Fromilid

Overdose

Symptoms of intoxication:

Reports indicate that the ingestion of large amounts of Fromilidromycin can be expected to produce gastrointestinal symptoms. One patient who had a history of bipolar disorder ingested eight grams of Fromilidromycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxemia.

Therapy of intoxication:

Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, Fromilidromycin serum levels are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

In the case of overdosage, Fromilidromycin IV (powder for solution for injection) should be discontinued and all other appropriate supportive measures should be instituted.

Fromilid price

Incompatibilities

Not applicable.

Preclinical safety data

In 4-week-studies in animals, toxicity of Fromilidromycin was found to be related to the dose and to the duration of the treatment. In all species, the first signs of toxicity were observed in the liver, in which lesions were seen within 14 days in dogs and monkeys. The systemic levels of exposure, related to this toxicity, are not known in detail, but toxic doses were clearly higher than the therapeutic doses recommended for humans. Other tissues affected included the stomach, thymus and other lymphoid tissues as well as the kidneys. At near therapeutic doses conjunctival injection and lacrimation occurred only in dogs. At a dose of 400 mg/kg/day some dogs and monkeys developed corneal opacities and/or oedema.

No mutagenic effects were found in in vitro- and in vivo -studies with Fromilidromycin

Studies on reproduction toxicity showed that administration of Fromilidromycin at doses 2x the clinical dose in rabbit (i.v.) and x10 the clinical dose in monkey (p.o.) resulted in an increased incidence of spontaneous abortions. These doses were related to maternal toxicity. No embryotoxicity or teratogenicity was noted in rat studies. Cardiovascular malformations were observed in rats treated with doses of 150 mg/kg/d. In mouse at doses x70 the clinical dose cleft palate occurred at varying incidence (3-30%).

Fromilidromycin has been found in the milk of lactating animals.

In 3-day old mice and rats, the LD50 values were approximately half those in adult animals. Juvenile animals presented similar toxicity profiles to mature animals although enhanced nephrotoxicity in neonatal rats has been reported in some studies. Slight reductions in erythrocytes, platelets and leukocytes have also been found in juvenile animals.

Fromilidromycin has not been tested for carcinogenicity.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Macrolides

ATC code: J01FA09

Mode of action:

Fromilidromycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The minimum inhibitory concentrations (MICs) of Fromilidromycin are generally two-fold lower than the MICs of erythromycin.

The 14-hydroxy metabolite of Fromilidromycin also has antimicrobial activity. The MICs of this metabolite are equal or twofold higher than the MICs of the parent compound, except for H. influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.

PK/PD relationship

Fromilidromycin is extensively distributed into body tissues and fluids. Due to the high tissue penetration, intracellular concentrations higher than serum concentrations. The main pharmacodynamic parameters to predict macrolidenactiviteit are unconvincing established. The time above the MIC (T / MIC) is the best determinant for the efficacy of Fromilidromycin. Because the concentrations of Fromilidromycin in the lung tissues and epithelial tissue fluid reaches the plasma concentrations exceed, the use of plasma concentrations based parameters are insufficient to accurately predict response for respiratory infections.

Mechanisms of resistance:

Resistance mechanisms against macrolide antibiotics include alteration of the target site of the antibiotic or are based on modification and/or the active efflux of the antibiotic. Resistance development can be mediated via chromosomes or plasmids, be induced or exist constitutively. Macrolideresistant bacteria generate enzymes which lead to methylation of residual adenine at ribosomal RNA and consequently to inhibition of the antibiotic binding to the ribosome. Macrolide-resistant organisms are generally cross-resistant to lincosamides and streptogramine B based on methylation of the ribosomal binding site. Fromilidromycin ranks among the strong inducers of this enzyme as well. Furthermore, macrolides have a bacteriostatic action by inhibiting the peptidyl transferase of ribosomes. A complete cross-resistance exists among Fromilidromycin, erythromycin and azithromycin. Methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae are resistant to macrolides such as Fromilidromycin.

Breakpoints:

The following breakpoints for Fromilidromycin, separating susceptible organisms from resistant organisms, have been established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST) 2010-04-27 (v 1.1)

A Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the table or footnotes However, pharmacodynamic data for calculation of macrolide, lincosamines and streptogramins non-species related breakpoints are not robust, hence IE.

B Erythromycin can be used to determine the susceptibility of the listed bacteria to the other macrolides (azithromycin, Fromilidromycin and roxithromycin

C Fromilidromycin is used for the eradication of H. pylori (MIC ≤0.25 mg/L for wild type isolates).

