Nevigramon^® (Capsules) Instructions for Use

Marketing Authorization Holder

Chinoin Pharmaceutical and Chemical Works Private, Co. Ltd. (Hungary)

ATC Code

J01MB02 (Nalidixic acid)

Active Substance

Nalidixic acid (Rec.INN registered by WHO)

Dosage Form

Nevigramon®

Capsules 500 mg: 56 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 0, opaque, with a yellow body and a yellow cap; the capsule contents are a powder from white to white with a yellowish tint.

Excipients: colloidal silicon dioxide – 19 mg, stearic acid – 11 mg.

Capsule shell composition quinoline yellow (E104) – 0.75%, sunset yellow FCF (E110) – 0.0059%, titanium dioxide (E171) – 2%, gelatin – up to 100%.

56 pcs. – polystyrene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antibacterial drug of the quinoline group

Pharmacotherapeutic Group

Antimicrobial agent, quinolone

Pharmacological Action

Nalidixic acid has pronounced antibacterial activity against gram-negative bacteria, including Proteus mirabilis, P. morganii, P. vulgaris and P.rettgeri; Escherichia coli, Enterobacter (Aerobacter) and Klebsiella.Pseudomonas strains are usually resistant to the drug.

Nalidixic acid acts by selectively inhibiting bacterial DNA synthesis. It acts bactericidally and bacteriostatically (depending on the sensitivity of the microorganism and the drug concentration).

At low concentrations, Nalidixic acid acts only on proliferating microorganisms by inhibiting DNA replication. In the case of longer exposure, it also inhibits bacterial RNA and protein synthesis. Its minimum inhibitory concentration (MIC) is 5 – 75 µg/ml, but even at concentrations below 10 µg/ml it is effective against many microorganisms.

Pharmacokinetics

Nalidixic acid is rapidly absorbed from the gastrointestinal tract, partially metabolized in the liver, and rapidly excreted through the kidneys. Bioavailability is 96%.

Unchanged Nalidixic acid appears in the urine along with its active metabolite, hydroxynalidixic acid, which has antibacterial activity similar to that of the parent compound. The hydroxymetabolite accounts for 30% of the biologically active drug in the blood and 85% in the urine. C_max of the active drug in serum averages 20 – 50 µg/ml 2 hours after taking 1 g of nalidixic acid on an empty stomach. T_1/2 is 1 – 2.5 h, but when using more precise determination methods, data of 6-7 h were obtained. About 93% of nalidixic acid and 63% of hydroxynalidixic acid are bound to plasma proteins. C_max of the active drug in urine after a single 1 g dose is about 250 µg/ml after 3-6 hours. Approximately 4% of nalidixic acid is excreted in the feces.

Nalidixic acid crosses the placenta, and small amounts appear in breast milk.

Indications

Treatment of infections caused by microorganisms sensitive to the drug

• Pyelonephritis;
• Cystitis;
• Urethritis;
• Prostatitis;
• Gastrointestinal infections;
• Cholecystitis.

Prevention of infections during operations on the kidneys, ureters, and bladder.

ICD codes

Dosage Regimen

The average dose for adults (including the elderly) is 4 g (2 capsules (1 g) – 4 times/day) for a period of at least 7 days. If it is necessary to continue the drug, the dose may be reduced to 1 caps. (0.5 g) – 4 times/day.

For children over 12 years of age (weighing more than 40 kg), a daily dose of 50 mg/kg, divided into 3-4 doses, is recommended.

Nevigramon^® capsules should be taken one hour before meals.

Adverse Reactions

Effect on the central nervous system drowsiness; weakness; headaches; dizziness. There are rare reports of toxic psychosis, increased intracranial pressure, or convulsions (in the presence of predisposing diseases – epilepsy, cerebral arteriosclerosis). Isolated cases of sixth cranial nerve palsy have been described. The mechanism of these reactions is unknown, but their signs and symptoms usually resolve quickly without consequences after drug withdrawal.

Effect on vision: visual disturbances (diplopia, decreased visual acuity, difficulty focusing) and color perception. These effects usually disappeared quickly when the dose was reduced or the drug was discontinued.

Gastrointestinal complaints epigastric pain, nausea, vomiting, and diarrhea.

Allergic reactions: rash, itching, urticaria, eosinophilia, arthralgia with stiffness and joint swelling, rarely – angioedema, anaphylactic shock, and anaphylactoid reactions.

