Roxihexal^® (Tablets) Instructions for Use

Marketing Authorization Holder

Hexal AG (Germany)

Manufactured By

Salutas Pharma, GmbH (Germany)

ATC Code

J01FA06 (Roxithromycin)

Active Substance

Roxithromycin (Rec.INN registered by WHO)

Dosage Forms

	Roxihexal®	Film-coated tablets, 50 mg: 10 or 20 pcs.
		Film-coated tablets, 150 mg: 10 or 20 pcs.
		Film-coated tablets, 300 mg: 7, 10 or 14 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, oblong, with a score on both sides.

Excipients: microcrystalline cellulose, povidone K30, poloxamer 188, magnesium stearate, isopropyl alcohol, purified water, titanium dioxide, hypromellose, PEG 400.

10 pcs. – blisters (1) – carton packs.
10 pcs. – blisters (2) – carton packs.

Film-coated tablets white, round, convex, with a smooth surface, with a score on one side and the marking “R150” on the other side.

Excipients: microcrystalline cellulose, povidone K30, poloxamer 188, magnesium stearate, isopropyl alcohol, purified water, titanium dioxide, hypromellose, PEG 400.

10 pcs. – blisters (1) – carton packs.
10 pcs. – blisters (2) – carton packs.

Film-coated tablets white, round, convex, with a smooth surface, with a score on one side and the marking “R300” on the other side.

Excipients: microcrystalline cellulose, povidone K30, poloxamer 188, magnesium stearate, isopropyl alcohol, purified water, titanium dioxide, hypromellose, PEG 400.

7 pcs. – blisters (1) – carton packs.
10 pcs. – blisters (1) – carton packs.
14 pcs. – blisters (1) – carton packs.

Clinical-Pharmacological Group

Antibiotic of the macrolide group

Pharmacotherapeutic Group

Antibiotic-macrolide

Pharmacological Action

A semi-synthetic antibiotic of the macrolide group. The mechanism of action is due to the inhibition of protein synthesis in the ribosomes of microorganisms.

Active against gram-positive bacteria: Streptococcus spp. (including Streptococcus pneumoniae), Bacillus cereus, Corynebacterium diphtheriae, Listeria monocytogenes; against aerobic gram-negative bacteria Bordetella pertussis, Campylobacter coli, Campylobacter jejuni, Gardnerella vaginalis, Haemophilus ducreyi, Helicobacter pylori, Legionella pneumophilia, Moraxella catarrhalis, Neisseria meningitides, Pasteurela multocida; against anaerobic bacteria Actinomyces spp., Bacteroides urealiticus, Clostridium spp. (except Clostridium difficile), Eubacterium spp., Peptococcus spp., Peptostreptococcus spp., Porphyromonas spp., Prevotella melaninogenica, Propionibacterium acnes.

The drug is also active against Borrelia burgdorferi, Enterococcus spp., Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Mycoplasma pneumoniae, Cryptosporidum spp., Mycobacterium tuberculosis, Rickettsia conorri, Rickettsia richttsii, Toxoplasma gondii.

Moderately sensitive to the drug are Haemophilus influenzae, Neisseria gonorrhoeae, Vibrio cholerae, Bacteroides oralis, Ureaplasma urealyticum, Staphylococcus aureus, Staphylococcus epidermidis.

Resistant to the drug are Bacteroides fragilis, Mycobacterium hominis, Enterobacter spp.

Pharmacokinetics

Absorption

When taken orally, Roxithromycin is rapidly absorbed from the gastrointestinal tract and is detected in the blood within 15 minutes. C_max in blood plasma is reached in approximately 2 hours. After a single oral dose of the drug in tablet form at a dose of 150 mg, the concentration of roxithromycin in the blood plasma in adults averages about 6.6 mg/l (from 5.4 to 7.9 mg/l). The kinetics of the drug relative to the administered dose is non-linear.

In adults taking the drug in 150 mg tablets at 12-hour intervals, therapeutically active concentrations are still detectable after 24 hours. When taking the drug 150 mg twice daily for 10 days, C_ss is reached between days 2 and 4 and is about 9.3 mg/l; when taking 300 mg twice daily for 11 days – 10.9 mg/l.

When taking the drug at a dose of 300 mg at 24-hour intervals for 11 days, C_max in blood plasma is about 10.9 mg/l.

In elderly patients taking the drug at a dose of 300 mg, C_max in plasma is reached in approximately 2.2 hours and is about 10.2 mg/l. After 24 hours, the concentration of roxithromycin in plasma is 3.3 mg/l.

