Spiracin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SPIRACIN (SPIRACIN)

Composition:

Active substance: spiramycin;

One film-coated tablet contains spiramycin 1,500,000 IU or

One film-coated tablet contains spiramycin 3,000,000 IU;

Excipients: microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate, maize starch, polysorbate 80, purified talc, crospovidone, film coating: Instacoat universal white (IC-U-1308): hypromellose, polyethylene glycol, talc, titanium dioxide E171.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets of 1,500,000 IU: elongated, biconvex tablets, white or almost white, film-coated, with a break line on one side and smooth on the other side;

Tablets of 3,000,000 IU: elongated, biconvex tablets, white or almost white, film-coated, smooth on both sides.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Macrolides. ATC code J01F A02.

Pharmacological properties.

Pharmacodynamics.

Spiramycin is an antibiotic with bactericidal activity belonging to the macrolide group.

ANTIMICROBIAL SPECTRUM OF ACTIVITY

The critical concentrations that allow differentiation of susceptible microbial species from those with intermediate susceptibility, and the latter from resistant species, are as follows: susceptible (< 1 mg/L) and resistant (> 4 mg/L).

The prevalence of acquired resistance in certain microbial species may vary depending on geographical location and specific time periods. Therefore, it is advisable to obtain local data on resistance prevalence, especially when treating severe infections.

The provided data allow only an estimation of the likelihood of bacterial strain susceptibility to this antibiotic. The prevalence of bacterial species resistance to spiramycin is presented in the table below:

The activity of spiramycin against Toxoplasma gondii has been demonstrated in vitro and in vivo.

* The prevalence of methicillin resistance among staphylococci is 30–50%, occurring predominantly in hospital settings.

Pharmacokinetics.

Absorption

Spiramycin absorption is rapid but incomplete. Food intake does not affect this process.

Distribution

After oral administration of 6,000,000 IU of spiramycin, the maximum plasma concentration is 3.3 μg/mL. The apparent elimination half-life from plasma is approximately 8 hours.

Spiramycin does not cross the blood-brain barrier. However, it is excreted into breast milk. Plasma protein binding is 10%.

Tissue and saliva distribution is very high (lungs: 20–60 μg/g, tonsils: 20–80 μg/g, infected sinuses: 75–110 μg/g, skeletal bones: 5–100 μg/g).

Ten days after discontinuation of treatment, spiramycin concentrations in the spleen, liver, and kidneys range from 5 to 7 μg/g.

Macrolides penetrate and accumulate in phagocytes (neutrophils, monocytes, peritoneal and alveolar macrophages).

In humans, concentrations within phagocytes are high.

These properties provide spiramycin with efficacy in treating infections caused by intracellular bacteria.

Metabolism

Spiramycin is metabolized in the liver, resulting in active metabolites whose chemical structures have not been identified.

Excretion

• Urine: 10% of the administered dose.
• A large amount of the drug is excreted via bile: spiramycin concentrations in bile are 15–40 times higher than in plasma.
• A significant amount of spiramycin is excreted in feces.

Clinical characteristics.

Indications.

Treatment of infections caused by microorganisms sensitive to spiramycin:

• Confirmed tonsillopharyngitis caused by β-hemolytic streptococci of group A (as an alternative to β-lactam antibiotic therapy, especially when β-lactams cannot be used);
• Acute sinusitis (due to the microbiological characteristics of the infection, macrolide use is indicated when β-lactam antibiotic therapy is not feasible);
• Superinfection in acute bronchitis;
• Exacerbation of chronic bronchitis;
• Community-acquired pneumonia in patients without risk factors, severe clinical symptoms, or clinical indicators suggesting pneumococcal etiology.

In suspected atypical pneumonia, macrolide use is appropriate regardless of disease severity or patient history.

• Skin infections with benign course: impetigo, impetiginization, ecthyma, infectious dermato-hypodermatitis (especially Besh's disease), erythrasma.
• Oral cavity infections.
• Nongonococcal genital infections.
• Chemoprophylaxis of recurrences of acute rheumatic fever in patients allergic to β-lactam antibiotics.
• Toxoplasmosis in pregnant women.
• Prophylaxis of meningococcal meningitis in individuals contraindicated for rifampicin:
  • • for eradication of the microorganism (Neisseria meningitidis) from the nasopharynx;
  • • spiramycin is indicated as prophylactic treatment: for patients after treatment and prior to returning to community life; for individuals who had contact with a patient who was expectorating sputum during the 10 days preceding their hospitalization.

Spiramycin is not intended for the treatment of meningococcal meningitis.

Official recommendations regarding appropriate use of antibacterial agents should be followed.

Contraindications.

