Froben Throat Oral Mucosa Spray 15 ml Flurbiprofen 0.25%

INDICATIONS

Froben Gola is indicated for the symptomatic treatment of irritative-inflammatory conditions also associated with pain in the oropharyngeal cavity (e.g. gingivitis, stomatitis, pharyngitis), also as a consequence of conservative or extractive dental therapy.

ACTIVE INGREDIENTS

• FROBEN THROAT 250mg/100ml Mouthwash 100 ml of solution contains: Active ingredient: Flurbiprofen 0.25 g Excipients with known effect: Ethanol, patent blue V(E131). • FROBEN THROAT 250mg/100ml Spray for oral mucosa 100 ml of solution contains: Active ingredient: Flurbiprofen 0.25 g Excipients with known effect: Ethanol, patent blue V(E131). For the full list of excipients, see section 6.1

EXCIPIENTS

Purified water, alcohol, patent blue VE 131, glycerol, mint essence, 40-polyoxyethylene hydrogenated castor oil, potassium bicarbonate, sodium saccharinate, sorbitol.

CONTRAINDICATIONS AND SIDE EFFECTS

Hypersensitivity to flurbiprofen or to any of the excipients listed in section 6.1. Froben Gola is also contraindicated in: • patients who have previously experienced hypersensitivity reactions (e.g. asthma, urticaria) after taking aspirin or other NSAIDs. • patients with a history of gastrointestinal bleeding or perforation related to previous treatment with NSAIDs. • patients with active or anamnestic ulcerative colitis, Crohn's disease, recurrent peptic ulcer or gastrointestinal bleeding (defined as two or more distinct episodes of demonstrated ulceration or bleeding). • patients with severe cardiac, renal or hepatic insufficiency (see section 4.4). Froben Gola is contraindicated during the third trimester of pregnancy.

DOSAGE

Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section 4.4). It is recommended to use this medicine for a maximum of three days. Dosage: • MOUTHWASH The recommended dose is two or three rinses or gargles per day with 10 ml of mouthwash. Can be diluted in water • SPRAY FOR ORAL MUCOSA The recommended dose is 2 sprays 3 times a day aimed directly at the affected part. Pediatric population No adequate data are available on the pediatric population; therefore the use of the medicine is not recommended.

CONSERVATION

Mouthwash: this medicine must not be stored above 25 C. Oral mucosa spray: this medicine must not be stored above 25 C; Keep the bottle in the outer carton to protect the medicine from light.