In children at a dose of 2.5 mg/kg/day in 2 divided doses, C_max in blood plasma is reached in approximately 2 hours and is 8.7-10.1 mg/l. Administration at 12-hour intervals maintains effective plasma concentrations for 24 hours.

Distribution

Roxithromycin penetrates well into tissues, especially into the lungs, palatine tonsils, and prostate gland, as well as into neutrophils and monocytes, stimulating their phagocytic activity. V_d is 31.2 l.

It practically does not penetrate the blood-brain barrier.

Binding to plasma proteins (mainly to acid glycoprotein, to a lesser extent to albumin and lipoproteins) is concentration-dependent, is about 96%, and decreases when the roxithromycin concentration increases above 4 mg/l.

Metabolism

Partially metabolized. Roxithromycin is detected in plasma only in unchanged form.

Excretion

T_1/2 of roxithromycin from blood plasma is dose-dependent and ranges from 8.3 to 10.5 hours.

The main part of the active substance is excreted in the feces. About 12% of the administered dose is excreted in the urine over 72 hours. In urine, Roxithromycin is detected in unchanged form (50%) and in the form of 3 metabolites. The main metabolite is the decladinyl derivative, the other two are N-monodemethyl- and N-dimethyl-derivatives. The same metabolites are found in feces.

Renal clearance is dose- and time-dependent.

Pharmacokinetics in special clinical situations

In children aged from 1 month to 13 years, T_1/2 is up to 20 hours.

In elderly patients, T_1/2 increases and is approximately 26-27 hours, AUC remains unchanged. In patients with renal failure, T_1/2 is 16 hours. In severe liver dysfunction, T_1/2 increases to 25 hours.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to the drug

• Infections of the upper respiratory tract (including tonsillitis, pharyngitis, sinusitis, otitis media);
• Infections of the lower respiratory tract (pneumonia, including atypical, bronchitis);
• Infections of the urogenital tract (except for gonococcal infections);
• Infections of the skin and soft tissues (including common acne);
• Odontogenic infections;
• Acute gastroenteritis (including that caused by Campylobacter jejuni);
• Duodenal ulcer and chronic gastritis (caused by Helicobacter pylori);
• Infections caused by Mycoplasama spp., Chlamydia spp., Legionella spp.;
• Chronic prostatitis;
• Prevention of rheumatic fever;
• Other infectious diseases in patients with known hypersensitivity to antibiotics of the penicillin group.

ICD codes

Dosage Regimen

Tablets 50 mg

Tablets 150 mg and 300 mg

Adults are prescribed 150 mg twice daily at 12-hour intervals. Prescribing a dose of 300 mg once daily is possible.

No dosage adjustment is required for elderly patients.

In severe liver dysfunction, the dose should be reduced by half.

In renal failure, dose adjustment is generally not required, because the excretion of roxithromycin and its metabolites by the kidneys is approximately 10% of the administered dose.

In concomitant renal and hepatic insufficiency, the concentration of roxithromycin in blood plasma should be monitored and the dose adjusted if necessary.

The duration of administration depends on the severity of the disease. After the symptoms disappear, treatment should be continued for at least another 2 days.

The duration of treatment for respiratory tract and ENT organ diseases is 5-12 days; for chronic osteomyelitis – up to 2-2.5 months; for chlamydial and mycoplasmal pneumonia – 14 days; for legionella pneumonia – up to 21 days; for streptococcal infections, urethritis, cervicitis, cervicovaginitis – no more than 10 days.

The tablets should be taken without chewing, with a sufficient amount of water, approximately 15 minutes before meals.

Adverse Reactions

From the digestive system nausea, vomiting, stomach pain, diarrhea are possible; rarely – increased activity of AST, ALT, GGT; extremely rarely – reversible liver failure.

Allergic reactions rarely – skin erythema, skin rash, edema.

Other in isolated cases – increased body temperature, headaches, tinnitus, increased number of eosinophils.

The frequency of adverse effects is 3-4%. As a rule, drug withdrawal is not required.

Contraindications

• Porphyria;
• First trimester of pregnancy;
• Concomitant use with ergot alkaloids (including ergotamine, dihydroergotamine);
• Concomitant use with terfenadine, astemizole, cisapride, pimozide;
• Hypersensitivity to roxithromycin and other components of the drug;
• Hypersensitivity to other antibiotics of the macrolide group.

Use in Pregnancy and Lactation

The drug is contraindicated for use in the first trimester of pregnancy.

