Celistar® for sore throat without sugar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Celista® From a sore throat sugar free

Composition:

Active substance: flurbiprofen;

1 lozenge contains flurbiprofen 8.75 mg;

Excipients: isomalt (E 953), maltitol (E 965), cochineal red A (E 124), sunset yellow (E 110), potassium acesulfame, macrogol 300, orange flavor, potassium hydroxide, levomenthol.

Pharmaceutical form. Lozenges.

Main physicochemical properties: Orange-colored, round-shaped lozenges with an orange flavor.

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

Pharmacological Properties

Pharmacodynamics

Flurbiprofen is a propionic acid derivative belonging to the group of non-steroidal anti-inflammatory drugs (NSAIDs), acting via inhibition of prostaglandin synthesis.

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 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.

Relief of sore throat symptoms, particularly throat swelling and inflammation of the mucous membranes, has been demonstrated through significant suppression (least squares mean difference) of throat pain, 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 is observed at 60 minutes (−9.9 mm), peaks at 120 minutes (−11.4 mm), and persists 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 (from −473.7 mm*hr to −529.1 mm*hr), difficulty in swallowing (from −458.4 mm*hr to −575.0 mm*hr), and throat swelling (from −482.4 mm*hr to −549.9 mm*hr), with statistically greater cumulative pain reduction at each time interval over 23 hours for all three parameters, and statistically significant greater hourly relief of throat pain during the 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 relief of sore throat was observed with flurbiprofen 8.75 mg therapy starting at 7 hours and continuing beyond antibiotic administration. The analgesic effect of flurbiprofen 8.75 mg was not diminished when patients used antibiotics for treatment of streptococcal tonsillitis.

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

The lozenge dissolves in the mouth within 5–12 minutes and provides a significant soothing and coating effect within 2 minutes of administration.

Children

No specific studies involving children have been conducted. Efficacy and safety studies of flurbiprofen 8.75 mg lozenges included children aged 12–17 years; however, the small sample size precludes drawing statistically significant conclusions.

Pharmacokinetics

Absorption

Flurbiprofen 8.75 mg lozenges dissolve within 5–12 minutes. Flurbiprofen is readily absorbed and detectable in blood within 5 minutes, with peak 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 dosage 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/Excretion

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 orally administered flurbiprofen is excreted unchanged.

Special patient groups

No differences in pharmacokinetic parameters have been observed between elderly 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 are not available; however, administration of flurbiprofen syrup and suppository formulations does not indicate significant differences in pharmacokinetic parameters compared to adults.

Clinical Characteristics.

Indications.

For short-term symptomatic relief of sore throat 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 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 perforation in history, severe colitis, hemorrhagic or hematopoietic disorders associated with previous NSAID therapy.
• Severe heart failure, severe renal impairment, or severe hepatic impairment.
• Third trimester of pregnancy.

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), except when low-dose aspirin (not exceeding 75 mg daily) has been prescribed by a physician, as this increases the risk of adverse reactions.

Flurbiprofen should be used with caution in combination with the following medicinal products:

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

antiplatelet agents: increased risk of gastrointestinal ulceration or bleeding;

antihypertensive agents (diuretics, ACE inhibitors, and angiotensin II antagonists): NSAIDs may reduce the effect of diuretics and other antihypertensive agents and may also enhance nephrotoxicity caused by cyclooxygenase inhibition, especially in patients with impaired renal function (adequate fluid intake is required);

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 in the gastrointestinal tract;

lithium: possible increase in serum lithium levels. Monitoring of the patient is recommended, with dose adjustment if necessary;

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

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

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

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

potassium-sparing diuretics: concomitant use may cause hyperkalemia (monitoring of serum potassium levels is recommended);

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;

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;

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

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.

Elderly patients. In elderly patients, the frequency of adverse reactions associated with NSAID use increases, particularly gastrointestinal bleeding or perforation, 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 with other NSAIDs, including COX-2 inhibitors, should be avoided.

Systemic lupus erythematosus and mixed connective tissue disease. Patients with systemic lupus erythematosus and mixed connective tissue disease have an increased risk of aseptic meningitis. However, this effect is usually not observed with short-term, limited use of medications such as flurbiprofen lozenges.

Cardiac, renal, and hepatic impairment. There have been reports of NSAIDs causing nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and renal failure, particularly when multiple analgesic agents are used in combination or with long-term chronic use. NSAID use may lead to dose-dependent reduction in prostaglandin production and may trigger renal failure. The highest risk of this reaction occurs 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 medications such as flurbiprofen lozenges.

Cardiovascular and cerebrovascular effects. 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 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 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.

Neurological effects. Analgesic-induced headache: prolonged use of analgesics or failure to follow recommendations may result in headache, which should not be treated with higher doses of the medication. In such cases, NSAID treatment should be discontinued and the patient should seek medical advice.

