INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
RULIDE (tablets)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form )

RULIDE (tablets)

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

Intracellular activity: Roxithromycin is highly concentrated in polymorphonuclear leukocytes 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 normal subject.
Distribution and Elimination: After administration of one tablet to a normal subject, the pharmacokinetic parameters are:

-	mean maximum concentration: 6,6 mg/L
-	mean concentration (12 hours after administration): 1,8 mg/L
-	mean elimination half-life: 10,5 hours

After repeated administration to a normal subject (150 mg every 12 hours), a plasma steady state is reached between the second and fourth day. The steady state concentrations are:

-	maximum concentration: 9,3 mg/L
-	minimum concentration: 3,6 mg/L

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: The following levels are obtained: in the lung (5,6 to 3,7 micrograms/g) and prostate (2,8 to 2,4 micrograms/g). These tissue concentrations are observed 6 hours and 12 hours respectively after repeated doses of 150 mg Roxithromycin. In the tonsils the levels obtained are 2,8 micrograms/g, 4,7 micrograms/g and 1,3 micrograms /g at 4,8 and 12 hours respectively, after repeated doses of 150 mg roxithromycin.
Binding to Plasma Protein: 96%: Roxithromycin is bound essentially to alpha₁ -acid glycoproteins. This binding is saturable and falls at Roxithromycin concentrations exceeding 5 mg/L.
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 pneumoniae, 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 macrolides.
Concomitant administration of roxithromycin with vasoconstrictive ergot (alkaloid) derivatives is contra-indicated since symptoms of ergotism have been described with other macrolides.

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.

DOSAGE AND DIRECTIONS FOR USE:
One tablet (150 mg) by mouth every 12 hours, before meals.
In the treatment of beta-haemolytic streptococcal infections, a therapeutic dose must be administered for at least 10 days.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:

-	Pregnancy: safety in pregnancy and lactation has not been established.
-	Although renal clearance of Roxithromycin is normally low, accumulation may occur in renal insufficiency.
-	In the elderly patient (>65 years), the half-life is prolonged.

The following side-effects may occur:

-	Gastrointestinal symptoms: nausea, vomiting, gastric pain, diarrhoea.
-	Symptoms of pancreatitis have been observed.
-	Hypersensitivity reactions: rash, urticaria, angio-oedema, purpura, bronchospasm, anaphylactic shock.
-	Dizziness, headache, paraesthesia.
-	Increases in ASAT, ALAT and/or alkaline phosphatase. Cholestatic or acute hepatocellular hepatitis. Disturbances of taste and/or smell have been reported.
-	Superinfection: use of roxithromycin may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Drug Interactions:

-	Concomitant administration contra-indicated: Vasoconstrictive ergot alkaloids.
-	Concomitant administrations not recommended:
•	Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended.
•	Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended.

Precautions for use:

•	No clinically significant interaction with warfarin has been found in studies in volunteers: however increases in prothrombin time or International Normalised Ratio (INR) have been reported in patients treated with roxithromycin and vitamin K antagonists. It is prudent practice to monitor INR during combined treatment with roxithromycin and vitamin K antagonists.
•	An in-vitro study has shown that roxithromycin can displace protein-bound disopyramide; such an effect in vivo may result in increased free serum levels of disopyramide. Consequently ECG and. if possible, disopyramide serum levels should be monitored.
•	Digoxin and other cardiac glycosides: Roxithromycin may increase the absorption of digoxin, resulting in cardiac glycoside toxicity Consequently, in patients treated with roxithromycin and digoxin or another cardiac glycoside, ECG and the serum level of the cardiac glycoside should be monitored.
•	Roxithromycin may increase the area under the concentration curve and the half-life of midazolam; therefore, the effects of midazolam may be enhanced and prolonged in patients treated with roxithromycin.
•	Caution should be exercised with patients receiving concomitant theophylline therapy as roxithromycin may increase serum theophylline levels, which may lead to theophylline toxicity.

Others:

•	Concomitant administration of roxithromycin and ranitidine does not alter the pharmacokinetic parameters. of roxithromycin:

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Treatment is symptomatic and supportive.

IDENTIFICATION:
White, biconvex, cylindrical, film-coated tablets, 9 mm in diameter engraved "164" on one side.

PRESENTATION:
Blister packs of 10 and 100 tablets.

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

REGISTRATION NUMBER:
V/20.1.1/205

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Hoechst Marion Roussel Limited
16th Road, Midrand

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
17 April 1991.

Hoechst Marion Roussel Ltd.
16th Road
Midrand

                RE2-B0899

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