adverse event reports of transient loss of consciousness including
some cases associated with vagal syndrome (see sections 4.7 and 4.8).
Consideration may be given to taking Ketek at bedtime, to reduce the potential impact of visual
disturbances and loss of consciousness.
Ketek should not be used during and 2 weeks after treatment with CYP3A4 inducers (such as
rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort). Concomitant treatment with
these medicinal products is likely to result in subtherapeutic levels of telithromycin and therefore
encompass a risk of treatment failure (see section 4.5)
.
Ketek is an inhibitor of CYP3A4 and should only be used under specific circumstances during
treatment with other medicinal products that are metabolised by CYP3A4. Patients with concomitant
treatment of pravastatin, rosuvastatin or fluvastatin should be carefully monitored for signs and
symptoms of myopathy and rhabdomyolysis (see sections 4.3 and 4.5).
In areas with a high incidence of erythromycin A resistance, it is especially important to take into
consideration the evolution of the pattern of susceptibility to telithromycin and other antibiotics
.
In community acquired pneumonia, efficacy has been demonstrated in a limited number of patients
with risk factors such as
pneumococcal bacteraemia
or age higher than 65 years.
Experience of treatment of infections caused by penicillin/or erythromycin resistant
S. pneumoniae
is
limited, but so far, clinical efficacy and eradication rates have been similar compared with the
treatment of susceptible
S. pneumoniae
. Caution should be taken when
S. aureus
is the suspected
pathogen and there is a likelihood of erythromycin resistance based on local epidemiology.
L. pneumophila
is highly susceptible to telithromycin
in vitro
, however, the clinical experience of the
treatment of pneumonia caused by
legionella
is limited
.
As for macrolides,
H. influenzae
is classified as intermediately susceptible. This should be taken into
account when treating infections caused by
H. influenzae.
4
Interaction studies have only been performed in adults.
Effect of Ketek on other medicinal product
Telithromycin is an inhibitor of CYP3A4 and a weak
inhibitor of CYP2D6.
In vivo
studies with
simvastatin, midazolam and cisapride have demonstrated a potent inhibition of intestinal CYP3A4 and
a moderate inhibition of hepatic CYP3A4. The degree of inhibition with different CYP3A4 substrates
is difficult to predict. Hence, Ketek should not be used during treatment with medicinal products that
are CYP3A4 substrates, unless plasma concentrations of the CYP3A4 substrate, efficacy or adverse
events can be closely monitored. Alternatively, interruption in the treatment with the CYP3A4
substrate should be made during treatment with Ketek.
Medicinal products with a potential to prolong QT interval
Ketek is expected to increase the plasma levels of cisapride, pimozide, astemizole and terfenadine.
This could result in QT interval prolongation and cardiac arrhythmias including ventricular
tachycardia, ventricular fibrillation and torsades de pointes. Concomitant administration of Ketek and
any of these medicinal products is contraindicated (see section 4.3).
Caution is warranted when Ketek is administered to patients taking other medicinal products with the
potential to prolong QT interval (see section 4.4).
Ergot alkaloid derivatives (such as ergotamine and dihydroergotamine)
By extrapolation from erythromycin A and josamycin, concomitant medication of Ketek and alkaloid
derivatives could lead to severe vasoconstriction (“ergotism”) with possibly necrosis of the
extremities. The combination is contraindicated (see section 4.3).
Statins
When simvastatin was coadministered with Ketek, there was a 5.3 fold increase in simvastatin C
max
, an
8.9 fold increase in simvastatin AUC, a 15-fold increase in simvastatin acid C
max
and an 11-fold
increase in simvastatin acid AUC. Ketek may produce a similar interaction with lovastatin and
atorvastatin which are also mainly metabolised by CYP3A4. Ketek should therefore not be used
concomitantly with simvastatin, atorvastastin, or lovastatin (see section 4.3). Treatment with these
agents should be interrupted during Ketek treatment. The exposure of pravastatin, rosuvastatin and to
a lesser extent fluvastatin, may be increased due to possible involvement of transporters proteins, but
this increase is expected to be lesser than interactions involving CYP3A4 inhibition. However,
patients should be carefully monitored for signs and symptoms of myopathy and rhabdomyolysis
when co-treated with pravastatin, rosuvastatin and fluvastatin.
Benzodiazepines
When midazolam was coadministered with Ketek, midazolam AUC was increased 2.2-fold after
intravenous administration of midazolam and 6.1-fold after oral administration. The midazolam half-
life was increased about 2.5-fold. Oral administration of midazolam concomitantly with Ketek should
be avoided. Intravenous dosage of midazolam should be adjusted as necessary and monitoring of the
patient be undertaken. The same precautions should also apply to the other benzodiazepines which are
metabolized by CYP3A4, (especially triazolam but also to a lesser extent alprazolam). For those
benzodiazepines which are not metabolized by CYP3A4 (temazepam, nitrazepam, lorazepam) an
interaction with Ketek is unlikely.
