Selexid 200 mg Film-coated Tablets

Film-coated tablet A white circular film-coated convex tablet embossed with an Assyrian lion on one side and 137 on the other.

4.1 Therapeutic indications Selexid is indicated for the treatment of infections due to mecillinam sensitive organisms (see section 5.1), including: • urinary tract infections • salmonellosis Preliminary experience in a small number of patients suggests that Selexid tablets may be a useful alternative antibiotic in the treatment of acute typhoid fever and in some carriers of salmonellae when antibiotic treatment is considered essential. Consideration should be given to official guidance on the appropriate use of antibacterial agents.4.2 Posology and method of administration **Posology** **Adults** Urinary tract infections: • Acute uncomplicated cystitis: 72 hour course of 2 tablets immediately followed by 1 tablet 3 times daily to a total of 10 tablets. • Chronic or recurrent bacteriuria: 2 tablets three to four times daily. Salmonellosis: • Enteric fever: 1.2-2.4 g daily for 14 days. • Salmonella carriers: 1.2-2.4 g daily for 2-4 weeks. **Pregnant women** Acute cystitis: 7 day course of 2 tablets immediately followed by 1 tablet 3 times daily to a total of 22 tablets. **Paediatric population** *Children weighing more than 40 kg* Urinary tract infections: • Acute uncomplicated cystitis: 72 hour course of 2 tablets immediately followed by 1 tablet 3 times daily to a total of 10 tablets. • Chronic or recurrent bacteriuria: 2 tablets three to four times daily. Salmonellosis: • Enteric fever: 1.2-2.4 g daily for 14 days. • Salmonella carriers: 1.2-2.4 g daily for 2-4 weeks. *Children weighing less than 40 kg* • Urinary tract infections: 20-40 mg/kg body weight, daily, in 3 to 4 divided doses. • Salmonellosis: 30-60 mg/kg body weight, daily, in 3 to 4 divided doses. **Elderly population** Renal excretion of mecillinam is delayed in the elderly, but significant accumulation of the drug is not likely at the recommended adult dosage of Selexid tablets. **Method of administration** Route of administration is oral. The tablets must be taken with at least half a glass of fluid, and preferably taken with or immediately after a meal.4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypersensitivity to penicillins and/or cephalosporins. Any conditions resulting in impaired transit through the oesophagus. Genetic metabolism anomalies known to be leading to severe carnitine deficiency, such as carnitine transporter defect, methylmalonic aciduria or propionic acidaemia.4.4 Special warnings and precautions for use During long term use, it is advisable to carry out routine liver and kidney function tests. Severe cutaneous adverse reactions (SCAR) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported in relation to beta-lactam treatment, including Selexid. When SCAR is suspected, Selexid should be discontinued immediately and appropriate therapy and/or measures should be taken. Pseudomembranous colitis caused by Clostridium difficile may occur. If diarrhoea occurs after use, the possibility of pseudomembranous colitis should be considered, and appropriate actions should be taken. Selexid tablets should be used with caution in patients with porphyria since pivmecillinam has been associated with acute attacks of porphyria. As with other antibiotics which are excreted mainly by the kidneys, raised blood levels of mecillinam may occur if repeated doses are given to patients with impaired renal function. Selexid tablets should be used with caution for long-term or frequently-repeated treatment, due to the possibility of carnitine depletion. Symptoms of carnitine depletion include muscle aches, fatigue, and confusion. Concurrent treatment with valproic acid, valproate or other medication liberating pivalic acid should be avoided due to increased risk of carnitine depletion. Interference with neonatal screening tests: The intake of pivmecillinam shortly before delivery may cause a false positive test for isovaleric acidemia in the newborn as part of neonatal screening. This may be due to the formation of pivaloylcarnitine simulating the presence of isovalerylcarnitine. It is therefore recommended to include a second tier screening test for each sample obtained from newborns tested positive for isovaleric acidaemia if those findings are suspected of being pivmecillinam-related false positive (see section 4.6). The tablets must be taken with at least half a glass of fluid due to risk of oesophageal ulceration.4.5 Interaction with other medicinal products and other forms of interaction Clearance of methotrexate from the body can be reduced by concurrent use of penicillins. Simultaneous administration of probenecid reduces the excretion of penicillins, and hence increases blood levels of the antibiotic. The bactericidal effect of penicillins may be hindered by concurrent administration of products with bacteriostatic effect, for instance erythromycin and tetracyclines. Concurrent treatment with valproic acid, valproate or other medication liberating pivalic acid should be avoided due to increased risk of carnitine depletion.4.6 Fertility, pregnancy and lactation **Pregnancy** A large amount of data on pregnant women (more than 40 000 pregnancy outcomes) indicate no malformative nor feto/neonatal toxicity of pivmecillinam. Selexid can be used for treatment of acute uncomplicated cystitis during pregnancy, if clinically needed. Some cases of false-positive newborn screening tests simulating the presence of isovaleric acidaemia have been reported. The intake of pivmecillinam shortly before delivery may cause a false positive test for isovaleric acidaemia in the newborn as part of neonatal screening (see section 