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Logo ROXITHROMYCIN - HEXAL 150 mg

SCHEDULING STATUS:
Schedule 4

PROPRIETARY NAME
(and dosage form):

ROXITHROMYCIN - HEXAL 150 mg
(film-coated tablet)

COMPOSITION:
Each tablet contains
Roxithromycin 150 mg.

PHARMACOLOGICAL CLASSIFICATION
A.20.1.1. Broad and medium spectrum antibiotics

PHARMACOLOGICAL ACTION
Roxithromycin is a semi-synthetic antibiotic belonging to the macrolide class. It has the following antibacterial spectrum in vitro:
- Streptococcus agalactiae
- Streptococcus pneumoniae (Pneumococcus)
- Neisseria meningitides (Meningococcus)
- Listeria monocytogenes
- Mycoplasma pneumoniae
- Chlamydia trachomatis
- Ureaplasma urealyticum
- Legionella pneumophila
- Helicobacter (campylobacter)
- Gardnerella vaginalis
- Bordetella pertussis
- Moraxella catarrhalis (Branhamella catarrhalis)
- Haemophilus ducreyi
The following organisms show variable in vitro sensitivity:
- Group A beta-haemolytic Streptococci (Streptococcus pyogenes)
- Staphylococcus aureus
- Haemophilus influenzae
- Staphylococcus epidermidis
Roxithromycin is highly concentrated in polymorphonuclear leucocytes and macrophages achieving intracellular concentrations greater than those outside the cell. Roxithromycin enhances the adhesive and chemotactic functions of these cells, which in the presence of infection produce phagocytosis and bacterial lysis. Roxithromycin also possesses intracellular bactericidal activity.

ABSORPTION
Roxithromycin is rapidly absorbed. The peak serum level is reached 2,2 hours after oral administration of 150 mg in the fasting subject. Administration of one tablet 15 minutes before a meal has no effect on the pharmacokinetics in a healthy subject.
DISTRIBUTION AND ELIMINATION
Following administration of a single oral dose of roxithromycin 150 mg to healthy subjects, mean plasma concentrations ranging from 6.6-7.9 mg/L are reached within 2 hours. The mean concentration (12 hours after administration) is 1.8 mg/L.
The elimination half-life of roxithromycin following administration of 150 mg and 300 mg doses ranges from 8.4 to 15.5 hours.
The half life of roxithromycin is prolonged in the elderly (27 hours); in patients with impairment of hepatic function (25 hours) and in patients with impairment of renal function (18 hours).
TISSUE DISTRIBUTION
Roxithromycin is extensively distributed throughout tissues and body fluids.
Maximum concentrations of roxithromycin in pulmonary tissue were 5.6 mg/L
6 hours after administration of 150 mg. Roxithromycin concentrations in bronchoalveolar lavage cells were 2 and 10 times higher than corresponding levels in plasma and epithelial fluid, respectively.
BINDING TO PLASMA PROTEIN
It is reported to be about 96% bound to plasma protein (mainly alpha
1-acid glycoprotein) at trough concentrations, but binding is saturable and only 86% is bound at usual peak concentrations.
METABOLISM
Roxithromycin is only partially metabolised, more than half the parent compound being excreted unchanged. Three metabolites have been identified in urine and faeces: the major metabolite is descladinose roxithromycin, with N-mono and N-di-demethyl roxithromycin as minor metabolites. The respective percentage of roxithromycin and these three metabolites is similar in urine and faeces.
EXCRETION
It is mainly excreted in faeces 72 hours after oral administration of 14C labelled roxithromycin, urinary radioactivity is only 12% of total excreted radioactivity (urine and faeces).

INDICATIONS
Roxithromycin is indicated for use in the treatment of mild to moderate infections of the ear, nose and throat, respiratory tract, in the skin and skin structure and genito-urinary tract caused by susceptible strains of organisms listed below:
Pharyngitis, tonsillitis, sinusitis and otitis media, due to Group A beta-haemolytic Streptococci and Streptococcus pneumoniae.
Pneumonia and acute bronchitis due to Streptococcus pneumoniae.
Atypical pneumonia due to Mycoplasma pneumoniae.
Pyoderma and erysipelas due to Staphylococcus aureus and Group A beta-haemolytic Streptococci.
Non-gonococcal urethritis in men, due to Chlamydia trachomatis and Ureaplasma urealyticum.

CONTRA-INDICATIONS
Known allergy to macrolide antibiotics. Hypersensitivity to any of the ingredients.

