Nitrofurantoin

Nitrofurantoin is the best known compound in the class of nitrofurans. This synthetic compound has been available for clinical use since 1953. Due to several reports of severe adverse effects, (primarily pulmonary reactions) during the 1970’s, the prescribing of nitrofurantoin decreased. During this time nitrofurantoin had been used for long-term prophylaxis of UTIs. Long-term low-dose usage as well as acute high dose usage or extreme high systemic concentrations due to renal insufficiency are risk factors for adverse events. Nowadays, nitrofurantoin has been re­vived for short-term treatment of community-acquired uncomplicated UTIs in patients with nor­mal kidney function due to the untenable resistance crisis. Even in countries with rather low resistance rates, such as Sweden, medical societies recommend nitrofurantoin as a first-line quinolone-sparing treatment to ease the selection pressure that would otherwise trigger co-resistance and, thus, lead to multi-drug resistance with limited or no remaining therapeutic options.

Literature overview

Nitrofurantoin products

Numerous manufacturers of generic nitrofurantoin produce the solid oral form of nitrofurantoin in three different formulations:

  • A macrocrystallized form
  • Nitrofurantoin monohydrate (sometimes synonymous with microcrystals)
  • A mixture of macrocrystals (75%) and the monohydrate (25%) contained in a delayed-release gel matrix

The formulations differ in their absorption properties as the macrocrystallized form shows a slower dissolution and absorption in comparison to the monohydrate. The reason for developing this formulation was reducing gastrointestinal side effects and not extending the half-lives. The crystal mixture is a delayed release formulation with an even slower release over time, thus supporting an ex­tended dosing interval according to very old clinical studies. Some companies that are selling furantoin products in Europe don’t disclose the composition of their products in the officially approved product information. In general, in Northern Europe nitrofurantoin monohydrate is predominantly used, in UK and Western Europe (incl. German speaking countries) nitrofurantoin macrocrystals.

Availability in Europe

In Europe, all three formulations are used while in some European countries other nitrofuran derivatives are available such as furazidin in Poland and Latvia or Nifurtoinol in Belgium. Most nitrofuran products are prescription drugs with a few exceptions, e.g. Poland. All nitrofurantoin products were approved by national authorities, leading to divergent information in the Summary of Product Characteristics (SPC) across Europe, some originated many decades ago.

Reviving nitrofurantoin

One of the work packages of the FP7 funded project AIDA (Preserving old antibiotics for the future) aims to examine the clinical effectiveness of nitrofurantoin vs fosfomycin-trometamol as well as to identify optimal dosing regimens and treatment duration based on sound PK/PD studies. Despite of 60 years of clinical usage, basic knowledge such as this has been either lost or has never been generated for nitrofurantoin. Resorting to the old antibiotic nitrofurantoin needs to be supported by new studies that are based on scientific principles and modern techniques. Studies that will contribute substantially to the safe usage of the old drug nitrofurantoin will include in vitro activity and PK/PD studies, animal PK/PD studies, pharmacokinetic studies in volunteers and patients, as well as a clinical study in outpatients with acute lower urinary tract infections at risk for multidrug resistant pathogens. Finally drug exposure values will be related to clinical outcome. Safety aspects will be meticulously monitored.

Regulatory aspects

The current product information of nitrofurantoin products based on purely national marketing authorisations are still in force within the EU. They were granted in accordance with old, disparate, national standards, dating from a time when medicines agencies did not exist and their content varies between countries. Processes for organising a systematic re-assessment of all old national approvals are essential to secure the effective and safe usage of approved drugs.

Due to limited capacity of EMA’s  Co-ordination Group for Mutual Recognition and Decentralised Procedures-Humans nitrofurantoin products have not yet proposed for re-evaluation and harmonisation in the EU. Drugs for serious infections and more widely usage are prioritised.

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