WARNINGS

General precautions Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section 4.2 and the sections below on gastrointestinal and cardiovascular risks). Use in elderly patients Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal. Gastrointestinal effects Flurbiprofen should be administered with caution to patients with a history of peptic ulcers and other gastrointestinal diseases as these conditions may be exacerbated. Gastrointestinal bleeding, ulcer or perforation have been reported with all NSAIDs at any time during treatment. These adverse events can be fatal and can occur with or without warning symptoms or in case of a previous history of serious gastrointestinal events. The risk of gastrointestinal haemorrhage, ulcer or perforation is higher with increasing dosage of flurbiprofen in patients with a history of ulcer, particularly if complicated by haemorrhage and perforation, and in the elderly. These patients should start treatment with the lowest available dose. Concomitant use of protective agents (misoprostol or proton pump inhibitors) should be considered for these patients and also for patients taking low doses of aspirin or other drugs that may increase the risk of gastrointestinal events (see section below and section 4.5). Patients with a history of gastrointestinal disease, especially if elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) in the initial stages of treatment. When gastrointestinal bleeding or ulceration occurs in patients taking Froben Gola, treatment should be suspended. Respiratory Disorders Cases of bronchospasm have been reported with flurbiprofen in patients with a history of bronchial asthma. Cardiac, renal and hepatic impairment Particular caution must be taken when treating patients with severely compromised renal, cardiac or hepatic function, as the use of NSAIDs can lead to deterioration of renal function. In such patients the dosage should be kept as low as possible and renal function should be monitored. The administration of an NSAID can cause a dose-dependent reduction in the formation of prostaglandins, accelerating renal failure. Patients at highest risk of developing this reaction are those with impaired kidney function, heart failure and liver dysfunction, those taking diuretics and elderly people. Renal function should be monitored in these patients (see also section 4.3). Flurbiprofen should be administered with caution in patients with a history of heart failure or hypertension as cases of edema have been reported in association with the administration of flurbiprofen. Cardiovascular and cerebrovascular effects Adequate monitoring and appropriate instructions are necessary in patients with a history of hypertension and/or mild to moderate congestive heart failure since, in association with the administration of flurbiprofen and treatment with NSAIDs, fluid retention and edema have been found. In these patients Froben Gola should be taken with caution. Clinical studies and epidemiological data suggest that the use of some NSAIDs, especially at high doses and for long-term treatments, may be associated with a modest increase in the risk of arterial thrombotic events such as myocardial infarction or stroke. There are insufficient data to exclude a similar risk for flurbiprofen. Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should be treated with flurbiprofen only after careful consideration. Similar considerations must be made before starting long-term treatment in patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking). Skin reactions Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. In the early stages of therapy, patients appear to be at higher risk: the onset of the reaction occurs in most cases within the first month of treatment. Flurbiprofen should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Renal effects Caution should be used when initiating treatment with NSAIDs such as flurbiprofen in patients with considerable dehydration. Hematological effects Flurbiprofen, like other NSAIDs, can inhibit platelet aggregation and prolong bleeding time. Systemic lupus erythematosus (SLE) and connective system diseases An increased risk of aseptic meningitis may occur in patients with Systemic Lupus Erythematosus (SLE) and connective system disorders (see section 4.8). The effects reported above have been reported in particular after the administration of formulations based on Flurbiprofen for systemic use. At the recommended doses, swallowing FROBEN GOLA does not cause any harm to the patient as these doses are significantly lower than those of the single dosage of the product systemically. The use of FROBEN GOLA, especially if prolonged, can give rise to local sensitization or irritation phenomena; in such cases it is necessary to interrupt the treatment and consult the doctor to institute, if necessary, a suitable therapy. Flurbiprofen should not be used for prolonged treatments. It is necessary to inform patients to seek medical advice if after short periods of treatment without appreciable results. Impairment of fertility The use of flurbiprofen may impair female fertility and is not recommended in women trying to become pregnant. In women who have difficulty conceiving or who are undergoing infertility investigations, discontinuation of treatment with flurbiprofen should be considered. Important information about some excipients FROBEN THROAT 250mg/100ml Mouthwash contains: • Sorbitol (E420). Patients with hereditary fructose intolerance should not be given this medicine. • Ethanol. This medicine contains 12 vol% ethanol (alcohol), e.g. up to 1 g per dose, equivalent to 24 ml of beer, 10 ml of wine per dose. It can be harmful to alcoholics. To be taken into consideration in pregnant or breastfeeding women, children and high-risk groups such as people with liver disease or epilepsy. For those who carry out sporting activities, the use of medicines containing ethyl alcohol can lead to positive anti-doping tests in relation to the blood alcohol concentration limits indicated by some sports federations. • Patent blue dye V(E131) which can cause allergic reactions. FROBEN THROAT 250mg/100ml Spray for oral mucosa contains: • Sorbitol. The additive effect of co-administration of medicinal products containing sorbitol (or fructose) and daily dietary intake of sorbitol (or fructose) should be considered. The sorbitol content in oral medicinal products may modify the bioavailability of other co-administered oral medicinal products. • Ethanol. This medicine contains 12 vol% ethanol (alcohol), e.g. up to 40 mg per dose, equivalent to 1 ml of beer, 0.4 ml of wine per dose. For those who carry out sporting activities, the use of medicines containing ethyl alcohol can lead to positive anti-doping tests in relation to the blood alcohol concentration limits indicated by some sports federations. • Patent blue dye V(E131) which can cause allergic reactions.

INTERACTIONS

Caution should be exercised in patients treated with any of the medicines listed below, as interactions have been reported in some patients. Diuretics, ACE inhibitors and angiotensin II antagonists: NSAIDs can reduce the effect of diuretics and other antihypertensive drugs. Diuretics may also increase the risk of NSAID nephrotoxicity. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) co-administration of an ACE inhibitor or an angiotensin II antagonist and agents that inhibit the cyclo-oxygenase system may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking Flurbiprofen concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in elderly patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and on a periodic basis thereafter. Lithium salts: decrease in lithium elimination. Methotrexate: caution is advised in case of concomitant administration of flurbiprofen and methotrexate as NSAIDs can increase the levels of methotrexate and therefore its toxic effects). Anticoagulants, such as warfarin: increased anticoagulant effect. Anti-aggregating agents: increased risk of gastrointestinal bleeding Selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding. Aspirin: As with other NSAID-containing medicines, concomitant administration of flurbiprofen and aspirin is generally not recommended due to the potential for increased side effects. Cardiac glycosides: NSAIDs can exacerbate heart failure, reduce glomerular filtration rate and increase plasma levels of cardiac glycosides. Cyclosporins: increased risk of nephrotoxicity with NSAIDs. Corticosteroids: increased risk of gastrointestinal ulcer or bleeding with NSAIDs. Cox-2 inhibitors and other NSAIDs: Concomitant use of other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to potential additive effects. Mifepristone: NSAIDs should not be taken for 8-12 days after administration of mifepristone as NSAIDs may reduce the effects of mifepristone. Quinolone Antibiotics: Results from animal studies suggest that NSAIDs may increase the risk of seizures associated with the use of quinolone antibiotics. Patients taking NSAIDs and Quinolones may have an increased risk of developing seizures. Tacrolimus: possible increased risk of nephrotoxicity in case of co-administration with NSAIDs. Zidovudine: increased risk of blood toxicity in case of co-administration with NSAIDs. There is evidence of an increased risk of haemarthrosis and haematoma in haemophilia patients affected by HIV in simultaneous treatment with Zidovudine and other NSAIDs. The interactions reported above have been reported in particular after the administration of Flurbiprofen-based formulations for systemic use. At the recommended doses of FROBEN GOLA, no interactions with other medicinal products or of any other nature have been reported. However, inform your doctor if you are taking other medicines.

SIDE EFFECTS

The following adverse reactions, reported in particular after the administration of formulations for systemic use, are reported according to the MedDRA classification. Frequency groupings are classified according to the following convention: very common (≥ 1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥ 1/10,000 to <1/1000), Very rare (<1/10,000) and Not Known (frequency cannot be estimated).

MedDRA system organ class: Frequency of Adverse Reactions.

Blood and lymphatic system disorders: Uncommon Anemia.

Blood and lymphatic system disorders: Very rare Leukopenia, agranulocytosis, aplastic anemia, neutropenia, thrombocytopenia, haemolytic anemia.

Immune system disorders: Uncommon Hypersensitivity

Immune system disorders: Rare Anaphylactic reaction.

Psychiatric disorders: Rare Depression, Confusional state.

Psychiatric disorders: Very rare Hallucination.

Nervous System Disorders: Common Migraine, dizziness.

Nervous System Disorders: Uncommon Paraesthesia.

Nervous System Disorders: Rare Drowsiness, Insomnia.

Nervous System Disorders: Not known Optic neuritis, cerebrovascular accident, headache.

Eye disorders: Uncommon Visual disturbances.

Ear and labyrinth disorders: Uncommon Tinnitus, vertigo.

Respiratory, thoracic and mediastinal disorders: Uncommon Asthma, dyspnoea.

Respiratory, thoracic and mediastinal disorders: Rare Bronchospasm.

Gastrointestinal disorders: Common Dyspepsia, diarrhoea, nausea, vomiting, abdominal pain, flatulence, constipation, melena, haematemesis, gastrointestinal haemorrhage.

Gastrointestinal disorders: Uncommon Gastritis, duodenal ulcer, gastric ulcer, mouth ulcer, gastrointestinal perforation.

Gastrointestinal disorders: Very rare Pancreatitis.

Gastrointestinal disorders: Not known Colitis and Crohn's disease.

Hepatobiliary disorders: Very rare Jaundice, cholestatic jaundice, abnormal liver function.

Hepatobiliary disorders: Not known Hepatitis.

Skin and subcutaneous tissue disorders: Uncommon Rash, urticaria, pruritus, purpura, angioedema, photosensitivity reactions

Skin and subcutaneous tissue disorders: Very rare Severe forms of bullous skin reactions (e.g. Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis).

Renal and urinary disorders: Rare Nephrotoxicity in various forms i.e. interstitial nephritis, nephrotic syndrome, renal failure and acute renal failure. (see paragraph 4.4).

Renal and urinary disorders: Not known Glomerulonephritis.

General disorders and administration site conditions: Common Fatigue, malaise, edema.

Cardiac disorders: Uncommon Heart failure.

Vascular disorders: Uncommon Hypertension.

Investigations: Common Liver function test abnormal, bleeding time prolonged.

Metabolism and nutrition disorders: Common Fluid retention.

Immune system disorders Hypersensitivity reactions have been reported following treatment with NSAIDs. These consist of: a) non-specific allergic reactions and anaphylaxis; b) reactions affecting the respiratory tract including asthma, even severe, bronchospasm or dyspnoea, or c) various skin disorders, such as various types of skin rashes, itching, urticaria, purpura, angioedema and, very rarely, exfoliative and bullous dermatitis (including Toxic Epidermal Necrolysis and erythema multiforme). Cardiac and vascular pathologies Cases of edema, hypertension and heart failure have been reported in association with treatment with NSAIDs. Clinical studies and epidemiological data suggest that the intake of some NSAIDs (especially if at high doses and in case of long-term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).Nervous System Pathologies Aseptic meningitis (especially in patients with existing autoimmune disorders such as Systemic Lupus Erythematosus and connective tissue disorders) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions that occur after authorization of the medicine is important, as it allows continuous monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetti-reazione-avversa.

OVERDOSE

Symptoms Symptoms of overdose may include nausea, vomiting, and gastrointestinal irritation. Treatment Treatment should include gastric lavage and, if necessary, correction of the serum electrolyte picture. There is no specific antidote for flurbiprofen.

PREGNANCY AND BREASTFEEDING

Fertility The use of FROBEN GOLA may negatively affect fertility and is not recommended in women who are trying to conceive. In women who have difficulty conceiving or who are undergoing fertility investigations, stopping taking FROBEN GOLA should be considered. Pregnancy Inhibition of prostaglandin synthesis can negatively affect pregnancy and/or embryo/foetal development. Results of epidemiological studies suggest an increased risk of miscarriage and cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in the early stages of pregnancy. The absolute risk of cardiac malformations increased from less than 1% to approximately 1.5%. The risk was thought to increase with the dose and duration of therapy. In animals, the administration of prostaglandin synthesis inhibitors has been shown to cause an increase in pre- and post-implantation loss and embryo-foetal mortality. Furthermore, an increased incidence of various malformations, including cardiovascular malformations, has been reported in animals to which prostaglandin synthesis inhibitors were administered during the organogenetic period. During the first and second trimester of pregnancy, flurbiprofen should not be administered unless strictly necessary. If flurbiprofen is used by a woman attempting to conceive or during the first and second trimester of pregnancy, the dose and duration of treatment should be kept as low as possible. During the third trimester of pregnancy, all inhibitors of prostaglandin synthesis can expose the fetus to: • Cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); • Renal dysfunction, which may progress to renal failure with oligohydramnios. The mother and the newborn, at the end of pregnancy, to: • Possible prolongation of bleeding time, an anti-aggregating effect which can occur even at very low doses; • Inhibition of uterine contractions resulting in delayed or prolonged labor. Consequently, flurbiprofen is contraindicated during the third trimester of pregnancy (see section 4.3). Breastfeeding In the few studies available so far, NSAIDs can appear in breast milk in very low concentrations. If possible, NSAIDs should be avoided during breastfeeding. See paragraph 4.4 Special warnings and precautions for use, regarding fertility in women.

EFFECTS ON DRIVING ABILITY

Side effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If these effects occur, patients should not drive or use machinery.