ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Tygacil 50 mg powder for solution for infusion.
2.
Each 5 ml Tygacil vial contains 50 mg of tigecycline. After reconstitution, 1 ml contains 10 mg of
tigecycline.
For a full list of excipients, see
section 6.1.
3.
Powder for solution for infusion.
Lyophilised orange cake or powder.
4.
Tygacil is indicated for the treatment of the following infections (see
sections 4.4
and
5.1)
:
•
Complicated skin and soft tissue infections, excluding diabetic foot infections (see section 4.4)
•
Complicated intra-abdominal infections
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Posology
The recommended dose for adults is an initial dose of 100 mg followed by 50 mg every 12 hours for 5
to 14 days.
The duration of therapy should be guided by the severity, site of the infection, and the patient’s
clinical response.
Hepatic insufficiency
No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh
A and Child Pugh B).
In patients with severe hepatic impairment (Child Pugh C), the dose of Tygacil should be reduced to
25 mg every 12 hours following the 100 mg loading dose. Patients with severe hepatic impairment
(Child Pugh C) should be treated with caution and monitored for treatment response (see
sections 4.4
and
5.2)
.
Renal insufficiency
No dosage adjustment is necessary in patients with renal impairment or in patients undergoing
haemodialysis (see
section 5.2)
.
2
Paediatric patients
Tygacil is not recommended for use in children and adolescents below 18 years due to the lack of data
on safety and efficacy (see
sections 5.2
and 4.4).
Method of administration:
Tygacil is administered only by intravenous infusion over 30 to 60 minutes (see
section 6.6
).
Hypersensitivity to the active substance or to any of the excipients. Patients hypersensitive to
tetracycline class antibiotics may be hypersensitive to tigecycline.
Anaphylaxis/anaphylactoid reactions, potentially life-threatening, have been reported with tigecycline
(see sections 4.3 and
4.8)
.
Cases of liver injury with a predominantly cholestatic pattern have been reported in patients receiving
tigecycline treatment, including some cases of hepatic failure with a fatal outcome. Although hepatic
failure may occur in patients treated with tigecycline due to the underlying conditions or concomitant
medications, a possible contribution of tigecycline should be considered (see
section 4.8)
.
Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics. Tigecycline
may have adverse reactions similar to tetracycline class antibiotics. Such reactions may include
photosensitivity, pseudotumor cerebri, pancreatitis, and anti-anabolic action which has led to increased
BUN, azotaemia, acidosis, and hyperphosphataemia (see
section 4.8)
.
Acute pancreatitis, which can be serious, has occurred (frequency: uncommon) in association with
tigecycline treatment (see
section 4.8)
. The diagnosis of acute pancreatitis should be considered in
patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities
suggestive of acute pancreatitis. Most of the reported cases developed after at least one week of
treatment. Cases have been reported in patients without known risk factors for pancreatitis. Patients
usually improve after tigecycline discontinuation. Consideration should be given to the cessation of
the treatment with tigecycline in cases suspected of having developed pancreatitis.
Experience in the use of tigecycline for treatment of infections in patients with severe underlying
diseases is limited.
In clinical trials in complicated skin and soft tissue infections, the most common type of infection in
tigecycline treated-patients was cellulitis (59 %), followed by major abscesses (27.5 %). Patients with
severe underlying disease, such as those that were immunocompromised, patients with decubitus ulcer
infections, or patients that had infections requiring longer than 14 days of treatment (for example,
necrotizing fasciitis), were not enrolled. A limited number of patients were enrolled with co-morbid
factors such as diabetes (20 %), peripheral vascular disease (7 %), intravenous drug abuse (2 %), and
HIV-positive infection (1 %). Limited experience is also available in treating patients with concurrent
bacteraemia (3 %). Therefore, caution is advised when treating such patients. The results in a large
study in patients with diabetic foot infection, showed that tigecycline was less effective than
comparator, therefore, tigecycline is not recommended for use in these patients (see section 4.1).
In clinical trials in complicated intra-abdominal infections, the most common type of infection in
tigecycline treated-patients was complicated appendicitis (51 %), followed by other diagnoses less
commonly reported
such as complicated cholecystitis (14 %), intra-abdominal abscess (10 %),
perforation of intestine (10 %) and gastric or duodenal ulcer perforation less than 24 hours (5 %). Of
3
these patients, 76 % had associated diffuse peritonitis (surgically-apparent peritonitis). There were a
limited number of patients with severe underlying disease such as immunocompromised patients,
patients with APACHE II scores > 15 (4 %), or with surgically apparent multiple intra-abdominal
abscesses (10 %). Limited experience is also available in treating patients with concurrent bacteraemia
(6 %). Therefore, caution is advised when treating such patients.
