1 Annex I Summary of Product Characteristics

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

1 1. Name of the Medicinal Product

TROVAN IV 5mg/ml Concentrate for Solution for Infusion. Trovofloxacin (as alatrofloxacin mesylate).

2. Qualitative and Quantitative Composition

20 ml of concentrate for solution for infusion containing 157.2 mg alatrofloxacin mesylate corresponding to 100 mg trovafloxacin. Alatrofloxacin is the bis-alanine derivative prodrug of the active moiety trovafloxacin.

3. Pharmaceutical Form

Concentrate for Solution for Infusion

4. Clinical Particulars

4.1 Therapeutic indications

Trovafloxacin is a synthetic broad spectrum quinolone antibacterial agent indicated for the treatment of the following infections in adults: • Pneumonia: Community Acquired Pneumonia and Nosocomial Pneumonia (mild, moderate and severe)

Note: Efficacy in patients with very severe nosocomial pneumonia and in particular infections due to less susceptible pathogens e.g. P. Aeruginosa has not been established. See also section 4.2.

• Complicated Intra-abdominal Infections and Acute Pelvic Infections • Complicated Skin and Soft Tissue Infections

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

In Adults The TROVAN IV Concentrate for Solution for Infusion contains alatrofloxacin, a prodrug, which is rapidly hydrolysed in serum to trovafloxacin. All doses are expressed in terms of trovafloxacin, the active moiety. It may be used in patients requiring parenteral therapy either due to the severity of their condition or inability to take oral medication. When the intravenous pharmaceutical form has been used as initial therapy, at either 300 mg or 200 mg daily, patients may be switched to oral treatment with TROVAN tablets, as a 200 mg single daily dose, when clinically indicated. On the basis of the high oral bioavailability of trovafloxacin (88%), adjustment of the dose is not required when switching between parenteral and oral administration.

Detailed information on recommended dosage for indicated infections is given in the following table:

Infection Dose (once daily) and Route of Administration Community Acquired Pneumonia 200 mg oral or i.v. followed by 200 mg oral for mild to moderate infections. For severe infections an initial 300mg i.v. dose may be necessary Nosocomial Pneumonia 300 mg i.v. followed by 200 mg oral Complicated Intra-abdominal 300 mg i.v. followed by 200 mg oral Infections and Acute Pelvic Infections Complicated Skin and Soft Tissue 200 mg oral or i.v. followed by 200 mg oral Infections Duration of therapy is typically 7 - 14 days as indicated by the severity of the infection. Infections due to less susceptible organisms, such as Pseudomonas aeruginosa, may require combination therapy.

In Children: The use of trovafloxacin in children and growing adolescents is not recommended. (see Section 4.3) As with other drugs in this class, arthropathy and chondrodysplasia have been observed in immature animals when administered at high doses. (see Section 5.3)

In the Elderly: No adjustment in dosage is necessary.

Impaired Renal Function: No adjustment in dosage is necessary.

Impaired Hepatic Function: No adjustment in the dosage or duration is required in patients with mild impairment (Child-Pugh A) of hepatic function. For moderate impairment (Child-Pugh B) of hepatic function, the potential for increased AUC due to reduced elimination should be taken into account, when its use is considered in such patients. No pharmacokinetic data are available in patients with severely (Child-Pugh C) impaired hepatic function (see Section 4.3).

Administration: TROVAN IV Concentrate for Solution for Infusion after dilution is for administration by intravenous infusion. This concentrate for solution for infusion must be diluted to a concentration of 1 - 2 mg/ml before administration and should be given as an intravenous infusion over a period of 60 minutes. This concentrate for solution for infusion must not be administered by bolus injection. This concentrate for solution for infusion can be diluted only with: 5% Dextrose Injection 0.45% Sodium Chloride Injection 5% Dextrose and 0.45% Sodium Chloride Injection 5% Dextrose and 0.2% Sodium Chloride Injection

3 Lactated Ringer’s and 5% Dextrose Injection

TROVAN IV should not be diluted with 0.9% Sodium Chloride Injection, (normal saline), alone or in combination with other diluents. A precipitate may form under these conditions. In addition, TROVAN IV should not be diluted with Lactated Ringer’s (see Section 6.2 Incompatibilities).

4.3 Contra-indications

Hypersensitivity to alatrofloxacin / trovafloxacin or other quinolones or related compounds. Patients with severely impaired hepatic function. Pregnancy and lactation (see also Section 4.6). Use in paediatric patients until the end of the growth phase. History of tendon disease with a fluoroquinolone. Patients with Glucose-6-phosphate dehydrogenase deficiency.

4.4 Special warnings and special precautions for use

• As with other quinolones, trovafloxacin should be used with caution in patients with known or suspected psychiatric disorders or CNS disorders such as epilepsy or other factors that predispose to psychiatric disorders or seizures respectively. • In clinical studies dizziness or light-headedness (usually mild, transient, and resolving on continued dosing) was the most frequently observed undesirable effect. These undesirable effects were more frequently reported in females. Patients should be informed of the potential for these undesirable effects and should be aware of how they react to this medication before driving or operating machinery. (See section 4.7) • As with other quinolones, patients should avoid prolonged exposure to strong sunlight or UV radiation during treatment with trovafloxacin. • Tendinitis and/or tendon rupture (particularly affecting the Achilles tendon) occurs in association with quinolone antibacterial agents. Such reactions have been particularly noted in older patients and those on corticosteroids. At the first sign of pain or inflammation, patients should discontinue trovafloxacin and rest the affected limb. If symptoms involve the Achilles tendon, measures should be taken to ensure that rupture of both tendons does not occur (e.g. both are supported with a suitable brace or heelpiece). • As with other broad spectrum antibacterial agents, rare cases of pseudomembranous colitis have been reported in patients receiving trovafloxacin. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of all antibacterial agents. • Rapid infusion of alatrofloxacin (≤ 30 minutes) can cause seizures in human subjects and consequently TROVAN IV 5mg/ml Concentrate for Solution for Infusion must be diluted before use and should be administered by slow intravenous infusion over a period of 60 minutes. • Trovafloxacin has not been studied in granulocytopenic patients, this should be taken into account when its use is considered in such patients.

4 • The safety of trovafloxacin has only been established for the recommended dosage regimens.Prolonged use or treatment with higher doses may be associated with higher incidences of undesirable effects. In a comparative study where oral trovafloxacin was administered for 28 days, a higher incidence of liver enzyme elevations was noted on trovafloxacin. These abnormalities mostly resolved during the 10 week follow-up after the medicinal product was discontinued. • Liver failure and pancreatitis have been reported very rarely. Patients developing symptoms consistent with hepatitis and/or pancreatitis should discontinue treatment immediately and should be monitored appropriately. • Allergic reactions including anaphylaxis have been reported very rarely with trovafloxacin. In the event of an allergic reaction, treatment with trovafloxacin should be discontinued immediately and adequate supportive procedures initiated.(See section 4.8)

4.5 Interaction with other medicaments and other forms of interaction

The absence of significant interactions has been demonstrated with the following: theophylline, warfarin, digoxin, omeprazole, cimetidine and cyclosporin.

4.6 Pregnancy and lactation

Trovafloxacin is contraindicated in pregnancy (See section 4.3) Trovafloxacin is secreted in breast milk and administration to nursing mothers is contraindicated. The safety of trovafloxacin in human pregnancy has not been evaluated. Fetotoxicity (e.g. increased mortality and decreased body weight) was evident in animal studies. Malformations of the axial skeleton of offspring consisting of fusions and agenesis of some vertebrae and ribs have been observed in animal studies. Other quinolones are reported to affect the axial skeleton. (see Section 5.3).

