Angi.net® lozenges

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANGINET® LOZENGES

Composition:

Active substance: flurbiprofen;

1 lozenge contains flurbiprofen 8.75 mg;

Excipients: isomaltite (E 953), maltitol liquid (E 965), macrogol 300, peppermint oil, honey flavor, lemon flavor.

Pharmaceutical form. Lozenges.

Main physicochemical properties: round, transparent, yellowish lozenges with a diameter of 19 ± 1 mm.

Pharmacotherapeutic group. Preparations used in throat disorders. Flurbiprofen. ATC code R02AX01.

Pharmacological properties.

Pharmacodynamics. Flurbiprofen is a propionic acid derivative from the group of non-steroidal anti-inflammatory drugs (NSAIDs) that acts by inhibiting the synthesis of prostaglandins. In humans, flurbiprofen exerts potent analgesic, antipyretic, and anti-inflammatory effects.

It has been demonstrated that a dose of 8.75 mg dissolved in artificial saliva inhibits prostaglandin synthesis in cultured human respiratory tract cells. According to whole blood assay studies, flurbiprofen is a mixed inhibitor of COX-1 and COX-2 with some selectivity towards COX-1.

Preclinical data suggest that the R(–)-enantiomer of flurbiprofen and other NSAIDs may affect the central nervous system; the proposed mechanism of action involves inhibition of COX-2 induced at the spinal cord level.

In an ex vivo model, penetration of flurbiprofen in the 8.75 mg lozenge formulation into human pharyngeal tissues, including deep layers, has been demonstrated.

Significant pain relief was observed in patients on average within 42.9 minutes after a single 8.75 mg dose of flurbiprofen administered locally to the throat via lozenge dissolution, with the first signs of pain relief (analgesic effect) appearing on average within 13.2 minutes.

Pain relief in the throat, including reduction of swelling and inflammation of the throat mucosa, was shown to result from significant pain suppression (least squares mean difference) beginning at 22 minutes (–5.5 mm), peaking at 70 minutes (–13.7 mm), and remaining significant for up to 240 minutes (–3.5 mm), including in patients with streptococcal and non-streptococcal infections. Swallowing difficulty reduction began at 20 minutes (–6.7 mm), peaked at 110 minutes (–13.9 mm), and persisted for 240 minutes (–3.5 mm). Reduction in the sensation of throat swelling was observed at 60 minutes (–9.9 mm), peaked at 120 minutes (–11.4 mm), and persisted for 210 minutes (–5.1 mm).

The efficacy of multiple doses, measured as the sum of pain intensity differences (SPID) over 24 hours, demonstrated significant reduction in throat pain intensity (from –473.7 mm*h to –529.1 mm*h), difficulty in swallowing (from –458.4 mm*h to –575.0 mm*h), and throat swelling (from –482.4 mm*h to –549.9 mm*h), with statistically greater cumulative pain reduction at each time interval over 23 hours for all three parameters and statistically significant greater hourly pain relief over a 6-hour evaluation period. Efficacy of multiple doses was also demonstrated at 24 hours and over 3 days.

In patients receiving antibiotics for treatment of streptococcal infection, statistically significant greater throat pain relief was observed with flurbiprofen 8.75 mg therapy at 7 hours and beyond after antibiotic administration. The analgesic effect of flurbiprofen 8.75 mg was not diminished by concomitant use of antibiotics for treatment of streptococcal tonsillitis.

Within 2 hours after the first dose of 8.75 mg flurbiprofen lozenges, significant reduction of certain accompanying symptoms of throat pain present at baseline was observed, including cough (50% vs. 4%), loss of appetite (84% vs. 57%), and high body temperature (68% vs. 29%).

The lozenge has been shown to be at least as effective as a topical spray containing flurbiprofen, based on differences in pain intensity before and 2 hours after administration.

The lozenge dissolves in the mouth within 5–12 minutes and provides significant soothing and coating effects within 2 minutes after administration.

Children

No specific studies involving children have been conducted. Studies on the efficacy and safety of 8.75 mg flurbiprofen lozenges included children aged 12–17 years; however, the small sample size indicates that statistically significant conclusions cannot be drawn.