Cyclosporin, tacrolimus, sirolimus
Due to its CYP3A4 inhibitory potential, telithromycin can increase blood concentrations of these
CYP34A4 substrates. Thus, when initiating telithromycin in patients already receiving any of theses
immunosuppressive agents, cyclosporin, tacrolimus or sirolimus levels must be carefully monitored
and their doses decreased as necessary. When telithromycin is discontinued, cyclosporin, tacrolimus or
sirolimus levels must be again carefully monitored and their dose increased as necessary.
5
Metoprolol
When metoprolol (a CYP2D6 substrate) was coadministered with Ketek, metropolol Cmax and AUC
were increased by approximately 38%, however, there was no effect on the elimination half-life of
metoprolol. The increase exposure to metoprolol may be of clinical importance in patients with heart
failure treated with metoprolol. In these patients, co-administration of Ketek and metoprolol, a
CYP2D6 substrate, should be considered with caution.
Digoxin
Ketek has been shown to increase the plasma concentrations of digoxin. The plasma trough levels,
C
max
, AUC and renal clearance were increased by 20%, 73%, 37% and 27% respectively, in healthy
volunteers. There were no significant changes in ECG parameters and no signs of digoxin toxicity
were observed. Nevertheless, monitoring of serum digoxin level should be considered during
concomitant administration of digoxin and Ketek.
Theophylline
There is no clinically relevant pharmacokinetic interaction of Ketek and theophylline administered as
extended release formulation. However, the co-administration of both medicinal products should be
separated by one hour in order to avoid possible digestive side effects such as nausea and vomiting.
Oral anticoagulants
Increased anticoagulant activity has been reported in patients simultaneously treated with
anticoagulants and antibiotics, including telithromycin. The mechanisms are incompletely known.
Although Ketek has no clinically relevant pharmacokinetic or pharmacodynamic interaction with
warfarin after single dose administration, more frequent monitoring of prothrombin time/INR
(International Normalised Ratio) values should be considered during concomitant treatment.
Oral contraceptives
There is no pharmacodynamic or clinically relevant pharmacokinetic interaction with low-dose
triphasic oral contraceptives in healthy subjects.
Effect of other medicinal products on Ketek
During concomitant administration of rifampicin and telithromycin in repeated doses, C
max
and AUC
of telithromycin were on average decreased by 79% and 86% respectively. Therefore,
concomitant
administration of CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine, phenobarbital, St
John’s wort) is likely to result in subtherapeutic levels of telithromycin and loss of effect. The
induction gradually decreases during 2 weeks after cessation of treatment with CYP3A4 inducers.
Ketek should not be used during and 2 weeks after treatment with CYP3A4 inducers.
Interaction studies with itraconazole and ketoconazole, two CYP3A4 inhibitors, showed that
maximum plasma concentrations of telithromycin were increased respectively by 1.22 and 1.51 fold
and AUC by respectively 1.54 fold and 2.0 fold. These changes in the pharmacokinetics of
telithromycin do not necessitate dosage adjustment as telithromycin exposure remains within a well
tolerated range.
The effect of ritonavir on telithromycin has not been studied and could lead to larger
increase in telithromycin exposure. The combination should be used with caution.
Ranitidine (taken 1 hour before Ketek) and antacid containing aluminium and magnesium hydroxide
has no clinically relevant influence on telithromycin pharmacokinetics.
4.6
There are no adequate data from the use of Ketek in pregnant women. Studies in animals have shown
reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Ketek should not be
used during pregnancy unless clearly necessary.
6
Telithromycin is excreted in the milk of lactating animals, at concentrations about 5 times those of
maternal plasma
.
Corresponding data for humans is not available. Ketek should not be used by breast-
feeding women.
Ketek
may cause undesirable effects such as visual disturbances, confusion or hallucination which
may reduce the capacity for the completion of certain tasks. In addition, rare cases of transient loss of
consciousness, which may be preceded by vagal symptoms, have been reported (see section 4.8).
Because of potential visual difficulties, loss of consciousness, confusion or hallucination, patients
should attempt to minimize activities such as driving a motor vehicle, operating heavy machinery or
engaging in other hazardous activities during treatment with Ketek. If patients experience visual
disorders, loss of consciousness, confusion or hallucination while taking Ketek, patients should not
drive a motor vehicle, operate heavy machinery or engage in other hazardous activities (see sections
4.4 and 4.8).
Patients should be informed that these undesirable effects may occur as early as after the first dose of
medication. Patients should be cautioned about the potential effects of these events on the ability to
drive or operate machinery.
