Pivmecillinam hydrochloride 200 mg film-coated tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Pivmecillinam hydrochloride 200 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 200 mg of pivmecillinam hydrochloride.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

White to off-white, round shaped, biconvex, film coated tablets debossed with ‘F’ on one side and ‘48’ on the other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

• • 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.

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 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.

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 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.

4.5 Interaction with other medicinal products and other forms of interaction

• 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women (more than 40 000 pregnancy outcomes) indicates no malformative nor feto/neonatal toxicity of pivmecillinam. Pivmecillinam 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 Pivmecillinam no effects on the breast-fed newborns/infants are anticipated. Pivmecillinam can be used during breast-feeding.

Fertility

There are no clinical studies on the effect of Pivmecillinam hydrochloride 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

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

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

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 Pivmecillinam 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 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Cellulose microcrystalline

Magnesium stearate

Film coating:

Hypromellose

Triacetin

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store below 30 °C.

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

6.5 Nature and contents of container

Pivmecillinam hydrochloride film-coated tablets are available in cold form laminate made of 25µ OPA/45µ aluminium foil/60µm PVC as forming material and plain 25µ Aluminium foil with 7gsm heat seal lacquer coating as the lidding material.

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

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Milpharm Limited

1 Roundwood Avenue,

Stockley Park, Uxbridge,

UB11 1AF

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 16363/0442

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

07/10/2015 / 12/05/2021

10 DATE OF REVISION OF THE TEXT

08/05/2026