Ambrobene FORTE (Solution) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Balkanpharma-Troyan, AD (Bulgaria)

Contact Information

TEVA (Israel)

ATC Code

R05CB06 (Ambroxol)

Active Substance

Ambroxol (Rec.INN registered by WHO)

Dosage Form

Ambrobene FORTE

Oral solution 30 mg/5 ml: 120 ml or 200 ml bottle with a measuring spoon

Dosage Form, Packaging, and Composition

Oral solution in the form of a clear liquid from colorless to brownish in color, with a raspberry smell.

Excipients : citric acid monohydrate – 2 mg, sorbitol liquid (crystallizing) 70% – 2250 mg, glycerol – 860 mg, methylparahydroxybenzoate – 6 mg, propylparahydroxybenzoate – 1.5 mg, propylene glycol – 150 mg, raspberry flavor – 2.5 mg, purified water – up to 5 ml.

120 ml – dark glass bottles (1) complete with a measuring spoon – cardboard packs^×.
200 ml – dark glass bottles (1) complete with a measuring spoon – cardboard packs^×.

^× protective stickers may additionally be applied.

Clinical-Pharmacological Group

Mucolytic and expectorant drug

Pharmacotherapeutic Group

Mucolytic expectorant

Pharmacological Action

Studies have shown that Ambroxol – the active substance of the drug Ambrobene FORTE – increases secretion in the airways, reduces sputum viscosity, enhances the production of pulmonary surfactant and stimulates the motor activity of the cilia of the ciliated epithelium. These effects lead to an increase in the flow and transport of mucus (mucociliary clearance), which improves sputum discharge and alleviates cough. When used concomitantly with antibiotics (amoxicillin, cefuroxime, erythromycin, doxycycline), it increases their concentration in the bronchial secretion.

In vitro and in animal studies, it was shown that Ambroxol has a local anesthetic (by blocking sodium channels of neurons) and anti-inflammatory (by reducing the release of cytokines from mononuclear or polymorphonuclear cells present in both blood and tissues) effects.

In patients with chronic obstructive pulmonary disease, long-term therapy with the drug Ambrobene FORTE (for 6 months) led to a significant reduction in the number and duration of exacerbations, as well as a significant reduction in the duration of antibiotic use, which was already evident after 2 months of therapy. The use of the drug Ambrobene FORTE also caused a statistically significant improvement in the clinical symptoms of the disease (difficult sputum discharge, cough, shortness of breath, pathological auscultatory signs) compared to placebo.

Thus, Ambroxol has a complex protective effect on the bronchopulmonary system by normalizing the natural function of mucociliary clearance and protecting against exacerbations of chronic respiratory diseases during long-term therapy.

Pharmacokinetics

Absorption

All immediate-release ambroxol dosage forms are characterized by rapid and almost complete absorption with a linear dose-dependence in the therapeutic concentration range. C_max of ambroxol in blood plasma after oral administration is reached in 1-2.5 h. Food intake does not affect the bioavailability of ambroxol.

Distribution

In the therapeutic concentration range, plasma protein binding is approximately 90%. Ambroxol is rapidly and extensively distributed from the blood into various tissues. V_d is 552 L. The highest concentrations of the active component of the drug are observed in the lungs.

Metabolism

Approximately 30% of the oral dose taken undergoes a first-pass effect through the liver. Ambroxol is metabolized mainly in the liver, where it is glucuronidated and cleaved (approximately 10% of the dose) to dibromanthranilic acid, in addition to the formation of some minor metabolites.

Studies using human liver microsomes have shown that the metabolism of ambroxol to dibromanthranilic acid occurs with the participation of the CYP3A4 isoenzyme.

Elimination

Within 3 days after oral administration of ambroxol, approximately 6% of the dose taken is detected in the urine in the form of the free compound and approximately 26% of the dose in the form of a conjugate.

The terminal T_1/2 of ambroxol is approximately 10 h.

The total clearance is approximately 660 ml/min; renal clearance after oral administration of ambroxol is approximately 8% of the total clearance.

It was found that the amount of the drug excreted in the urine over 5 days was 83% of the dose (using a radioactive labeling method).

Pharmacokinetics in special patient groups

In patients with impaired liver function, the elimination of ambroxol is slowed, leading to an increase in its plasma concentration by approximately 1.3-2 times. Since Ambroxol has a wide therapeutic range, dose adjustment is not required.

No clinically significant influence of age and gender on the pharmacokinetics of ambroxol was found, therefore dose adjustment is not required.

Indications

Acute and chronic respiratory diseases accompanied by the production of viscous sputum

• Acute and chronic bronchitis;
• Pneumonia;
• COPD;
• Bronchial asthma with difficult sputum discharge;
• Bronchiectasis.

ICD codes

Dosage Regimen

Orally, after meals. The drug should not be taken immediately before bedtime.

1 measuring spoon (5 ml) contains 30 mg of ambroxol.

Adults and children over 12 years

For the first 2-3 days, take 5 ml of oral solution (1 measuring spoon) 3 times/day, then the dose should be reduced to 5 ml of oral solution (1 measuring spoon) 2 times/day.

If it is necessary to enhance the therapeutic effect, 10 ml 2 times/day can be prescribed.

Children from 6 to 12 years

2.5 ml of oral solution (1/2 measuring spoon) 2-3 times/day.

