Metronidazole

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MİTROZYD (MITROZYD)

Composition:

Active substance: azithromycin;

1 vial contains azithromycin dihydrate equivalent to 500 mg of azithromycin;

Excipients: citric acid monohydrate; sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical characteristics: lyophilized solid or powder, white to almost white.

Pharmacotherapeutic group.

Antibacterials for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin.

ATC code J01FA10.

Pharmacological properties.

Pharmacodynamics.

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by insertion of a nitrogen atom into the lactone ring of erythromycin A. The mechanism of action of azithromycin involves inhibition of bacterial protein synthesis through binding to the 50S ribosomal subunit and suppression of peptide translocation.

Mechanism of resistance.

Resistance to azithromycin may be inherent or acquired. Complete cross-resistance exists among Streptococcus pneumoniae, beta-hemolytic group A streptococci, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides, and lincosamides.

Macrolides administered intravenously are active against Legionella pneumophila. Macrolides are used in the treatment of infections caused by Campylobacter jejuni. Azithromycin is indicated for the treatment of infections caused by S. typhi and Shigella spp.

The prevalence of acquired resistance among isolated species may vary depending on geographical location and time; therefore, local information on resistance patterns is necessary, especially when treating severe infections. Expert advice should be sought if local resistance prevalence renders the efficacy of the drug questionable for at least some types of infections.

Antimicrobial spectrum of azithromycin

MRSA (methicillin-resistant Staphylococcus aureus) has a very high prevalence of acquired resistance to macrolides and is listed here due to rare susceptibility to azithromycin.

Pharmacokinetics.

In patients with community-acquired pneumonia who received daily 500 mg intravenous infusions of azithromycin over 1 hour at a concentration of 2 mg/mL, the mean maximum concentration (Cmax) ± SD (standard deviation) was 3.63 ± 1.60 µg/mL, while the trough concentration (at 24 hours) was 0.2 ± 0.15 µg/mL, and AUC24 was 9.6 ± 4.80 µg·h/mL.

In healthy volunteers who received a 500 mg intravenous infusion of azithromycin over 3 hours at a concentration of 1 mg/mL, the mean Cmax ± SD, trough concentration (at 24 hours), and A0UC24 were 1.14 ± 0.14 µg/mL, 0.18 ± 0.02 µg/mL, and 8.03 µg·h/mL, respectively.

After oral administration, significantly higher levels of azithromycin were found in various tissues such as lungs, tonsils, or prostate, where azithromycin concentrations were up to 50 times higher than in plasma. High concentrations of azithromycin were recorded in genital tissue 96 hours after administration of a single 500 mg oral dose of azithromycin.

The mean volume of distribution is approximately 30 L/kg. The elimination half-life is 2–4 days in both plasma and tissues.

Metabolism occurs via demethylation, hydroxylation, and hydrolysis.

Plasma clearance is approximately 600 mL/min. The primary route of elimination of azithromycin is via the liver. High concentrations of unchanged drug were found in bile, along with numerous microbiologically inactive metabolites. Approximately 12% of an intravenously administered dose was excreted unchanged in urine within 3 days after administration, with the majority excreted within the first 24 hours.

In patients with severe renal dysfunction (glomerular filtration rate < 10 mL/min), a 33% increase in systemic exposure to azithromycin was observed. No differences in pharmacokinetics were observed in patients with mild or moderate hepatic dysfunction.

Clinical characteristics.

Indications.

Infections requiring initial intravenous therapy caused by microorganisms sensitive to azithromycin:

− Community-acquired pneumonia;

− Inflammatory pelvic disease.

Contraindications.

Azithromycin is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any other macrolide or ketolide antibiotic, or to any component of the drug.

Due to the theoretical possibility of ergotism, azithromycin should not be co-administered with ergot derivatives.

Interaction with other medicinal products and other forms of interaction.

Azithromycin should be administered with caution in patients receiving other medicinal products that may prolong the QT interval.

Antacids. In studies evaluating the effect of concomitant antacid administration on the pharmacokinetics of azithromycin, no overall changes in bioavailability were observed, although plasma peak concentrations of azithromycin were reduced by approximately 25%. Patients should not take azithromycin and antacids simultaneously. Oral administration of antacids does not affect the distribution of intravenously administered azithromycin.

Cetirizine. In healthy volunteers, co-administration of azithromycin for 5 days with cetirizine 20 mg at steady state did not result in pharmacokinetic interactions or significant changes in QT interval.

Didanosine. Concomitant administration of daily doses of 1200 mg azithromycin with didanosine showed no effect on the pharmacokinetics of didanosine compared to placebo.

Digoxin. Concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin has been reported to increase serum levels of P-glycop游戏副本

Special precautions for use.

Allergic reactions. As with erythromycin and other macrolide antibiotics, isolated cases of serious allergic reactions have been reported, including angioneurotic edema and anaphylaxis (in rare cases resulting in death). Some of these reactions caused by azithromycin were associated with recurrent symptoms and required prolonged observation and treatment.

