Flubrix® spray

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

Composition:

Active substance: flurbiprofen;

1 dose contains flurbiprofen 8.75 mg;

Excipients: betadex; sodium hydrogen phosphate, dodecahydrate; citric acid, monohydrate; methylparahydroxybenzoate (E218); sodium saccharin; hydroxypropyl betadex; sodium hydroxide; peppermint flavoring; cherry flavoring; N,2,3-trimethyl-2-isopropyl-butanamide; purified water.

Pharmaceutical form. Oromucosal spray, solution.

Main physicochemical properties: clear solution, colorless to slightly yellowish, with a characteristic odor.

Pharmacotherapeutic group. Preparations used in throat disorders.

Other preparations used in throat disorders. Flurbiprofen.

ATC code R02AX01.

Pharmacological Properties

Pharmacodynamics

Flurbiprofen is a non-steroidal anti-inflammatory drug (NSAID), a propionic acid derivative, which acts by inhibiting the synthesis of prostaglandins. Flurbiprofen exerts potent analgesic, antipyretic, and anti-inflammatory effects. In vitro studies using human cell cultures have demonstrated that a single dose dissolved in artificial saliva reduces swelling of the respiratory mucosa. According to whole blood assay studies, flurbiprofen is a mixed inhibitor of COX-1/COX-2 with some selectivity towards COX-1.

Preclinical studies indicate that the R(−)-enantiomer of flurbiprofen and related NSAIDs may affect the central nervous system; the likely mechanism involves inhibition of COX-2 induction at the spinal cord level.

A single dose of flurbiprofen 8.75 mg (three sprays) applied directly to the throat mucosa has been shown to alter the severity of pharyngitis, including swelling and inflammation, as indicated by statistically significant changes in the area under the curve (AUC) from baseline during active treatment compared to placebo [mean difference (standard deviation)]: from 0 to 2 hours [−1.82 (1.35) vs. −1.13 (1.14)], from 0 to 3 hours [−2.01 (1.405) vs. −1.31 (1.233)], and from 0 to 6 hours [−2.14 (1.551) vs. −1.50 (1.385)]. Significant differences in AUC from baseline between 0 and 6 hours compared to placebo were also observed for other pharyngitis symptoms, including pain intensity [−22.50 (17.894) vs. −15.64 (16.413)], difficulty swallowing [−22.50 (18.260) vs. −16.01 (15.451)], throat swelling [−20.97 (18.897) vs. −13.80 (15.565)], and relief of sore throat [3.24 (1.456) vs. 2.47 (1.248)]. Changes from baseline at individual time points for various pharyngitis parameters were significant starting from 5 minutes up to 6 hours.

In patients receiving antibiotics for streptococcal infection, symptom relief of pharyngitis was statistically greater after taking flurbiprofen 8.75 mg lozenges 7 hours and beyond after antibiotic administration. The analgesic effect of flurbiprofen 8.75 mg lozenges is not diminished when antibiotics are used to treat patients infected with streptococcal throat infection.

Efficacy has also been demonstrated after multiple dosing over 3 days. Flubriks® spray is a simple and convenient medicinal product that, upon application to the inflamed area of the throat, restores voice while simultaneously soothing and softening the throat.

Pharmacokinetics

Absorption

A single dose of flurbiprofen 8.75 mg (3 sprays) is delivered directly to the throat; flurbiprofen is readily absorbed and detectable in blood within 2–5 minutes. Maximum plasma concentration is observed 30 minutes after administration, but remains at a relatively low average level of 1.6 µg/mL—approximately 4 times lower than that achieved with a 50 mg tablet. Flubriks® spray is bioequivalent to flurbiprofen 8.75 mg lozenges. Flurbiprofen absorption occurs from the oral cavity via passive diffusion. The rate of absorption depends on the dosage form. The peak concentration achieved after administration of the oromucosal spray is reached faster than after administration of an equivalent orally ingested dose.

Distribution

Flurbiprofen rapidly distributes throughout the body and binds to plasma proteins.

Metabolism/Excretion

Flurbiprofen is 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 orally administered flurbiprofen is excreted unchanged from the body.