The duration of treatment is 7-14 days. If further use is necessary, a doctor should be consulted.

If symptoms of the disease persist for 4-5 days from the start of administration, it is recommended to consult a doctor.

Adverse Reactions

According to WHO, adverse reactions are classified according to the frequency of their development as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Immune system disorders: rare – hypersensitivity reactions; frequency unknown – anaphylactic reactions, including anaphylactic shock, angioedema and pruritus.

Nervous system disorders: common – dysgeusia (taste disturbances).

Respiratory, thoracic and mediastinal disorders common – pharyngeal hypesthesia (reduced sensitivity in the pharynx); frequency unknown – dry throat.

Gastrointestinal disorders: common – nausea, oral hypesthesia (reduced sensitivity in the oral cavity); uncommon – dry mouth, vomiting, diarrhea, dyspepsia, abdominal pain.

Skin and subcutaneous tissue disorders: rare – rash, urticaria; frequency unknown – severe skin adverse reactions (including erythema multiforme exudativum, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome) and acute generalized exanthematous pustulosis).

Contraindications

• Hypersensitivity to ambroxol or other components of the drug;
• Pregnancy (I trimester);
• Breastfeeding period;
• Hereditary fructose intolerance (due to the presence of sorbitol in the composition, see section “Special Precautions”).
• Children under 6 years of age.

With caution the drug Ambrobene FORTE should be taken during pregnancy (II and III trimesters), in case of renal and/or hepatic insufficiency.

Use in Pregnancy and Lactation

Pregnancy

Ambroxol crosses the placental barrier.

Preclinical studies have not revealed any direct or indirect adverse effects on pregnancy, embryonic/fetal, postnatal development, or labor.

Extensive clinical experience with the use of ambroxol after the 28th week of pregnancy has not found evidence of a negative effect of the drug on the fetus. Nevertheless, caution should be exercised when using the drug during pregnancy. It is especially not recommended to take Ambrobene FORTE in the first trimester of pregnancy. In the II and III trimesters of pregnancy, use is possible only if the potential benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

Ambroxol may be excreted in breast milk. Although no adverse reactions have been observed in breastfed infants, it is not recommended to use Ambrobene FORTE oral solution during lactation.

Fertility

Preclinical studies of ambroxol have not revealed a negative effect on fertility.

Use in Hepatic Impairment

The drug should be used with caution in hepatic insufficiency.

Use in Renal Impairment

The drug should be used with caution in renal insufficiency.

Pediatric Use

Contraindicated for use in children under 6 years of age.

Special Precautions

Should not be combined with antitussive agents that impede sputum discharge.

There are isolated reports of severe skin lesions such as Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), acute generalized exanthematous pustulosis (AGEP) and erythema multiforme exudativum, coinciding in time with the prescription of expectorant drugs such as Ambrobene FORTE. In most cases, they can be explained by the severity of the underlying disease and/or concomitant therapy. In patients with Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell’s syndrome), fever, body aches, rhinitis, cough and sore throat may appear in the early phase. With symptomatic treatment, “cold remedies” may be erroneously prescribed. If new skin and mucous membrane lesions appear, it is recommended to discontinue ambroxol treatment and seek immediate medical attention.

In patients with impaired bronchial motility and with a large amount of sputum (for example, in the rare primary ciliary dyskinesia syndrome), the drug should be used with caution, as it may cause sputum accumulation.

In patients with impaired kidney function or severe liver disease, the drug should not be used without a doctor’s prescription. When taking ambroxol, as with any drug that is metabolized in the liver and excreted by the kidneys, accumulation of ambroxol metabolites formed in the liver should be expected in patients with severe renal failure.

Excipients

The drug Ambrobene FORTE may cause allergic reactions (possibly delayed type) due to the content of methylparahydroxybenzoate, propylparahydroxybenzoate and propylene glycol.

The drug contains sorbitol, therefore patients with rare hereditary fructose intolerance should not take the drug Ambrobene FORTE. Sorbitol may have a mild laxative effect. 1 measuring spoon (5 ml of oral solution) contains 1.575 g of sorbitol, which corresponds to 0.14 XE.

Effect on ability to drive vehicles and operate machinery

No cases of the drug’s influence on the ability to drive vehicles and operate machinery have been identified. Studies on the effect of the drug on the ability to drive vehicles and engage in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions have not been conducted.

Overdose

No specific symptoms of overdose in humans have been described.

There are reports of accidental overdose and/or medical error, which resulted in symptoms of known adverse reactions: nausea, dyspepsia, vomiting, diarrhea, abdominal pain.

Treatment artificial vomiting, gastric lavage within the first 1-2 h after taking the drug, symptomatic therapy.

Drug Interactions

No clinically significant, undesirable interactions with other drugs have been reported. When used concomitantly, it increases the penetration into the bronchial secretion of amoxicillin, cefuroxime, erythromycin, doxycycline.

Simultaneous use of ambroxol and antitussive drugs (for example, codeine) is not recommended, because due to the suppression of the cough reflex, there may be a risk of sputum accumulation in the lumen of the airways with difficult discharge.

Storage Conditions

The drug should be stored in the original packaging (carton), in a place inaccessible to children at a temperature not exceeding 25°C (77°F). Shelf life – 3 years. Do not use after the expiration date.

After first opening the bottle, the drug is suitable for use within 28 days.

Dispensing Status

The drug is dispensed without a 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.