Hepatic function impairment. Since the liver is the main route of elimination of azithromycin, caution should be exercised when prescribing azithromycin to patients with severe hepatic disease. Cases of fulminant hepatitis have been reported during azithromycin therapy, leading to life-threatening liver failure. Some patients may have had pre-existing liver disease or may have been taking other hepatotoxic medicinal products.

Liver function tests should be performed if symptoms of hepatic dysfunction develop, such as rapidly developing asthenia accompanied by jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy.

If hepatic dysfunction is detected, azithromycin should be discontinued.

Ergot derivatives. In patients taking ergot derivatives, concomitant administration of some macrolide antibiotics has led to rapid development of ergotism. There are no data on a possible interaction between ergot derivatives and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin should not be administered concurrently with ergot derivatives.

Superinfections. As with other antibiotics, monitoring for signs of superinfection caused by resistant organisms, including fungi, is recommended.

Diarrhea associated with Clostridium difficile (CDAD) has been reported with nearly all antibacterial agents, including azithromycin, with severity ranging from mild diarrhea to fatal colitis. Antibacterial therapy alters the normal gut flora, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hyper-toxin-producing strains of C. difficile are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients with diarrhea following antibiotic use. A careful medical history is necessary, as CDAD may occur up to two months after antibacterial therapy.

Renal function impairment. In patients with severe renal dysfunction (glomerular filtration rate < 10 mL/min), systemic exposure to azithromycin increased by 33%.

Prolongation of cardiac repolarization and QT interval, increasing the risk of cardiac arrhythmia and ventricular tachyarrhythmia (torsade de pointes), has been observed with other macrolide antibiotics, including azithromycin. Since conditions associated with an increased risk of ventricular arrhythmias (including ventricular tachyarrhythmia) may lead to cardiac arrest, azithromycin should be used with caution in patients with risk factors for arrhythmia (particularly women and elderly patients), namely:

• patients with congenital or documented acquired prolongation of the QT interval;
• patients currently receiving treatment with other medicinal products known to prolong the QT interval, e.g., class IA (quinidine, procainamide) and class III (dofetilide, amiodarone, sotalol) antiarrhythmics, cisapride, terfenadine, neuroleptics such as pimozide; antidepressants (such as citalopram), and fluoroquinolones such as moxifloxacin and levofloxacin;
• patients with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• patients with clinically significant bradycardia, cardiac arrhythmia, or severe heart failure.

Myasthenia gravis. Exacerbation of symptoms of myasthenia gravis or new onset of myasthenic syndrome has been reported in patients receiving azithromycin therapy.

Streptococcal infections. Azithromycin is generally effective in the treatment of streptococcal pharyngitis. However, there are no data demonstrating the efficacy of azithromycin in the prevention of rheumatic fever. An antimicrobial agent with anaerobic activity should be used in combination with azithromycin if anaerobic microorganisms are suspected to be involved in the infection.

The safety and efficacy of the medicinal product for the prevention or treatment of Mycobacterium avium complex in children have not been established.

The safety and efficacy of intravenous azithromycin have been evaluated only within the time frames described in clinical trials involving patients with community-acquired pneumonia and pelvic inflammatory disease.

Azithromycin for injection must be reconstituted and diluted according to instructions and administered as an intravenous infusion over at least 60 minutes. The drug must not be administered as an intravenous bolus or by intramuscular injection.

This medicinal product contains approximately 188 mg of sodium (as hydroxide) per vial. This should be taken into account when prescribing the drug to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Reproductive toxicity studies in animals have shown that azithromycin can cross the placental barrier, but no teratogenic effects were observed. The safety of azithromycin during pregnancy has not been established. Therefore, azithromycin should be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Period of breastfeeding

Azithromycin has been reported to pass into human milk, but appropriate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion in human breast milk have not been conducted. Therefore, the use of azithromycin during breastfeeding is possible only if the expected benefit to the mother outweighs the potential risk to the infant.

Fertility

Fertility studies in rats demonstrated a decreased pregnancy rate following azithromycin administration. The relevance of these findings to humans is unknown.

Ability to affect reaction speed when driving or operating machinery.

There is no evidence that azithromycin impairs the ability to drive or operate machinery. However, the possibility of adverse reactions such as dizziness, somnolence, and visual disturbances should be considered.

Dosage and Administration

Adults.

Community-acquired pneumonia. 500 mg intravenously once daily for at least 2 days, followed by oral therapy with 500 mg azithromycin as a single daily dose. Total duration of treatment is 7–10 days. Transition to oral therapy should be performed upon physician's recommendation and according to clinical response.

Pelvic inflammatory disease, including sexually transmitted infections such as endometritis and salpingitis. 500 mg intravenously once daily for 1–2 days, followed by oral therapy with 250 mg azithromycin once daily as a single daily dose. Total duration of treatment is 7 days. Transition to oral therapy should be performed upon physician's recommendation and according to clinical response.

Elderly patients.

Dose adjustment is not required for elderly patients.