Consideration should be given to the use of combination antibacterial therapy whenever tigecycline is
to be administered to severely ill patients with complicated intra-abdominal infections (cIAI)
secondary to clinically apparent intestinal perforation or patients with incipient sepsis or septic shock
(see
section 4.8
).
The effect of cholestasis in the pharmacokinetics of tigecycline has not been properly established.
Biliary excretion accounts for approximately 50 % of the total tigecycline excretion. Therefore,
patients presenting with cholestasis should be closely monitored.
Prothrombin time or other suitable anticoagulation test should be used to monitor patients if
tigecycline is administered with anticoagulants (see section 4.5).
Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in
severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients
who present with diarrhoea during or subsequent to the administration of any antibacterial agent (see
The use of tigecycline may result in overgrowth of non-susceptible organisms, including fungi.
Patients should be carefully monitored during therapy. If super infection occurs, appropriate measures
should be taken (see
section 4.8)
.
Results of studies in rats with tigecycline have shown bone discolouration. Tigecycline may be
associated with permanent tooth discolouration in humans if used during tooth development (see
Tygacil should not be used in children under 8 years of age because of teeth discolouration, and is not
recommended in adolescents below 18 years due to the lack of data on safety and efficacy (see
Interaction studies have only been performed in adults.
Concomitant administration of tigecycline and warfarin (25 mg single-dose) to healthy subjects
resulted in a decrease in clearance of R-warfarin and S-warfarin by 40 % and 23 %, and an increase in
AUC by 68 % and 29 %, respectively. The mechanism of this interaction is still not elucidated.
Available data does not suggest that this interaction may result in significant INR changes. However,
since tigecycline may prolong both prothrombin time (PT) and activated partial thromboplastin time
(aPTT), the relevant coagulation tests should be closely monitored when tigecycline is
co-administered with anticoagulants (see
section 4.4
). Warfarin did not affect the pharmacokinetic
profile of tigecycline.
Tigecycline is not extensively metabolised. Therefore, clearance of tigecycline is not expected to be
affected by active substances that inhibit or induce the activity of the CYP450 isoforms.
In vitro
,
tigecycline is neither a competitive inhibitor nor an irreversible inhibitor of CYP450 enzymes (see
Tigecycline in recommended dosage did not affect the rate or extent of absorption, or clearance of
digoxin (0.5 mg followed by 0.25 mg daily) when administered in healthy adults. Digoxin did not
affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment is necessary when
tigecycline is administered with digoxin.
4
In
in vitro
studies, no antagonism has been observed between tigecycline and other commonly used
antibiotic classes.
Concurrent use of antibiotics with oral contraceptives may render oral contraceptives less effective.
There are no adequate data from the use of tigecycline in pregnant women. Results from animal
studies have shown tigecycline may cause foetal harm when administered during pregnancy (see
section 5.3)
. The potential risk for humans is unknown. As it is known for tetracycline class
antibiotics, tigecycline may also induce permanent dental defects (discolouration and enamel defects)
and a delay in ossification processes in foetuses, exposed
in utero
during the last half of gestation, and
in children under eight years of age due to the enrichment in tissues with a high calcium turnover and
formation of calcium chelate complexes (see
section 4.4
). Tigecycline should not be used during
pregnancy unless clearly necessary.
It is not known whether this medicinal product is excreted in human milk. In animal studies
tigecycline is excreted into milk of lactating rats. Because a potential risk to the breast-feeding infant
cannot be ruled out, when treating with tigecycline, caution should be exercised and interruption of
breast-feeding should be considered (see
section 5.3)
.
No studies on the effects of tigecycline on the ability to drive and use machines have been performed.
Dizziness may occur and this may have an effect on driving and use of machines (see section 4.8).
The total number of patients treated with tigecycline in Phase 3 clinical studies was 1415. Adverse
reactions were reported in approximately 41 % of patients treated with tigecycline. Treatment was
discontinued due to adverse reactions in 5 % of patients.
In clinical trials, the most common drug-related treatment emergent adverse reactions were reversible
nausea (20 %) and vomiting (14 %), which usually occurred early (on treatment days 1-2) and were
generally mild or moderate in severity.
Adverse reactions reported with Tygacil, including clinical trials and post-marketing experience, are
listed below:
Frequency categories are expressed as: 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)
For adverse reactions identified from post-marketing experience with Tygacil derived from
spontaneous reports for which the frequency cannot be estimated, the frequency grouping is
categorized as not known.
Infections and infestations:
Common: Abscess, infections
Uncommon: Sepsis/septic shock
In Phase 3 clinical studies, infection-related serious adverse events were more frequently
reported for subjects treated with tigecycline (6.7 %) vs comparators (4.6 %). Significant
differences in sepsis/septic shock with tigecycline (1.5 %) vs comparators (0.5 %) were
observed.