Pharmacokinetics.

Absorption

8.75 mg flurbiprofen lozenges dissolve within 5–12 minutes. Flurbiprofen is readily absorbed and detectable in blood within 5 minutes, with maximum plasma concentration observed at 40–45 minutes after administration, remaining at a low average level of 1.4 µg/mL—approximately 4.4 times lower than that achieved with a 50 mg tablet. Absorption of flurbiprofen occurs in the oral cavity via passive diffusion. The rate of absorption depends on the pharmaceutical form, with peak concentrations achieved more rapidly after lozenge administration than after oral intake of an equivalent dose.

Distribution.

Flurbiprofen is rapidly distributed throughout the body and binds to plasma proteins.

Metabolism/elimination.

Flurbiprofen is primarily metabolized via hydroxylation and excreted by the kidneys. The elimination half-life ranges from 3 to 6 hours. Flurbiprofen passes into breast milk only in minimal amounts (less than 0.05 µg/mL). Approximately 20–25% of flurbiprofen is excreted unchanged following oral administration.

Special patient groups.

No differences in pharmacokinetic parameters were observed between elderly individuals and young adult volunteers after oral administration of flurbiprofen in tablet form.

Pharmacokinetic data in children under 12 years of age following administration of 8.75 mg flurbiprofen have not been obtained; however, administration of flurbiprofen syrup and suppositories does not indicate significant differences in pharmacokinetic parameters compared to adults.

Clinical Characteristics

Indications. For short-term symptomatic relief of sore throat pain in adults and children aged 12 years and older.

Contraindications.

• Hypersensitivity to flurbiprofen or to any of the excipients of the medicinal product.
• History of hypersensitivity reactions (e.g., bronchial asthma, bronchospasm, rhinitis, angioedema, or urticaria) after intake of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs).
• Recurrent peptic ulcer/bleeding in history or in the phase of exacerbation (two or more episodes confirmed by characteristic clinical manifestations) and intestinal ulcers.
• Gastrointestinal bleeding or perforations in history, severe forms of colitis, hemorrhagic or hemopoietic disorders associated with previous NSAID therapy.
• Third trimester of pregnancy.
• Severe heart failure, severe renal failure, or severe hepatic failure.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of flurbiprofen with the following should be avoided:

other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors: concomitant use of two or more NSAIDs should be avoided, as this increases the risk of adverse effects (particularly gastrointestinal adverse reactions such as ulcers and bleeding);

acetylsalicylic acid (at low doses): unless aspirin has been prescribed by a physician at low doses (not exceeding 75 mg per day), because this increases the risk of adverse reactions.

Flurbiprofen should be used with caution in combination with the following agents:

anticoagulants: NSAIDs may enhance the effect of anticoagulants such as warfarin;

antiplatelet agents: increased risk of gastrointestinal ulceration or bleeding;

antihypertensive agents (diuretics, angiotensin-converting enzyme [ACE] inhibitors, and angiotensin II antagonists): NSAIDs may reduce the efficacy of diuretics and other antihypertensive agents and may enhance nephrotoxicity caused by cyclooxygenase inhibition, especially in patients with impaired renal function. (Patients should receive adequate fluid intake);

alcohol: increases the risk of adverse reactions, particularly gastrointestinal bleeding;

cardiac glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of glycosides. Monitoring of the patient is recommended, with dose adjustment if necessary;

cyclosporine: increased risk of nephrotoxicity;

corticosteroids: increase the risk of adverse reactions, particularly in the gastrointestinal tract;

lithium: possible increase in serum lithium levels—appropriate monitoring and, if necessary, dose adjustment are required;

methotrexate: administration of NSAIDs within 24 hours before or after methotrexate may lead to increased methotrexate concentration and enhanced toxicity;

mifepristone: NSAIDs should not be taken within 8–12 days after mifepristone administration, as NSAIDs may reduce the efficacy of mifepristone;

oral antidiabetic agents: blood glucose levels may change (increased monitoring of blood glucose levels is recommended);

