Roxithromycin .............................. 150 mg
Excipients q.s ……………… 1 tablet
Film coated tablet.
Product description: A white to off-white, round, film-coated tablet, plain on both sides, undamaged edges.
Box of 3 blisters x 10 film coated tablets.
Pharmacotherapeutic group: Antibacterials for systemic use. ATC code: J01FA06.
Roxithromycin is a macrolide antibiotic.
Absorption
Absorption is rapid. Roxithromycin appears to be stable in an acid medium and the antibiotic is found in serum from the 15th minute. The serum peak is 2.2 hours after taking 150 mg on an empty stomach. It has been shown that taking the drug ¼ hour before a meal does not lead to changes in pharmacokinetics in healthy subjects.
Distribution
The pharmacokinetic parameters, after a single tablet intake in normal subjects, are as follows:
- Average maximum plasma concentration: 6.6 mg/l
- Concentration (12 hours after 1 intake) on average: 1.8 mg/l
- Mean elimination half-life: 10.5 hours.
After administration of repeated doses in normal subjects (150 mg every 12 hours for 10 days), at the plasma level, the steady state is reached between the 2nd and 4th day. Steady-state plasma concentrations are as follows:
- Maximum concentration: 9.3 mg/l
- Minimum concentration: 3.6 mg/l.
Due to the absence of accumulation of the product, the daily dose can therefore be given in 2 doses, 12 hours apart, which ensures a plasma concentration of the antibiotic effective on sensitive germs for 24 hours.
Macrolides penetrate and accumulate in phagocytes (neutrophils, monocytes, peritoneal and alveolar macrophages).
Intraphagocytic concentrations are high in humans.
These properties explain the activity of roxithromycin on intracellular bacteria.
Tissue spread
Good, especially in lung tissue, tonsils, prostate tissue, 6 and 12 hours after repeated doses of roxithromycin.
Plasma protein binding: 96%; roxithromycin binds primarily to alpha 1 acid glycoprotein. This binding is saturable and decreases for a concentration of roxithromycin greater than 4 mg/l.
Very low passage of roxithromycin in milk has been observed: less than 0.05% of the quantity present in the administered dose.
Biotransformation
Roxithromycin is relatively poorly biotransformed (by CYP3A), more than half of the product being excreted unchanged.
Three structures have been identified in urine and faeces: descladinose roxithromycin, the most abundant derivative, and N-mono and N-didemethyl roxithromycin, minor metabolites.
The proportions of roxithromycin and its three derivatives are similar in urine and faeces.
Based on in vitro studies, roxithromycin demonstrated weak inhibition of CYP3A, but did not inhibit CYP1A2, CYP2C9, CYP2C19, or CYP2D6.
Elimination
Elimination is mainly faecal:
After oral administration of roxithromycin-14C, urinary radioactivity represents in 72 hours only 12% of the total excreted in urine and faeces.
Attention is drawn, particularly among vehicle drivers and machine users, to the risks of dizziness associated with the use of this medication.
Visual disturbances and blurred vision may influence the ability to drive or use machines (see section Undesirable effects).
Special warnings
Hepatic insufficiency
In case of severe hepatic insufficiency, the administration of roxithromycin is not recommended. In mild to moderate hepatic impairment, roxithromycin should be used with caution. If administration is necessary, liver tests should be regularly monitored and possibly a reduction in dosage should be given.
Renal insufficiency
The renal elimination of roxithromycin and its metabolites are low (approximately 10% of the oral dose), which means that the dosages cannot be modified in the event of renal insufficiency.
Age
In the elderly, the half-life is prolonged. However, after repeated administration of 150 mg every 12 hours, the maximum plasma concentrations and the area under the curve, at steady state between 2 doses of roxithromycin, are not different from those obtained in young patients. It is therefore not necessary to modify the dosage in the elderly.
Association with ergot alkaloids
Severe vasoconstriction ("ergotism") with possible necrosis of the extremities has been reported with macrolides in combination with vasoconstrictor ergot alkaloids.
It is necessary to verify the absence of treatment with these alkaloids before any prescription of roxithromycin (see sections Contraindications; Interactions).
Concomitant administration of roxithromycin with dopaminergic ergot alkaloids is not recommended (see section Interactions).
Serious bullous reactions
Cases of severe bullous skin reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported for roxithromycin. If symptoms or signs of AGEP, SJS, or TEN (e.g., progressive skin rashes often accompanied by blistering or mucosal lesions) are observed, roxithromycin therapy should be discontinued.