4.4). **Breast-feeding** Mecillinam is excreted in human milk, but at therapeutic doses of Selexid no effects on the breast-fed newborns/infants are anticipated. Selexid can be used during breast‑feeding. **Fertility** There are no clinical studies on the effect of Selexid on fertility. A pre-clinical study did not show an effect on fertility in rats.4.7 Effects on ability to drive and use machines Selexid has no or negligible influence on the ability to drive or use machines.4.8 Undesirable effects The estimation of the frequency of undesirable effects is based on an analysis of pooled data from clinical studies and spontaneous reporting. The most frequently reported undesirable effects are nausea and diarrhoea. Anaphylactic reactions and fatal pseudomembranous colitis (see section 4.4) have been reported. Severe cutaneous adverse reactions (SCAR) including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported (see section 4.4). Undesirable effects are listed by MedDRA SOC and the individual undesirable effects are listed starting with the most frequently reported. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Very common ≥ 1/10 Common ≥ 1/100 and < 1/10 Uncommon ≥ 1/1,000 and < 1/100 Rare ≥ 1/10,000 and < 1/1,000 Very Rare < 1/10,000 Not known (cannot be estimated from the available data) | | | | --- | --- | | **Infections and infestations** | | | Common: | Vulvovaginal mycotic infection | | Uncommon: | Clostridium difficile colitis | | **Blood and lymphatic system disorders** | | | Uncommon: | Thrombocytopenia | | **Immune system disorders** | | | Uncommon: | Anaphylactic reaction | | Not known: | Anaphylactic shock | | **Metabolism and nutrition disorders** | | | Uncommon: | Carnitine decreased | | **Nervous system disorders** | | | Uncommon: | Headache Dizziness | | **Ear and labyrinth disorders** | | | Uncommon: | Vertigo | | **Gastrointestinal disorders** | | | Common: | Diarrhoea Nausea | | Uncommon: | Vomiting Abdominal pain Dyspepsia Oesophageal ulcer Oesophagitis Mouth ulceration | | **Hepatobiliary disorders** | | | Uncommon: | Hepatic function abnormal | | **Skin and subcutaneous tissue disorders** | | | Uncommon: | Rash\* Urticaria Pruritus | | Not known: | Severe cutaneous adverse reactions\\ including acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis Angioedema | | **General disorders and administration site conditions** | | | Uncommon: | Fatigue | *\Various types of rash reactions such as erythematous, macular or maculo-papular have been reported* *\\*Very few cases have been reported post-marketing, frequency cannot be established* Class adverse reactions of beta-lactam antibiotics: Slight reversible increase in ASAT, ALAT, alkaline phosphatase, and bilirubin Neutropenia Eosinophilia **Paediatric population** Frequency, type and severity of adverse reactions in children are expected to be the same as in adults, based on limited data. **Reporting of suspected adverse reactions** Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.4.9 Overdose There has been no experience of overdosage with Selexid. However, excessive doses of Selexid are likely to induce nausea, vomiting, abdominal pain and diarrhoea. Treatment should be restricted to symptomatic and supportive measures.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: antibacterial products for systemic use, penicillins with extended spectrum, ATC code: J01CA08 Selexid is an orally active antibiotic. Chemically it is the pivaloyloxymethylester of the amidinopenicillanic acid, mecillinam. On oral administration it is well absorbed and subsequently hydrolysed in the body to mecillinam, the active antibacterial agent, by non-specific esterases present in blood, gastro-intestinal mucosa and other tissues. Selexid is highly active against most enterobacteriaceae, including E. coli, Klebsiella, Proteus, Enterobacter, Serratia, Salmonella, Shigella and Yersina. Selexid is less active against gram positive bacteria and organisms such as Pseudomonas aeruginosa and Streptococcus faecalis are practically resistant to mecillinam. Whilst Selexid, like the penicillins and cephalosporins, interferes with the biosynthesis of the bacterial cell wall, the target of the inhibition is different. This different mode of action is probably responsible for the synergistic action which has been found, both in vitro and in vivo, between Selexid and various penicillins and cephalosporins.5.2 Pharmacokinetic properties Peak serum levels of mecillinam averaging 5 microgram/ml are reached after 1 hour following a dose of 10 mg/kg body weight in children and 400 mg in adults. The serum half-life is 1.2 hours. The protein binding amounts to 5-10%. Approximately 50% of the administered dose is excreted as mecillinam in the urine within the first six hours. Mecillinam is partly excreted with bile, giving rise to biliary concentrations about 3 times the serum levels. Concurrent administration of probenecid delays the renal excretion of mecillinam, producing more sustained serum levels. The absorption of Selexid is practically unaffected by taking the tablets with food.5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or toxicity to reproduction. No carcinogenicity data are available for pivmecillinam or the active drug mecillinam.

6.1 List of excipients Cellulose microcrystalline Hydroxypropyl cellulose Magnesium stearate Hypromellose Simethicone Paraffin, synthetic6.2 Incompatibilities Not applicable.6.3 Shelf life 3 years6.4 Special precautions for storage Store below 25°C in a dry place.6.5 Nature and contents of container Aluminium/PVC-Aluminium blister packs containing 10 or 18 tablets.6.6 Special precautions for disposal and other handling No special requirements for disposal.