4.7 Effects on ability to drive and use machines

Trovafloxacin may cause undesirable effects such as dizziness or light-headedness (usually mild, transient and resolving on repeated dosing). In clinical studies these undesirable effects were reported more frequently in female patients. Patients should be informed of the potential for these side effects and should be aware of how they react to this medication before driving or operating machinery (See section 4.4).

4.8 Undesirable effects

In multiple dose clinical studies the following undesirable events with possible, probable or unknown relationship to trovafloxacin were observed:

NERVOUS: Dizziness (or light-headedness), headache, paraesthesia, tremor and vertigo. Tonic seizure associated with rapid intravenous infusion (≤ 30 minutes) has been reported. CARDIOVASCULAR: Phlebitis, thrombophlebitis GASTROINTESTINAL: Diarrhoea, nausea, vomiting, abdominal pain, constipation, dyspepsia, flatulence and gastritis and rarely pseudomembraneous colitis. GENERAL: Intravenous site reactions, asthenia, fatigue and flushing. MUSCULOSKELETAL: Tendinitis. PSYCHIATRIC: Anorexia, nervousness, insomnia, somnolence, confusion. HYPERSENSITIVITY AND SKIN: Rash, pruritus, urticaria, photosensitivity. SPECIAL SENSES: Eye pain, photophobia, visual disturbances, taste perversion. LABORATORY ABNORMALITIES: Transient, asymptomatic elevations in hepatic transaminases. (See below and warnings in section 4.4)

Post Marketing Experience: During the post-marketing period the following undesirable effects, not included in the above list, were reported:

HYPERSENSITIVITY AND SKIN Very rare anaphylaxis, Stevens-Johnson syndrome HEPATOBILIARY Very rare hepatitis, liver failure ( including acute hepatic necrosis) DIGESTIVE Very rare pancreatitis

4.9 Overdose

Information on overdosage is limited, single oral doses of up to 1000 mg have been administered to healthy volunteers without significant adverse effects. Doses of up to 400 mg have been administered intravenously in multiple doses without significant undesirable effects. Trovafloxacin is not efficiently removed by dialysis. Patients should be carefully observed and given symptomatic and supportive treatment.

5. Pharmacological Properties

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Antibacterial Agent fluoroquinolone ATC Code: J01M A

Mechanism of action:

6 Trovafloxacin has in vitro activity and clinical efficacy against a wide range of Gram- negative and Gram-positive organisms, aerobes, anaerobes and atypical micro- organisms at concentrations achieved in serum following administration of the recommended doses. The mode of action results from the interference with the enzyme DNA gyrase, an essential enzyme involved in the replication, transcription and repair to bacterial DNA, and with Topoisomerase IV, an enzyme known to affect the partitioning of the bacterial chromosome. The minimum bactericidal concentrations (MBC) are generally similar to the minimum inhibitory concentration (MIC) and the ratio of MBC:MIC does not usually exceed 2. In vitro studies have shown additive effects when trovafloxacin is combined with other antibacterial agents such as beta-lactams, aminoglycosides, clindamycin, vancomycin, or metronidazole. Synergy with beta-lactams (ceftazidime, ampicillin/sulbactam or imipenem), gentamicin or amikacin has only been reported to occur with a few strains of enterococci and Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.

Effect on gut flora in humans: In a pharmacodynamic study in healthy human volunteers administration of multiple doses of trovafloxacin (200mg daily) for up to 10 days produced no clinically significant effect on the gut flora. However, pseudomembranous colitis has been reported rarely in patients who have been treated with therapeutic regimens of trovafloxacin.

Susceptibility: The following preliminary MIC breakpoints, separating susceptible from intermediately susceptible and intermediately susceptible from resistant organisms are suggested: S ≤ 1 mg/l, R> 2 mg/l The prevalence of acquired resistance may vary geographically and with time for selected species and local information of resistance is desirable, particularly when treating severe infections. This information gives only approximate guidance on probabilities whether micro-organisms will be susceptible to trovafloxacin. Where resistance patterns for particular species are known to vary within the European Union this is shown below.

Gram-negative aerobes: Acinetobacter calcoaceticus subs. anitratus Acinetobacter lwoffi Bordetella bronchiseptica Citrobacter freundii Enterobacter aerogenes Enterobacter agglomerans Enterobacter cloacae* 0 - 20% Escherichia coli* 0 - 20% Haemophilus influenzae* Haemophilus parainfluenzae* Klebsiella oxytoca* Klebsiella pneumoniae* 0 - 15% Legionella pneumophila* Moraxella catarrhalis* Morganella morganii Neisseria gonorrhoeae* Proteus mirabilis* Proteus vulgaris Serratia marcescens 10 - 65%

Anaerobes: Bacteroides distasonis Bacteroides fragilis* Bacteroides intermedius Bacteroides ovatus Bacteroides thetaiotaomicron* Clostridium difficile Corynebacterium species* Gardnerella vaginalis* Fusobacterium nucleatum Fusobacterium necroforum Peptococcus niger Peptococcus species

Category with European range of resistance where this is known to vary Peptostreptococcus species* Prevotella intermedia Prevotella oralis Propionibacterium acnes

Other micro-organisms: Chlamydia pneumoniae* Chlamydia trachomatis* Mycoplasma hominis Mycoplasma pneumoniae* Ureaplasma urealyticum

Intermediate (in vitro moderately susceptible) Gram-positive aerobes: Staphylococcus epidermidis* including methicillin-resistant

Gram-negative aerobes: Stenotrophomonas (Xanthomonas) maltophilia Providencia stuartii Pseudomonas aeruginosa* 10 - 40% Anaerobes: Bacteroides uniformis Bacteroides vulgatus Prevotella bivia Prevotella melaninogenica

Resistant Gram-positive aerobes: Methicillin-resistant Staphylococcus aureus Gram-negative aerobes: Acinetobacter baumanii Alcaligenes xylosoxidans spp. denitrificans Burkholderia cepacia

Other micro-organisms:

Mycobacterium tuberculosis Mycobacterium avium complex

* Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical indications.

Resistance In vitro studies indicate that resistance to trovafloxacin develops slowly by multiple step mutations. Resistance to trovafloxacin in vitro occurs at a general frequency of between 1x10-7 and 1x10-9. The mode of action differs from other classes of antibacterial agents such as penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines. There is no cross-resistance between trovafloxacin and these agents. Cross resistance among quinolones, with Gram negative organisms is likely. Some Gram positive and anaerobic micro-organisms resistant to other quinolones may be sensitive to trovafloxacin. As with all antibiotic therapy, the empirical selection of antibacterial therapy should include consideration of epidemiological data on resistance patterns for potential pathogens.

5.2 Pharmacokinetic properties

Absorption Alatrofloxacin is rapidly hydrolysed to trovafloxacin in plasma following intravenous infusion. Patients may be switched from parenteral to oral therapy when clinically appropriate. Trovafloxacin is well absorbed from the gastro-intestinal tract after oral administration. The absolute bioavailability is approximately 88%. Absorption is not affected by food. Serum concentrations increase proportionately with dose and the elimination half-life is approximately 11 hours. Maximum serum concentrations following oral administration are achieved after 1 - 2 hours. Steady-state concentrations are achieved by the third daily dose.