Precautions for use
QT interval prolongation
Under certain conditions, macrolides, including roxithromycin, have the potential to prolong the QT interval. Therefore, roxithromycin should be used with caution in patients with congenital prolonged QT syndrome, proarrhythmic conditions (e.g. uncorrected hypokalaemia or hypomagnesaemia, bradycardia), and in patients receiving treatments that may prolong the QT interval (see sections Interactions; Undesirable effects).
Myasthenia gravis
As with other macrolides, roxithromycin may aggravate myasthenia gravis.
Clinical monitoring in case of prolonged treatment.
Monitoring of hepatic function, renal function and blood count is recommended, particularly in the event of prolonged treatment (e.g., treatment duration greater than 2 weeks) (See section Undesirable effects).
Clostridium difficile infection
Cases of Clostridium difficile associated diarrhea (CDAD) have been reported with the use of virtually all antibiotics, including roxithromycin (see section Undesirable effects). The severity can range from mild diarrhea to life-threatening pseudomembranous colitis. Antibiotic treatment alters the flora of the colon, leading to overgrowth of C. difficile.
C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients who present with diarrhea following antibiotic use and roxithromycin should be discontinued immediately. It is important that this diagnosis be considered in patients who present with diarrhea during or after taking an antibiotic.
Excipients
This medicine contains less than 1 mmol of sodium (23 mg) per tablet, that is to say essentially "sodium-free".
Pregnancy
It is preferable, as a precautionary measure, not to use roxithromycin during pregnancy. Indeed, the clinical data are insufficient, although the animal data do not show any malformative or foetotoxic effect at doses higher than 200 mg/kg/day or 40 times the therapeutic dose in humans.
Breastfeeding
Passage of most macrolides into breast milk has been documented, with concentrations in breast milk equal to or greater than plasma concentrations. However, the quantities ingested by the newborn remain low compared to pediatric dosages. The major risk is a change in the child's intestinal flora. As a result, breastfeeding is possible. In the event of the occurrence of digestive disorders in the infant (intestinal candidiasis, diarrhea), it is necessary to interrupt breastfeeding (or the medicine).
When taking cisapride in newborns or breastfed infants, the administration of macrolides to the mother is contraindicated as a precautionary measure, due to the potential risk of interaction in the child (torsade de pointes).
Contraindicated combinations (see section Contraindications)
+ Colchicine
Increased side effects of colchicine, with potentially fatal consequences.
+ Cisapride
Increased risk of ventricular arrhythmias, in particular torsades de pointes.
+ Ergotamine, dihydroergotamine
Ergotism with possibility of necrosis of the extremities (decreased hepatic elimination of ergotamine and inhibition of hepatic elimination of dihydroergotamine).
Combinations not recommended (see section Special warnings and precautions for use - Special warnings).
+ Dopaminergic ergot alkaloids (bromocriptine, cabergoline, lisuride, pergolide) (see section Special warnings and precautions for use).
Increase in plasma concentrations of dopaminergic with possible increase in its activity or appearance of overdose signs.
+ Medicines that may cause torsades de pointes (see section Special warnings and precautions for use).
(amiodarone, amisulpride, arsenious, bepridil, chlorpromazine, citalopram, cyamemazine, diphemanil, disopyramide, dofetilide, dolasetron, domperidone, dronedarone, droperidol, erythromycin, escitalopram, flupentixol, fluphenazine, halofantrine, haloperidol, hydroquinidine, ibutilide, levofloxacin, levomepromazine, levomepromazine, mequitazine, methadone, mizolastine, moxifloxacin, pentamidine, pimozide, pipamperone, pipotiazine, prucalopride, quinidine, sertindole, sotalol, spiramycin, sulpiride, sultopride, tiapride, toremifene, vandetanib, vincamine, zuclopenthixol).
This serious heart rhythm disorder can be caused by a number of medicines, antiarrhythmics or not. Hypokalemia (in particular induced by hypokalaemic drugs) is a factor contributing as well as causing bradycardia (in particular induced by bradycardic drugs) or pre-existing prolongation of the QT interval, congenital or acquired. Medicines causing this adverse effect include class Ia and III antiarrhythmics, and certain neuroleptics. Other molecules not belonging to these classes are also involved.
Increased risk of ventricular arrhythmias, in particular torsades de pointes.
Clinical and electrocardiographic monitoring during the association.
Combinations subject to precautions for use
+ Bradycardic
Increased risk of ventricular arrhythmias, in particular torsades de pointes. Clinical and electrocardiographic monitoring.