Gastrointestinal effects. NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as their condition may worsen. During treatment with any NSAID at any stage, gastrointestinal bleeding, ulcers, or perforations—potentially fatal—have been reported, regardless of the presence of warning symptoms or prior 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. However, this effect is usually not observed with short-term, limited use of medications such as flurbiprofen lozenges. Such patients should start treatment with the lowest available dose. Patients requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk should be considered for combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors). 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 medications that increase the risk of peptic ulcer or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), SSRIs, or antiplatelet agents such as acetylsalicylic acid. If gastrointestinal bleeding or ulceration occurs in patients receiving flurbiprofen, the drug should be discontinued.

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 infectious inflammation exacerbation (e.g., development of necrotizing fasciitis) have been observed 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 lozenges. Anti-infective antibiotic therapy should be considered. Treatment should be re-evaluated if symptoms worsen or new symptoms appear. Treatment should be discontinued if irritation in the oral cavity occurs.

Important information on excipients.

This medicinal product contains isomalt (E 953) and maltitol (E 965). Patients with rare hereditary fructose intolerance should not take this medicinal product. It may have a mild laxative effect. The caloric value is 2.3 kcal/g for both maltitol and isomalt.

The product also contains the colorants sunset yellow FCF (E 110) and carmine red A (E 124), which may cause allergic reactions.

Celesta® contains potassium compounds, which should be taken into account in patients with impaired or reduced renal function or in patients on a potassium-controlled diet.

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 after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac malformations 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 has resulted in increased incidence of various developmental abnormalities, particularly in the cardiovascular system. Flurbiprofen should not be used during the first two trimesters of pregnancy, except when absolutely necessary. If flurbiprofen is used by a woman attempting to conceive or during the first or second trimester of pregnancy, the lowest possible dose for the shortest duration should be used.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose the following risks:

For the fetus:

• cardiopulmonary toxicity (characterized by premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure associated with oligohydramnios.

For the mother at the end of pregnancy and the newborn:

• prolonged bleeding time, antiplatelet effect, which may develop even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, flurbiprofen is contraindicated during the third trimester of pregnancy.

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 breastfed infants, the use of this medicinal product is not recommended in women who are breastfeeding.

Fertility.

There is some evidence that medicinal products 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.

Studies on the ability to influence reaction speed when driving or operating machinery have not been conducted.

Administration and Dosage.

Lozenges should be sucked until completely dissolved.

Dosage.

Use the lowest effective dose for the shortest duration necessary to relieve symptoms. If symptoms do not improve, worsen, or persist for more than 3 days, medical advice should be sought.

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

Adults and adolescents (aged 12 years and older).

Take 1 lozenge every 3–6 hours as needed for pain relief. Maximum daily dose: 5 lozenges.

Elderly patients.

Due to limited clinical experience, general dosage recommendations cannot currently be provided for elderly patients. In elderly patients, there is an increased risk of severe adverse reactions (see section "Special Warnings and Precautions for Use").

Hepatic impairment.

Dose reduction is not required in patients with mild to moderate hepatic dysfunction. Flurbiprofen is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Renal impairment.

Dose reduction is not required in patients with mild to moderate renal dysfunction. Flurbiprofen is contraindicated in patients with severe renal impairment (see section "Contraindications").

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. Other possible symptoms include tinnitus, headache, and gastrointestinal bleeding. In more severe poisoning, toxic effects on the central nervous system may occur, 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, likely due to interaction with circulating blood coagulation factors. Acute renal failure and liver damage may also occur. In patients with bronchial asthma, an exacerbation of asthma symptoms is possible.

Treatment. Treatment should be symptomatic and supportive, including maintaining airway patency and monitoring cardiac function and vital signs until the patient stabilizes. Oral administration of activated charcoal is recommended within 1 hour after ingestion of a potentially toxic dose, or gastric lavage may be performed. For frequent or prolonged muscle spasms, treatment should include intravenous administration of diazepam or lorazepam. In case of bronchial asthma, bronchodilators should be used. 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) may be associated with a slightly increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). There is insufficient data to exclude such a risk with the use of 8.75 mg flurbiprofen lozenges.

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

All adverse reactions are listed by system organ class and frequency: 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), frequency not known (cannot be estimated from the available data).

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

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

Psychiatric disorders:
uncommon – insomnia.

Cardiovascular disorders:
frequency not known – edema, arterial hypertension, heart failure.

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

Immune system disorders:
rare – anaphylactic reactions.

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

General disorders:
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 are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

The shelf life refers to the use of the medicinal product up to the last day of the indicated month.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging.

12 lozenges in a blister; 1 blister per carton.

Prescription status. Over-the-counter.

Manufacturer. LOZI’S FARMACEUTICAS S.L.

Manufacturer's address and place of business.

Campus Empresarial, Lecaroz, 31795, Navarra, Spain.

Marketing Authorization Holder. JSC "Pharmaceutical Company "Darnitsya".

Address of the Marketing Authorization Holder.

13, Boryspilska Street, Kyiv, 02093, Ukraine.