INTERACTIONS:
Roxithromycin and other macrolide antibiotics have the potential to interact with a large number of drugs through their action on hepatic cytochrome P450 isoenzymes, particularly CYP1A2 and CYP3A4. Macrolides inhibit drug metabolism by microsomal cytochromes by competitive inhibition and by the formation of inactive complexes.
Concomitant administrations contra-indicated:
Concomitant administration of roxithromycin with vasoconstrictive ergot (alkaloid) derivatives is contra-indicated since symptoms or ergotism have been described with other macrolides.
Roxithromycin may inhibit the metabolism of pimozide, resulting in increased serum concentrations of this agent. Elevated serum levels of pimozide have been associated with adverse cardiovascular effects including QT interval prolongation, torsades de pointes, cardiac arrhythmia, and sudden death. The concomitant administration of roxithromycin with pimozide is contra-indicated.
Concomitant administrations not recommended:
Terfenadine and Astemizole
Enzyme inhibiting drugs such as roxithromycin and other macrolides may lead to the decreased hepatic metabolism of terfenadine and astemizole resulting in increased serum concentrations of terfenadine and astemizole. This may result in prolonged QT intervals, severe ventricular arrhythmias, typically torsades de pointe.
Cisapride
Cisapride which is metabolized by hepatic CYP3A isoenzymes has been associated with QT interval prolongation and/or cardiac arrhythmias (typically torsades de pointe) as a result of an increase in its serum levels subsequent to interaction with significant inhibitors of the isoenzyme, including some macrolide antibiotics.
Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended.
Precautions for use:
Warfarin
Although roxithromycin has a lesser inhibiting effect on cytochrome P450 enzymes than other macrolide antibiotics, some reports have suggested that roxithromycin may potentiate the effects of warfarin when given concomitantly to severely ill, elderly or compromised patients. Therefore the concurrent administration of roxithromycin and warfarin may result in the inhibition of warfarin metabolism, and increase the risk of bleeding.
In patients receiving oral anticoagulant therapy with warfarin, the prothrombin time ratio or international normalised ratio (INR) should be closely monitored with the addition and withdrawal of treatment with roxithromycin, and should be reassessed periodically during concurrent therapy. Adjustment of the warfarin dose may be necessary in order to maintain the desired level of anticoagulation.
Disopyramide
Roxithromycin displaces disopyramide from protein-binding sites in vitro. Concurrent administration of these two drugs in vivo may result in increased disopyramide serum concentrations. Consequently ECG and, if possible disopyramide levels should be monitored.
Digoxin
In approximately 10% - 15% of patients, digoxin is degraded extensively by bacteria in the gastrointestinal tract. Roxithromycin has the potential to decrease the amount of gastrointestinal flora, resulting in decreased digoxin breakdown in these patients.
Thus, the co-administration of digoxin and roxithromycin may result in increased serum digoxin levels resulting in digoxin toxicity. Serum digoxin levels should be carefully monitored when roxithromycin is added to or withdrawn from therapy. Patients should be observed for signs and symptoms of digoxin toxicity (nausea, vomiting, and arrhythmias).
Midazolam
Macrolide antibiotics may inhibit hepatic enzymes responsible for benzodiazepine metabolism, leading to increased plasma concentrations of benzodiazepines through reduced clearance, prolonged half life and increased volume of distribution resulting in benzodiazepine toxicity (CNS depression, ataxia, lethargy).
Patients receiving concurrent macrolide antibiotics and benzodiazepine must be observed for enhanced CNS effects. Patients should be warned regarding the potential for drug hangover. Smaller benzodiazepine doses (dose reduction by 25% to 50%) may be required if the patient is receiving concurrent macrolide antibiotic dosing.
Theophylline
Caution should be exercised with patients receiving concomitant theophylline therapy as roxithromycin may increase theophylline levels, which may lead to theophylline toxicity.
Others:
The concomitant administration of cimetidine may increase plasma concentration of roxithromycin. Cimetidine inhibits hepatic microsomal enzymes and may reduce the metabolism of roxithromycin, leading to increased effects.
Concomitant administration of roxithromycin and ranitidine does not alter the pharmacokinetic parameters of roxithromycin.

PREGNANCY AND LACTATION
Safety in pregnancy and lactation has not been established.

WARNINGS
In patients with severe impaired liver function (i.e. cirrhosis with jaundice and/or ascites), caution should be observed and the recommended daily dose of 150 mg twice daily should be halved to 150 mg daily.
Attention should be paid to the possibility of cross-resistance between clarithromycin and other macrolide antibiotics as well as lincomycin and clindamycin.

DOSAGE AND DIRECTIONS FOR USE
150 mg        :        One tablet by mouth 12 hourly, before meals

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The following side-effects may occur:
- Gastro-intestinal disturbances: abdominal discomfort and cramp, nausea, vomiting and diarrhoea.
- Symptoms of pancreatitis have been observed.
- Supra-infection with resistant organisms may occur. Repeated evaluation of the patients condition is essential. If supra-infection occurs during therapy, appropriate measures should be taken. Pseudomonas colitis has been reported.
- Hypersensitivity reactions appear to be uncommon and may include pruritis, urticaria, skin rash, angio-oedema, purpura, bronchospasm as well as occasional cases of anaphylaxis. Hypersensitivity reactions may also be responsible for the hepatotoxicity sometimes reported in patients receiving macrolide antibiotics. Symptoms indicative of cholestasis, including upper abdominal pain (sometimes very severe), nausea and vomiting, abnormal liver function values, raised serum bilirubin and usually jaundice, may be accompanied by rash, fever and eosinophilia. Symptoms usually occur initially in patients who have been receiving the drug for more than 10 days, although they may develop more quickly in patients given the drug in a previous course of treatment.
- Dizziness, headache, paraesthesia.
- Disturbances in taste and/or smell have been reported.
- Although renal clearance of roxithromycin is normally low, accumulation may occur in renal insufficiency.
- In the elderly patient (more than 65 years), the half-life is prolonged.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
See side effects and special precautions.
Treatment is symptomatic and supportive.

IDENTIFICATION
ROXITHROMYCIN-HEXAL 150        White, round, convex film-coated tablets with a smooth surface without scratches, scored on one face, embossed on one side: R 150.
Diameter : 9.0 +0.2 mm
Thickness : 4.2 +0.3 mm

PRESENTATION
ROXITHROMYCIN-HEXAL 150: PVC/aluminium blister packs of 10 tablets

STORAGE INSTRUCTIONS
Store in a cool, dry place, below 25°C.
Protect from light.
Keep out of reach of children.

REGISTRATION NUMBER:
35/20.1.1/0222

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Hexal Pharma (SA) (PTY) Ltd
10 Fangio Road
Mahogany Ridge, Westmead
Pinetown

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
MAY 2002

        ROXAP1

Updated on this site: January 2003
Source: Pharmaceutical Industry

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