5
Blood and the lymphatic system disorders:
Common: Prolonged activated partial thromboplastin time (aPTT), Prolonged prothrombin time (PT)
Uncommon: Increased International Normalised Ratio (INR)
Not known: thrombocytopenia
Immune system disorders:
Not known: Anaphylaxis/anaphylactoid reactions (see
sections 4.3
and
4.4
)
Metabolism and nutrition disorders:
Uncommon: Hypoproteinaemia
Nervous system disorders:
Common: Dizziness
Vascular disorders:
Common: Phlebitis
Uncommon: Thrombophlebitis
Gastrointestinal disorders:
Very Common: Nausea, vomiting, diarrhoea
Common: Abdominal pain, dyspepsia, anorexia
Uncommon: Acute pancreatitis (see
section 4.4
)
Hepato-biliary disorders:
Common: Elevated aspartate aminotransferase (AST) in serum, and elevated alanine aminotransferase
(ALT) in serum, hyperbilirubinaemia
AST and ALT abnormalities in Tygacil-treated patients were reported more frequently in the
post therapy period than in those in comparator-treated patients, which occurred more often on
therapy.
Skin and subcutaneous tissue disorders:
Common: Pruritus, rash
General disorders and administration site conditions:
Common: Headache
Uncommon: Injection site reaction, injection site inflammation, injection site pain, injection site
oedema, injection site phlebitis
Investigations:
Common: Elevated amylase in serum, increased blood urea nitrogen (BUN)
6
In all Phase 3 and 4 cSSSI and cIAI studies, death occurred in 2.3 % (52/2216) of patients receiving
tigecycline and 1.5% (33/2206) of patients receiving comparator drugs.
Antibiotic Class Effects:
Pseudomembranous colitis which may range in severity from mild to life threatening (see
section 4.4)
Overgrowth of non-susceptible organisms, including fungi (see
section 4.4)
Tetracycline Class Effects:
Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics. Tetracycline
class adverse reactions may include photosensitivity, pseudotumour cerebri, pancreatitis, and anti-
anabolic action which has led to increased BUN, azotaemia, acidosis, and hyperphosphataemia (see
Tigecycline may be associated with permanent tooth discolouration if used during tooth development
(see
section 4.4
).
No specific information is available on the treatment of overdosage. Intravenous administration of
tigecycline at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased
incidence of nausea and vomiting. Tigecycline is not removed in significant quantities by
haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Tetracyclines, ATC code: J01AA12.
Mode of action
Tigecycline, a glycylcycline antibiotic, inhibits protein translation in bacteria by binding to the 30S
ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome.
This prevents incorporation of amino acid residues into elongating peptide chains.
In general, tigecycline is considered bacteriostatic. At 4 times the minimum inhibitory concentration
(MIC), a 2-log reduction in colony counts was observed with tigecycline against
Enterococcus
spp.,
Staphylococcus aureus
, and
Escherichia coli
.
Mechanism of resistance
Tigecycline is able to overcome the two major tetracycline resistance mechanisms, ribosomal
protection and efflux. Cross-resistance between tigecycline and minocycline-resistant isolates among
the
Enterobacteriaceae
due to multi-drug resistance (MDR) efflux pumps has been shown. There is no
target-based cross-resistance between tigecycline and most classes of antibiotics.
Tigecycline is vulnerable to chromosomally-encoded multidrug efflux pumps of
Proteeae
and
Pseudomonas aeruginosa.
Pathogens of the family
Proteeae
(
Proteus
spp.,
Providencia
spp., and
Morganella
spp.) are generally less susceptible to tigecycline than other members of the
Enterobacteriaceae.
Decreased susceptibility in both groups has been attributed to the overexpression
of the non-specific AcrAB multi-drug efflux pump. Decreased susceptibility in
Acinetobacter
baumannii
has been attributed to the overexpression of the AdeABC efflux pump.
7
Breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on
Antimicrobial Susceptibility Testing (EUCAST) are as follows:
Staphylococcus
spp. S
≤
0.5 mg/L and R > 0.5 mg/L
Streptococcus
spp. other than
S. pneumoniae
S
≤
0.25 mg/L and R > 0.5 mg/L
Enterococcus
spp. S ≤ 0.25 mg/L and R > 0.5 mg/L
Enterobacteriaceae S ≤ 1
(^)
mg/L and R > 2 mg/L
(^)
Tigecycline has decreased
in vitro
activity against
Proteus, Providencia
, and
Morganella
spp.
For anaerobic bacteria there is clinical evidence of efficacy in polymicrobial intra-abdominal
infections, but no correlation between MIC values, PK/PD data and clinical outcome. Therefore, no
breakpoint for susceptibility is given. It should be noted that the MIC distributions for organisms of
the genera Bacteroides and Clostridium are wide and may include values in excess of 2 mg/L
tigecycline.
