Adults

ROMAC is indicated for the treatment of the following types of mild to   moderately severe infections in adults caused by or likely to be caused by susceptible micro-organisms:

q  URTI: acute pharyngitis, tonsillitis, sinusitis

q  LRTI: acute bronchitis and acute exacerbations of chronic bronchitis; community acquired pneumonia

q  Skin and skin structure infections

q  Non gonococcal urethritis.

Children

 ROMAC tablets are indicated for the treatment of the following mild to moderately severe infections in children caused by or likely to be caused by susceptible micro-organisms:

q  Acute pharyngitis

q  Acute tonsillitis

q  Impetigo

Appropriate culture and sensitivity tests should be performed when necessary to determine an organism’s susceptibility and thus treatment suitability. Therapy with Roxithromycin may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued

Route of administration: Oral

         Adults

ROMAC should be taken at least 15 minutes before food or on an empty stomach (i.e. more than 3 hours after a meal).

The recommended dosage is 300mg per day which may be taken according to one of the following alternative dosage regimens:

For atypical pneumonia, the recommended dosage is one 150 mg tablet twice daily.

ROMAC 150mg and 300mg film-coated tablets must be swallowed whole with a drink.

The usual duration of treatment is 5 to 10 days depending on the indication and clinical response.

Streptococcal throat infections require at least 10 days of therapy. A small proportion of patients with non-gonococcal genital infections may require 20 days for complete cure.

Children

The recommended dose and duration of treatment should NOT be exceeded in children (see Precautions).

ROMAC should be taken at least 15 minutes before food or on an empty stomach (i.e. more than 3 hours after a meal).

ROMAC is administered twice daily at a dose of 5 to 8 mg/kg per day.

For children 40 kg and over: One ROMAC 150 mg tablet morning and evening.

The usual duration of treatment is five to ten days depending on the indication and clinical response. Streptococcal throat infections require ten days of therapy. The duration of treatment should not exceed ten days.

The safety of Roxithromycin has not been demonstrated in patients with impaired hepatic or renal function. Caution should be exercised if Roxithromycin is administered to patients with impaired hepatic or renal function. If administered to patients with severe impaired hepatic function (eg. hepatic cirrhosis with jaundice and/or ascites), consideration should be given to reducing the daily dosage to half the usual dosage.

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.

When indicated, incision, drainage or other appropriate surgical procedures should be performed in conjunction with antibiotic therapy.

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 Clostridium difficile should be considered. Fluids, electrolytes and protein replacement therapy should be provided when indicated.

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

Roxithromycin, like erythromycin, has been shown in vitro to elicit a concentration – dependent lengthening in cardiac action potential duration. Such an effect is manifested only at supra – therapeutic concentrations. Accordingly, the recommended doses should not be exceeded.

In certain conditions macrolides, including roxithromycin, have the potential to prolong the QT interval. Therefore Roxithromycin should be used with caution in patients with congenital prolongation of the QT interval, with ongoing proarrhythmic conditions (ie uncorrected hypokalemia or hypomagnesaemia, clinically significant bradycardia), and in patients receiving Class IA and III antiarrhythmic agents (see INTERACTIONS WITH OTHER MEDICINES).

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

Severe bullous reactions:  Cases of severe bullous skin reactions such as Stevens Johnson syndrome (SJS) or toxic epidermal necrosis (TEN) have been reported with Roxithromycin.   If symptoms or signs of SJS   or TEN (e.g. progressive  skin rash often with blisters  or mucosal  lesions) are present,  the treatment  should be discontinued.

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-1acid glycoprotein, such as disopyramide.

Roxithromycin does not appear to interact with oral contraceptives containing oestrogens and progestogens, prednisolone, carbamazepine, ranitidine or antacids.

Theophylline

A study in normal subjects concurrently administered Roxithromycin and theophylline has shown some increase in 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.

Ergot alkaloids

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.

Disopyramide

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.

Terfenadine

Certain  macrolides  are capable of a pharmacokinetic   interaction  with terfenadine 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  and studies  in a limited  number  of healthy volunteers  have not shown any pharmacokinetic   interaction  or relevant ECG changes,  the association  of Roxithromycin  and terfenadine  is not recommended.

Astemizole, Cisapride, Pimozide

Other drugs, such as astemizole, cisapride or pimozide, which are metabolized 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 therefore 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; therefore, concomitant administration of Roxithromycin and such drugs is not recommended.

Warfarin

While no interaction was observed in volunteer studies, Roxithromycin appears to interact with warfarin. Increases in prothrombin time (international normalized 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 Vitamin K antagonists.

