Roxithromycin

Roxithromycin is a weak CYP3A inhibitor. The effect of roxithromycin on exposure to drugs predominantly cleared by CYP3A metabolism would be expected to be 2-fold or less. Caution should be exercised when roxithromycin is concomitantly prescribed with drugs metabolised by CYP3A (such as rifabutin and bromocriptine).

Caution should be exercised if roxithromycin is administered to patients with impaired hepatic function, as its serum half life is increased in patients with hepatic failure. If administered to patients with severe hepatic insufficiency (e.g. hepatic cirrhosis with jaundice and/or ascites), the dose should be reduced by half to 150 mg once daily.

While no interaction was observed in volunteer studies, roxithromycin appears to interact with warfarin. Increases in prothrombin time (international normalised ratio (INR)) have been reported in patients treated concomitantly with roxithromycin and warfarin or the related vitamin K antagonist phenprocoumon, and severe bleeding episodes have occurred as a consequence. INR should be monitored during combined treatment with roxithromycin and warfarin.

A study in healthy volunteers has shown that roxithromycin may increase the absorption of digoxin. This effect, common to other macrolides, may very rarely result in cardiac glycoside toxicity. This may be manifested by symptoms such as nausea, vomiting, diarrhoea, headache or dizziness. Cardiac glycoside toxicity may also elicit heart conduction and/or rhythm disorders. Consequently, in patients treated with roxithromycin and digoxin or another cardiac glycoside, ECG and, if possible, the serum level of the cardiac glycoside should be monitored. This is mandatory if symptoms suggesting cardiac glycoside overdosage have occurred.

Roxithromycin, like other macrolides, should be used with caution in patients receiving class IA and III antiarrhythmic agents.

Other drugs, such as astemizole, cisapride or pimozide, which are metabolised by the hepatic isozyme CYP3A4, have been associated with QT interval prolongation and/or cardiac arrhythmias (typically torsades de pointes) as a result of an increase in their serum level subsequent to interaction with significant inhibitors of this isozyme, including some macrolide antibacterials.

Although roxithromycin has no or limited ability to complex CYP3A4 and hence to inhibit the metabolism of other drugs processed by this isozyme, a potential for clinical interaction of roxithromycin with the above mentioned drugs cannot be either ascertained or ruled out in confidence. Thus, concomitant administration of roxithromycin and such drugs is not recommended.

A slight increase in plasma concentrations of cyclosporin A has been observed. This does not generally necessitate altering the usual dosage.

An in vitro study has shown that roxithromycin can displace protein bound disopyramide; such an effect in vivo could result in increased serum levels of disopyramide. Consequently, ECG and, if possible, disopyramide serum levels should be monitored.

Roxithromycin, like other macrolides, may increase the area under the midazolam concentration-time curve and the midazolam half-life. Thus, the effects of midazolam may be enhanced and prolonged in patients treated with roxithromycin. There is no conclusive evidence for an interaction between roxithromycin and triazolam.

Some macrolide antibiotics (e.g. erythromycin) may increase serum levels of terfenadine. This can result in severe cardiovascular adverse events, including QT prolongation, torsades de pointes and other ventricular arrhythmias. Such a reaction has not been documented with roxithromycin, which has a much lower affinity for cytochrome P450 than erythromycin. However, in the absence of a systematic interaction study, concomitant administration of roxithromycin and terfenadine is not recommended.

A study in normal subjects concurrently administered roxithromycin and theophylline has shown some increase in the plasma concentration of the latter. While a change in dosage is usually not required, patients with high levels of theophylline at commencement of treatment should have levels monitored.

Cases of severe bullous skin reactions such as Stevens Johnson Syndrome or Toxic Epidermal Necrosis have been reported with roxithromycin. If symptoms or signs of SJS or TEN (eg. progressive skin rash often with blisters or mucosal lesions) are present, roxithromycin treatment should be discontinued.

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases, appropriate therapy with a suitable oral antibacterial agent effective against Cl. difficile should be considered. Fluids, electrolytes and protein replacement therapy should be provided when indicated.

Drugs that delay peristalsis, e.g. opiates and diphenoxylate with atropine, may prolong and/or worsen the condition and should not be used.

As with other macrolides, roxithromycin may have the potential to aggravate myasthenia gravis.

Ventricular arrhythmias associated with prolonged QT interval, including ventricular tachycardia and torsades de pointes have been reported with macrolide antibiotics including roxithromycin. Prescribers should consider the risk of QT prolongation (which can be fatal) when weighing the risks and benefits of roxithromycin for at-risk groups including:

• Patients predisposed to QT interval prolongation such as those with a history of torsades de pointes or congenital long QT syndrome.
• Patients taking other medication known to prolong the QT interval such as antiarrhythmics of classes IA and III; antipsychotic agents; antidepressants; and fluoroquinolones.
• Patients with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia.
• Patients with clinically relevant bradycardia, cardiac arrhythmia or cardiac insufficiency.

(Category B1)

Reproductive studies in rats, mice and rabbits at doses of 100, 400 and 135 mg/kg/day, respectively, did not demonstrate evidence of developmental abnormalities. In rats, at doses above 180 mg/kg/day, there was evidence of embryotoxicity and maternotoxicity. The safety of roxithromycin for the human fetus has not been established.

Small amounts of roxithromycin are excreted in the breast milk. Breastfeeding or treatment of the mother should be discontinued as necessary.

Carcinogenicity, mutagenicity, impairment of fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of roxithromycin. Roxithromycin has shown no mutagenic potential in standard laboratory tests for gene mutation and chromosomal damage.

There was no effect on the fertility of rats treated with roxithromycin at oral doses up to 180 mg/kg/day.

Attention should be drawn to the possibility of dizzy sensations.

Roxithromycin is generally well tolerated. In clinical trials, treatment discontinuation due to adverse reactions occurred in only 1.2% of adult patients and 1.0% of children. The following side effects or serious adverse events possibly associated with roxithromycin have been reported.

Gastrointestinal: Nausea, vomiting, epigastric pain, diarrhoea (very rarely containing blood), anorexia, flatulence, pseudomembranous colitis. In clinical studies, the incidence of gastrointestinal events was higher with the 300 mg once daily dosage regimen than with 150 mg twice daily. Symptoms of pancreatitis have been observed; most patients have received other drugs for which pancreatitis is a known adverse effect.

Hypersensitivity: Urticaria, rash, pruritus, angioedema. Rarely, serious allergic reactions may occur, e.g. asthma, bronchospasm, anaphylactic like reactions, purpura, glottic oedema, generalised oedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome and Toxic Epidermal Necrosis (TEN).

Hepatic: Moderate increases in serum transaminases (AST and ALT) and/or alkaline phosphatase levels have been observed and are somewhat more likely to occur in the elderly (>65 years). Acute cholestatic hepatitis and acute hepatocellular injury are rarely reported.

Other: Eosinophilia, bronchospasm, hallucination, confusion, headache, dizziness, paraesthesia, tinnitus, malaise, moniliasis (candidiasis), pancreatitis, QT prolongation, disorders of taste and/or smell, temporary deafness, hypoacusis and vertigo.