Special populations

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

Clinical characteristics.

Indications.

For short-term symptomatic relief of acute sore throat in adults.

Contraindications.

• Hypersensitivity to flurbiprofen or to any of the other components of the medicinal product.
• Hypersensitivity reactions (e.g. bronchial asthma, bronchospasm, rhinitis, angioedema or urticaria) following the administration of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs).
• Recurrent peptic ulcer/bleeding in medical history or in the phase of exacerbation (two or more episodes confirmed by characteristic clinical manifestations) and intestinal ulcers.
• Gastrointestinal bleeding in medical history or perforation, severe colitis, hemorrhagic or hemopoietic disorders associated with previous NSAID therapy.
• Third trimester of pregnancy.
• Severe heart failure, severe renal failure or severe hepatic failure.
• Pediatric age (under 18 years).

Interaction with other medicinal products and other forms of interaction.

Concomitant use of flurbiprofen with the following should be avoided:

Acetylsalicylic acid, unless acetylsalicylic acid has been prescribed by a physician in low doses (not exceeding 75 mg per day), as this may lead to adverse reactions;

Other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, as this increases the risk of adverse effects (particularly gastrointestinal adverse reactions such as ulcers and bleeding).

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

Anticoagulants. Nonsteroidal anti-inflammatory drugs may enhance the effect of anticoagulants such as warfarin.

Antihypertensive agents and diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists. Nonsteroidal anti-inflammatory drugs may reduce the therapeutic effect of these agents. The risk of nephrotoxicity is increased.

Corticosteroids increase the risk of gastrointestinal bleeding or ulcers.

Cardiac glycosides. 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.

Antiplatelet agents and selective serotonin reuptake inhibitors: increased risk of gastrointestinal bleeding.

Lithium. Possible increase in serum lithium levels.

Metotrexate. Administration of NSAIDs within 24 hours before or after metotrexate may lead to increased methotrexate concentrations and enhanced toxicity.

Ciclosporins. Increased risk of nephrotoxicity.

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

Tacrolimus. Increased risk of nephrotoxicity.

Zidovudine. When NSAIDs are used concomitantly, there is an increased risk of hematological toxicity.

Quinolone antibiotics increase the risk of seizures.

Oral antidiabetic agents. Blood glucose levels may change (enhanced monitoring of blood glucose levels is recommended).

Phenytoin. Possible increase in plasma phenytoin levels. Patient monitoring is required, with dose adjustment if necessary.

Potassium-sparing diuretics. Hyperkalemia may occur.

Probenecid, sulfinpyrazone. Medicinal products containing probenecid or sulfinpyrazone may delay the elimination of flurbiprofen.

Alcohol. The risk of adverse reactions, particularly gastrointestinal bleeding, is increased.

Special precautions for use.

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

Infections. In isolated cases, exacerbations of infectious inflammation (e.g., development of necrotizing fasciitis) have been reported in temporal association with systemic NSAID use. Patients should be advised to seek immediate medical attention if signs of bacterial infection occur or if their condition worsens during treatment with flurbiprofen spray. The need for antibiotic therapy should be considered.

In cases of purulent bacterial pharyngitis/tonsillitis, patients should consult a physician, as treatment may need to be revised.

Treatment should not exceed three days.

If symptoms worsen or new symptoms appear, patients should consult a physician, as treatment should be re-evaluated.

If oral irritation occurs, flurbiprofen treatment should be discontinued.

Masking symptoms of underlying infections.

Epidemiological studies suggest that systemic nonsteroidal anti-inflammatory drugs (NSAIDs) may mask symptoms of infection, potentially leading to delayed initiation of appropriate treatment and thus worsening the course of infection. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. If Flubrix® spray is used while the patient suffers from fever or pain associated with infection, monitoring for progression of the infection is recommended.

In elderly patients, the frequency of adverse reactions caused by nonsteroidal anti-inflammatory agents is increased, particularly gastrointestinal bleeding or perforation, which may be fatal.

