Pivmecillinam 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 Pivmecillinam hydrochloride 200 mg film-coated 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.

Posology

Adults and 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.

Dosage in the elderly:

Renal excretion of mecillinam is delayed in the elderly, but significant accumulation of the drug is not likely at the recommended adult dosage of Pivmecillinam hydrochloride tablets.

Method of administration

Route of administration is oral. The tablet must be taken with at least half a glass of fluid and preferably taken with or immediately after a meal.

• 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.

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 Pivmecillinam. When SCAR is suspected, Pivmecillinam 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.

• Pivmecillinam 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.

• Concurrent treatment with valproic acid, valproate or other medication liberating pivalic acid should be avoided due to increased risk of carnitine depletion.

• Pivmecillinam hydrochloride film-coated 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.

• 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 the risk of oesophageal ulceration.

• Simultaneous administration of probenecid reduces the excretion of penicillins and hence increases the blood level of the antibiotic.

• Clearance of methotrexate from the body can be reduced by concurrent use of penicillins.

• Concurrent treatment with valproic acid, valproate or other medication liberating pivalic acid should be avoided due to increased risk of carnitine depletion.

• The bactericidal effect of penicillins may be hindered by concurrent administration of products with bacteriostatic effect, for instance erythromycin and tetracyclines.

Pregnancy

The drug, as mecillinam, crosses the placenta. Although tests in two animal species have shown no teratogenic effects, in keeping with current practice, use during pregnancy should be avoided.

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 Pivmecillinam no effects on the breast-fed newborns/infants are anticipated. Pivmecillinam can be used during breast-feeding.

Fertility

There are no clinical studies with Pivmecillinam hydrochloride regarding fertility. A pre-clinical study did not show an effect on fertility in rats.

Pivmecillinam hydrochloride has no or negligible influence on the ability to drive and use machines.

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 adverse reactions 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 to < 1/10

Uncommon ≥ 1/1,000 to < 1/100

Rare ≥ 1/10,000 to < 1/1,000

Very Rare < 1/10,000

Not known (cannot be estimated from the available data)

*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 aspartate aminotransferase (ASAT), alanine aminotransferase (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. or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no experience of overdose with Pivmecillinam hydrochloride tablets. However, excessive doses are likely to induce nausea, vomiting abdominal pain and diarrhoea. Treatment should be restricted to symptomatic and supportive measures.

Pharmacotherapeutic group: antibacterials products for systemic use, penicillins with extended spectrum;

ATC code J01CA08.

Pivmecillinam hydrochloride 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.

Pivmecillinam hydrochloride 200 mg film-coated tablets is highly active against most enterobacteriaceae, including E. coli, Klebsiella, Proteus, Enterobacter, Serratia, Salmonella, Shigella and Yersina.

Pivmecillinam hydrochloride 200 mg film-coated tablets is less active against gram positive bacteria and organisms such as Pseudomonas aeruginosa and Streptococcus faecalis are practically resistant to mecillinam.

Whilst Pivmecillinam, 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 Pivmecillinam and various penicillins and cephalosporins.

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 Pivmecillinam is practically unaffected by taking the tablets with food.

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.

Tablet core:

Cellulose microcrystalline

Magnesium stearate

Film coating:

Hypromellose

Triacetin

Not applicable.

2 years.

Store below 30 ° C.

Store in the original package in order to protect from moisture.

Pivmecillinam hydrochloride film-coated tablets are available in PVC/OPA/aluminum/PVC/Paper/PET/aluminum foil blister pack.

Pack sizes: 2, 10, 14 and 100 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.