In 2461 patients treated by Ketek in phase III clinical trials, and during post-marketing experience, the
following undesirable effects possibly or probably related to telithromycin have been reported. This is
shown below.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System organ
class
Very
common
(≥ 1/10)
Common
(≥1/100 to
<1/10 )
Uncommon
(≥1/1,000 to
<1/100)
Rare
(≥1/10,000 to
<1/1,000)
Very rare
(< 1/10,000)
Frequency
unknown
(cannot be
estimated
from
available
data)*
Cardiac
disorders
Flush
Palpitations
Atrial
arrhythmia,
hypotension,
bradycardia
QT/QTc
interval
prolongation
Blood and the
lymphatic
system disorders
Eosinophilia
Nervous system
disorders
Dizziness,
headache,
disturbance of
taste
Vertigo
somnolence,
nervousness,
insomnia,
Transient loss
of
consciousness,
paraesthesia
Parosmia
Cases of
rapid onset of
exacerbation
of myasthenia
gravis have
been reported
(see sections
4.3 and 4.4).
Ageusia,
anosmia,
Eye disorders
Blurred
vision
Diplopia
7
System organ
class
Very
common
(≥ 1/10)
Common
(≥1/100 to
<1/10 )
Uncommon
(≥1/1,000 to
<1/100)
Rare
(≥1/10,000 to
<1/1,000)
Very rare Frequency
(< 1/10,000) unknown
(cannot be
estimated
from
available
data)*
Gastro-intestinal
disorders
Diarrhoea Nausea,
vomiting,
gastro-
intestinal
pain,
flatulence
Oral
Candida
infection,
stomatitis
anorexia,
constipation
Pseudo-
membranous
colitis
Pancreatitis
Skin and
subcutaneous
tissue disorders
Rash,
urticaria,
pruritus
Eczema
Erythema
multiforme
Musculoskeletal
and connective
tissue disorders
Muscle
cramps
Arthralgia,
myalgia
Immune system
disorders
Angio-
neurotic
oedema,
anaphylactic
reactions
including
anaphylactic
shock, hyper-
sensitivity
Hepato-biliary
disorders
Increase in
liver enzymes
(AST, ALT,
alkaline
phosphatase)
Hepatitis
Cholestatic
jaundice
Severe
hepatitis and
liver failure
(see section
4.4)
Reproductive
system disorders
Vaginal
Candida
infection
Psychiatric
disorders
Confusion,
hallucination
*post-marketing experience
Visual disturbances (<1%) associated with the use of Ketek, including blurred vision, difficulty
focusing and diplopia, were mostly mild to moderate. They typically occurred within a few hours after
the first or second dose, recurred upon subsequent dosing, lasted several hours and were fully
reversible either during therapy or following the end of treatment. These events have not been
associated with signs of ocular abnormality (see sections 4.4 and 4.7).
In clinical trials the effect on QTc was small (mean of approximately 1 msec). In comparative trials,
similar effects to those observed with clarithromycin were seen with an on-therapy ΔQTc >30 msec in
7.6% and 7.0% of cases, respectively. No patient in either group developed a ΔQTc >60 msec. There
were no reports of TdP or other serious ventricular arrhythmias or related syncope in the clinical
program and no subgroups at risk were identified.
4.9
In the event of acute overdose the stomach should be emptied. The patients should be carefully
observed and given symptomatic and supportive treatment. Adequate hydration should be maintained.
8
Blood electrolytes (especially potassium) must be controlled. Due to the potential for the prolongation
of the QT interval and increased risk of arrhythmia, ECG monitoring must take place
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: macrolides, lincosamides and streptogramins, ATC Code: J01FA15.
Telithromycin is a semisynthetic derivative of erythromycin A belonging to the ketolides, a class of
antibacterial agents related to macrolides.
Mode of action
Telithromycin inhibits protein synthesis by interacting with domains II and V of the 23S ribosomal
RNA of the 50S ribosome subunit. Furthermore, telithromycin is able to block the formation of the
50S and 30S ribosomal subunits.
The affinity of telithromycin for the 50S ribosomalsubunits of organisms susceptible to erythromycin
A is 10 fold higher than that of erythromycin A..
Pharmacokinetic/Pharmacodynamic (PK/PD) relationship:
The AUC/MIC ratio has been shown to be the PK/PD parameter that correlates best with the efficacy
of telithromycin.
Mechanisms of resistance
Telithromycin does not induce expression of macrolide-lincosamide-streptogramin B (MLS
B
)-
mediated resistance
in vitro
in
Staphylococcus aureus
,
Streptococcus pneumoniae
, or
Streptococcus
pyogenes
.
In some organisms that are resistant to erythromycin A due to inducible expression of the MLS
B
resistance determinant, the affinity of telithromycin for the 50S ribosomal subunit is more than 20-fold
that of erythromycin A.
Telithromycin is not active against organisms that constitutively express the MLS
B
resistance
determinant (cMLS
B
). The majority of methicillin-resistant
S. aureus
(MRSA) express cMLS
B
.
In
in vitro
studies the activity of telithromycin was reduced against organisms that express the
erythromycin
erm
(B) or
mef
(A) related resistance mechanisms.
Exposure to telithromycin
in vitro
did select for pneumococcal mutants with increased MICs of
telithromycin, generally resulting in MIC values of ≤1 mg/l.
Streptococcus pneumoniae
does not demonstrate cross-resistance between erythromycin A and
telithromycin.
Streptococcus pyogenes
that show high-level resistance to erythromycin A are cross-resistant to
telithromycin
.