There is limited evidence of the clinical efficacy of tigecycline against enterococci. However,
polymicrobial intra-abdominal infections have shown to respond to treatment with tigecycline in
clinical trials.
Susceptibility
The prevalence of acquired 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.
Pathogen
Commonly Susceptible Species
Gram-positive Aerobes
Enterococcus
spp.
†
Staphylococcus aureus
*
Staphylococcus epidermidis
Staphylococcus haemolyticus
Streptococcus agalactiae
*
Streptococcus anginosus
group
*
(includes
S. anginosus, S. intermedius and
S. constellatus
)
Streptococcus pyogenes
*
Viridans group streptococci
Gram-negative Aerobes
Citrobacter freundii
*
Citrobacter koseri
Escherichia coli
*
Klebsiella oxytoca
*
Anaerobes
Clostridium perfringens
†
Peptostreptococcus
spp.
†
Prevotella
spp.
Species for which acquired resistance may be a problem
Gram-negative Aerobes
Acinetobacter baumannii
Burkholderia cepacia
8
Pathogen
Enterobacter aerogenes
Enterobacter cloacae*
Klebsiella pneumoniae*
Morganella morganii
Proteus
spp.
Providencia
spp.
Serratia marcescens
Stenotrophomonas maltophilia
Anaerobes
Bacteroides fragilis
group†
Inherently resistant organisms
Gram-negative Aerobes
Pseudomonas aeruginosa
*denotes species against which it is considered that activity has been satisfactorily demonstrated in
clinical studies.
† see
section 5.1,
Breakpoints
above.
5.2 Pharmacokinetic properties
Absorption
Tigecycline is administered intravenously and therefore has 100 % bioavailability.
Distribution
The
in vitro
plasma protein binding of tigecycline ranges from approximately 71 % to 89 % at
concentrations observed in clinical studies (0.1 to 1.0 μg/ml). Animal and human pharmacokinetic
studies have demonstrated that tigecycline readily distributes to tissues.
In rats receiving single or multiple doses of
14
C-tigecycline, radioactivity was well distributed to most
tissues, with the highest overall exposure observed in bone marrow, salivary glands, thyroid gland,
spleen, and kidney. In humans, the steady-state volume of distribution of tigecycline averaged 500 to
700 L (7 to 9 L/kg), indicating that tigecycline is extensively distributed beyond the plasma volume
and concentrates into tissues.
No data are available on whether tigecycline can cross the blood-brain barrier in humans.
In clinical pharmacology studies using the therapeutic dosage regimen of 100 mg followed by 50 mg
q12h, serum tigecycline steady-state C
max
was 866±233 ng/ml for 30-minute infusions and 634±97
ng/ml for 60-minute infusions. The steady-state AUC
0-12h
was 2349±850 ng•h/ml.
Metabolism
On average, it is estimated that less than 20 % of tigecycline is metabolised before excretion. In
healthy male volunteers, following the administration of
14
C-tigecycline, unchanged tigecycline was
the primary
14
C-labelled material recovered in urine and faeces, but a glucuronide, an N-acetyl
metabolite and a tigecycline epimer were also present.
In vitro
studies in human liver microsomes indicate that tigecycline does not inhibit metabolism
mediated by any of the following 6 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6,
and 3A4 by competitive inhibition. In addition, tigecycline did not show NADPH-dependency in the
inhibition of CYP2C9, CYP2C19, CYP2D6 and CYP3A, suggesting the absence of mechanism-based
inhibition of these CYP enzymes.
9
Elimination
The recovery of the total radioactivity in faeces and urine following administration of
14
C-tigecycline
indicates that 59 % of the dose is eliminated by biliary/faecal excretion, and 33 % is excreted in urine.
Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline.
Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.
The total clearance of tigecycline is 24 L/h after intravenous infusion. Renal clearance is
approximately 13 % of total clearance. Tigecycline shows a polyexponential elimination from serum
with a mean terminal elimination half-life after multiple doses of 42 hours although high
interindividual variability exists.
Special populations
Hepatic Insufficiency
The single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild
hepatic impairment. However, systemic clearance of tigecycline was reduced by 25 % and 55 % and
the half-life of tigecycline was prolonged by 23 % and 43 % in patients with moderate or severe
hepatic impairment (Child Pugh B and C), respectively (see
section 4.2)
.
Renal Insufficiency
The single dose pharmacokinetic disposition of tigecycline was not altered in patients with renal
insufficiency (creatinine clearance <30 ml/min, n=6). In severe renal impairment, AUC was 30 %
higher than in subjects with normal renal function (see
section 4.2)
.