phenytoin: possible increase in plasma phenytoin levels; appropriate monitoring and, if necessary, dose adjustment are recommended;

potassium-sparing diuretics: concomitant use may lead to hyperkalemia;

probenecid, sulfinpyrazone, medicinal products containing probenecid or sulfinpyrazone: may cause delayed elimination of flurbiprofen;

quinolone antibiotics: animal studies indicate that NSAIDs increase the risk of seizures associated with quinolone antibiotics. Patients taking NSAIDs and quinolones have an increased risk of developing seizures;

selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal ulceration or bleeding;

tacrolimus: possible increased risk of nephrotoxicity when NSAIDs are used concomitantly with tacrolimus;

zidovudine: increased risk of hematological toxicity when NSAIDs are used concomitantly with zidovudine.

Studies conducted to date have not revealed interactions between flurbiprofen and tolbutamide or antacids.

Special precautions for use

Adverse effects can be minimized by using the lowest effective dose required to control symptoms for the shortest duration necessary.

In elderly patients, the frequency of adverse reactions associated with NSAIDs is increased, particularly gastrointestinal bleeding or perforations, which may be fatal.

Respiratory effects. Bronchospasm may occur in patients suffering from bronchial asthma or allergic diseases, or with a history of these conditions. Flurbiprofen lozenges should be used with caution in such patients.

Other NSAIDs. Concomitant use of flurbiprofen lozenges with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided.

Systemic lupus erythematosus and mixed connective tissue disease. Patients with systemic lupus erythematosus and mixed connective tissue disorders have an increased risk of aseptic meningitis.

Cardiac, renal, and hepatic impairment. Nephrotoxicity. There have been reports that NSAIDs may cause nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and renal failure, particularly with concomitant use of multiple analgesic agents or with long-term regular use. NSAID use may lead to dose-dependent reduction in prostaglandin production and provoke renal failure. The highest risk of this reaction exists in patients with impaired renal, cardiac, or hepatic function, patients taking diuretics, and elderly patients. Renal function should be monitored in such patients. However, this effect is usually not observed with short-term, limited use of drugs such as flurbiprofen lozenges.

Cardiovascular and cerebrovascular effects. Flurbiprofen lozenges should be initiated with caution (after consultation with a physician) in patients with a history of elevated blood pressure and/or heart failure, as fluid retention, increased blood pressure, and edema have been reported during use of nonsteroidal anti-inflammatory drugs.

Clinical trials and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and for prolonged periods) increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). There is insufficient data to exclude such risk with the use of 5 lozenges per day.

Hepatic effects. Mild to moderate liver function impairment may occur.

Neurological effects. Analgesic-induced headache: prolonged use of analgesics or failure to follow recommended dosing may result in headache, which should not be treated with increased doses of the medicinal product.

Gastrointestinal effects. During treatment with all NSAIDs, gastrointestinal bleeding, ulcers, or perforations, including fatal cases, have been reported at any stage of therapy, which may occur independently of the presence or absence of warning symptoms or a history of severe gastrointestinal disorders. The risk increases with higher NSAID doses, in patients with a history of peptic ulcer disease, especially complicated by bleeding or perforation, and in elderly patients. These patients should begin treatment with the lowest available dose. Combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors) is recommended for such patients and for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risk. Patients should consult a physician if any unusual gastrointestinal symptoms occur (especially gastrointestinal bleeding), particularly at the beginning of treatment. The product should be used with caution in patients receiving concomitant therapy with drugs that increase the risk of peptic ulcer or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid. Treatment with flurbiprofen should be discontinued if gastrointestinal bleeding or ulceration occurs. NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as their condition may worsen.

Skin and subcutaneous tissue. Rarely, severe skin reactions, which may be fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, may occur during NSAID use. Flurbiprofen lozenges should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Infections. Since isolated cases of exacerbation of infectious inflammation (e.g., development of necrotizing fasciitis) have been observed in temporal association with systemic NSAID use as a class, patients are advised to seek immediate medical attention if signs of bacterial infection occur or if their condition worsens during treatment with flurbiprofen lozenges. Anti-infective antibiotic therapy should be considered.