9
Breakpoints
The recommended European Committee for Antimicrobial Susceptibility Testing (EUCAST) MIC
clinical breakpoints are presented below:
Pathogen Susceptible Resistant
Streptococcus A, B, C, G
≤0.25 mg/l >0.5 mg/l
Streptococcus pneumoniae
≤0.25 mg/l >0.5 mg/l
Haemophilus influenzae
1
≤0.12 mg/l >8 mg/l
Moraxella catarrhalis
≤0.25 mg/l >0.5 mg/l
1
The correlation between macrolide MICs and clinical outcome is weak for
H.influenzae
. Therefore
the MIC breakpoint for telithromycin was set to categorise wild-type
H.influenzae
as having
intermediate susceptibility.
Antibacterial spectrum
The prevalence of resistance may vary geographically and with time for selected species and local
information on resistance is desirable, particularly when treating severe infections. As necessary,
expert advice should be sought when the local prevalence of resistance is such that the utility of the
agent in at least some types of infections is questionable.
Commonly susceptible species
Aerobic Gram-positive bacteria
Staphylococcus aureus
methicillin susceptible (MSSA)*
Streptococcus pneumoniae
*
Streptococcus
species
Viridans group streptococci
Aerobic Gram- negative bacteria
Haemophilus influenzae
$*
Haemophilus parainfluenzae
$
Legionella pneumophila
Moraxella catarrhalis
*
Other
Chlamydophila pneumoniae*
Chlamydia psittaci
Mycoplasma pneumoniae
*
Species for which acquired resistance may be a problem
Aerobic Gram-positive bacteria
Staphylococcus aureus
methicillin resistant (MRSA)+
Streptococcus pyogenes
*
Inherantly resistant organisms
Aerobic Gram- negative bacteria
Acinetobacter
Enterobacteriaceae
Pseudomonas
Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical indications.
$ natural intermediate susceptibility
+ Telithromycin is not active against organisms that constitutively express the MLS
B
resistance
determinant (cMLS
B
). More than 80%of MRSA express cMLS
B
.
10
5.2 Pharmacokinetic properties
Absorption
Following oral administration, telithromycin is fairly rapidly absorbed. A mean maximum plasma
concentration of about 2 mg/l is reached within 1-3 hour after dose with once-daily dosing of
telithromycin 800 mg. The absolute bioavailability is about 57% after a single dose of 800 mg. The
rate and extent of absorption is unaffected by food intake, and thus Ketek tablets can be given without
regard to food.
Mean steady-state trough plasma concentrations of
between 0.04 and
0.07 mg/l are reached within 3 to
4
days with once-daily dosing of telithromycin 800 mg. At steady-state AUC is approximately 1.5 fold
increased compared to the single dose.
Mean peak and trough plasma concentrations at steady state in patients were 2.9
±
1.6 mg/l (range 0.02-
7.6 mg/l) and 0.2
±
0.2 mg/l (range 0.010 to 1.29 mg/l), during a therapeutic 800 mg once-daily dose
regimen.
Distribution
The in vitro protein binding is approximately 60% to 70%. Telithromycin is widely distributed
throughout the body. The volume of distribution is 2.9±1.0 l/kg. Rapid distribution of telithromycin
into tissues results in significantly higher telithromycin concentrations in most target tissues than in
plasma. The maximum total tissue concentration in epithelial lining fluid, alveolar macrophages,
bronchial mucosa, tonsils and sinus tissue were 14.9±11.4 mg/l, 318.1±231 mg/l, 3.88±1.87 mg/kg,
3.95±0.53 mg/kg and 6.96±1.58 mg/kg, respectively. The total tissue concentration 24 h after dose in
epithelial lining fluid, alveolar macrophages, bronchial mucosa, tonsils and sinus tissue were
0.84±0.65 mg/l, 162±96 mg/l, 0.78±0.39 mg/kg, 0.72±0.29 mg/kg and 1.58±1.68 mg/kg, respectively.
The mean maximum white blood cell concentration of telithromycin was 83±25 mg/l.
Metabolism
Telithromycin is metabolized primarily by the liver. After oral administration, two-thirds of the dose is
eliminated as metabolites and one-third unchanged. The main circulating compound in plasma is
telithromycin. Its principal circulating metabolite represents approximately 13% of telithromycin
AUC, and has little antimicrobial activity compared with the parent medicinal product. Other
metabolites were detected in plasma, urine and faeces and represent less or equal than 3% of plasma
AUC.
Telithromycin is metabolized both by CYP450 isoenzymes and non-CYP enzymes. The major
CYP450 enzyme involved in the metabolism of telithromycin is CYP3A4. Telithromycin is an
inhibitor of CYP3A4 and CYP2D6, but has no or limited effect on CYP1A, 2A6, 2B6, 2C8, 2C9,
2C19 and 2E1.