Elderly Patients
No overall differences in pharmacokinetics were observed between healthy elderly subjects and
younger subjects (see
section 4.2
).
Paediatric Patients
The pharmacokinetics of tigecycline in patients less than 18 years of age has not been established (see
Gender
There were no clinically relevant differences in the clearance of tigecycline between men and women.
AUC was estimated to be 20 % higher in females than in males.
Race
There were no differences in the clearance of tigecycline based on race.
Weight
Clearance, weight-normalised clearance, and AUC were not appreciably different among patients with
different body weights, including those weighing ≥ 125 kg. AUC was 24 % lower in patients weighing
≥ 125 kg. No data is available for patients weighing 140 kg and more.
5.3 Preclinical safety data
In repeated dose toxicity studies in rats and dogs, lymphoid depletion/atrophy of lymph nodes, spleen
and thymus, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone
marrow hypocellularity, and adverse renal and gastrointestinal effects have been seen with tigecycline
at exposures of 8 and 10 times the human daily dose based on AUC in rats and dogs, respectively.
These alterations were shown to be reversible after two weeks of dosing.
Bone discolouring was observed in rats which was not reversible after two weeks of dosing.
10
Results of animal studies indicate that tigecycline crosses the placenta and is found in foetal tissues. In
reproduction toxicity studies, decreased foetal weights in rats and rabbits (with associated delays in
ossification) and foetal loss in rabbits have been observed with tigecycline. Tigecycline was not
teratogenic in the rat or rabbit.
Results from animal studies using
14
C-labelled tigecycline indicate that tigecycline is excreted readily
via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is
little or no systemic exposure to tigecycline in the nursing pups as a result of exposure via maternal
milk.
Lifetime studies in animals to evaluate the carcinogenic potential of tigecycline have not been
performed, but short-term genotoxicity studies of tigecycline were negative.
Bolus intravenous administration of tigecycline has been associated with a histamine response in
animal studies. These effects were observed at exposures of 14 and 3 times the human daily dose
based on the AUC in rats and dogs respectively.
No evidence of photosensitivity was observed in rats following administration of tigecycline.
6.
6.1 List of excipients
Lactose monohydrate
Hydrochloric acid, sodium hydroxide (for pH adjustment)
6.2 Incompatibilities
The following active substances should not be administered simultaneously through the same Y-site as
Tygacil: Amphotericin B, amphotericin B lipid complex, diazepam esomeprazole, omeprazole and
intravenous solutions that could result in an increase of pH above 7.
Tygacil must not be mixed with other medicinal products for which compatibility data are not
available (see section 6.6).
6.3 Shelf life
24 months.
Once reconstituted and diluted in the bag or other suitable infusion container (e.g. glass bottle),
tigecycline should be used immediately.
6.4 Special precautions for storage
Store at or below 25°C.
For storage conditions of the reconstituted product see section 6.3.
6.5 Nature and contents of container
5 ml Type 1 clear glass vials fitted with grey butyl rubber stoppers and snap-off aluminium crimp
seals. Tygacil is distributed in a ten vial tray pack.
6.6 Special precautions for disposal and other handling
The lyophilised powder should be reconstituted with 5.3 ml of sodium chloride 9 mg/ml (0.9 %)
solution for injection, dextrose 50 mg/ml (5 %) solution for injection, or Lactated Ringer’s solution for
injection to achieve a concentration of 10 mg/ml of tigecycline. The vial should be gently swirled until
11
the medicinal product is dissolved. Thereafter, 5 ml of the reconstituted solution should be
immediately withdrawn from the vial and added to a 100 ml intravenous bag for infusion or other
suitable infusion container (e.g., glass bottle).
For a 100 mg dose, reconstitute using two vials into a 100 ml intravenous bag or other suitable
infusion container (e.g., glass bottle). Note: The vial contains a 6 % overage. Thus, 5 ml of
reconstituted solution is equivalent to 50 mg of the active substance. The reconstituted solution should
be yellow to orange in colour; if not, the solution should be discarded. Parenteral products should be
inspected visually for particulate matter and discolouration (e.g., green or black) prior to
administration.
Tygacil may be administered intravenously through a dedicated line or through a Y-site. If the same
intravenous line is used for sequential infusion of several active substances, the line should be flushed
before and after infusion of Tygacil with either sodium chloride 9 mg/ml (0.9 %) solution for injection
or dextrose 50 mg/ml (5 %) solution for injection. Injection should be made with an infusion solution
compatible with tigecycline and any other medicinal product(s) via this common line (see
section 6.2)
This medicinal product is for single use only; any unused solution should be discarded.
Compatible intravenous solutions include: sodium chloride 9 mg/ml (0.9 %) solution for injection,
dextrose 50 mg/ml (5 %) solution for injection, and Lactated Ringer’s solution for injection.