Bronchospasm may occur in patients with bronchial asthma or allergic conditions, as well as in those with a history of bronchospasm.

Concomitant use of flurbiprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, is not recommended.

Systemic lupus erythematosus and systemic connective tissue diseases increase the risk of aseptic meningitis; however, this effect is usually not observed with short-term, limited use of drugs such as flurbiprofen spray.

Cardiac, renal, and hepatic impairment.

NSAIDs may cause nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and renal failure. NSAID use may lead to dose-dependent reduction in prostaglandin production and provoke renal failure. Patients at greatest risk include those with pre-existing renal impairment, heart failure, hepatic dysfunction, patients taking diuretics, and elderly patients; however, this effect is usually not observed with short-term, limited use of drugs such as flurbiprofen spray.

Hepatic function impairment (see sections "Contraindications" and "Adverse reactions").

Effects on the cardiovascular and cerebrovascular systems: Flurbiprofen-containing products should be used 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 NSAID therapy.

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 events (e.g., myocardial infarction or stroke). There are insufficient data to exclude such a risk with the use of 5 doses per day (1 dose = 3 sprays).

Neurological symptoms. Prolonged use of analgesics or use without medical indication may lead to medication-overuse headache, which cannot be treated by increasing the dose of the drug.

Gastrointestinal effects: NSAIDs should be used with caution in patients with a history of ulcerative colitis or Crohn’s disease, as their condition may worsen.

During use of all NSAIDs, gastrointestinal bleeding, ulcers, and perforations have been reported, which may be fatal, both in patients with and without prior symptoms or serious gastrointestinal adverse events in their history.

The risk of gastrointestinal bleeding, ulcers, and perforation increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients; however, this effect is usually not observed during short-term, limited use of drugs such as flurbiprofen spray. Patients with a history of gastrointestinal toxicity, particularly elderly individuals, should inform their physician of any unusual abdominal symptoms (especially gastrointestinal bleeding).

The drug should be used with caution in patients receiving concomitant therapy with medications that increase the risk of peptic ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in a patient receiving flurbiprofen, treatment should be discontinued.

Hematological effects. Flurbiprofen, like other NSAIDs, may inhibit platelet aggregation and prolong bleeding time. Flurbiprofen spray should be used with caution in patients with potential for abnormal bleeding.

Skin reactions, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely. Patients should discontinue treatment with flurbiprofen at the first sign of rash, mucosal lesions, or other signs of hypersensitivity (see section "Adverse reactions").

The medicinal product contains methylparahydroxybenzoate, which may cause allergic reactions (possibly delayed).

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 with gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac malformation increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of treatment. In animal studies, administration of prostaglandin synthesis inhibitors resulted in increased pre- and post-implantation loss and embryolethality. Additionally, an increased incidence of various developmental abnormalities, including cardiovascular malformations, was observed in animals treated with prostaglandin synthesis inhibitors during organogenesis. Flurbiprofen should not be used during the first and second trimesters of pregnancy.

The drug is contraindicated during the third trimester of pregnancy, as all prostaglandin synthesis inhibitors may cause:

in the fetus: cardiopulmonary toxicity (premature closure of the ductus arteriosus and development of pulmonary hypertension), renal dysfunction that may progress to renal failure, oligohydramnios or polyhydramnios;

in the mother and newborn: prolonged bleeding due to anti-aggregatory effect, which may occur even at very low doses; inhibition of uterine contractions leading to delayed or prolonged labor.

Breastfeeding. Small amounts of flurbiprofen have been detected in breast milk, but no adverse effects of flurbiprofen on breastfed newborns have been observed. Nevertheless, use of the drug during breastfeeding should be avoided.

Fertility. There is evidence that drugs which inhibit cyclooxygenase/prostaglandin synthesis may adversely affect female fertility, particularly ovulation. Fertility is restored after discontinuation of treatment.

Ability to influence reaction speed when driving or operating machinery.

Dizziness, drowsiness, fatigue, and visual disturbances may occur during NSAID use. If these adverse effects occur, driving or operating machinery is not recommended.