D The correlation between H. influenzae macrolide MICs and clinical outcome is weak. Therefore, breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzae as intermediate.

Fromilidromycin is used for the eradication of H. pylori; minimum inhibitory concentration (MIC) ≤ 0.25 μg/ml which has been established as the susceptible breakpoint by the Clinical and Laboratory Standards Institute (CLSI).

Susceptibility:

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalance of resistance is such that the utility of the agent in atleast some types of infections is questionable.

# > 10% resistance in at least one country of the European Union

* Species against efficacy has been demonstrated in clinical investigations (if susceptible)

+ Indicates species for which a high rate of resistance (i.e. greater than 50%) have been observed in one or more area/country/region(s) of the EU

§ Breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzae as intermediate

Other information:

Susceptibility and resistance of Streptococcus pneumoniae and Streptococcus spp. to Fromilidromycin can be predicted by testing erythromycin.

Most available clinical experience from controlled randomised clinical trials indicate that Fromilidromycin 500 mg twice daily in combination with another antibiotic e.g. amoxicillin or metronidazole and e.g. omeprazole (given at approved levels) for 7 days achieve > 80% H. pylori eradication rate in patients with gastro-duodenal ulcers. As expected, significantly lower eradication rates were observed in patients with baseline metronidazole-resistant H. pylori isolates. Hence, local information on the prevalence of resistance and local therapeutic guidelines should be taken into account in the choice of an appropriate combination regimen for H. pylori eradication therapy. Furthermore, in patients with persistent infection, potential development of secondary resistance (in patients with primary susceptible strains) to an antimicrobial agent should be taken into the considerations for a new retreatment regimen.

Pharmacokinetic properties

Absorption:

Fromilidromycin is rapidly and well absorbed from the gastrointestinal tract - primarily in the jejunum - but undergoes extensive first-pass metabolism after oral administration. The absolute bioavailability of a 250-mg Fromilidromycin tablet is approximately 50%. Food slightly delays the absorption but does not affect the extent of bioavailability. Therefore, Fromilidromycin tablets may be given without regard to food. Due to its chemical structure (6-O-Methylerythromycin) Fromilidromycin is quite resistant to degradation by stomach acid. Peak plasma levels of 1 - 2 μg/ml Fromilidromycin were observed in adults after oral administration of 250 mg twice daily. After administration of 500 mg Fromilidromycin twice daily the peak plasma level was 2.8 μg/ml. After administration of 250 mg Fromilidromycin twice daily the microbiologically active 14-hydroxy metabolite attains peak plasma concentrations of 0.6 μg/ml. Steady state is attained within 2 days of dosing.

Distribution:

Fromilidromycin penetrates well into different compartments with an estimated volume of distribution of 200-400 l. Fromilidromycin provides concentrations in some tissues that are several times higher than the circulating drug levels. Increased levels have been found in both tonsils and lung tissue. Fromilidromycin also penetrates the gastric mucus.

Fromilidromycin is approximately 70% bound to plasma proteins at therapeutic levels.

Biotransformation and elimination:

Fromilidromycin is rapidly and extensively metabolised in the liver. Metabolism is in the liver involving the P450 cytochrome system. Three metabolites are described: N-demethyl Fromilidromycin, decladinosyl Fromilidromycin and 14-hydroxy Fromilidromycin. The pharmacokinetics of Fromilidromycin is non-linear due to saturation of hepatic metabolism at high doses. Elimination half-life increased from 2-4 hours following administration of 250 mg Fromilidromycin twice daily to 5 hours following administration of 500 mg Fromilidromycin twice daily. The half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours following administration of 250 mg Fromilidromycin twice daily.

Approximately 20 -40% of Fromilidromycin is excreted as the unchanged active substance in the urine. This proportion is increased when the dose is increased. An additional 10% to 15% is excreted in the urine as 14-hydroxy metabolite. The rest is excreted in the faeces.Renal insufficiency increases Fromilidromycin levels in plasma, if the dose is not decreased. Total plasma clearance has been estimated to approximately 700 mL/min (11,7 mL/s), with a renal clearance of approximately 170 mL/min (2,8 mL/s).

Special populations:

Renal impairment: Reduced renal insufficiency function results in increased plasma levels of Fromilidromycin and the active metabolite levels in plasma.

Special precautions for disposal and other handling

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