When administered through a Y-site, compatibility of Tygacil diluted in sodium chloride 0.9 % for
injection is demonstrated with the following medicinal products or diluents: amikacin, dobutamine,
dopamine HCl, gentamicin, haloperidol, Lactated Ringer’s, lidocaine HCl, metoclopramide, morphine,
norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine
HCl, theophylline, and tobramycin.
7.
Wyeth Europa Ltd.
Huntercombe Lane South
Taplow, Maidenhead
Berkshire, SL6 0PH
United Kingdom
8.
EU/1/06/336/001
9.
Date of first authorisation: 24 April 2006.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu/
12
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
13
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Wyeth Pharmaceuticals
New Lane
Havant
Hampshire, PO9 2NG
United Kingdom
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 Marketing Authorisation Holder must ensure that the system of pharmacovigilance as described in
version 3.0 presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is placed on the market.
The Marketing Authorisation Holder commits to performing the studies and additional
pharmacovigilance activities detailed in the Pharmacovigilance Plan.
The Marketing Authorisation Holder commits to performing the studies and additional
pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in version 4.0 of
the Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation
and any subsequent updates of the RMP agreed by the CHMP.
The MAH will continue to submit yearly Periodic Safety Update Reports, unless otherwise specified
by the CHMP.
14
ANNEX
III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Tygacil 50 mg powder for solution for infusion
Tigecycline
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 50 mg tigecycline.
3.
LIST OF EXCIPIENTS
Each vial contains 100 mg of lactose monohydrate. The pH is adjusted with hydrochloric acid, and if
necessary sodium hydroxide.
4.
10 vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the
package leaflet
before use for directions on reconstitution and dilution.
For intravenous use after reconstitution and dilution.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store at or below 25°C.
17
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Wyeth Europa Ltd.
Huntercombe Lane South
Taplow, Maidenhead
Berkshire, SL6 0PH
United Kingdom
EU/1/06/336/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
18
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Tygacil 50 mg powder for infusion
Tigecycline
For IV use only
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
19
B. PACKAGE LEAFLET
20
PACKAGE LEAFLET INFORMATION FOR THE USER
Tygacil 50 mg powder for solution for infusion
tigecycline
Read all of this leaflet carefully before you are given this medicine.
-
If you have any 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 Tygacil is and what it is used for
3.
How Tygacil is given
4.
Possible side effects
5.
How to store Tygacil
6.
Further information
1.
WHAT TYGACIL IS AND WHAT IT IS USED FOR
Tygacil is an antibiotic of the glycylcycline group that works by stopping the growth of bacteria that
cause infections.
Your doctor prescribed Tygacil because you have one of the following types of serious infections:
•
Complicated infection of the skin and soft tissues
Tygacil is not indicated for the treatment of diabetic foot infections.
•
Complicated infection in the abdomen
2.
BEFORE YOU RECEIVE TYGACIL
Do not use Tygacil
•
If you are allergic (hypersensitive) to tigecycline, the active substance of Tygacil. If you are
allergic to tetracycline class antibiotics (e.g., minocycline, doxycycline, etc.), you may be
allergic to tigecycline.
Take special care with Tygacil
•
Tell your doctor immediately if you develop symptoms of an allergic reaction.
•
Tell your doctor immediately if you develop severe abdominal pain, nausea, and vomiting.
These may be symptoms of acute pancreatitis.
•
Tell your doctor if you are suffering from diarrhoea before you are given Tygacil. If you
develop diarrhoea during or after your treatment, tell your doctor at once. Do not take any
diarrhoea medicine without first checking with your doctor.
•
Tell your doctor if you have or previously had any side effects due to antibiotics belonging to
the tetracycline class (e.g., skin sensitization to sun light, staining on developing teeth, pancreas
inflammation, and alteration of certain laboratory values aimed at measuring how well your
blood clots).
21
-
Keep this leaflet. You may need to read it again.
2.
Before you receive Tygacil
•
In certain serious infections, your doctor may consider to use Tygacil in combination with other
antibiotics.
•
Tell your doctor if you are taking certain medicines (named anticoagulants) aimed at avoiding
an excess of blood clotting (see also Using other medicines in this leaflet).
•
Tell your doctor if you are taking the contraceptive pill as you may need an additional method
of contraception while receiving Tygacil (see also Using other medicines in this leaflet).
•
Tell your doctor if you have, or previously had liver problems. Depending on the condition of
your liver, your doctor may reduce the dose to avoid potential side effects.
•
While antibiotics including Tygacil fight certain bacteria, other bacteria and fungi may continue
to grow. This is called overgrowth. Your doctor will monitor you for any potential infections
and treat you if necessary.