Masking symptoms of underlying infections. Epidemiological studies indicate that systemic nonsteroidal anti-inflammatory drugs (NSAIDs) may mask symptoms of infection, potentially delaying appropriate treatment and thereby worsening the course of infection. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. If ANGHI.NET® LOZENGES are used while the patient suffers from fever or pain associated with infection, monitoring for infection progression is recommended.

Sugar intolerance. This medicinal product is contraindicated in patients with rare hereditary fructose intolerance, glucose/galactose malabsorption, or sucrase-isomaltase deficiency.

If symptoms worsen or new symptoms develop, treatment should be re-evaluated.

Treatment should be discontinued if irritation in the oral cavity occurs.

Effects on female fertility. Flurbiprofen use may impair fertility in women; therefore, this medicinal product is not recommended for women attempting to conceive. Discontinuation of this medicinal product should be considered in women experiencing difficulty conceiving or undergoing infertility investigations.

Use during pregnancy or breastfeeding.

Pregnancy. Clinical data on the use of ANGHI.NET® LOZENGES during pregnancy are lacking. Even though systemic exposure is lower compared to oral administration, it is unknown whether the systemic exposure achieved after local use of ANGHI.NET® LOZENGES may be harmful to the embryo/fetus. ANGHI.NET® LOZENGES should not be used during the first and second trimesters of pregnancy unless clearly necessary. If used, the dose should be as low as possible and the duration of treatment as short as possible.

Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of heart defects increased from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy. In animal studies, prostaglandin synthesis inhibitors administered during organogenesis resulted in increased incidence of various developmental abnormalities, including cardiovascular malformations.

From the 20th week of pregnancy, flurbiprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction following second-trimester treatment, most of which resolved after treatment cessation.

Flurbiprofen should not be used during the first two trimesters of pregnancy except when absolutely necessary. If flurbiprofen is used by women attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose should be used for the shortest possible duration.

Fetal monitoring for oligohydramnio and arterial duct constriction should be considered after exposure to flurbiprofen for several days starting from the 20th gestational week. Flurbiprofen treatment should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, systemic use of prostaglandin synthesis inhibitors, including ANGHI.NET® LOZENGES, may cause cardiopulmonary and renal toxicity in the fetus; cardiopulmonary toxicity (characterized by premature closure of the arterial duct and pulmonary hypertension); impaired renal function, which may progress to renal failure associated with oligohydramnios;

At late stages of pregnancy, prolonged bleeding may occur in both mother and child, along with delayed onset of labor; prolonged bleeding time, antiplatelet effect, which may develop even at very low doses; uterine contraction inhibition, leading to delayed or prolonged labor. Therefore, ANGHI.NET® LOZENGES are contraindicated during the last trimester of pregnancy (see section "Contraindications").

Breastfeeding. Flurbiprofen has been detected in breast milk at very low concentrations in some studies. It is unlikely to have a negative effect on the breastfed infant. However, due to possible adverse effects of NSAIDs on infants, ANGHI.NET® LOZENGES are not recommended for use in breastfeeding mothers.

Fertility. There is some evidence that drugs inhibiting prostaglandin synthesis/cyclooxygenase may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of the drug.

Ability to influence reaction speed when driving or operating machinery.

No studies on the ability to influence reaction speed when driving or operating machinery have been conducted.

Method of Administration and Dosage.

Lozenges should be sucked until completely dissolved.

For adults and children aged 12 years and older, take 1 lozenge every 3–6 hours as needed for pain relief. The maximum daily dose is 5 lozenges.

The lowest effective dose for the shortest duration necessary to relieve symptoms should be used (see section "Special Instructions").

If symptoms persist, worsen, or last longer than 3 days, medical advice should be sought.

The medicinal product should not be used for more than 3 consecutive days.

While sucking, the lozenge should be moved around the entire oral cavity to prevent irritation of the mucous membrane at the site of dissolution.