Skin reactions photosensitivity reactions: redness and blistering of the skin, completely resolving within a period of two weeks to two months after discontinuation of nalidixic acid; however, blisters may reappear under the influence of sunlight or with minor skin surface damage for up to three months after drug discontinuation.

Other cholestasis, paresthesia, metabolic acidosis, thrombocytopenia, leukopenia, or hemolytic anemia, sometimes accompanied by glucose-6-phosphate dehydrogenase deficiency, are rarely encountered.

Adverse effects such as: dysphoria and myalgia have not been noted for Nevigramon^®.

Contraindications

• Known hypersensitivity to nalidixic acid or other components of the drug;
• Epilepsy;
• Parkinson’s disease;
• Cerebral vascular atherosclerosis (severe form);
• Renal and/or hepatic insufficiency;
• Glucose-6-phosphate dehydrogenase deficiency;
• Porphyria;
• Children under 12 years of age;
• First trimester of pregnancy;
• Breastfeeding period.

Use with caution in persons aged 12 to 18 years.

Use in Pregnancy and Lactation

The safety of Nevigramon^® use during pregnancy has not been established. Therefore, the drug should be used during pregnancy only if the expected benefit outweighs the potential risk, especially in the first trimester of pregnancy (Nalidixic acid crosses the placental barrier and affects developing cartilage tissue) and in the last month of pregnancy, due to consequences for the newborn: a significant increase in the level of nalidixic acid in the blood of the newborn immediately after birth.

Since Nalidixic acid passes into breast milk, it is contraindicated during breastfeeding.

Use in Hepatic Impairment

Contraindication: hepatic insufficiency.

Use in Renal Impairment

Contraindication: renal insufficiency.

Pediatric Use

Contraindication: children under 12 years of age. Use with caution in children aged 12 to 18 years.

Geriatric Use

No dose adjustment is required.

Special Precautions

Nalidixic acid and related compounds have been shown to cause erosions in the cartilage tissue of joints and other signs of arthropathy in most immature animals. Until the clinical significance of this phenomenon is clarified, caution should be exercised when prescribing nalidixic acid to persons under 18 years of age. If arthralgia occurs, treatment with nalidixic acid should be discontinued.

Patients should be warned to avoid direct sunlight, and if photosensitivity develops, the course of treatment with Nevigramon^® should be discontinued.

Caution should be exercised and treatment should be discontinued if the patient develops signs or symptoms of increased intracranial pressure, psychosis, or other toxic manifestations.

If bacterial resistance to nalidixic acid develops, it usually occurs within the first 48 hours. Cross-resistance has been observed between nalidixic acid and other quinolone derivatives, such as oxolinic acid and cinoxacin.

If methods based on copper reduction, such as Benedict’s or Fehling’s solutions, are used to analyze the urine of patients receiving Nevigramon^®, a false positive reaction for glucose may be obtained. Therefore, it is recommended to use specific glucose oxidase methods.

False values may be obtained when determining 17-keto and ketogenic steroids in urine in assays based on the measurement of vanillylmandelic acid in urine. In such cases, the Porter-Silber test for 17-hydroxycorticosteroids can be used.

Effect on ability to drive vehicles and operate machinery

During treatment, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Patients who have taken a dose exceeding the recommended one may experience: toxic psychosis, convulsions, increased intracranial pressure, or metabolic acidosis. Nausea, vomiting, and lethargy may also occur after an overdose.

If symptoms of overdose develop, careful medical supervision of the patient in a hospital setting is recommended. Treatment should be symptomatic and supportive.

Drug Interactions

Nalidixic acid may enhance the effect of oral anticoagulants such as warfarin or bishydroxycoumarin due to competitive binding to plasma proteins. In case of simultaneous use, appropriate monitoring of prothrombin time or international normalized ratio (INR) is necessary, and a change in the anticoagulant dose may be required.

Since bacterial cell proliferation is a necessary condition for the manifestation of the antibacterial action of nalidixic acid, the action of nalidixic acid may be suppressed in the presence of other antibacterial compounds, especially bacteriostatic substances such as: tetracycline, chloramphenicol or nitrofurantoin (the latter is an antagonist of nalidixic acid in vitro ).

Probenecid inhibits the secretion of nalidixic acid in the renal tubules and may reduce its effectiveness against genitourinary infections, while increasing the risk of systemic side effects.

Concomitant use of nalidixic acid and melphalan was accompanied by gastrointestinal toxicity.

Storage Conditions

Store protected from light at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 5 years. Do not use the drug after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.