Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2017 Publisher: Teva Pharma (New Zealand) Limited, PO Box 128 244, Remuera, Auckland 1541, Telephone: 0800 800 097
Arrow – Roxithromycin is contraindicated in the following conditions:
Prolonged or repeated use of antibiotics including roxithromycin may result in superinfection by resistant organisms. In the event of superinfection, roxithromycin should be discontinued and appropriate therapy instituted.
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 (e.g. Lomotil), 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.
Cases of severe bullous skin reactions such as Stevens Johnson Syndrome or Toxic Epidermal Necrosis have been reported with roxithromycin (see Undesirable effects). 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.
Severe vasoconstriction (“ergotism”) with possibly necrosis of the extremities has been reported when macrolide antibiotics have been associated with vasoconstrictive ergot alkaloids. Absence of treatment by these alkaloids must always be checked before prescribing roxithromycin.
Increased INR levels have been reported in patients when Arrow – Roxithromycin and coumarin anticoagulants are used concomitantly. Patients using Arrow – Roxithromycin and coumarin anticoagulants should be closely monitored (see Interaction with other medicines and other forms of interaction).
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:
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.
In the elderly and those with renal failure, dosage reduction is not required for the normally short course of treatment.
In young animal studies, high oral doses of roxithromycin were associated with bone growth plate abnormalities. However, no abnormalities were observed in the animals at doses resulting in unbound plasma roxithromycin concentrations that were 10 to 15 times higher than the unbound concentration measured in children receiving the therapeutic dose. The maintenance of such safety margins is primarily dependent on high affinity binding of roxithromycin to plasma alpha-1-acid glycoprotein and will be compromised by any circumstances attenuating the extent of this binding. It is recommended that the approved paediatric dosage regimen (i.e. 5 to 8 mg/kg/day for a maximum of ten days) be adhered to strictly.
Neutropenia was observed in children treated with roxithromycin. 31.6% of 402 children in clinical trials had a neutrophil count below the lower limit of the normal range (3,500/mm³) at the conclusion of therapy with roxithromycin. Of these, 4% had a neutrophil count of less than 1,500/mm³ and 1.2% had a count of less than 1,000/mm³. It is not known whether this is an effect of the drug, or whether it reflects a normal fluctuation of the neutrophil count or a response to infection in children.
No dosage adjustment is required in elderly patients.
Roxithromycin has a much lower affinity for cytochrome P450 than erythromycin, and consequently has fewer interactions. Interactions may be observed, however, with drugs that bind to alpha-1-acid glycoprotein, e.g. disopyramide.
Roxithromycin does not appear to interact with oral contraceptives, prednisolone, carbamazepine, ranitidine or antacids.
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.
Reactions of ergotism with possible peripheral necrosis have been reported after concomitant therapy of macrolides with vasoconstrictive ergot alkaloids, particularly ergotamine and dihydroergotamine. Because a clinical interaction with roxithromycin cannot be excluded, administration of roxithromycin to patients taking ergot alkaloids is contraindicated. Absence of treatment with these alkaloids must always be checked before prescribing roxithromycin.
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.
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.
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.
Roxithromycin, like other macrolides, should be used with caution in patients receiving class IA and III antiarrhythmic agents (see Special warnings and precautions for use).
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, 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.
A slight increase in plasma concentrations of theophylline and cyclosporin A has been observed. This does not generally necessitate altering the usual dosage.
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).
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.
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) (see Special warnings and precautions for use).
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.
Not applicable.
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