+ Antivitamin K (acenocoumarol, fluindione, phenindione, warfarin)
Increased effect of vitamin K antagonist and risk of bleeding. More frequent monitoring of INR. Possible adaptation of the dosage of vitamin K antagonist during treatment with macrolide and after its discontinuation.
Special problems of INR imbalance
Numerous cases of increased activity of oral anticoagulants have been reported in patients receiving antibiotics. The marked infectious or inflammatory context, patient's age and general condition appear as risk factors. In these circumstances, it appears difficult to distinguish between the infectious pathology and its treatment in the occurrence of the INR imbalance.
However, certain classes of antibiotics are more implicated: these include fluoroquinolones, macrolides, cyclins, cotrimoxazole and certain cephalosporins.
+ Atorvastatin, simvastatin
Increased risk of adverse effects (concentration-dependent) such as rhabdomyolysis.
Use lower doses of cholesterol-lowering medicines.
+ Ciclosporin
Risk of increased ciclosporin blood concentrations and serum creatinine.
Assay of ciclosporin blood concentrations, monitoring of renal function and adjustment of dosage during the combination and after discontinuation of the macrolide.
+ Digoxin and other digitalis
Increase in digoxinemia by increasing its absorption.
Clinical monitoring (symptomatology and ECG control) and possibly digoxinemia during treatment with azithromycin and after its discontinuation.
This clinical monitoring is mandatory if symptoms suggesting an overdose of digitalis occur.
The cardiac toxicity of digitalis can manifest itself by the following symptoms: nausea, vomiting, diarrhoea, headache or dizziness, cardiac arrhythmias or conduction disturbances.
Associations to consider
+ Midazolam
Slight increase in sedation.
+ Theophylline (and, by extrapolation, aminophylline)
Risk of increased theophyllinemia, particularly in children. However, this generally does not require a change in the usual dosage.
+ Roxithromycin is a weak CYP3A4 inhibitor. It can decrease up to 2 times, the elimination of medicines metabolized mainly by CYP3A. Caution should be exercised when co-prescribing roxithromycin with a medicine metabolised by CYP3A (such as rifabutin and bromocriptine).
The table below summarizes the adverse reactions identified during clinical trials and recorded in the pharmacovigilance database, by system organ category and by frequency. Frequency categories are defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); and frequency not known (cannot be estimated from the available data).
Please inform your doctor of all undesirable effects upon drug administration.
Management
Gastric lavage and symptomatic treatment. There is no specific antidote.
Store in dry places, not exceeding 30oC, protect from light.
Therapeutic indications derive from the antibacterial activity and the pharmacokinetic characteristics of roxithromycin. Therapeutic indications take into account both the clinical studies to which this medicine has given rise and its place in the range of antibacterial products currently available.
Roxithromycin is indicated for the treatment of infections caused by susceptible microorganisms:
- Pharyngitis due to group A beta-hemolytic streptococcus, as an alternative to treatment with beta-lactams, particularly when the latter cannot be used.
- Acute sinusitis. Given the microbiological profile of these infections, macrolides are indicated when treatment with a beta-lactam is impossible.
- Superinfections of acute bronchitis.
- Exacerbations of chronic bronchitis.
- Community-acquired pneumonia in patients:
+ without risk factors,
+ without signs of clinical severity,
+ in the absence of clinical elements suggestive of a pneumococcal etiology.
If atypical pneumonia is suspected, macrolides are indicated regardless of severity and terrain.
- Benign skin infections: impetigo, ecthyma, eczama, infectious dermohypodermitis (particularly erysipelas), erythema;
- Non-gonococcal genital infections.
Official recommendations for the appropriate use of antibacterials should be considered.
This medicine must never be used in the following situations:
Hypersensitivity to the active substance or to any of the excipients listed in section Excipients or to macrolides.
Association with:
+ vasoconstrictor ergot alkaloids: dihydroergotamine, ergotamine (see section Interactions),
+ colchicine (see section Interactions),
+ cisapride (see section Interactions).
- Breastfeeding mothers treated with cisapride (see section Use in pregnancy and lactation).
METHOD OF ADMINISTRATION
For oral administration.
POSOLOGY
Adults: 300 mg per day, i.e. one 150-mg tablet in the morning and evening, preferably before meals.
Pediatric population: Not applicable
Duration of the treatment
The duration of treatment for pharyngitis is 10 days
Or as directed by the physician.
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