Digoxin and Other Cardiac Glycosides

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 which may suggest cardiac glycoside overdosage occur.

Midazolam

Roxithromycin, like other macrolides, may increase the area under the midazolam concentration- time curve and the midazolam half-life; therefore 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.

Theophylline and Cyclosporin

A slight increase in plasma concentrations of theophylline or cyclosporin A has been observed.

This does not generally necessitate altering the usual dosage.

1-1-1       Use during pregnancy

Reproductive studies in rats, mice and rabbits at doses of 100, 400 and 135mg/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 foetus has not been established.

1-1-2       Use during lactation

Small amounts of Roxithromycin are excreted in the breast milk. Breast feeding or treatment of the mother should be discontinued as necessary

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 (dyspepsia), diarrhoea (sometimes containing blood), anorexia, flatulence. 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  had received  other drugs for which pancreatitis  is a known  adverse reaction,  pseudomembranous   colitis

 Infections  and infestations:

Superinfection:  As with other antibiotics, the use of Roxithromycin,  especially  if prolonged,  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.

        Ear and labyrinth  disorders:  

       Temporary deafness,  hypoacusis, vertigo

Blood and lymphatic  system  disorders:

Eosinophilia, agranulocytosis, neutropenia,  thrombocytopenia

Respiratory,  thoracic  and mediastinal  disorders:

Bronchospasm.

Hypersensitivity 

Urticaria, rash, pruritus, angioedema. Rarely, serious allergic reactions may occur such as asthma, bronchospasm, anaphylactic-like reactions, anaphylactic shock, purpura, glottic oedema, generalised oedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome.

Liver

Moderate increase in serum transaminases, AST-ALT and/or alkaline phosphatase levels have been observed and are somewhat more likely to occur in the elderly (> 65 years of age). Acute cholestatic hepatitis and acute hepatocellular injury (sometimes with jaundice), are rarely reported.

Others

Hallucination, headache, dizziness, paraesthesia, tinnitus, malaise, moniliasis, disorders of taste and/or smell.

To report any side effect (s):

Saudi Arabia: National Pharmacovigilance & Drug Safety Centre (NPC)

q  Fax: +966-11-205-7662

q  Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

q  Toll free phone: 8002490000

q  E-mail: npc.drug@sfda.gov.sa

q  Website: www.sfda.gov.sa/npc

Symptomatic treatment should be provided as required. There is no specific antidote

Pharmacotherapeutic group: Antibacterial, Macrolids

 ATC Code: J01FA06

Roxithromycin is a semi-synthetic macrolide antibiotic. It is very similar in composition, chemical structure and mechanism of action to erythromycin, azithromycin, or clarithromycin. Roxithromycin 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), and Haemophilus ducreyi. 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.

Mechanism of action

Roxithromycin prevents bacteria from growing, by interfering with their protein synthesis. Roxithromycin binds to the subunit 50S of the bacterial ribosome, and thus inhibits the translocation of peptides. Roxithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particularly Legionella pneumophila

Absorption

Roxithromycin is absorbed after oral administration with an absolute bioavailability approximately 50%. Peak plasma concentrations following administration of 150mg and 300mfilm-coated tablets are achieved in young and elderly adult patients approximately 1 to 2 hourpost-dose.  However, Rulide D 50 mg tablets for suspension appear to be absorbed more slowthan the Rulide film-coated tablets, with peak plasma concentrations achieved approximatelhours post dose.

As food intake decreases absorption, Rulide should be administered at least 15 minutes beforfood or, alternatively, on an empty stomach (i.e. more than 3 hours after a meal).

Absorption is not linear; with increasing doses in the range 150mg to 300mg, peak plasma levand AUC do not increase in proportion to the dose.

After repeated administration of 2.5mg/kg every 12 hours to children, the average peak plasconcentration at steady state was 9mg/L and the AUC was 61mg.h/L.

Following administration of a single oral dose of Rulide 150 mg to healthy young adults, the mpeak plasma concentration was 6.6 mg/L and the AUC was 69mg.h/L. At steady state followdoses of 150 mg twice daily, the mean peak plasma concentration was 9.3 mg/L and the AUC w 71mg.h/L.

In elderly patients, the mean peak plasma concentration following a single 150 mg dose wasmg/L and the AUC was 148mg.h/L. At steady state, a dosage regimen of 150 mg twice daiproduced a mean peak plasma concentration of 11.3mg/L and an AUC of 83mg.h/L.