Plasma concentrations associated with doses of trovafloxacin: Dose Route of Peak concentration Peak concentration Trough (mg) Administration (single dose) (multiple dose) concentration (mg/l) (mg/l) (24 hours) (mg/l) 100 oral 1.0 1.1 0.2 200 oral 2.1 3.1 0.5 200 iv 2.7 3.1 0.6 300 iv 3.6 4.4 0.8

Distribution Trovafloxacin is widely distributed throughout the body. Rapid distribution of trovafloxacin into tissues results in higher concentrations in most target tissues than in plasma or serum. Tissue to serum concentration ratios ranged from approximately 0.5 to 1 in intestinal and uterine tissues, in skin, bone and kidney the ratio was in the range from 1 to 2. Concentrations in the liver were approximately 5 times those observed in serum. Studies of penetration in lung tissue indicated that tissue to serum ratios were greater than 2 and accumulation in bronchio-alveolar macrophages provided concentrations approximately 20 times that observed in serum. Ratios of concentrations in body fluids to serum were 0.25 for cerebrospinal fluid, 0.4 for peritoneal fluid, 1.8 for vaginal fluid and 14.9 for bile. Plasma protein binding is approximately 76%.

Metabolism Alatrofloxacin is rapidly hydrolysed to trovafloxacin in plasma. Trovafloxacin is metabolised by conjugation. 2.5 % of the dose is found in the serum in the form of the microbiologically active N-acetyl metabolite.

Elimination Approximately 50% of a dose is excreted unchanged (43 % in the faeces and 6% in the urine) with another 13% appearing in the urine in the form of the ester glucuronide and 9% appearing in the faeces as the N-acetyl metabolite. Other minor metabolites (diacid, sulphate, hydroxycarboxylic acid) have been identified in both urine and faeces. In patients with mild or moderate hepatic impairment, AUC values of trovafloxacin are increased compared to those in healthy volunteers. In patients with moderate hepatic impairment, the AUC after multiple dosing with trovafloxacin is increased by approximately 50%; however, the peak concentration is not affected. No pharmacokinetic data are available in patients with severe hepatic insufficiency. The pharmacokinetics of trovafloxacin are not affected by mild to moderate renal impairment. Trovafloxacin serum concentrations are not significantly altered in subjects with severe renal insufficiency (creatinine clearance < 20 ml/min). In patients on haemodialysis, maximal plasma concentrations were lower, but AUC was comparable to that in healthy volunteers.

5.3 Preclinical safety data

Acute and Repeated Dose Studies: Preclinical findings were associated with class effects of quinolones e.g. arthropathy, testicular degeneration, CNS effects and skeletal malformations in foetuses. Furthermore, anaemia was observed in rats.

Reproductive Function Studies: Studies with trovafloxacin orally did not demonstrate any teratogenic effect at oral doses of up to 75 mg/kg in rats and 45 mg/kg in rabbits. Studies using the prodrug given intravenously achieved much higher foetal exposure, in rats and rabbits given intravenous doses of 20 and 50 mg/kg/day skeletal malformations were observed. These findings are consistent with the known effects of quinolones on skeletal development. (see Section 4.6) Fetotoxicity (e.g. increased mortality and decreased body weight) was evident in a pre- and post-natal development test.

Mutagenicity: Four in vitro and one in vivo mutagenicity tests have been conducted with both trovafloxacin and alatrofloxacin. The results of these studies did not indicate any mutagenic potential.

Carcinogenicity: No studies have been conducted in animals to determine the carcinogenic potential of trovafloxacin or alatrofloxacin.

Other studies:

12 Alatrofloxacin produces a hypersensitivity reaction in an animal model. Trovafloxacin did not show any antigenic potential in the same animal model. Following intravenous infusion alatrofloxacin is rapidly converted to trovafloxacin.

6. Pharmaceutical Particulars

6.1 List of excipients

TROVAN IV Concentrate for Solution for Infusion: Hydrochloric acid and/or Sodium hydroxide q.s. for pH 3.6 - 3.9, Water for Injections

6.2 Incompatibilities

6.3 Shelf life

18 months When the dilution of TROVAN IV Concentrate for Solution for Infusion does take place under aseptic conditions, the shelf life of the diluted product is: 24 hours at 2 - 8°C, or 24 hours at 15 - 25°C.

6.4 Special precautions for storage

Store below 30°C. Do not freeze. Sensitive to light. Keep vials in original packaging until use. After dilution the solution should be protected from exposure to light.

6.5 Nature and contents of container

Neutral glass vials containing 20 ml of concentrate for solution for infusion. The vials are sealed with butyl teflon-faced stoppers and aluminium overseals with polypropylene flip-off button.

6.6 Instructions for use and handling, and disposal (if appropriate)

TROVAN IV Concentrate for Solution for Infusion is supplied in single-use vials containing a concentrated solution of alatrofloxacin mesylate in Water for Injections (equivalent to 100 mg trovafloxacin). Each ml contains alatrofloxacin mesylate equivalent to 5 mg trovafloxacin. The solution should be visually inspected before use, only clear solution without visual particles should be used. Any unused solution should be discarded. The concentrate should be diluted to 1 - 2 mg/ml in a suitable diluent - see Section 4.2 and given by slow intravenous infusion over a period of 60 minutes. This concentrate for solution for infusion must not be administered by bolus injection. This concentrate for solution for infusion can be diluted only with 5% Dextrose Injection 0.45% Sodium Chloride Injection 5% Dextrose and 0.45% Sodium Chloride Injection 5% Dextrose and 0.2% Sodium Chloride Injection Lactated Ringer’s and 5% Dextrose Injection

Normal saline, 0.9% Sodium Chloride Injection can be used for flushing I.V. lines prior to or after administration of TROVAN IV.

7. Marketing Authorisation Holder

Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom

8. Number(s) in the Community Register of Medicinal Products

EU/1/98/060/001

9. Date of First Authorisation/Renewal of Authorisation

03 July 1998

10. Date of Revision of the Text

15 1. Name of the Medicinal Product

TROVAN IV 5mg/ml Concentrate for Solution for Infusion Trovofloxacin (as alatrofloxacin mesylate).

2. Qualitative and Quantitative Composition

40 ml of concentrate for solution for infusion containing 314.5 mg alatrofloxacin mesylate corresponding to 200 mg trovafloxacin. Alatrofloxacin is the bis-alanine derivative prodrug of the active moiety trovafloxacin.

3. Pharmaceutical Form

Concentrate for Solution for Infusion

4. Clinical Particulars

4.1 Therapeutic indications

Note: Efficacy in patients with very severe nosocomial pneumonia and in particular infections due to less susceptible pathogens e.g. P. Aeruginosa has not been established. See also section 4.2.

• Complicated Intra-abdominal Infections and Acute Pelvic Infections • Complicated Skin and Soft Tissue Infections

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Detailed information on recommended dosage for indicated infections is given in the following table:

In the Elderly: No adjustment in dosage is necessary.

Impaired Renal Function: No adjustment in dosage is necessary.

17 Lactated Ringer’s and 5% Dextrose Injection

4.3 Contra-indications

4.4 Special warnings and special precautions for use

18 • The safety of trovafloxacin has only been established for the recommended dosage regimens. Prolonged use or treatment with higher doses may be associated with higher incidences of undesirable effects. In a comparative study where oral trovafloxacin was administered for 28 days, a higher incidence of liver enzyme elevations was noted on trovafloxacin. These abnormalities mostly resolved during the 10 week follow-up after the medicinal product was discontinued. • Liver failure and pancreatitis have been reported very rarely. Patients developing symptoms consistent with hepatitis and/or pancreatitis should discontinue treatment immediately and should be monitored appropriately. • Allergic reactions including anaphylaxis have been reported very rarely with trovafloxacin. In the event of an allergic reaction, treatment with trovafloxacin should be discontinued immediately and adequate supportive procedures initiated.(See section 4.8)

4.5 Interaction with other medicaments and other forms of interaction

The absence of significant interactions has been demonstrated with the following: theophylline, warfarin, digoxin, omeprazole, cimetidine and cyclosporin.