Since elderly patients may have impaired cardiac conduction, caution is recommended when administering azithromycin due to the risk of developing cardiac arrhythmias, including torsade de pointes.

Patients with renal impairment.

For patients with mild renal impairment (glomerular filtration rate 10–80 mL/min), the same dosage as for patients with normal renal function may be used. Azithromycin should be administered with caution in patients with severe renal impairment (glomerular filtration rate < 10 mL/min).

Patients with hepatic impairment.

Since azithromycin is metabolized in the liver and excreted via bile, the drug should not be administered to patients with severe hepatic impairment. Studies on azithromycin treatment in such patients have not been conducted.

Administration method

This medicinal product should be administered as an intravenous infusion over 3 hours at a concentration of 1 mg/mL or over 1 hour at a concentration of 2 mg/mL. Higher concentrations should be avoided, as local infusion site reactions were observed in all subjects receiving infusions with concentrations exceeding 2 mg/mL.

The infusion duration of azithromycin should be at least 60 minutes.

MIZROZID must not be administered as an intravenous bolus or intramuscularly.

PREPARATION OF INFUSION SOLUTION

Step 1

Prepare the concentrated solution for infusion by adding 4.8 mL of sterile water for injection to the vial containing MIZROZID powder. Shake the vial until the powder is completely dissolved. Each 1 mL of the reconstituted concentrate contains 100 mg of azithromycin. The resulting solution should be clear and colorless.

Step 2

Dilute the obtained 5 mL of concentrate with an appropriate infusion solution to obtain the final infusion solution containing azithromycin at a concentration of 1 mg/mL or 2 mg/mL (see Table 1 below).

Table 1

Preparation of the final infusion solution

The concentrate for infusion solution can be diluted with:

0.9% sodium chloride solution;

0.45% sodium chloride solution;

5% aqueous solution of d-glucose;

Ringer's solution;

5% d-glucose solution in 0.3% sodium chloride solution;

5% d-glucose solution in 0.45% sodium chloride solution.

Before administration, the reconstituted and diluted solutions must be visually inspected for the presence of particles. Only clear, particle-free solutions should be used. If the solution contains particles, it must be discarded. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Children.

The safety and efficacy of intravenous administration of azithromycin for the treatment of infections in children have not been established.

Overdose.

Clinical experience with azithromycin indicates that adverse effects associated with doses higher than recommended are similar to those observed with usual therapeutic doses and may include diarrhea, nausea, vomiting, and reversible hearing loss.

In case of overdose, administration of activated charcoal and implementation of general symptomatic and supportive treatment measures are recommended.

Adverse reactions

When intravenous or oral azithromycin was used in the treatment of non-hospitalized pneumonia, the most frequently reported adverse events were diarrhea/loose stools, nausea, stomach pain, and vomiting. With intravenous administration of azithromycin, local inflammation/pain at the infusion site was reported. The frequency and severity of these reactions were similar to those observed during infusion of 500 mg azithromycin over 1 hour (2 mg/mL as 250 mL infusion) or over 3 hours (1 mg/mL as 500 mL infusion).

In adult women receiving intravenous or oral azithromycin for pelvic inflammatory disease, the most commonly reported adverse events were diarrhea, nausea, vaginitis, stomach pain, anorexia, rash, and pruritus. When azithromycin was administered concomitantly with metronidazole, the majority of women experienced adverse events such as nausea, stomach pain, vomiting, infusion site irritation, stomatitis, dizziness, or dyspnea.

The table below lists adverse reactions identified from clinical studies and post-marketing surveillance for all dosage forms of azithromycin, organized by system organ class and frequency. Adverse reactions reported during post-marketing surveillance are indicated in italics. Frequency groupings were defined according to the following scale: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each frequency group, adverse events are listed in order of decreasing severity.

Table 2

Adverse reactions that may be associated with azithromycin, based on data from clinical studies and post-marketing surveillance

Information on adverse reactions that may be associated with the prevention and treatment of Mycobacterium Avium Complex is based on data from clinical studies and post-marketing observations. These adverse reactions differ in type or frequency from those reported with the use of immediate-release and extended-release dosage forms:

Table 3

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

The reconstituted solution is chemically and physically stable for 24 hours when stored at a temperature not exceeding 25 °C, or for 7 days if stored at a temperature between 2 and 8 °C. From a microbiological standpoint, the reconstituted solution should be used immediately.

Incompatibilities.

Use only the solvents specified in the section “Instructions for use and dosage”.

Packaging.

Glass vials stoppered with a rubber stopper and sealed with an aluminium crimp cap fitted with a flip-off cap providing a tamper-evident seal.

1 vial or 10 vials of lyophilisate per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

IMMAKUL LIFESCIENCES PRIVATE LIMITED

IMMACULE LIFESCIENCES PRIVATE LIMITED

Manufacturer's address and place of business.

Village Thanthewal, Ropar Road, Nalagarh, District Solan, Himachal Pradesh, 174101, India

Marketing Authorisation Holder.

M.BIOTECH LIMITED

Address of the Marketing Authorisation Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom