Boehringer Ingelheim Ltd Consumer Healthcare

Lysopadol^® 20 mg Lozenges

One lozenge contains 20 mg of ambroxol hydrochloride.

Excipient(s): Sorbitol (1.37 g per lozenge), lactose monohydrate (less than 1 mg per lozenge)

For a full list of excipients, see section 6.1.

Lozenge

Round, white tablet, both sides flat with bevelled edges.

Pain relief of mild to moderate symptoms of acute sore throat.

Adults and children over 12 years of age: up to 6 lozenges to be sucked per day.

Lysopadol 20 mg Lozenges should not be used for more than 3 days. In case of persistent symptoms or high fever, the patient should consult a doctor. Lysopadol 20 mg Lozenges should not be used in children under 12 years of age.

Lysopadol 20 mg Lozenges should not be used in patients known to be hypersensitive to ambroxol or to any of the excipients. Patients with fructose intolerance should not receive Lysopadol 20 mg Lozenges since they contain significant amounts of sorbitol.

Lysopadol 20 mg Lozenges should not be used in children under 12 years of age.

There have been very few reports of severe skin lesions such as Stevens-Johnson Syndrome and toxic epidermal necrolysis (TEN) in temporal association with the administration of expectorants such as ambroxol hydrochloride. Mostly these could be explained by the severity of the patient's underlying disease and/or concomitant medication.

In addition during the early phase of a Stevens-Johnson Syndrome or TEN a patient may first experience non-specific influenza-like prodromes like e.g. fever, aching body, rhinitis, cough and sore throat. Misled by these non-specific influenza-like prodromes it is possible that a symptomatic treatment is started with a cough and cold medication. Therefore if new skin or mucosal lesions occur, medical advice should be sought immediately and treatment with ambroxol hydrochloride discontinued as a precaution.

Dyspnoea may be observed in the context of an underlying disease e.g. swollen throat. Local allergic reactions (see section 4.8: angioneurotic oedema) may also cause dyspnoea. The local anaesthetic properties of ambroxol may contribute to an altered perception in the pharyngeal space (see section 4.8: oral and pharyngeal hypoaesthesia).

Lysopadol 20 mg Lozenges are not suitable for the treatment of oral ulcers. In such a case medical advice should be sought.

In the presence of impaired renal function or severe hepatopathy, Lysopadol 20 mg Lozenges may be used only after consulting a physician. As for any medication with hepatic metabolism followed by renal elimination, accumulation of the metabolites of ambroxol generated in the liver can be expected in the presence of severe renal insufficiency.

This product contains 8.2 g of sorbitol per maximum recommended daily dose (1.37 g per lozenge). Patients with the rare hereditary condition of fructose intolerance should not take this medicine.

One Lysopadol 20 mg Lozenge contains less than 1 mg of lactose. This amount does not normally cause problems in lactose intolerant people. Nevertheless, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should exercise caution.

No clinically relevant unfavourable interaction with other medications has been reported.

Fertility:

Animal studies do not indicate direct or indirect harmful effects with respect to fertility.

Pregnancy:

Ambroxol hydrochloride crosses the placental barrier. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Extensive clinical experience after the 28^th week of pregnancy has shown no evidence of harmful effects on the foetus. Nonetheless, the usual precautions regarding the use of drugs during pregnancy should be observed. Especially during the first trimester, the use of Lysopadol 20 mg Lozenges is not recommended.

Lactation:

Ambroxol hydrochloride is excreted in breast milk. Although unfavourable effects on breastfed infants would not be expected, Lysopadol 20 mg Lozenges are not recommended for use in nursing mothers.

There is no evidence for an effect on ability to drive and use machines.

Studies on the effects on the ability to drive and use machines have not been performed.

Frequency estimate:

Very common: 10 %

Common: 1 % and <10 %

Uncommon: 0.1 % and <1 %

Rare: 0.01 % and < 0.1 %

Very rare: < 0.01 %

Not known: cannot be estimated from the available data

Immune system disorders, skin and subcutaneous tissue disorders

Not known: anaphylactic reactions including anaphylactic shock, angioedema, rash, urticaria, pruritus and other hypersensitivity

Nervous system disorders

Common: dysgeusia (e.g. changed taste).

Gastrointestinal disorders and respiratory, mediastinal and thoracic disorders

Common: oral and pharyngeal hypoaesthesia (see section 4.4), nausea

Uncommon: diarrhoea, upper abdominal pain, dyspepsia, dry mouth

Not known: vomiting, dry throat

No specific overdose symptoms have been reported in man to date. Based on accidental overdose and/or medication error reports the observed symptoms are consistent with the known side effects of Lysopadol 20 mg Lozenges at recommended doses and may need symptomatic treatment.

Pharmacotherapeutic group: Throat preparations (Anaesthetics, local),

ATC code: R02 AD

A local anaesthetic effect of ambroxol hydrochloride has been observed in the rabbit eye model and is likely to result from sodium channel blocking properties: ambroxol hydrochloride blocks hyperpolarised cloned neuronal voltage-gated sodium channels in vitro; binding was reversible and concentration-dependent.

This property is in accordance with the ancillary observations of rapid pain relief when using inhaled ambroxol hydrochloride in other diseases of the upper respiratory tract.

Lysopadol 20 mg Lozenges act locally on the oral and pharyngeal mucosa.

Clinical studies confirmed the pain relieving effects of Lysopadol 20 mg Lozenges in patients with sore throat due to an acute viral pharyngitis.

Except one, clinical trials have shown a rapid onset of action with duration of effect for at least three hours.

In vitro, ambroxol hydrochloride seems to exert an anti-inflammatory effect. Cytokine release from blood mononuclear and polymorphonuclear cells but also from tissue-bound mononuclear and polymorphonuclear cells was found to be significantly reduced by ambroxol hydrochloride in vitro.

Lysopadol 20 mg Lozenges have been shown to reduce redness in sore throat significantly.

Absorption:

Absorption of all non-delayed oral forms of ambroxol hydrochloride is rapid and complete, with dose linearity in the therapeutic range. Maximum plasma levels are reached within 1 to 2.5 hours following oral administration of the immediate-release formulation and after a median of 6.5 hours for the slow release formulation.

The absolute bioavailability after a 30 mg tablet was found to be 79%.

The slow release capsule showed a relative availability of 95% (dose-normalized) in comparison to a daily dose of 60 mg (30 mg twice daily) administered as immediate-release tablet.

Due to the additional absorption via the oral mucosa, administration of lozenge results approximately 25% (90% confidence interval = 116-134%) increase in total exposure compared to syrup formulation.

The increased exposure does not negatively affect ambroxol hydrochloride pharmacodynamics in the proposed indication.

Distribution:

Distribution of ambroxol hydrochloride from blood to tissue is rapid and pronounced, with the highest concentration of the active substance found in the lungs. The volume of distribution following oral administration was estimated to be 552 L. In the therapeutic range, plasma protein binding was found to be approximately 90%.

Metabolism and elimination:

About 30% of an orally administered dose is eliminated via first pass metabolism.

Ambroxol hydrochloride is primarily metabolized in the liver by glucuronidation and some cleavage to dibromanthranilic acid (approximately 10% of dose) aside from some minor metabolites. Studies in human liver microsomes have shown that CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromanthranilic acid.

Within 3 days of oral administration, approximately 6% of the dose is found in free form, while approximately 26 % of the dose is recovered in a conjugated form in the urine.

Ambroxol hydrochloride is eliminated with a terminal elimination half-life of approximately 10 hours. Total clearance is in the range of 660 mL/min, with renal clearance accounting for approximately 8% of the total clearance.

Pharmacokinetics in special populations:

In patients with hepatic dysfunction elimination of ambroxol hydrochloride is reduced, resulting in approximately 1.3 to 2-fold higher plasma levels.

Due to the high therapeutic range of ambroxol hydrochloride, dose adjustments are not necessary.

Others:

Age and gender were not found to affect the pharmacokinetics of ambroxol hydrochloride to a clinically relevant extent, and thus there is no necessity for adjustment of dosage regimens.

Food was not found to influence the bioavailability of ambroxol hydrochloride.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

Peppermint Aroma (Gum arabic, Chinese peppermint oil, Maltodextrin, Lactose monohydrate)

Sorbitol

Saccharin sodium

Macrogol 6000

Talc

Not applicable

3 years

Do not store above 30° C.

Polypropylene/Aluminium-blister.

Pack sizes: 8, 10, 16, 20, 24, 30, 32, 40, 48, 50 lozenges/package.

Not all pack sizes may be marketed.

No special requirements.

Boehringer Ingelheim Limited,

Consumer Healthcare,

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom

PA 7/63/1

June 2011