4.6 Pregnancy and lactation

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

In multiple dose clinical studies the following undesirable events with possible, probable or unknown relationship to trovafloxacin were observed:

Post Marketing Experience: During the post-marketing period the following undesirable effects, not included in the above list, were reported:

HYPERSENSITIVITY AND SKIN Very rare anaphylaxis, Stevens-Johnson syndrome HEPATOBILIARY Very rare hepatitis, liver failure ( including acute hepatic necrosis) DIGESTIVE Very rare pancreatitis

4.9 Overdose

5. Pharmacological Properties

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Antibacterial Agent fluoroquinolone ATC Code: J01M A

Mechanism of action:

20 Trovafloxacin has in vitro activity and clinical efficacy against a wide range of Gram- negative and Gram-positive organisms, aerobes, anaerobes and atypical micro- organisms at concentrations achieved in serum following administration of the recommended doses. The mode of action results from the interference with the enzyme DNA gyrase, an essential enzyme involved in the replication, transcription and repair to bacterial DNA, and with Topoisomerase IV, an enzyme known to affect the partitioning of the bacterial chromosome. The minimum bactericidal concentrations (MBC) are generally similar to the minimum inhibitory concentration (MIC) and the ratio of MBC:MIC does not usually exceed 2. In vitro studies have shown additive effects when trovafloxacin is combined with other antibacterial agents such as beta-lactams, aminoglycosides, clindamycin, vancomycin, or metronidazole. Synergy with beta-lactams (ceftazidime, ampicillin/sulbactam or imipenem), gentamicin or amikacin has only been reported to occur with a few strains of enterococci and Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.

Category with European range of resistance where this is known to vary Susceptible Gram-positive aerobes: Corynebacterium jeikeium Enterococcus faecalis* 15 - 40% Enterococcus faecium 15 - 40% Staphylococcus aureus* - methicillin susceptible Staphylococcus haemolyticus* Staphylococcus hominis* Staphylococcus saprophyticus Staphylococcus simulans* Streptococcus agalactiae* Streptococcus anginosus* Streptococcus equisimilis* Streptococcus pneumoniae* Streptococcus pyogenes* Streptococcus viridans* Gram-negative aerobes: Acinetobacter calcoaceticus subs. anitratus Acinetobacter lwoffi Bordetella bronchiseptica Citrobacter freundii Enterobacter aerogenes Enterobacter agglomerans Enterobacter cloacae* 0 - 20% Escherichia coli* 0 - 20% Haemophilus influenzae* Haemophilus parainfluenzae* Klebsiella oxytoca* Klebsiella pneumoniae* 0 - 15% Legionella pneumophila* Moraxella catarrhalis* Morganella morganii Neisseria gonorrhoeae* Proteus mirabilis* Proteus vulgaris Serratia marcescens 10 - 65% Anaerobes: Bacteroides distasonis Bacteroides fragilis* Bacteroides intermedius Bacteroides ovatus Bacteroides

23 thetaiotaomicron* Clostridium difficile Corynebacterium species* Gardnerella vaginalis* Fusobacterium nucleatum Fusobacterium necroforum Peptococcus niger Peptococcus species

Category with European range of resistance where this is known to vary Peptostreptococcus species* Prevotella intermedia Prevotella oralis Propionibacterium acnes Other micro-organisms: Chlamydia pneumoniae* Chlamydia trachomatis* Mycoplasma hominis Mycoplasma pneumoniae* Ureaplasma urealyticum Intermediate (in vitro moderately susceptible) Gram-positive aerobes: Staphylococcus epidermidis* including methicillin-resistant Gram-negative aerobes: Stenotrophomonas (Xanthomonas) maltophilia Providencia stuartii Pseudomonas aeruginosa* 10 - 40% Anaerobes: Bacteroides uniformis Bacteroides vulgatus Prevotella bivia Prevotella melaninogenica Resistant Gram-positive aerobes: Methicillin-resistant Staphylococcus aureus Gram-negative aerobes: Acinetobacter baumanii Alcaligenes xylosoxidans spp. denitrificans Burkholderia cepacia

Other micro-organisms:

Mycobacterium tuberculosis Mycobacterium avium complex

* Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical indications.

5.2 Pharmacokinetic properties

5.3 Preclinical safety data

Mutagenicity: Four in vitro and one in vivo mutagenicity tests have been conducted with both trovafloxacin and alatrofloxacin. The results of these studies did not indicate any mutagenic potential.

Carcinogenicity: No studies have been conducted in animals to determine the carcinogenic potential of trovafloxacin or alatrofloxacin.

Other studies:

27 Alatrofloxacin produces a hypersensitivity reaction in an animal model. Trovafloxacin did not show any antigenic potential in the same animal model. Following intravenous infusion alatrofloxacin is rapidly converted to trovafloxacin.

6. Pharmaceutical Particulars

6.1 List of excipients

TROVAN IV Concentrate for Solution for Infusion: Hydrochloric acid and/or Sodium hydroxide q.s. for pH 3.6 - 3.9, Water for Injections

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

Store below 30°C. Do not freeze. Sensitive to light. Keep vials in original packaging until use. After dilution the solution should be protected from exposure to light.

6.5 Nature and contents of container

Neutral glass vials containing 40 ml of concentrate for solution for infusion. The vials are sealed with butyl teflon-faced stoppers and aluminium overseals with polypropylene flip-off button.

6.6 Instructions for use and handling, and disposal (if appropriate)

Normal saline, 0.9% Sodium Chloride Injection can be used for flushing I.V. lines prior to or after administration of TROVAN IV.

7. Marketing Authorisation Holder

Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom

8. Number(s) in the Community Register of Medicinal Products

EU/1/98/060/002

9. Date of First Authorisation/Renewal of Authorisation

03 July 1998

10. Date of Revision of the Text

30 1. Name of the Medicinal Product

TROVAN IV 5mg/ml. Concentrate for Solution for Infusion Trovofloxacin (as alatrofloxacin mesylate).

2. Qualitative and Quantitative Composition

60 ml of concentrate for solution for infusion containing 471.7 mg alatrofloxacin mesylate corresponding to 300 mg trovafloxacin. Alatrofloxacin is the bis-alanine derivative prodrug of the active moiety trovafloxacin.

3. Pharmaceutical Form

Concentrate for Solution for Infusion

4. Clinical Particulars

4.1 Therapeutic indications

Note: Efficacy in patients with very severe nosocomial pneumonia and in particular infections due to less susceptible pathogens e.g. P. Aeruginosa has not been established. See also section 4.2.

• Complicated Intra-abdominal Infections and Acute Pelvic Infections • Complicated Skin and Soft Tissue Infections

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Detailed information on recommended dosage for indicated infections is given in the following table:

In the Elderly: No adjustment in dosage is necessary.

Impaired Renal Function: No adjustment in dosage is necessary.