Elderly patients: At present, due to limited clinical experience, no general dosage recommendations can be given for elderly patients. In elderly patients, there is an increased risk of severe adverse reactions.

Hepatic impairment: Dose adjustment is not required in patients with mild to moderate liver dysfunction. Flurbiprofen is contraindicated in patients with severe hepatic insufficiency (see section "Special Instructions").

Renal impairment: Dose adjustment is not required in patients with mild to moderate renal dysfunction. Flurbiprofen is contraindicated in patients with severe renal insufficiency (see section "Special Instructions").

Children.

Do not use in children under 12 years of age.

Overdose.

Symptoms. In most patients, ingestion of a clinically significant amount of NSAIDs causes only nausea, vomiting, epigastric pain, or less commonly, diarrhea. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, such as drowsiness, occasionally excitement, visual disturbances, disorientation, or coma. Severe intoxication may lead to metabolic acidosis and prolonged prothrombin time, possibly due to interaction with circulating blood clotting factors. Acute renal failure and liver damage may occur. In patients with bronchial asthma, an exacerbation of asthma may be triggered.

Treatment. Treatment should be symptomatic and supportive, including ensuring airway patency and monitoring cardiac function and vital signs until the patient's condition stabilizes. Oral administration of activated charcoal is recommended within 1 hour after ingestion of a potentially toxic dose. In cases of frequent or prolonged muscle spasms, treatment should include intravenous administration of diazepam or lorazepam. Bronchodilators should be used in patients with bronchial asthma. There is no specific antidote for flurbiprofen.

Side effects

Hypersensitivity reactions to NSAIDs have been reported, which may include:

• non-specific allergic reactions and anaphylaxis;
• respiratory tract reactivity, for example: bronchial asthma, exacerbation of bronchial asthma, bronchospasm, dyspnea;
• various skin reactions, for example: pruritus, urticaria, angioneurotic edema;
• rarely – exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

With NSAID treatment, events such as edema, arterial hypertension, and heart failure have been reported. Clinical trials and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and during prolonged treatment) is associated with a small increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). There is insufficient data to exclude such risk with the use of flurbiprofen 8.75 mg lozenges.

The adverse reactions listed below were observed during short-term use of flurbiprofen at over-the-counter doses.

(Very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥ 1/10000 to < 1/1000; very rare: < 1/10000; frequency not known: cannot be estimated from available data).

Blood and lymphatic system disorders: frequency not known: anemia, thrombocytopenia.

Immune system disorders: rare: anaphylactic reactions.

Psychiatric disorders: uncommon: insomnia.

Cardiac and cerebrovascular disorders: frequency not known: edema, arterial hypertension, heart failure.

Nervous system disorders: common: dizziness, headache, paraesthesia; uncommon: somnolence.

Respiratory, thoracic and mediastinal disorders: common: throat irritation; uncommon: exacerbation of bronchial asthma and bronchospasm, dyspnea, wheezing, oral blisters, pharyngeal hypoaesthesia.

Gastrointestinal disorders: common: diarrhea, oral ulcers, nausea, oral pain, oral paraesthesia, oropharyngeal pain, oral discomfort (sensation of warmth, burning, or tingling in the mouth); uncommon: abdominal distension, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, glossodynia, dysgeusia, oral dysaesthesia, vomiting.

Hepatobiliary disorders: frequency not known: hepatitis.

Skin and subcutaneous tissue disorders: uncommon: various skin rashes, pruritus; frequency not known: severe skin reactions such as bullous reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis.

General disorders and administration site conditions: uncommon: pyrexia, pain.

If adverse reactions occur, treatment should be discontinued and medical advice should be sought.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C.

Keep out of reach of children.

Packaging.

12 lozenges in a blister, 2 blisters together with the instruction for medical use in a cardboard carton.

Supply category. Over-the-counter (without prescription).

Manufacturer. LOZY’S PHARMACEUTICALS, S.L.

Manufacturer’s location and address of the place of business.

Cámpus Empresarial, Lekaroz, 31795, Navarra, Spain / Campus Empresarial, Lekaroz, 31795, Navarra, Spain.