• Hypersensitivity to spiramycin or to any of the excipients of the medicinal product.
• Patients belonging to the risk group for QT interval prolongation, namely:
  • patients with personal or family history of congenital QT interval prolongation (except cases where this diagnosis has been excluded by ECG);
  • patients with QT interval prolongation caused by medicinal products or of metabolic or cardiovascular origin.
• Combination with medicinal products that may cause torsades de pointes ventricular tachycardia, such as:
  • class Ia antiarrhythmic agents (quinidine, hydroquinidine, disopyramide);
  • class III antiarrhythmic agents (amiodarone, sotalol, dofetilide, ibutilide);
  • sultopride (a neuroleptic of the benzamide group);
  • others: arsenic compounds, diphenamid, intravenous dolasetron, mizolastine, levofloxacin, moxifloxacin, prucalopride, toremifene, intravenous vinpocetine, intravenous erythromycin, dronedarone, mequitazine, citalopram, disopyramide, dofetilide, domperidone, escitalopram, hydroquinidine, vandetanib (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Ventricular tachycardia of the torsades de pointes type.

This serious cardiac arrhythmia can be induced by certain antiarrhythmic agents or other drugs. Intravenous spiramycin belongs to the group of medicinal products that may cause torsades de pointes ventricular tachycardia. Risk factors include hypokalemia (induced by potassium-depleting diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide), bradycardia (see "Medicinal products causing bradycardia"), and existing QT interval prolongation, whether congenital or acquired.

Medicinal products affecting QT interval prolongation.

Spiramycin, like other macrolides, should be administered with caution in patients receiving medicinal products that may prolong the QT interval (e.g., class IA and III antiarrhythmic agents, tricyclic antidepressants, certain antibacterial agents, neuroleptics) (see section "Special warnings and precautions for use").

Contraindicated combinations (see section "Contraindications").

Medicinal products causing torsades de pointes ventricular tachycardia: class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide), class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), sultopride (a benzamide-group neuroleptic), others (arsenic compounds, diphenamid, intravenous dolasetron, intravenous erythromycin, levofloxacin, mizolastine, moxifloxacin, prucalopride, toremifene, intravenous vinpocetine), dronedarone, mequitazine, citalopram, disopyramide, dofetilide, domperidone, escitalopram, hydroquinidine, vandetanib.

Increased risk of ventricular rhythm disorders, including torsades de pointes ventricular tachycardia.

Unrecommended combinations.

Antiparasitic agents capable of inducing torsades de pointes ventricular tachycardia (halofantrine, lumefantrine, pentamidine).

Increased risk of ventricular rhythm disorders, including torsades de pointes ventricular tachycardia.

If possible, one of the drugs should be discontinued. If combined therapy cannot be avoided, QT interval should be assessed beforehand and ECG monitoring should be performed.

Neuroleptics capable of inducing torsades de pointes ventricular tachycardia (amisulpride, chlorpromazine, tiapride, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipothiazine, sulpiride, tiapride, zuclopenthixol).

Increased risk of ventricular rhythm disorders, including torsades de pointes ventricular tachycardia.

Methadone.

Increased risk of ventricular rhythm disorders, including torsades de pointes ventricular tachycardia.

Combinations requiring special precautions during use.

β-blockers in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol), medicinal products causing bradycardia (including class Ia antiarrhythmics, β-blockers, certain class III antiarrhythmics, certain calcium antagonists, cardiac glycosides, pilocarpine, cholinesterase inhibitors (ambenonium, donepezil, galantamine, memantine, neostigmine, pyridostigmine, rivastigmine)).

Increased risk of ventricular rhythm disorders, including torsades de pointes ventricular tachycardia.

Clinical monitoring and ECG monitoring are required.

Medicinal products causing hypokalemia (potassium-depleting diuretics, alone or in combination with other agents, stimulant laxatives, glucocorticoids, tetracosactide, intravenous amphotericin B).

Increased risk of ventricular rhythm disorders, including torsades de pointes ventricular tachycardia.

Correction of low potassium levels before administration of the drug is necessary, along with monitoring of clinical status, electrolyte levels, and ECG parameters.

Azithromycin, clarithromycin, roxithromycin.

Increased risk of ventricular rhythm disorders, including torsades de pointes ventricular tachycardia.

During combined use, clinical monitoring and ECG monitoring are required.

Levodopa.

In combination with carbidopa: inhibition of carbidopa absorption and reduced plasma concentrations of levodopa.

Clinical monitoring and, if necessary, adjustment of levodopa dosage.

Hydroxyzine.

Increased risk of ventricular rhythm disorders, including torsades de pointes ventricular tachycardia.

Specific warnings regarding imbalance of the international normalized ratio (INR).

Numerous cases of increased activity of oral anticoagulants have been reported in patients receiving antibiotic therapy. Severe degree of infection or pronounced inflammatory process, patient age, and general condition are contributing risk factors. Under these circumstances, it is difficult to determine to what extent the infection itself or its treatment causes INR imbalance. However, certain classes of antibiotics are more likely to cause such imbalance, namely: fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and certain cephalosporins.

Special precautions for use

Severe skin reactions have been reported during the use of Spiramycin, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis (AGEP). Patients must be informed about the signs and symptoms of these conditions, and skin condition should be carefully monitored.

If any signs or symptoms of Stevens-Johnson syndrome, toxic epidermal necrolysis (e.g., progressive skin rash, often with blistering or mucosal involvement) or AGEP (see section "Adverse reactions") occur, the drug must be discontinued. Further use of spiramycin, either as monotherapy or in combination with other drugs, is contraindicated.