32 Lactated Ringer’s and 5% Dextrose Injection

4.3 Contra-indications

4.4 Special warnings and special precautions for use

33 • The safety of trovafloxacin has only been established for the recommended dosage regimens.Prolonged use or treatment with higher doses may be associated with higher incidences of undesirable effects. In a comparative study where oral trovafloxacin was administered for 28 days, a higher incidence of liver enzyme elevations was noted on trovafloxacin. These abnormalities mostly resolved during the 10 week follow-up after the medicinal product was discontinued. • Liver failure and pancreatitis have been reported very rarely. Patients developing symptoms consistent with hepatitis and/or pancreatitis should discontinue treatment immediately and should be monitored appropriately. • Allergic reactions including anaphylaxis have been reported very rarely with trovafloxacin. In the event of an allergic reaction, treatment with trovafloxacin should be discontinued immediately and adequate supportive procedures initiated.(See section 4.8)

4.5 Interaction with other medicaments and other forms of interaction

The absence of significant interactions has been demonstrated with the following: theophylline, warfarin, digoxin, omeprazole, cimetidine and cyclosporin.

4.6 Pregnancy and lactation

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

In multiple dose clinical studies the following undesirable events with possible, probable or unknown relationship to trovafloxacin were observed:

Post Marketing Experience: During the post-marketing period the following undesirable effects, not included in the above list, were reported:

HYPERSENSITIVITY AND SKIN Very rare anaphylaxis, Stevens-Johnson syndrome HEPATOBILIARY Very rare hepatitis, liver failure ( including acute hepatic necrosis) DIGESTIVE Very rare pancreatitis

4.9 Overdose

5. Pharmacological Properties

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Antibacterial Agent fluoroquinolone ATC Code: J01M A

Mechanism of action:

35 Trovafloxacin has in vitro activity and clinical efficacy against a wide range of Gram- negative and Gram-positive organisms, aerobes, anaerobes and atypical micro- organisms at concentrations achieved in serum following administration of the recommended doses. The mode of action results from the interference with the enzyme DNA gyrase, an essential enzyme involved in the replication, transcription and repair to bacterial DNA, and with Topoisomerase IV, an enzyme known to affect the partitioning of the bacterial chromosome. The minimum bactericidal concentrations (MBC) are generally similar to the minimum inhibitory concentration (MIC) and the ratio of MBC:MIC does not usually exceed 2. In vitro studies have shown additive effects when trovafloxacin is combined with other antibacterial agents such as beta-lactams, aminoglycosides, clindamycin, vancomycin, or metronidazole. Synergy with beta-lactams (ceftazidime, ampicillin/sulbactam or imipenem), gentamicin or amikacin has only been reported to occur with a few strains of enterococci and Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.

38 thetaiotaomicron* Clostridium difficile Corynebacterium species* Gardnerella vaginalis* Fusobacterium nucleatum Fusobacterium necroforum Peptococcus niger Peptococcus species

Other micro-organisms:

Mycobacterium tuberculosis Mycobacterium avium complex

* Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical indications.

5.2 Pharmacokinetic properties

5.3 Preclinical safety data

Mutagenicity: Four in vitro and one in vivo mutagenicity tests have been conducted with both trovafloxacin and alatrofloxacin. The results of these studies did not indicate any mutagenic potential.

Carcinogenicity: No studies have been conducted in animals to determine the carcinogenic potential of trovafloxacin or alatrofloxacin.

Other studies:

42 Alatrofloxacin produces a hypersensitivity reaction in an animal model. Trovafloxacin did not show any antigenic potential in the same animal model. Following intravenous infusion alatrofloxacin is rapidly converted to trovafloxacin.

6. Pharmaceutical Particulars

6.1 List of excipients

TROVAN IV Concentrate for Solution for Infusion: Hydrochloric acid and/or Sodium hydroxide q.s. for pH 3.6 - 3.9, Water for Injections

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

Store below 30°C. Do not freeze. Sensitive to light. Keep vials in original packaging until use. After dilution the solution should be protected from exposure to light.

6.5 Nature and contents of container

Neutral glass vials containing 60 ml of concentrate for solution for infusion. The vials are sealed with butyl teflon-faced stoppers and aluminium overseals with polypropylene flip-off button.

6.6 Instructions for use and handling, and disposal (if appropriate)

Normal saline, 0.9% Sodium Chloride Injection can be used for flushing I.V. lines prior to or after administration of TROVAN IV.

7. Marketing Authorisation Holder

Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom

8. Number(s) in the Community Register of Medicinal Products

EU/1/98/060/003

9. Date of First Authorisation/Renewal of Authorisation

03 July 1998

10. Date of Revision of the Text

ANNEX III B LABELLING AND PACKAGE LEAFLET

B. PACKAGE LEAFLET

47 USER PACKAGE LEAFLET

Please read this leaflet carefully !

This leaflet contains a summary of important information about TROVAN IV Concentrate for Solution for Infusion. Please read it carefully. You should keep this leaflet, as you may want to read it again.

If you do not understand or you have more questions, please ask your doctor or pharmacist.

1- NAME OF THE MEDICINAL PRODUCT

TROVAN IV 5mg/ml Concentrate for Solution for Infusion. Trovafloxacin (as alatrofloxacin mesylate).

2- FULL STATEMENT OF THE ACTIVE SUBSTANCES & EXCIPIENTS

What does TROVAN IV contain ?

Active Substance:

20ml of the concentrate for solution for infusion, contains 157.2mg of alatrofloxacin mesylate corresponding to 100mg of trovafloxacin.

Other Excipients :

Water for Injections, Sodium hydroxide, Hydrochloric acid

3- PHARMACEUTICAL FORM AND CONTENTS.

TROVAN IV 5mg/ml Concentrate for Solution for Infusion is presented in vials containing : 20ml

4- PHARMACO-THERAPEUTIC GROUP.

What is TROVAN IV Concentrate for Solution for Infusion ?

This is one of a group of medicines called quinolone antibiotics. It is a ‘broad- spectrum’ antibiotic. This means that it kills a wide variety of the bacteria or “germs” which cause infections.

5- NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AND OF THE MANUFACTURING AUTHORISATION HOLDER.

48 Marketing Authorisation Manufacturing Authorisation Holder : Holder : Pfizer Limited Pfizer S.A., Ramsgate Rd., Zone Industrielle de Poce-sur-Cisse Sandwich B.P. 109, 37401 Amboise Cedex Kent CT13 9NJ France United Kingdom

6- THERAPEUTIC INDICATIONS

Why are you being treated with TROVAN IV Concentrate for Solution for Infusion ?

TROVAN IV Concentrate for Solution for Infusion is used in Adults for bacterial infections:

• Pneumonia (chest infections) • Abdominal and pelvic infections • Severe skin and Skin structure infections

This product has been prescribed for you personally and you should not pass it on to others.

7- LIST OF INFORMATION NECESSARY BEFORE RECEIVING THE MEDICINAL PRODUCT.

CONTRA-INDICATIONS

When should you NOT receive TROVAN IV Concentrate for Solution for Infusion ?

• You should not receive TROVAN IV Concentrate for Solution for Infusion if you are allergic to alatrofloxacin / trovafloxacin or any other quinolone antibiotic. If in doubt, talk to your doctor or pharmacist. • TROVAN IV Concentrate for Solution for Infusion should not be given if you are pregnant, or are planning to become pregnant. • TROVAN IV Concentrate for Solution for Infusion should not be given if you are breast-feeding. • TROVAN IV Concentrate for Solution for Infusion should not be given if you have a history of tendon disease with other quinolone antibiotics. • TROVAN IV Concentrate for Solution for Infusion should not be given if you have severe impairment of liver function. • TROVAN IV Concentrate for Solution for Infusion should not be given if you have glucose-6-phosphate dehydrogenase deficiency (a rare hereditary disease). • TROVAN IV Concentrate for Solution for Infusion is intended for treatment of adults and should not be given to children or growing adolescents.

