This information is intended for use by health 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

Treatment of adults with acute uncomplicated cystitis due to mecillinam sensitive organisms.

4.2 Posology and method of administration

Posology

Adults: The usual dose is 200 mg two times daily for 7 days, alternatively 200 mg 3 times daily for 5 days.

Paediatric population:

Pivmecillinam hydrochloride should not be used in children and adolescents below 18 years because the efficacy and safety have not yet been established.

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. . Dosage adjustment is not necessary (see section 5.2).

Renal impairment

Renal excretion of mecillinam is delayed in patients with reduced kidney function, but significant accumulation of the drug is not likely at the recommended adult dosage of Pivmecillinam hydrochloride. Dosage adjustment is not necessary (see section 5.2).

Hepatic impairment

Dosage adjustment is not necessary.

Method of administration

Pivmecillinam hydrochloride must be taken with at least half a glass of liquid. Pivmecillinam hydrochloride may be taken with food

4.3 Contraindications

Pivmecillinam hydrochloride is contra-indicated in patients with:

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Hypersensitivity to penicillins 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 and propionic acidaemia.

4.4 Special warnings and precautions for use

• Pseudomembranous colitis caused by Clostridium difficile may occur. If diarrhoea occurs after use, the possibility of pseudomembranous colitis should be considered, and appropriate precaution should be taken.

• Pivmecillinam Aurobindo should not be used by patients suffering from porphyria as pivmecillinam has been connected to acute attacks of porphyria.

• 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.

• 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 mecillinam 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 mecillinam 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 1000 pregnancy outcomes) indicate no malformative nor feto/neonatal toxicity of pivmecillinam/mecillinam. Pivmecillinam can be used during pregnancy if clinically needed

Lactation 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.

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.

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

Infections and infestations

Common:

Vulvovaginal mycotic infection

Uncommon:

Clostridium difficile colitis

Blood and lymphatic system disorders

Uncommon:

Thrombocytopenia

Immune system disorders

Uncommon:

Anaphylactic reaction

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

Pruritis

General disorders and administration site conditions

Uncommon:

Fatigue

*Various types of rash reactions such as erythematous, macular or maculo-papular skin reactions have been reported.

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.

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 for systemic use, penicillins with extended spectrum;

ATC code J01CA08.

Mechanism of action

Pivmecillinam hydrochloride is an orally active antibiotic, containing the pro-drug pivmecillinam. This 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. Mecillinam is a betalactam with a narrow-spectrum of activity. It is mainly active against Gram-negative bacteria and works by interfering with the biosynthesis of the bacterial cell wall.

Mecillinam exerts high specificity against penicillin-binding protein 2 (PBP-2) in the Gram-negative cell wall, unlike the majority of other beta-lactam agents, which preferentially bind Gram-negative PBP-1A, -1B or -3. Synergy has been observed when mecillinam is combined with other beta-lactam antibiotics, including ampicillin, amoxicillin, cefoxitin, cefalotin, cefazolin, cefradine, cefamandole, ceftazidime and ceftriaxone, against selected isolates of most Enterobacteriaceae.

Pivmecillinam has low impact on the normal skin, oral, intestinal and vaginal microflora.

Resistance

As a narrow-spectrum antibiotic active against Gram-negative bacilli, pivmecillinam is unlikely to contribute to the widespread of resistant bacterial strains. The exclusive action of pivmecillinam on PBP-2 results in the low cross-resistance with other beta-lactams (penicillins and cephalosporins). Mecillinam has limited susceptibility to most of the beta-lactamases (including ESBL) produced by Enterobacteriaceae. In Enterobacteriaceae, resistance to mecillinam may be due to marked production of some beta-lactamases and modification of penicillin binding proteins.

Susceptibility testing breakpoints

EUCAST: S ≤ 8 mg/L / R > 8 mg/L (for E. coli, Klebsiella spp. and P. mirabilis)

Generally sensitive species

Gram negative microorganisms

Enterobacter spp.

Escherichia coli

Klebsiella spp.

Proteus mirabilis

Naturally resistant species

Gram positive microorganisms

Enterococcus faecalis

Enterococcus faecium

Staphylococcus saprophyticus*

Gram negative microorganisms

Pseudomonas spp.

*Due to the high concentrations of mecillinam in urine, clinical effect is normally obtained in acute uncomplicated cystitis caused by S. saprophyticus.

Pharmacokinetic/pharmacodynamic relationship(s)

As a beta-lactam antibiotic, the bacteriological effect of Pivmecillinam hydrochloride in the treatment of acute uncomplicated cystitis is expected to depend on time above MIC.

Clinical efficacy against specific pathogens

Efficacy has been demonstrated in clinical studies against the pathogens that were susceptible to mecillinam in vitro in the treatment of acute uncomplicated cystitis. Mecillinam is a beta-lactam with a narrow spectrum of activity against Gram-negative bacilli. Mecillinam is highly active against E. coli, Klebsiella spp., Proteus spp., and Enterobacter spp.. Staphylococcus. saprophyticus, which exhibits borderline susceptibility in vitro, is susceptible in vivo due to the high concentration of mecillinam excreted in urine.

5.2 Pharmacokinetic properties

Absorption, Distribution, Biotransformation

Pivmecillinam hydrochloride is the pro-drug of mecillinam that is hydrolysed in the body to mecillinam, the active antibacterial agent (see section 5.1).

Following oral administration of 400 mg pivmecillinam peak concentrations of approximately 3 μg/mL is attained within 1-1½ hours after dosing. The bioavailability of orally administered pivmecillinam is approximately 60-70%. Bioavailability of Pivmecillinam hydrochloride tablets is not affected by taking the tablets with food.

Elimination

The elimination half-life of mecillinam is about 1 hour. It is excreted primarily in the urine with some biliary excretion. Mecillinam is to a large extent excreted by the kidneys by filtration and active tubular secretion. Probenecid, which inhibits tubular secretion, also inhibits the elimination of mecillinam. Approximately 60- 70% of the mecillinam reaching the systemic circulation is excreted unchanged in urine; almost all within the first 6 hours after dosing resulting in urine concentrations > 200 mg/L after oral administration of one 400 mg tablet.

The elimination of mecillinam is reduced by approximately 75% in patients with severe renal impairment (see section 4.2).

Low concentrations of mecillinam are observed in foetuses, breast milk, and amniotic fluid. The protein binding of mecillinam in human serum is 5-10%.

Linearity/non-linearity

Mecillinam displays linear pharmacokinetics in the clinically relevant range.

Gender differences in the pharmacokinetics of mecillinam have not been reported.

Clinically relevant accumulation of mecillinam does not take place at dosing up to four times daily and there are no indications that the pharmacokinetics change over time during repeated dosing.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction and development. No genotoxicity or carcinogenicity studies have been performed with 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 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.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

Milpharm Limited

Ares Block, Odyssey Business Park

West End Road

Ruislip HA4 6QD

United Kingdom

8. Marketing authorisation number(s)

PL 16363/0442

9. Date of first authorisation/renewal of the authorisation

07.10.2015

10. Date of revision of the text

30.07.2018