Elimination
After oral administration of radiolabelled telithromycin, 76% of the radioactivity was recovered from
faeces, and 17% from the urine. Approximately one-third of telithromycin was eliminated unchanged;
20% in faeces and 12% in urine. Telithromycin displays moderate non-linear pharmacokinetics. The
non-renal clearance is decreased as the dose is increased
.
The total clearance (mean ±SD
)
is
approximately 58±5 l/h after an intravenous administration with renal clearance accounting for about
22% of this. Telithromycin displays a tri-exponential decay from plasma, with a rapid distribution
half-life of 0.17 h. The main elimination half-life of telithromycin is 2-3 h and the terminal, less
important, half-life is about 10 h at the dose 800 mg once daily.
11
Special populations
-Renal impairment
In a multiple-dose study, 36 subjects with varying degrees of renal impairment, a 1.4-fold increase in
C
max,ss
, and a 2-fold increase in AUC (0-24)
ss
at 800 mg multiple doses in the severe renally impaired
group (CLCR < 30 mL/min) compared to healthy volunteers were observed and a reduced dosage of
Ketek is recommended (See Section 4.2.). Based on observed data, a 600 mg daily dose is
approximately equivalent with the target exposure observed in healthy subjects. Based on simulation
data, an alternating daily dosing regimen of 800 mg and 400 mg in patients with severe renal
impairment can approximate the AUC (0-48h) in healthy subjects receiving 800 mg once daily.
The effect of dialysis on the elimination of telithromycin has not been assessed.
-Hepatic impairment
In a single-dose study (800 mg) in 12 patients and a multiple-dose study (800 mg) in 13 patients with
mild to severe hepatic insufficiency (Child Pugh Class A, B and C), the C
max
, AUC and t
1/2
of
telithromycin were similar compared to those obtained in age- and sex-matched healthy subjects. In
both studies, higher renal elimination was observed in the hepatically impaired patients. Due to limited
experience in patients with decreased metabolic capacity of the liver, Ketek should be used with
caution in patients with hepatic impairment (see also section 4.4).
-Elderly subjects
In subjects over 65 (median 75 years), the maximum plasma concentration and AUC of telithromycin
were increased approximately
2 fold
compared with those achieved in young healthy adults. These
changes in pharmacokinetics do not necessitate dosage adjustment.
-Paediatric patients
Limited data, obtained in paediatric patients 13 to 17 years of age, showed that telithromycin
concentrations in this age group were similar to the concentrations in patients 18 to 40 years of age.
-Gender
The pharmacokinetics of telithromycin is similar between males and females.
5.3 Preclinical safety data
Repeated dose toxicity studies of 1, 3 and 6 month duration with telithromycin conducted in rat, dog
and monkey showed that the liver was the principal target for toxicity with elevations of liver
enzymes, and histological evidence of damage. These effects showed a tendency to regress after
cessation of treatment. Plasma exposures based on free fraction of active substance, at the no observed
adverse effect levels ranged from 1.6 to 13 times the expected clinical exposure.
Phospholipidosis (intracellular phospholipid accumulation) affecting a number of organs and tissues
(e.g., liver, kidney, lung, thymus, spleen, gall bladder, mesenteric lymph nodes, GI-tract) has been
observed in rats and dogs administered telithromycin at repeated doses of 150 mg/kg/day or more for 1
month and 20 mg/kg/day or more for 3-6 months. This administration corresponds to free active
substance systemic exposure levels of at least 9 times the expected levels in human after 1 month and
less than the expected level in humans after 6 months, respectively. There was evidence of
reversibility upon cessation of treatment. The significance of these findings for humans is unknown.
In similarity to some macrolides, telithromycin caused a prolongation of Qtc interval in dogs and on
action potential duration in rabbit Purkinje fibers in vitro. Effects were evident at plasma levels of free
drug 8 to 13 times the expected clinical level. Hypokalaemia and quinidine had additive/supra-additive
effects in vitro while potentiation was evident with sotalol. Telithromycin, but not its major human
metabolites, had inhibitory activity on HERG and Kv1.5 channels.
12
Reproduction toxicity studies showed reduced gamete maturation in rat and adverse effects on
fertilization. At high doses embryotoxicity was apparent and an increase in incomplete ossification and
in skeletal anomalies was seen. Studies in rats and rabbits were inconclusive with respect to potential
for teratogenicity, there was equivocal evidence of adverse effects on foetal development at high
doses.
Telithromycin, and its principal human metabolites, were negative in tests on genotoxic potential
in
vitro
and
in vivo
. No carcinogenicity studies have been conducted with telithromycin.
6.
6.1
List of excipients
Tablet core:
Microcrystalline cellulose
Povidone K25
Croscarmellose sodium
Magnesium stearate
Tablet coating:
Talc
Macrogol 8000
Hypromellose 6 cp
Titanium dioxide E171
Yellow iron oxide E172
Red iron oxide E172
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
No special precautions for storage.
6.5 Nature and contents of container
Two tablets are contained in each blister cavity.
Available as packs of 10, 14, 20 and 100 tablets.
Opaque PVC/Aluminium blisters
Available as pack of 5 x 2 tablets.