PRECAUTIONS FOR USE

When should TROVAN IV Concentrate for Solution for Infusion be used with caution?

If you have ever suffered from a psychiatric disorder, convulsions (epilepsy) or any other brain or spinal cord disease, you should tell your doctor before receiving TROVAN IV Concentrate for Solution for Infusion.

TROVAN IV Concentrate for Solution for Infusion should be used with caution in patients with granulocytopenia (blood cell disorder).

What should be taken into consideration for children ?

TROVAN IV Concentrate for Solution for Infusion is not recommended for use in children and growing adolescents.

What should be taken into consideration for elderly patients ?

No special changes in dose are required for elderly patients.

What should be taken into consideration in patients with kidney problems ?

No special changes in dose are required.

What should be taken into consideration in patients with liver problems ?

No special changes in dose or duration of treatment are necessary in patients with mild liver problems. In moderate liver impairment elimination of trovafloxacin by the liver may be reduced resulting in increased exposure, this should be considered when treating such patients.

DRIVING AND USING MACHINES

Can I drive after receiving TROVAN IV Concentrate for Solution for Infusion ?

If you feel dizzy or light-headed after receiving TROVAN IV Concentrate for Solution for Infusion, you should not drive or operate machinery.

SPECIAL WARNINGS

Rapid infusion of quinolones, including TROVAN IV Concentrate for Solution for Infusion, (less than 30 minutes) can cause seizures in human subjects and consequently TROVAN IV Concentrate for Infusion must be diluted before use and should be administered by slow intravenous infusion over a period of 60 minutes.

This medicine may make your skin more sensitive to sunlight or UV light than it is normally. You should cover-up when out in strong sunlight and should not use a sun- bed or other means of UV exposure whilst taking the medicine.

In the event of skin rash or other possible signs of allergic reaction you should stop taking the medication and check with your doctor immediately.

Occasionally, medicines of this type (quinolone antibiotics) cause tendon pain. If inflammation or pain on movement develops, which affects your feet or limbs, you should stop taking this medicine, rest the affected limb and inform your doctor immediately.

Occasionally, antibiotics may cause severe diarrhoea. If you develop diarrhoea after taking this medicine, you should check with your doctor immediately.

Very rarely inflammation of the liver or pancreas has been seen in patients receiving TROVAN IV. If you develop symptoms such as yellowing of the skin and eyes or severe upper stomach pain with nausea and vomiting, you should stop taking this medication and see your doctor immediately.

You should be aware of the potential for trovafloxacin to cause dizziness or lightheadedness.

INTERACTIONS

52 Can TROVAN IV Concentrate for Solution for Infusion be taken with other medicines?

The absence of significant interactions has been demonstrated with the following: theophylline, warfarin, digoxin, omeprazole, cimetidine and cyclosporin. You should tell your doctor about all the medicines which you are taking.

53 8- INSTRUCTIONS FOR PROPER USE

Adult Dosage

Your Doctor will decide how much TROVAN IV Concentrate for Solution for Infusion you should receive.

The following table shows the most common adult doses and length of treatment used for different infections :

Infection Dose Pneumonia (Chest infections) : Your doctor will either give you one 200mg tablet or you will receive 200mg of TROVAN IV Concentrate for Solution for Infusion, followed by one 200mg tablet, once each day for mild to moderate infections. For more severe infections, you may get an initial dose of 300mg TROVAN IV. Pneumonia (Chest infections) Your doctor will give you 300mg of caught in hospital : TROVAN IV Concentrate for Solution for Infusion each day, then when your condition improves, 200mg (i.v. or in tablet form) once each day. Abdominal & Pelvic infections : Your doctor will give you 300mg of TROVAN IV Concentrate for Solution for Infusion each day, then when your condition improves, 200mg (IV or in tablet form) once each day. Severe Skin infections : Your doctor will give you 200mg of TROVAN IV Concentrate for Solution for Infusion or a 200mg TROVAN tablet, then when your condition improves, you will be given a 200mg tablet once each day.

The severity of your infection determines the length of time which you have to take TROVAN IV Concentrate for Solution for Infusion and is usually between 7 and 14 days.

Use in children:

TROVAN IV Concentrate for Solution for Infusion is not recommended for use in children and growing adolescents.

Method of Preparation & Administration

Preparation :

54 • Aseptic technique must be used in the preparation of the final intravenous solution as no preservative or bacteriostatic agent is present in this product. • Each TROVAN IV Concentrate for Solution for Infusion vial must be further diluted with an appropriate solution, prior to intravenous administration (see compatibility & stability section). • As the vials are for single use only, any unused portion of the solution should be discarded. • Prior to dilution & administration, carefully inspect the vial visually for particles and discoloration.

Administration :

• Withdraw the appropriate volume of concentrate from the vials of TROVAN IV Concentrate for Solution for Infusion. • Dilute with a suitable intravenous solution to a final concentration of 1 - 2 mg/ml (see compatibility & stability section). • Infuse the resulting solution over a period of 60 minutes by either direct infusion or through a Y - type intravenous infusion set, which may already be in place. • The required dosage of TROVAN IV Concentrate for Solution for Infusion should be prepared according to the following chart :

Dosage Strength (mg) Volume to Diluent Volume Total Volume Infusion (trovafloxacin withdraw (ml) (ml) Concentration equivalent) (ml) (mg/ml) 50mg 10 15 25 2 50mg 10 40 50 1 100mg 20 30 50 2 100mg 20 80 100 1 200mg 40 60 100 2 200mg 40 160 200 1 300mg 60 90 150 2 300mg 60 240 300 1

Sample Calculation :

To prepare a 200mg dose at an infusion concentration of 2mg/ml (as trovafloxacin), withdraw 40ml of TROVAN IV Concentrate for Solution for Infusion from a vial and dilute with 60ml of a compatible intravenous fluid, to produce a total infusion solution volume of 100ml.

Compatibility & Stability :

• Additives or other medication should not be added to TROVAN IV Concentrate for Solution for Infusion in single dose vials or infused simultaneously through the same intravenous line. • If the same intravenous line is to be used for further sequential infusion of other drugs, the line should be flushed before and after infusion of TROVAN IV Concentrate for Solution for Infusion with a compatible infusion solution.

55 Normal saline (0.9% Sodium Chloride injection) can be used for flushing I.V. lines prior to or after administration of TROVAN IV.

• If TROVAN IV Concentrate for Solution for Infusion is to be given at the same time as another drug, each drug should be given separately, according to the recommended dosage and route of administration.

The following list of intravenous fluids are physically and chemically compatible with TROVAN IV Concentrate for Solution for Infusion at concentrations of 1 to 2 mg/ml for at least 24 hours when refrigerated, or 24 hours when stored at 15 - 25oC, when prepared aseptically. Solutions may be stored in glass or plastic (PVC) intravenous containers :

5% Dextrose Injection, 0.45% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, 5% Dextrose and 0.2% Sodium Chloride Injection, Lactated Ringer’s and 5% Dextrose Injection,

Normal Saline (0.9% Sodium Chloride Injection) SHOULD NOT be used as a diluent. TROVAN IV should not be diluted with 0.9% Sodium Chloride Injection, (normal saline) , alone or in combination with other diluents. A precipitate may form under these conditions. In addition TROVAN IV should not be diluted with Lactated Ringers.

How quickly will TROVAN IV Concentrate for Solution for Infusion start to work ?

Depending on the severity of the infection, you should start to feel better within a few days.

What if I do not feel better ?