Since the active substance is not excreted by the kidneys, dosage adjustment is not required in patients with renal insufficiency.

Very rare cases of haemolytic anaemia have been observed in patients with glucose-6-phosphate dehydrogenase deficiency. Therefore, the use of spiramycin in such patients is not recommended.

QT interval prolongation

Prolongation of the QT interval has been reported in patients receiving macrolides, including spiramycin.

Caution should be exercised when administering spiramycin to patients with known risk factors for QT interval prolongation, such as:

• uncorrected electrolyte imbalances (e.g., hypokalaemia, hypomagnesaemia);
• congenital long QT syndrome;
• cardiac diseases (e.g., heart failure, myocardial infarction, bradycardia);
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, certain antibiotics, and certain antipsychotics);
• elderly individuals, neonates, and women may be more susceptible to QT interval prolongation.

(See sections "Interaction with other medicinal products and other forms of interaction", "Method of administration and dosage", "Overdose", and "Adverse reactions").

Use during pregnancy or breastfeeding

Pregnancy

Spiramycin may be prescribed during pregnancy if necessary. No teratogenic or fetotoxic effects have been observed to date following widespread use of the drug in pregnant women.

Period of breastfeeding

A significant amount of spiramycin is excreted in breast milk. Cases of gastrointestinal disturbances in newborns have been reported. Therefore, breastfeeding should be discontinued during treatment with Spiramycin.

Ability to influence the speed of reactions while driving or operating machinery

No effects of the medicinal product on the ability to drive or operate machinery have been observed.

Method of Administration and Dosage.

Tablets containing 3,000,000 IU of spiramycin must not be administered to children.

Tablets containing 1,500,000 IU of spiramycin must not be administered to children under 6 years of age due to the risk of developing laryngospasm.

Film-coated tablets must not be crushed or divided.

The tablets should be swallowed whole with a glass of water.

For patients with normal renal function, the drug Spiracin is recommended in the following doses:

Adults – 6,000,000–9,000,000 IU (2–6 tablets per day in 2–3 divided doses);

Children aged 6 years and older – 1,500,000–3,000,000 IU per 10 kg of body weight per day in 2–3 divided doses.

The duration of therapy for tonsillopharyngitis is 10 days.

Prophylaxis of meningococcal meningitis.

Adults: 3,000,000 IU every 12 hours for 5 days;

Children: 75,000 IU per 1 kg of body weight every 12 hours for 5 days.

For patients with renal insufficiency, dosage adjustment is not required.

Children.

Tablets containing 3,000,000 IU of spiramycin must not be administered to children.

Tablets containing 1,500,000 IU of spiramycin must not be administered to children under 6 years of age due to the risk of developing laryngospasm.

Overdose.

The toxic dose of spiramycin is unknown.

After administration of high doses, signs of gastrointestinal disturbances may occur, including nausea, vomiting, and diarrhea.

Cases of QT interval prolongation, which resolved after discontinuation of the drug, have been observed in newborns treated with high doses of spiramycin, as well as after intravenous administration of spiramycin in patients belonging to the risk group for QT interval prolongation. In case of spiramycin overdose, ECG monitoring of QT interval duration is recommended, especially if other risk factors are present (hypokalemia, congenital QTc prolongation, concomitant use of medicinal products that cause QT interval prolongation and/or bidirectional (polymorphic) ventricular tachycardia (torsades de pointes)).

There is no specific antidote.

In case of overdose, symptomatic treatment is recommended.

Adverse Reactions

Adverse reactions are listed by system-organ class and frequency. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Gastrointestinal system

Common: abdominal pain, nausea, vomiting, stomach discomfort, diarrhea.

Very rare: pseudomembranous colitis.

Cardiovascular system

Frequency not known: QT interval prolongation, ventricular arrhythmia, ventricular tachycardia, bidirectional (polymorphic) ventricular tachycardia (torsades de pointes), which may lead to cardiac arrest (see section "Special precautions for use").

Skin and appendages

Common: rash.

Frequency not known: urticaria, pruritus, angioneurotic edema, anaphylactic shock, Stevens–Johnson syndrome, toxic epidermal necrolysis, DRESS (see section "Special precautions for use**"**).

Nervous system

Very common: in individual cases – transient paresthesia.

Common: transient dysgeusia.

Hepatic system

Very rare: abnormal liver function test results.

Frequency not known: mixed or, in rarer cases, cholestatic hepatocellular hepatitis.

Blood

Frequency not known: leukopenia, neutropenia, hemolytic anemia (see section "Special precautions for use").

Shelf life. 2 years.

Storage conditions.

Store in a dry, protected from light place at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

SIMPEX PHARMA PVT. LTD.

Manufacturer's address and location.

C7 to C13 and C59 to C64, Sigdha Development Center (SIDCUL), Sigdha, Kotdwar - 246149 Distt. Pauri Garhwal, Uttarakhand, India

Marketing Authorization Holder.

SIMPEX PHARMA PVT. LTD.

Address of Marketing Authorization Holder.

B-4/160, Safdarjung Enclave, New Delhi – 110029, India.