•
Tygacil is not to be used in children or adolescents (under 18 years of age). In children less
than 8 years, tigecycline may induce permanent dental defects such as staining on the
developing teeth.
Using other medicines
Always tell your doctor if you are taking or have recently taken any other medicines, including
medicines you buy without a prescription.
Tygacil may prolong certain tests that measure how well your blood is clotting. It is important that you
tell your doctor if you are taking medicines to avoid an excess of blood clotting. If this were the case,
your doctor will monitor you closely.
Tygacil may interfere with the contraceptive pill (birth control pill). Talk to your doctor about the need
for an additional method of contraception while receiving Tygacil.
Pregnancy and breast-feeding
Tygacil may cause foetal harm. If you are pregnant, or are planning to become pregnant, talk to your
doctor before receiving Tygacil.
It is not known if Tygacil passes into breast milk in humans. Ask your doctor for advice before
breast-feeding your baby.
Driving and using machines
Tygacil may cause side effects such as dizziness. This may impair your ability to drive or operate
machinery.
3.
HOW TYGACIL IS GIVEN
Tygacil will be given to you by a doctor or a nurse.
The recommended dose is 100 mg given initially, followed by 50 mg every 12 hours. This dose is
given intravenously (directly into your blood stream) over a period of 30 to 60 minutes.
A course of treatment usually lasts for 5 to 14 days. Your doctor will decide how long you should be
treated.
If you receive more Tygacil than you should
If you are concerned that you may have been given too much Tygacil, talk to your doctor or nurse
immediately.
If you miss a dose of Tygacil
If you are concerned that you may have missed a dose, talk to your doctor or nurse immediately.
22
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Tygacil may have side effects, although not everybody gets them.
The most common side effects reported in at least 1 in 10 patients receiving Tygacil are:
•
Nausea, vomiting, diarrhoea.
Common side effects reported in at least 1 in 100 patients but in less than 1 in 10 patients receiving
Tygacil are:
•
Abscess (collection of pus), infections
•
Laboratory measurements of decreased ability to form blood clots
•
Dizziness
•
Vein irritations from the injection, including pain, inflammation, swelling and clotting
•
Abdominal pain, dyspepsia (stomach ache and indigestion), anorexia (loss of appetite)
•
Increases in liver enzymes, hyperbilirubinaemia (excess of bile pigment in the blood)
•
Pruritus (itching), rash
•
Headache
•
Increase in amylase, which is an enzyme found in the salivary glands and pancreas, increased
blood urea nitrogen (BUN).
Uncommon side effects reported in at least 1 in 1,000 patients but less than 1 in 100 patients receiving
Tygacil are:
•
Sepsis (severe infection in the body and blood stream)/septic shock (serious medical condition
which can lead to multiple organ failure and death as a result of sepsis)
•
Low protein levels in the blood
•
Acute pancreatitis (inflamed pancreas which may result in severe abdominal pain, nausea, and
vomiting)
•
Jaundice, inflammation of the liver
•
Injection site reaction (pain, redness, inflammation).
Other side effects reported (frequency not known) in patients receiving Tygacil are:
•
Anaphylaxis/anaphylactoid reactions (that may range from mild to severe, including a sudden,
generalised allergic reaction that may lead to a life-threatening shock [e.g. difficulty in
breathing, drop of blood pressure, fast pulse]).
•
Low platelet levels in the blood (which may lead to an increased bleeding tendency and
bruising/haematoma)
•
Liver failure
Pseudomembranous colitis may occur with most antibiotics including Tygacil. This consists of severe,
persistent or bloody diarrhoea associated with abdominal pain or fever, which can be a sign of serious
bowel inflammation, which may occur during or after your treatment.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE TYGACIL
Keep out of the reach and sight of children.
Tygacil should be stored at or below 25°C.
Do not use Tygacil after the expiry date which is stated on the vial.
23
Storage after preparation
Once the powder has been made into a solution and diluted ready for use, it should be given to you
almost immediately.
6.
FURTHER INFORMATION
What Tygacil contains
The active substance is tigecycline. Each vial contains 50 mg of tigecycline.
The other ingredients are lactose monohydrate, hydrochloric acid, and sodium hydroxide.
What Tygacil looks like and contents of the pack
Tygacil is supplied in a vial and looks like an orange powder or cake before it is diluted. These vials
are distributed to the hospital in a ten tray pack. The powder should be mixed in the vial with a small
amount of solution. The vial should be gently swirled until the medicine is dissolved. Thereafter, the
solution should be immediately withdrawn from the vial and added to a 100 ml intravenous bag or
other suitable infusion container in the hospital.
The Tygacil solution should be yellow to orange in colour after dissolving; if it is not, the solution
should be discarded.
Marketing Authorisation Holder:
Wyeth Europa Ltd.