Method of Administration and Dosage

For oromucosal use. For short-term use only. The recommended dose for adults is 1 dose (3 sprays) applied to the back of the oral cavity every 3–6 hours as needed, but not exceeding 5 doses per day.

Do not inhale during spraying.

The use of this medicinal product is not recommended for more than 3 days.

Before first use, the spray pump must be primed. To do this, turn the nozzle away from yourself and press the cap at least four times until a clear, homogeneous mist is produced. This ensures that the medicinal product fills the spray pump and the spray is ready for use.

Before administering each subsequent dose, turn the nozzle away from yourself, press the cap at least once, and confirm that a clear, homogeneous mist is produced. The spray function must be checked before each use.

Use the lowest effective dose necessary to control symptoms for the shortest duration (see section "Special Warnings and Precautions for Use").

Elderly patients should use the lowest possible effective dose for the shortest duration.

Children

The safety and efficacy of Flubrix® spray in children (under 18 years of age) have not been established.

Overdose

Symptoms. In most patients who have ingested clinically significant amounts of nonsteroidal anti-inflammatory drugs, symptoms may include nausea, vomiting, epigastric pain, or very rarely, 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, sometimes excitement, visual disturbances, disorientation, or coma. Seizures may occasionally occur. Severe intoxication may lead to metabolic acidosis and prolonged prothrombin time due to effects on blood coagulation factors. Acute renal failure and liver damage may develop. In patients with bronchial asthma, worsening of the disease may be observed.

Treatment. Treatment should be symptomatic and supportive, including airway management, monitoring of cardiac and vital signs until stabilization. Oral administration of activated charcoal or gastric lavage is recommended if the patient presents within 1 hour after ingestion of a potentially toxic dose. Electrolyte imbalances in serum should be corrected as needed. Bronchodilators should be administered in cases of bronchial asthma. There is no specific antidote for flurbiprofen.

Adverse reactions.

Hypersensitivity reactions to NSAIDs have been reported, including:

• Non-specific allergic reactions and anaphylaxis;
• Respiratory tract reactivity, such as bronchial asthma, exacerbation of bronchial asthma, bronchospasm, dyspnea;
• Various skin reactions, such as pruritus, urticaria, Quincke's edema, and less frequently—exfoliative and bullous dermatitis (including epidermal necrolysis and erythema multiforme).

Events such as edema, arterial hypertension, and heart failure have been reported with NSAID treatment. There is insufficient data to exclude such risks when using oromucosal spray or flurbiprofen solution.

The adverse reactions listed below were observed during short-term use of flurbiprofen. The frequency of adverse reactions is defined as follows: 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), not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

Not known: anemia, thrombocytopenia.

Cardiovascular and cerebrovascular system disorders:

Not known: edema, arterial hypertension, heart failure.

Nervous system disorders:

Common: dizziness, headache, paresthesia (tingling, numbness, pruritus);
Uncommon: somnolence.

Respiratory, thoracic and mediastinal disorders:

Common: throat irritation;
Uncommon: exacerbation of bronchial asthma, bronchospasm, dyspnea, wheezing, oral blisters, pharyngeal hypoaesthesia.

Gastrointestinal disorders:

Common: diarrhea, oral ulcers, nausea, oral pain, oral paresthesia, oropharyngeal pain, oral discomfort (sensation of warmth, burning, or tingling in the mouth);
Uncommon: abdominal distension, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, burning mouth syndrome, dysgeusia, oral dysaesthesia, vomiting.

Skin and subcutaneous tissue disorders:

Uncommon: various skin rashes, pruritus;
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.

Immune system disorders:

Rare: anaphylactic reactions.

Psychiatric disorders:

Uncommon: insomnia.

Hepatobiliary disorders:

Not known: hepatitis.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Shelf life after first opening of the bottle – 6 months.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children. Do not store in the refrigerator and do not freeze.

Packaging. 15 ml in a bottle. 1 bottle per carton.

Availability category. Over-the-counter.

Manufacturer. JSC "Farmak".

Manufacturer's address.
74, Kyrylivska Street, Kyiv, 04080, Ukraine.