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. 2 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). 5 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