Adequate and strictly controlled studies on the safety of Roxihexal during pregnancy have not been conducted. Prescribing the drug in the second and third trimesters of pregnancy is possible only for vital indications and under medical supervision.

Roxithromycin is excreted in breast milk in small amounts (about 0.05%), therefore, prescribing the drug during breastfeeding is possible only under careful medical supervision.

In experimental studies, the absence of teratogenic and embryotoxic effects of the drug was shown.

Use in Hepatic Impairment

Use with caution in patients with severe hepatic insufficiency. If it is necessary to use the drug in this category of patients, regular monitoring of liver function and dose adjustment should be carried out.

In severe liver dysfunction, the dose should be reduced by half.

In concomitant renal and hepatic insufficiency, the concentration of roxithromycin in blood plasma should be monitored and the dose adjusted if necessary.

Use in Renal Impairment

In renal failure, dose adjustment is generally not required, because the excretion of roxithromycin and its metabolites by the kidneys is approximately 10% of the administered dose.

In concomitant renal and hepatic insufficiency, the concentration of roxithromycin in blood plasma should be monitored and the dose adjusted if necessary.

Pediatric Use

Tablets 50 mg

Geriatric Use

The drug should be prescribed with caution to patients over 65 years of age (an increase in C_ss in blood plasma is possible). In such cases, dose adjustment of the drug is required.

Special Precautions

Use with caution in patients with severe hepatic insufficiency. If it is necessary to use the drug in this category of patients, regular monitoring of liver function and dose adjustment should be carried out.

The drug should be prescribed with special caution and under the condition of regular ECG monitoring to patients with hypokalemia, AV conduction disorders, with arrhythmia, or with an increased QT interval.

The drug should be prescribed with caution to patients over the age of 65 years (an increase in plasma C_ss is possible). In such cases, dose adjustment of the drug is required.

In case of prolonged diarrhea or if an intestinal disease (pseudomembranous colitis) is suspected, RoxiHEXAL must be discontinued. Drugs that reduce intestinal peristalsis should not be taken.

If severe hypersensitivity reactions (e.g., anaphylaxis) develop, the drug should be discontinued immediately and emergency measures should be taken, such as the use of antihistamines, corticosteroids, sympathomimetics, and, if necessary, artificial ventilation.

There is cross-resistance between roxithromycin and erythromycin.

With prolonged or repeated use, the development of resistant microorganisms or fungal infections is possible.

1 tablet of RoxiHEXAL corresponds to less than 0.01 XE.

Overdose

Treatment: gastric lavage, symptomatic therapy. Hemodialysis is not effective. A specific antidote is not available.

Drug Interactions

With the concomitant use of macrolides and dihydroergotamine or non-hydrogenated ergot alkaloids with vasoconstrictive properties, the development of ergotism is possible – spasm of arterial vessels up to the development of necrosis of the extremities (concomitant use is contraindicated).

With the concomitant use of RoxiHEXAL with theophylline, the elimination of theophylline from the body decreases and the manifestations of its side effects are enhanced (regular monitoring of the plasma concentration of theophylline is recommended, especially if it was 15 mg/l or more before starting roxithromycin).

Roxithromycin reduces the effectiveness of indirect anticoagulants. With concomitant use with vitamin K antagonists, an increase in prothrombin time is possible.

With concomitant use with digoxin, an increase in the plasma concentration of digoxin and an increase in its side effects are possible. The same interaction is manifested when using RoxiHEXAL with other cardiac glycosides.

With concomitant use with midazolam, its AUC and T_1/2 increase, so an increase in the intensity and duration of action of midazolam is possible.

Roxithromycin reduces the degree of binding of disopyramide to plasma proteins, which leads to an increase in the concentration of free disopyramide in the blood plasma.

With the concomitant use of terfenadine and antibiotics of the macrolide group, an increase in the plasma concentration of terfenadine is possible. This can lead to the development of a severe “torsades de pointes” type arrhythmia (despite the absence of such data regarding roxithromycin, the concomitant use of RoxiHEXAL and terfenadine is contraindicated).

With the concomitant use of RoxiHEXAL with astemizole, cisapride, or pimozide, the plasma concentrations of these drugs increase (concomitant use is contraindicated).

With concomitant use with cyclosporine, a slight increase in the plasma concentration of cyclosporine is possible (dose adjustment, as a rule, is not required).

There is no drug interaction of Roxihexal^® with antacids, histamine H₁-receptor blockers, carbamazepine, and warfarin.

Storage Conditions

List B. The drug should be stored at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.