If your infection gets worse, or you do not start to feel better within a few days, or a new infection develops, tell your doctor.

9- DESCRIPTION OF UNDESIRABLE EFFECTS UNDER NORMAL USE

Does TROVAN IV Concentrate for Solution for Infusion cause any undesirable effects?

TROVAN IV Concentrate for Solution for Infusion may cause some undesirable effects :

• Intravenous site reactions • Nausea • Dizziness or light-headedness (usually mild and wears off with treatment ) • Headache • Vomiting

56 • Rash • Diarrhoea • Pruritus

If any of these undesirable effects are troublesome, severe, or do not wear off as treatment goes on, tell your doctor.

If you notice any other undesirable effects which are not mentioned in this leaflet, please inform your doctor or pharmacist.

10- STORAGE PRECAUTIONS

• Do NOT take this medicine after the expiry date shown on the pack. • Store TROVAN IV Concentrate for Solution for Infusion below 30 oC. • Do not freeze • Sensitive to light • Keep vials in original packaging until use • After dilution the solution should be protected from exposure to light • After dilution, discard any unused solution

As with all medicines, keep TROVAN IV Concentrate for Solution for Infusion out of the reach of children

11- DATE ON WHICH THE PACKAGE LEAFLET WAS LAST REVISED

57 12- OTHER INFORMATION

The information in this leaflet is about TROVAN IV Concentrate for Solution for Infusion only. For further information on TROVAN tablets, please see the Summary of Product Characteristics or User Package Leaflet for this product.

• If you have any further questions please consult your doctor or pharmacist • For any other information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

Belgique / België /Belgien Danmark Deutschland Pfizer S.A. Pfizer A/S Pfizer GmbH Rue Léon Theodor 102 Lautrupvang 8 Pfizerstraße 1 B-1090 Bruxelles / Brussel DK-2750 Ballerup D-76139 Karlsruhe +32 (0)2 421 15 11 +45 36 38 05 05 +49 (0)721 61 01 01

España France Ελλάδα Pfizer S.A. Pfizer S.A. Pfizer Hellas A.E. Avenida de Europa 20-B 86, rue de Paris Οδός Αλκέτου 5 Park Empresarial La Moraleja F-91407 Orsay Cedex GR-116 33 Αθήνα E-28108 Alcobendas (Madrid) +34 (91) 490 97 79 +33 (0)1 69 18 66 66 +30 (0)1 7517981

Italia Republic of Ireland Luxembourg Pfizer Italiana S.p.A. Pfizer (Ireland) Limited Pfizer S.A. Via Valbondione, 113 Parkway House Rue Léon Theodor 102 Ballymount Road Lower I-00188 Roma IRL-Dublin 12 B-1090 Bruxelles/Brussel Belgique +39 (0)6 33 18 21 +353 1800 633 363 +32 (0)2 421 15 11

Nederland Österreich Portugal Pfizer BV Pfizer Corporation Austria Laboratórios Pfizer, Lda. Postbus 37 Ges.m.b.H. Apartado 30 NL-2900 AA Capelle aan den Seidengasse 33-35 P-2830 Coina IJssel A-1070 Wien +31 (0)10 406 42 00 +43 (0)1 521 15-0 +351 (0)1 227 8200

Suomi / Finland Sverige United Kingdom Pfizer Oy Pfizer AB Pfizer Limited Lars Sonckin kaari 4 Box 501 Ramsgate Rd FI-02600 Espoo SE-183 25 TÄBY Sandwich, Kent GB-CT13 9NJ +358 (0)9 43 00 40 +46 (0)8 519 062 00 +44 (0)1304 61 61 61

58 USER PACKAGE LEAFLET

Please read this leaflet carefully !

If you do not understand or you have more questions, please ask your doctor or pharmacist.

1- NAME OF THE MEDICINAL PRODUCT

TROVAN IV 5mg/ml Concentrate for Solution for Infusion. Trovafloxacin (as alatrofloxacin mesylate)

2- FULL STATEMENT OF THE ACTIVE SUBSTANCES & EXCIPIENTS

What does TROVAN IV contain ?

Active Substance:

40ml of the concentrate for solution for infusion, contains 314.5mg of alatrofloxacin mesylate corresponding to 200mg of trovafloxacin.

Other Excipients :

Water for Injections, Sodium hydroxide, Hydrochloric acid

3- PHARMACEUTICAL FORM AND CONTENTS.

TROVAN IV 5mg/ml Concentrate for Solution for Infusion is presented in vials containing : 40ml

4- PHARMACO-THERAPEUTIC GROUP.

What is TROVAN IV Concentrate for Solution for Infusion ?

5- NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AND OF THE MANUFACTURING AUTHORISATION HOLDER.

59 Marketing Authorisation Manufacturing Authorisation Holder : Holder : Pfizer Limited Pfizer S.A., Ramsgate Rd., Zone Industrielle de Poce-sur-Cisse Sandwich B.P. 109, 37401 Amboise Cedex Kent CT13 9NJ France United Kingdom

6- THERAPEUTIC INDICATIONS

Why are you being treated with TROVAN IV Concentrate for Solution for Infusion ?

TROVAN IV Concentrate for Solution for Infusion is used in Adults for bacterial infections:

• Pneumonia (chest infections) • Abdominal and pelvic infections • Severe skin and Skin structure infections

This product has been prescribed for you personally and you should not pass it on to others.

7- LIST OF INFORMATION NECESSARY BEFORE RECEIVING THE MEDICINAL PRODUCT.

CONTRA-INDICATIONS

When should you NOT receive TROVAN IV Concentrate for Solution for Infusion ?

PRECAUTIONS FOR USE

When should TROVAN IV Concentrate for Solution for Infusion be used with caution?

TROVAN IV Concentrate for Solution for Infusion should be used with caution in patients with granulocytopenia (blood cell disorder).

What should be taken into consideration for children ?

TROVAN IV Concentrate for Solution for Infusion is not recommended for use in children and growing adolescents.

What should be taken into consideration for elderly patients ?

No special changes in dose are required for elderly patients.

What should be taken into consideration in patients with kidney problems ?

No special changes in dose are required.

What should be taken into consideration in patients with liver problems ?

DRIVING AND USING MACHINES

Can I drive after receiving TROVAN IV Concentrate for Solution for Infusion ?

If you feel dizzy or light-headed after receiving TROVAN IV Concentrate for Solution for Infusion, you should not drive or operate machinery.

SPECIAL WARNINGS

In the event of skin rash or other possible signs of allergic reaction you should stop taking the medication and check with your doctor immediately.

Occasionally, antibiotics may cause severe diarrhoea. If you develop diarrhoea after taking this medicine, you should check with your doctor immediately.

You should be aware of the potential for trovafloxacin to cause dizziness or lightheadedness.

INTERACTIONS

63 Can TROVAN IV Concentrate for Solution for Infusion be taken with other medicines?

64 8- INSTRUCTIONS FOR PROPER USE

Adult Dosage

Your Doctor will decide how much TROVAN IV Concentrate for Solution for Infusion you should receive.

The following table shows the most common adult doses and length of treatment used for different infections :

The severity of your infection determines the length of time which you have to take TROVAN IV Concentrate for Solution for Infusion and is usually between 7 and 14 days.

Use in children:

TROVAN IV Concentrate for Solution for Infusion is not recommended for use in children and growing adolescents.

Method of Preparation & Administration

Preparation :

65 • Aseptic technique must be used in the preparation of the final intravenous solution as no preservative or bacteriostatic agent is present in this product. • Each TROVAN IV Concentrate for Solution for Infusion vial must be further diluted with an appropriate solution, prior to intravenous administration (see compatibility & stability section). • As the vials are for single use only, any unused portion of the solution should be discarded. • Prior to dilution & administration, carefully inspect the vial visually for particles and discoloration.