Opaque PVC/Aluminium perforated unit dose blisters.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
13
7.
Aventis Pharma S.A.
20, Avenue Raymond Aron
F-92160 ANTONY
France
8.
EU/1/01/191/001-005
9.
Date of first authorisation: 9 July 2001
Date of first renewal: 9 July 2006
Detailed information on this product is available on the website of the European Medicines Agency
(EMA) http://www.ema.europa.eu
14
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
15
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release:
sanofi-aventis S.p.A.
Strada Statale No 17, km22
67019 Scoppito (L’Aquila)
Italy
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to medical prescription
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
OTHER CONDITIONS
The holder of this marketing Authorisation will have to submit yearly PSURs.
16
ANNEX III
LABELLING AND PACKAGE LEAFLET
17
A. LABELLING
18
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
Ketek 400 mg film-coated tablets
Telithromycin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 400 mg of telithromycin
3.
LIST OF EXCIPIENTS
4.
10 film-coated tablets
14 film-coated tablets
20 film-coated tablets
100 film-coated tablets
5 x 2 film-coated tablets
5.
METHOD AND, ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use
Oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {month/year}
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
19
Aventis Pharma S.A.
20, Avenue Raymond Aron
F-92160 ANTONY
France
12. MARKETING AUTORISATION NUMBER(S)
EU/1/01/191/001 10 tablets
EU/1/01/191/002 14 tablets
EU/1/01/191/003 20 tablets
EU/1/01/191/004 100 tablets
EU/1/01/191/005 5x2 tablets
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ketek
20
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Ketek 400 mg film-coated tablets
Telithromycin
2.
Aventis Pharma S.A.
3.
EXPIRY DATE
EXP {month/year}
4.
BATCH NUMBER
Batch {number}
21
B. PACKAGE LEAFLET
22
PACKAGE LEAFLET: INFORMATION FOR THE USER
Ketek 400 mg film-coated tablets
Telithromycin
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have further questions, ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Ketek is and what it is used for
2.
Before you take
Ketek.
3.
Possible side effects
5.
How to store Ketek
6.
Further Information
1. WHAT KETEK IS AND WHAT IT IS USED FOR
Ketek is an antibiotic of the type macrolides. Antibiotics stop the growth of bacteria which cause
infections.
Ketek is used to treat infections due to bacteria against which the medicine is active.
-
In adults, Ketek is used to treat infections of the throat, infections of the sinuses (hollow cavities in
the bones around the nose) and chest infections in patients with long standing breathing
difficulties and lung infection (pneumonia).
-
In adolescents of 12 years and older, Ketek is used to treat infections of the throat.
2.
BEFORE YOU TAKE KETEK
Do not take Ketek:
-
if you suffer from
myasthenia gravis,
a rare disease which causes muscle weakness.
-
if you are
allergic
(hypersensitive) to telithromycin, to any of the macrolide antibiotics or to any
of the other ingredients of Ketek. If in doubt, talk to your doctor or pharmacist.
-
if you have had a liver disease (
hepatitis
and/or
jaundice)
while taking Ketek in the past.
- if you are taking certain medicinal products to control the blood level of
cholesterol
or other lipids
like simvastatin, lovastatin, or atorvastatin, as the side effects of these medicinal products could be
increased.
-
if you or someone in your family are known to have an
abnormality of electrocardiogram
(ECG) called “long QT syndrome”.
-
while
taking other medicines
containing any of the following active substances:
ergotamine or dihydroergotamine (tablets or inhaler for migraine)
terfenadine or astemizole (allergic problems)
cisapride (digestive problems)
pimozide (psychiatric problems)
23
4.
How to take
Ketek.
- if you have
kidney problems
(severely impaired renal function) and/or
liver problems
(severely
impaired hepatic function), do not take Ketek while taking other medicines containing any of the
following active substances:
ketoconazole (anti fungal treatment)
a medicine called protease inhibitor (anti HIV treatment)
Take special care with Ketek:
-
if you have had certain
heart problems
such as coronary heart disease, ventricular arrhythmias,
bradycardia (changes in heart rate or electrocardiogram) or if you have had certain abnormal blood
tests due to medical conditions such as low levels of potassium (hypokalaemia), low levels of
magnesium (hypomagnesaemia).
-
if you develop severe or prolonged or bloody
diarrhoea
during or after taking Ketek tablets,
consult your doctor immediately since it may be necessary to interrupt the treatment. This may be
a sign of bowel inflammation which can occur following treatment with antibiotics.
-
if you have
liver disease
.
-
if you experience
visual disturbances
(blurred vision, difficulty in focusing, double vision)
-
if you experience
fainting
(transient loss of consciousness)
If any of these apply to you, or if you are not sure, tell your doctor before taking Ketek.
Ketek tablets are
not recommended
for use in children and adolescents less than 12 years old.
Refer also to sections “Do not take Ketek”, “Taking other medicines” and “Driving and using
machines”.
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription, as some of them could affect or be affected by Ketek.
