INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUBRIX® (FLUBRIX)

Composition:

Active substance: flurbiprofen;

1 lozenge contains flurbiprofen – 8.75 mg;

Excipients: sucrose, glucose solution, macrogol 300, peppermint oil, levomenthol, potassium hydroxide.

Pharmaceutical form. Lozenges.

Main physicochemical properties: round lozenges, pale yellow to brown in color, 19 mm ± 1 mm in size.

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

Pharmacological Properties

Pharmacodynamics

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

A dose of 8.75 mg dissolved in artificial saliva has been shown to inhibit prostaglandin synthesis in cultured human respiratory tract cells. According to whole blood assay studies, flurbiprofen is a mixed inhibitor of cyclooxygenase-1 (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 induction at the spinal cord level.

In an ex vivo model, penetration of flurbiprofen from 8.75 mg lozenges into human pharyngeal tissues has been demonstrated, particularly into deeper tissue layers.

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

Pain relief in the throat, including reduction of swelling and inflammation of the mucous membrane, has been demonstrated to occur due to significant pain reduction (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), particularly in patients with streptococcal and non-streptococcal infections. Improvement in swallowing difficulty begins at 20 minutes (–6.7 mm), peaks at 110 minutes (–13.9 mm), and persists for 240 minutes (–3.5 mm). Reduction in the sensation of throat swelling occurs by 60 minutes (–9.9 mm), peaks at 120 minutes (–11.4 mm), and remains evident for 210 minutes (–5.1 mm).

The efficacy of multiple doses, measured as the sum of pain intensity differences 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 pain relief in the throat 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 when patients received antibiotics for treatment of streptococcal tonsillitis.

Two hours after the first dose of 8.75 mg flurbiprofen lozenges, significant reduction was observed in some concomitant symptoms of throat pain present at baseline, 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 flurbiprofen spray, based on differences in pain intensity before and 2 hours after administration of the products.

The lozene 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. Efficacy and safety studies of 8.75 mg flurbiprofen lozenges have been performed in children aged 12–17 years; however, the small sample size precludes statistically significant conclusions.

Pharmacokinetics

Maximum plasma concentration of flurbiprofen is observed 30–40 minutes after dissolving the lozenge in the oral cavity. Peak flurbiprofen concentrations after lozenge administration are achieved more rapidly than after swallowing an equivalent dose, although plasma concentration levels are similar in both cases. Flurbiprofen is rapidly distributed throughout the body. The drug is actively metabolized via methylation and hydroxylation, followed by renal elimination. The main metabolites are 4’-hydroxy-flurbiprofen and 3’-hydroxy-4’-methoxy-flurbiprofen. Approximately 70% of each dose is excreted in urine within 24 hours. The elimination half-life is 3–6 hours.

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) following administration of acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs).
Recurrent peptic ulcer/bleeding in history or in the active phase, or intestinal ulcers (two or more episodes confirmed by characteristic clinical symptoms).
Gastrointestinal bleeding or perforation in history, severe forms of colitis, hemorrhagic or hematopoietic 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: simultaneous use of two or more NSAIDs is not recommended, as this increases the risk of adverse effects (particularly gastrointestinal adverse reactions such as ulcers and bleeding);
acetylsalicylic acid (at low doses), except when low-dose aspirin (not exceeding 75 mg per day) has been prescribed by a physician — since 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 inhibitors, and angiotensin II receptor antagonists): NSAIDs may reduce the efficacy of diuretics and other antihypertensive agents and may enhance nephrotoxicity due to 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: increased risk of adverse reactions, particularly gastrointestinal;

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

methotrexate: administration of NSAIDs within 24 hours before or after methotrexate may lead to increased methotrexate concentrations 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 fluctuate (enhanced monitoring of blood glucose levels is recommended);

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

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

probenecid, sulfinpyrazone, or 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 receiving both NSAIDs and quinolones have an increased risk of developing seizures;

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

tacrolimus: 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 the use of 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 such 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 or mixed connective tissue disease have an increased risk of aseptic meningitis.

Cardiac, renal and hepatic insufficiency. Nephrotoxicity. There have been reports that NSAIDs may cause nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and renal failure, particularly when multiple analgesic agents are used in combination or with prolonged regular use. NSAID use may lead to dose-dependent reduction in prostaglandin production and may provoke renal failure. The highest risk of this reaction exists in patients with pre-existing renal impairment, heart failure, hepatic dysfunction, those 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.

Effects on the cardiovascular and cerebrovascular systems. Caution (after consultation with a physician) is advised when initiating treatment 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 NSAID use.

Clinical trials and epidemiological data indicate 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 a risk with the use of 5 lozenges per day.