Administration :

Sample Calculation :

Compatibility & Stability :

66 Normal saline (0.9% Sodium Chloride injection) can be used for flushing I.V. lines prior to or after administration of TROVAN IV.

5% Dextrose Injection, 0.45% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, 5% Dextrose and 0.2% Sodium Chloride Injection, Lactated Ringer’s and 5% Dextrose Injection,

How quickly will TROVAN IV Concentrate for Solution for Infusion start to work ?

Depending on the severity of the infection, you should start to feel better within a few days.

What if I do not feel better ?

If your infection gets worse, or you do not start to feel better within a few days, or a new infection develops, tell your doctor.

9- DESCRIPTION OF UNDESIRABLE EFFECTS UNDER NORMAL USE

Does TROVAN IV Concentrate for Solution for Infusion cause any undesirable effects?

TROVAN IV Concentrate for Solution for Infusion may cause some undesirable effects :

• Intravenous site reactions • Nausea • Dizziness or light-headedness (usually mild and wears off with treatment ) • Headache • Vomiting

67 • Rash • Diarrhoea • Pruritus

If any of these undesirable effects are troublesome, severe, or do not wear off as treatment goes on, tell your doctor.

If you notice any other undesirable effects which are not mentioned in this leaflet, please inform your doctor or pharmacist.

10- STORAGE PRECAUTIONS

As with all medicines, keep TROVAN IV Concentrate for Solution for Infusion out of the reach of children

11- DATE ON WHICH THE PACKAGE LEAFLET WAS LAST REVISED

68 12- OTHER INFORMATION

69 USER PACKAGE LEAFLET

Please read this leaflet carefully !

If you do not understand or you have more questions, please ask your doctor or pharmacist.

1- NAME OF THE MEDICINAL PRODUCT

TROVAN IV 5mg/ml Concentrate for Solution for Infusion. Trovafloxacin (as alatrofloxacin mesylate).

2- FULL STATEMENT OF THE ACTIVE SUBSTANCES & EXCIPIENTS

What does TROVAN IV contain ?

Active Substance:

60ml of the concentrate for solution for infusion, contains 471.7mg of alatrofloxacin mesylate corresponding to 300mg of trovafloxacin.

Other Excipients :

Water for Injections, Sodium hydroxide, Hydrochloric acid

3- PHARMACEUTICAL FORM AND CONTENTS.

TROVAN IV 5mg/ml Concentrate for Solution for Infusion is presented in vials containing : 60ml

4- PHARMACO-THERAPEUTIC GROUP.

What is TROVAN IV Concentrate for Solution for Infusion ?

5- NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AND OF THE MANUFACTURING AUTHORISATION HOLDER.

70 Marketing Authorisation Manufacturing Authorisation Holder : Holder : Pfizer Limited Pfizer S.A., Ramsgate Rd., Zone Industrielle de Poce-sur-Cisse Sandwich B.P. 109, 37401 Amboise Cedex Kent CT13 9NJ France United Kingdom

6- THERAPEUTIC INDICATIONS

Why are you being treated with TROVAN IV Concentrate for Solution for Infusion ?

TROVAN IV Concentrate for Solution for Infusion is used in Adults for bacterial infections:

• Pneumonia (chest infections) • Abdominal and pelvic infections • Severe skin and Skin structure infections

This product has been prescribed for you personally and you should not pass it on to others.

7- LIST OF INFORMATION NECESSARY BEFORE RECEIVING THE MEDICINAL PRODUCT.

CONTRA-INDICATIONS

When should you NOT receive TROVAN IV Concentrate for Solution for Infusion ?

PRECAUTIONS FOR USE

When should TROVAN IV Concentrate for Solution for Infusion be used with caution?

TROVAN IV Concentrate for Solution for Infusion should be used with caution in patients with granulocytopenia (blood cell disorder).

What should be taken into consideration for children ?

TROVAN IV Concentrate for Solution for Infusion is not recommended for use in children and growing adolescents.

What should be taken into consideration for elderly patients ?

No special changes in dose are required for elderly patients.

What should be taken into consideration in patients with kidney problems ?

No special changes in dose are required.

What should be taken into consideration in patients with liver problems ?

DRIVING AND USING MACHINES

Can I drive after receiving TROVAN IV Concentrate for Solution for Infusion ?

If you feel dizzy or light-headed after receiving TROVAN IV Concentrate for Solution for Infusion, you should not drive or operate machinery.

SPECIAL WARNINGS

In the event of skin rash or other possible signs of allergic reaction you should stop taking the medication and check with your doctor immediately.

Occasionally, antibiotics may cause severe diarrhoea. If you develop diarrhoea after taking this medicine, you should check with your doctor immediately.

You should be aware of the potential for trovafloxacin to cause dizziness or lightheadedness.

INTERACTIONS

74 Can TROVAN IV Concentrate for Solution for Infusion be taken with other medicines?

75 8- INSTRUCTIONS FOR PROPER USE

Adult Dosage

Your Doctor will decide how much TROVAN IV Concentrate for Solution for Infusion you should receive.

The following table shows the most common adult doses and length of treatment used for different infections :

The severity of your infection determines the length of time which you have to take TROVAN IV Concentrate for Solution for Infusion and is usually between 7 and 14 days.

Use in children:

TROVAN IV Concentrate for Solution for Infusion is not recommended for use in children and growing adolescents.

Method of Preparation & Administration

Preparation :

76 • Aseptic technique must be used in the preparation of the final intravenous solution as no preservative or bacteriostatic agent is present in this product. • Each TROVAN IV Concentrate for Solution for Infusion vial must be further diluted with an appropriate solution, prior to intravenous administration (see compatibility & stability section). • As the vials are for single use only, any unused portion of the solution should be discarded. • Prior to dilution & administration, carefully inspect the vial visually for particles and discoloration.

Administration :

Sample Calculation :

Compatibility & Stability :

77 Normal saline (0.9% Sodium Chloride injection) can be used for flushing I.V. lines prior to or after administration of TROVAN IV.

5% Dextrose Injection, 0.45% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, 5% Dextrose and 0.2% Sodium Chloride Injection, Lactated Ringer’s and 5% Dextrose Injection,

How quickly will TROVAN IV Concentrate for Solution for Infusion start to work ?

Depending on the severity of the infection, you should start to feel better within a few days.

What if I do not feel better ?

If your infection gets worse, or you do not start to feel better within a few days, or a new infection develops, tell your doctor.

9- DESCRIPTION OF UNDESIRABLE EFFECTS UNDER NORMAL USE

Does TROVAN IV Concentrate for Solution for Infusion cause any undesirable effects?

TROVAN IV Concentrate for Solution for Infusion may cause some undesirable effects :

• Intravenous site reactions • Nausea • Dizziness or light-headedness (usually mild and wears off with treatment ) • Headache

78 • Vomiting • Rash • Diarrhoea • Pruritus

If any of these undesirable effects are troublesome, severe, or do not wear off as treatment goes on, tell your doctor.

If you notice any other undesirable effects which are not mentioned in this leaflet, please inform your doctor or pharmacist.

10- STORAGE PRECAUTIONS

As with all medicines, keep TROVAN IV Concentrate for Solution for Infusion out of the reach of children

11- DATE ON WHICH THE PACKAGE LEAFLET WAS LAST REVISED

79 12- OTHER INFORMATION