These
medicines
must not be taken with Ketek:
- medicinal products to control the blood level of
cholesterol
or other lipids like simvastatin, as the
side effects of the medicinal products could be increased.
-
other medicines containing any of the
following active substances
:
ergotamine or dihydroergotamine (tablets or inhaler for migraine)
terfenadine or astemizole (allergic problems)
cisapride (digestive problems)
pimozide (psychiatric problems)
- if you have
kidney problems
(severely impaired renal function) and/or
liver problems
(severely
impaired hepatic function), other medicines containing any of the
following active substances
:
ketoconazole (anti fungal treatment)
a medicine called protease inhibitor (antiHIV treatment)
It is important to
tell your doctor
if you are taking:
-
medicines containing phenytoin, and carbamazepine (for epilepsy)
-
rifampicin (antibiotic)
-
phenobarbital or St John’s wort, (herbal medicine used to treat mild depressions)
-
medicines like tacrolimus, cyclosporin and sirolimus (for organ transplantation)
-
metoprolol (for heart disorders)
-
ritonavir (anti HIV medicine).
Taking
Ketek with food and drink
Ketek may be taken with or without food.
Pregnancy and Breast-feeding
If you are pregnant
do not take
Ketek tablets as the safety of Ketek in pregnancy is insufficiently
established. If you are breast-feeding do not take Ketek tablets.
24
Driving and using machines
Limit driving or other hazardous activities while taking Ketek. If you have vision problems, faint or
experience confusion or hallucination while taking Ketek, do not drive, operate heavy machinery, or
engage in dangerous activities.
Taking Ketek tablets may cause side effects such as visual disturbances, confusion or hallucination,
which may reduce the capacity to carry out certain tasks. Rare cases of fainting (transient loss of
consciousness), which may be preceded by a general feeling of being sick (e.g. nausea, stomach
upsets) have been reported. These symptoms may appear as early as after the first dose of Ketek.
3.
HOW TO TAKE KETEK
Your doctor will tell you how many Ketek tablets to take, at what time and for how long.
The usual duration of treatment is 5 days for infections of the throat, infections of the sinuses, chest
infections in patients with long standing breathing difficulties and 7 to 10 days for pneumonia.
The recommended dose of Ketek for adults and children of 12 years and older is two tablets of 400 mg
once daily (800 mg once daily).
If you have kidney problems (severe renal insufficiency) you should take alternating daily doses of
800 mg (two tablets of 400 mg) and 400 mg (one tablet of 400 mg), starting with the 800 mg dose.
Swallow the tablets whole with a glass of water.
It is best to take tablets at the same time each day. If possible take the tablets before going to bed,
to
reduce the potential impact of visual disturbances and loss of consciousness.
If you take more
Ketek than you should
If you accidentally take one tablet too many, nothing is likely to happen. If you accidentally take
several tablets too many, contact your doctor or pharmacist. If possible, take your tablets or the box
with you to show the doctor or pharmacist.
If you forget to take Ketek
If you forget to take a dose, take it as soon as possible. However, if it is nearly time for your next dose
skip the missed dose and take the next tablet at the usual time.
If you stop taking Ketek
Take the complete course of tablets prescribed by your doctor, even if you begin to feel better before
you have finished them all. If you stop taking the tablets too soon, the infection may return, or your
condition may get worse.
If you stop taking the tablets too soon you may also create a bacterial resistance to the medicine.
If you feel you are suffering from a side effect, tell a doctor immediately to get advice before taking
the next dose.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
25
4.
POSSIBLE SIDE EFFECTS
Like all medicines Ketek can cause side effects, although not everybody gets them. Most of them are
mild and transient, but very rare cases of serious adverse liver reactions and liver failure, including
fatal cases, have been reported.
The side effects are described into the following frequencies
very common: affects more than 1 user in 10
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
rare: affects 1 to 10 users in 10,000
very rare: affects less than 1 user in 10,000
If you notice
any of the following, stop taking Ketek and
tell your doctor immediately
:
-
Allergic or skin reactions such as face swelling, general allergic reactions including allergic
shock, or serious skin conditions associated with red spots, blisters (frequency not known).
-
Severe, persistent or bloody diarrhoea associated with abdominal pain or fever, which can be a
sign of serious bowel inflammation which may occur very rarely following treatment with
antibiotics (very rare).
-
Signs and symptoms of liver disease (hepatitis) such as yellowing of skin and eyes, dark urine,
itching, loss of appetite or abdominal pain (uncommon).
-
Worsening of a condition called myasthenia gravis, a rare disease which causes muscle
weakness (frequency unknown).
The above serious side effects may require urgent medical attention.
The other side effects listed below are given with an estimation of the frequency with which they may
occur with Ketek:
Very common
side effects
diarrhoea, usually mild and temporary.
Common
side effects
-
nausea, vomiting, abdominal pain, flatulence (excess wind)
-
dizziness, headaches, disturbance of taste
-
vaginal
Candida
infection (fungal infection associated with local itching, burning and white
discharge)
-
increase in liver enzymes (detected by blood test).