Huntercombe Lane South
Taplow, Maidenhead
Berkshire, SL6 0PH
United Kingdom
Manufacturer:
Wyeth Pharmaceuticals
New Lane
Havant
Hampshire PO9 2NG
United Kingdom
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Luxembourg/Luxemburg
Pfizer S.A. / N.V.
Tél/Tel: +32 (0)2 554 62 11
Magyarország
Pfizer Kft.
Tel: +36 1 488 3700
България/Eesti/Latvija/Lietuva/
Slovenija
Wyeth Whitehall Export GmbH
Teл/Tel/Tãlr:+43 1 89 1140
Malta
Vivian Corporation Ltd.
Tel: +35621 344610
Česká Republika
Pfizer s.r.o.
Tel: +420-283-004-111
Nederland
Wyeth Pharmaceuticals B.V.
Tel: +31 23 567 2567
Danmark
Pfizer ApS
Tlf: +45 44 201 100
Norge
Pfizer AS
Tlf: +47 67 526 100
Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055-51000
Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0
Ελλάδα
Pfizer Hellas A.E.
Τηλ.: +30 210 6785 800
Polska
Pfizer Polska Sp. z o.o.,
Tel.: +48 22 335 61 00
24
España
Pfizer, S.A.
Télf:+34914909900
Portugal
Laboratórios Pfizer, Lda.
Tel: (+351) 21 423 55 00
France
Pfizer
Tél +33 1 58 07 30 00
România
Pfizer Romania S.R.L
Tel: +40 (0) 21 207 28 00
Ireland
Wyeth Pharmaceuticals
Tel: +353 1 449 3500
Slovenská Republika
Pfizer Luxembourg SARL, organizačná
zložka
Tel: + 421 2 3355 5500
Ísland
Icepharma hf
Tel: +354 540 8000
Suomi/Finland
Pfizer Oy
Puh/Tel: +358 (0)9 430 040
Italia
Wyeth Lederle S.p.A.
Tel: +39 06 927151
Sverige
Pfizer AB
Tel: +46 (0)8 550 520 00
Kύπρος
Wyeth Hellas (Cyprus Branch) AEBE
Tηλ: +357 22 817690
United Kingdom
Wyeth Pharmaceuticals
Tel: +44 1628 415330
This leaflet was last approved in {MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMEA)
website: http://www.emea.europa.eu/
25
The following information is intended for medical or healthcare professionals only:
Instructions for use and handling (
see also
3. HOW TYGACIL IS GIVEN
in this leaflet
)
The lyophilised powder should be reconstituted with 5.3 ml of sodium chloride 9 mg/ml (0.9 %)
solution for injection, dextrose 50 mg/ml (5 %) solution for injection, or Lactated Ringer’s solution for
injection to achieve a concentration of 10 mg/ml of tigecycline. The vial should be gently swirled until
the active substance is dissolved. Thereafter, 5 ml of the reconstituted solution should be immediately
withdrawn from the vial and added to a 100 ml intravenous bag for infusion or other suitable infusion
container (e.g. glass bottle).
For a 100 mg dose, reconstitute using two vials into a 100 ml intravenous bag for infusion or other
suitable infusion container (e.g. glass bottle).
Note: The vial contains a 6 % overage. Thus, 5 ml of reconstituted solution is equivalent to 50 mg of
the active substance. The reconstituted solution should be yellow to orange in colour; if not, the
solution should be discarded. Parenteral products should be inspected visually for particulate matter
and discolouration (e.g. green or black) prior to administration.
Tygacil may be administered intravenously through a dedicated line or through a Y-site. If the same
intravenous line is used for sequential infusion of several active substances, the line should be flushed
before and after infusion of Tygacil with either sodium chloride 9 mg/ml (0.9 %) solution for injection
or dextrose 50 mg/ml (5 %) solution for injection. Injection should be made with an infusion solution
compatible with tigecycline and any other medicinal product(s) via this common line.
Compatible intravenous solutions include: sodium chloride 9 mg/ml (0.9 %) solution for injection,
dextrose 50 mg/ml (5 %) solution for injection, and Lactated Ringer’s solution for injection.
When administered through a Y-site, compatibility of Tygacil diluted in sodium chloride 0.9 % for
injection is demonstrated with the following medicinal products or diluents: amikacin, dobutamine,
dopamine HCl, gentamicin, haloperidol, Lactated Ringer’s, lidocaine HCl, metoclopramide, morphine,
norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine
HCl, theophylline, and tobramycin.
Tygacil must not be mixed with other medicinal products for which compatibility data are not
available.
Once reconstituted and diluted in the bag or other suitable infusion container (e.g. glass bottle)
tigecycline should be used immediately.
For single use only, any unused solution should be discarded.
26
Source: European Medicines Agency
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