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

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

Gastrointestinal effects. During treatment with all NSAIDs at any stage of therapy, gastrointestinal bleeding, ulcers, or perforations, which may be fatal, have been reported, regardless of the presence 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, especially complicated by bleeding or perforation, and in elderly patients. Such patients should begin treatment with the lowest available dose. Combined therapy with protective agents (e.g., misoprostol or proton pump inhibitors) is recommended for these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing the risk of gastrointestinal disorders. Patients should consult a physician if any unusual gastrointestinal symptoms occur (especially gastrointestinal bleeding), particularly at the beginning of treatment. Caution is advised when administering the drug to 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. If gastrointestinal bleeding or ulceration occurs in patients receiving flurbiprofen, treatment should be discontinued. NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (e.g., ulcerative colitis, Crohn’s disease), as their condition may worsen.

Skin and subcutaneous tissue effects. Very 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 the use of systemic NSAIDs, 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 as necessary.

Masking symptoms of underlying infections. Epidemiological studies suggest that systemic nonsteroidal anti-inflammatory drugs (NSAIDs) may mask symptoms of infection, potentially delaying appropriate treatment and thereby worsening the course of infection. Such symptom masking has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. If Flubrix® is used while the patient has fever or pain related to infection, monitoring for progression of the infection is recommended.

Sugar intolerances. This medicinal product should not be used in patients with rare hereditary fructose intolerance, glucose/galactose malabsorption, or sucrase-isomaltase deficiency.

Flubrix® lozenges may be harmful to teeth.

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

If irritation in the oral cavity occurs, treatment should be discontinued.

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

Use during pregnancy or breastfeeding.

Pregnancy. Inhibition of prostaglandin synthesis may adversely 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 increases 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, administration of prostaglandin synthesis inhibitors during organogenesis resulted in increased incidence of various developmental abnormalities, including cardiovascular malformations.

There are no clinical data on the use of flurbiprofen during pregnancy. Even though the systemic exposure to flurbiprofen achieved after local administration is lower than with oral use, it is unknown whether this exposure could be harmful to the embryo/fetus. Flurbiprofen 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.

During the third trimester of pregnancy, systemic use of prostaglandin synthesis inhibitors, including flurbiprofen, may cause cardiovascular effects (characterized by premature closure of the ductus arteriosus and pulmonary hypertension) and nephrotoxicity in the fetus, which may progress to renal failure associated with oligohydramnios. At late stages of pregnancy, prolonged bleeding may occur in both mother and child, antiplatelet effects may develop even at very low doses, and labor may be delayed. Therefore, Flubrix® is contraindicated during the third 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 the potential adverse effects of NSAIDs on infants, Flubrix**®** is not recommended for use in women who are breastfeeding.

Fertility. There is some evidence that drugs which inhibit 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 of the medicinal product to affect reaction speed when driving or operating machinery have been conducted.

Method of Administration and Dosage

Lozenges should be sucked until completely dissolved. Adults and children aged 12 years and older should take 1 lozenge every 3–6 hours as needed for pain relief. The maximum daily dose is 5 lozenges.

Use the lowest effective dose for the shortest duration necessary to relieve symptoms (see section "Special Instructions"). If symptoms do not improve, worsen, or persist for more than 3 days, consult a physician.

It is not recommended to use the medicinal product for more than 3 consecutive days.

While sucking, move the lozenge 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, general dosage recommendations cannot be provided for elderly patients. Elderly patients have an increased risk of severe adverse reactions.

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, likely due to interaction with circulating blood coagulation factors. Acute renal failure and liver damage may occur. In patients with bronchial asthma, exacerbation of asthma symptoms is possible.

Treatment. Treatment should be symptomatic and supportive, including maintenance of airway patency and continuous monitoring of 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. For frequent or prolonged muscle spasms, intravenous administration of diazepam or lorazepam is indicated. Bronchodilators should be used in cases of bronchial asthma. There is no specific antidote for flurbiprofen.

Adverse Reactions

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, and less frequently – exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Edema, arterial hypertension, and heart failure have been reported in connection with NSAID therapy. Clinical trials and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and during long-term treatment) is associated with a slightly increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). There is insufficient data to exclude such risk when using 8.75 mg flurbiprofen 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: ≥1/1,000 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).

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

Immune system disorders: rare – anaphylactic reactions.

Psychiatric disorders: uncommon – insomnia.

Cardiac, vascular 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 a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store at temperatures not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging. 8 or 12 lozenges in blisters. 2 blisters per carton.

Availability. Over-the-counter.

Manufacturer. Loziers Pharmaceuticals S.L.

Manufacturer’s address. Campus Empresarial, Lekaros, Navarra, 31795, Spain.

Marketing Authorization Holder. JSC "Farmak".

Address of Marketing Authorization Holder. 63, Kyrylivska St., Kyiv, 04080, Ukraine.