Uncommon
or rare side effects
-
constipation, loss of appetite (anorexia)
-
inflammation in the mouth, fungal infection in the mouth (
Candida
infection)
-
liver problem (hepatitis)
-
rash, hives (urticaria), itching, eczema
-
drowsiness, difficulties to fall asleep (insomnia), nervousness, vertigo,
-
tingling of the hands or feet (paraesthesia)
-
visual disturbances (blurred vision, difficulty in focusing, double vision),
-
flushes, fainting (transient loss of consciousness)
-
changes in heart rate (e.g. slow beating) or abnormality of electrocardiogram (ECG),
-
low blood pressure (hypotension)
-
increase of certain white blood cells, detected by blood test (eosinophilia).
Very rare
side effects
-
disturbance of smell, muscle cramps.
26
Additional side effects (frequency unknown) which may occur with Ketek are:
-
abnormality of electrocardiogram (ECG), called prolongation of QT interval
-
inflamed pancreas
-
joint and muscle pain
-
confusion
-
hallucination (seeing or hearing things that are not there)
-
loss of taste and smell
-
liver failure has been reported.
If any of these undesirable effects are troublesome, severe, or do not wear off as treatment goes on, tell
your doctor.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
5.
HOW TO STORE KETEK
Keep out of the reach and sight of children.
Do not use Ketek after the expiry date which is stated on the pack.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Ketek contains
-
The active substance is telithromycin
-
The other ingredients are microcrystalline cellulose, povidone K25, croscarmellose sodium,
magnesium stearate in the tablet core as well as talc, macrogol 8000 , hypromellose 6 cp,
titanium dioxide E171, yellow iron oxide E172, red iron oxide E172 in the film-coating.
What Ketek looks like and contents of the pack
Ketek 400 mg tablets are light orange, oblong, biconvex, film-coated tablet imprinted with “H3647”
on one side and “400” on the other.
Ketek tablets are presented in blister packs. Two tablets are contained in each blister cavity.
They are available in packs of 10, 5x2, 14, 20 and 100 tablets. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
The marketing authorisation holder of Ketek is:
Aventis Pharma S.A.
20 Avenue Raymond Aron
F-92160 ANTONY
France
The manufacturer of
Ketek is:
sanofi-aventis S.p.A.
Strada Statale No 17, km 22
I-67019 Scoppito (L’Aquila), Italy
27
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00
Luxembourg/Luxemburg
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)
България
sanofi-aventis Bulgaria EOOD
Тел.: +359 (0)2 970 53 00
Magyarország
sanofi-aventis zrt., Magyarország
Tel.: +36 1 505 0050
Česká republika
sanofi-aventis, s.r.o.
Tel: +420 233 086 111
Malta
sanofi-aventis Malta Ltd.
Tel: +356 21493022
Danmark
sanofi-aventis Denmark A/S
Tlf: +45 45 16 70 00
Nederland
sanofi-aventis Netherlands B.V.
Tel: +31 (0)182 557 755
Deutschland
Sanofi-Aventis Deutschland GmbH
Tel: +49 (0)180 2 222010
Norge
sanofi-aventis Norge AS
Tlf: +47 67 10 71 00
Eesti
sanofi-aventis Estonia OÜ
Tel: +372 627 34 88
Österreich
sanofi-aventis GmbH
Tel: +43 1 80 185 – 0
Ελλάδα
sanofi-aventis AEBE
Τηλ: +30 210 900 16 00
Polska
sanofi-aventis Sp. z o.o.
Tel.: +48 22 280 00 00
España
sanofi-aventis, S.A.
Tel: +34 93 485 94 00
Portugal
sanofi-aventis - Produtos Farmacêuticos, S.A.
Tel: +351 21 35 89 400
France
sanofi-aventis France
Tél: 0 800 222 555
Appel depuis l’étranger : +33 1 57 63 23 23
România
sanofi-aventis România S.R.L.
Tel: +40 (0)21 317 31 36
Ireland
sanofi-aventis Ireland Ltd.
Tel: +353 (0) 1 403 56 00
Slovenija
sanofi-aventis d.o.o.
Tel: +386 1 560 48 00
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
sanofi-aventis Pharma Slovakia s.r.o.
Tel: +421 2 57 103 777
Italia
sanofi-aventis S.p.A.
Tel: +39 02 393 91
Suomi/Finland
sanofi-aventis Oy
Puh/Tel: +358 (0) 201 200 300
Κύπρος
sanofi-aventis Cyprus Ltd.
Τηλ: +357 22 871600
Sverige
sanofi-aventis AB
Tel: +46 (0)8 634 50 00
28
Latvija
sanofi-aventis Latvia SIA
Tel: +371 67 33 24 51
United Kingdom
sanofi-aventis
Tel: +44 (0) 1483 505 515
Lietuva
UAB sanofi-aventis Lietuva
Tel: +370 5 2755224
This leaflet was last approved in
29
Source: European Medicines Agency
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