Following administration of a single oral dose of Rulide 300 mg to healthy young adults, the mpeak plasma concentration was 9.7 mg/L and the AUC was 98mg.h/L. At steady state followdoses of 300 mg once daily, the mean peak plasma concentration was 10.9mg/L and the AUC w77mg.h/L.

In elderly patients, the mean peak plasma concentration following a single 300 mg dose was 10.8 mg/L and the AUC was 197mg.h/L.

Distribution

Roxithromycin is 92-96% bound to plasma proteins (principally alpha-1-acid glycoprotein, but also albumin) at concentrations less than 4.2mg/L. The binding is saturable: in subjects with normal plasma levels of alpha-1-acid glycoprotein, the extent of binding decreases when plasma concentrations of roxithromycin exceed 4.2mg/L. At a plasma concentration of 8.4mg/L, approximately 87% of the drug is protein bound.

Roxithromycin is highly concentrated in polymorphonuclear leucocytes and macrophages, where levels 30 times those in serum have been reported.

Elimination

The mean half-life of Roxithromycin is approximately 12 hours in young adults and 20 hours in children. The apparently longer half life in children does not cause excessive accumulation: Cmin and AUC values are comparable for adults and children.

The half-life is prolonged to 25 hours in adults with impaired hepatic function and 18 hours in adults with renal insufficiency.

The mean half-life in elderly patients is approximately 27 hours.

Metabolism

Roxithromycin undergoes limited metabolism in the body, presumably in the liver. The major metabolite is descladinose roxithromycin. Two minor metabolites have also been identified. Plasma levels of roxithromycin are approximately twice those of all metabolites; a similar ratio is seen in the urine and faeces.

Approximately 7% of a dose is excreted in the urine and 13% is eliminated via the lungs. Faecal excretion, which represents the unabsorbed fraction and the small proportion excreted by the liver, accounts for approximately 53% of the dose. The fate of the remainder is unknown.

When roxithromycin plasma levels are above 4.2mg/L, renal clearance increases because reduced plasma protein binding (see ‘Distribution’) causes increased levels of unbound roxithromycin, which may be excreted by the kidneys.   

Microbiology

Roxithromycin is bacteriostatic at low concentrations and bactericidal at high concentrations. It binds to the 50S subunit of the 70S ribosome thereby disrupting bacterial protein synthesis.

A prolonged post antibiotic effect has been observed with roxithromycin. Whilst the clinical significance of this remains uncertain, it supports the rationale for once daily dosing. Although clinical data has demonstrated the efficacy and safety of once daily dosing in adults, this has not been demonstrated in children.

At plasma concentrations achieved with the recommended therapeutic doses, roxithromycin has been demonstrated to have in vitro and clinical activity against the following microorganisms:

Streptococcus pneumoniae, Streptococcus pyogenes, Mycoplasma pneumoniae, Moraxella catarrhalis, Ureaplasma urealyticum, Chlamydia spp.

Roxithromycin has been demonstrated to have clinical activity against the following microorganisms which are partially sensitive in vitro to roxithromycin:

Haemophilus influenzae, Staphylococcus aureus (except MRSA).

The following strains of microorganisms are resistant:

Multiresistant Staphylococcus aureus, Enterobacteriaceae, Pseudomonas spp., Acinetobacter spp.

Susceptibility Tests

Dilution or diffusion techniques – either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (eg NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small-uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Note: The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.

Using the NCCLS method of susceptibility testing with a 15mcg roxithromycin disc, susceptible  organisms other than Haemophilus influenzae produce zones of inhibition 21mm or greater.  A zone size of 10 to 20mm should be considered intermediate and a zone size of 9mm or less indicates resistance. A bacterial isolate may be considered susceptible if the MIC value for roxithromycin is less than or equal to 1 mg/L. Organisms are considered resistant if the MIC value is greater than 8 mg/L.

For Haemophilus influenzae, zones of inhibition 10 mm or greater indicate susceptibility when CO₂ considered susceptible if the MIC value for roxithromycin is less than or equal to 8mg/L.

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 to180mg/kg/day.  

q  Microcrystalline Cellulose 50 micrometer 

q  Colloidal anhydrous silica

q  Croscarmellose sodium

q  Magnesium Stearate

q  Hydroxypropyl cellulose

q  Polyethylene glycol 4000

q  Titanium dioxide

q  Hydroxyl propyl methyl cellulose Type 2910

q  Polyethylene glycol 400

Not applicable

      ROMAC 150 Tablets should not be stored at a temperature above 30ºC

ROMAC 150 Tablets are packed in boxes of 10 Tablets blistered in aluminium foil

No special requirements.

 Any unused product or waste material should be disposed of in accordance with local requirements.