Lomecomb^® (Tablets) Instructions for Use

Marketing Authorization Holder

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

J04AM (Combined anti-tuberculosis drugs)

Dosage Form

Lomecomb®

Film-coated tablets: 50, 100, or 500 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light brown or pinkish-brown in color, oval in shape, biconvex; the tablet cross-section is white to white with a creamy or yellowish tint.

Excipients: povidone (type K90), macrogol 6000, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.

Shell composition hypromellose, hypromellose phthalate, macrogol 6000, glycerol, talc, titanium dioxide, red iron oxide dye or ready-made mixture Opadry^® red color [hypromellose, hypromellose phthalate, macrogol 6000, glycerol, talc, titanium dioxide, red iron oxide dye], or Vivacoat^® red color [hypromellose, hypromellose phthalate, macrogol 6000, glycerol, talc, titanium dioxide, red iron oxide dye].

50 pcs. – polypropylene jars (1) – cardboard packs.
100 pcs. – polypropylene jars (1) – cardboard packs.
50 pcs. – polyethylene jars (1) – cardboard packs.
100 pcs. – polyethylene jars (1) – cardboard packs.
500 pcs. – polyethylene bags (1) – polyethylene containers (for hospitals).

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Combined antitubercular agent

Pharmacological Action

Lomecomb^® is a combined five-component drug containing a fixed amount of isoniazid, lomefloxacin hydrochloride, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride.

Isoniazid has a bactericidal effect on actively dividing Mycobacterium tuberculosis cells. Its mechanism of action involves the inhibition of the synthesis of mycolic acids, which are a component of the mycobacterial cell wall. For Mycobacterium tuberculosis, the minimum inhibitory concentration (MIC) of the drug is 0.025-0.05 mg/L. Isoniazid has a moderate effect on slowly and rapidly growing atypical mycobacteria.

Lomefloxacin

A broad-spectrum antimicrobial bactericidal agent from the fluoroquinolone group. It acts on the bacterial enzyme DNA gyrase, which provides supercoiling, forms a complex with its tetramer (gyrase subunits A2B2) and disrupts DNA transcription and replication, leading to the death of the microbial cell. Beta-lactamases produced by pathogens do not affect the activity of lomefloxacin. Highly active against gram-negative aerobic microorganisms: Neisseria gonorrhoeae, Neisseria meningitidis, Escherichia coli, Citrobacter diversus, Klebsiella pneumoniae, Enterobacter cloacae, Proteus vulgaris, Salmonella spp., Shigella spp., Moraxella catarrhalis, Morganella morganii, Haemophilus influenzae and parainfluenzae, Legionella pneumophila, Pseudomonas aeruginosa.

Moderately sensitive to the drug are Staphylococcus aureus, Staphylococcus epidermidis, Serratia liquefaciens and marcescens, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Chlamydia trachomatis, Hafnia alvei, Citrobacter freundii, Aeromonas hydrophila, Proteus mirabilis and Proteus stuartii, Providencia rettgeri and Providencia alcalifaciens, Klebsiella oxytoca, Klebsiella ozaenae, Enterobacter aerogenes, Enterobacter agglomerans. Resistant to the drug are Streptococcus spp., Pseudomonas cepacia, Ureaplasma urealyticum, Treponema pallidum, Mycoplasma hominis and anaerobic bacteria.

It acts on both extracellularly and intracellularly located Mycobacterium tuberculosis, reduces the duration of their excretion from the body, and ensures faster resorption of infiltrates. It acts on most microorganisms at low concentrations (the concentration required to inhibit the growth of 90% of strains is usually no more than 1 µg/ml). Resistance develops rarely.

Pyrazinamide

The target of pyrazinamide is the gene for mycobacterial fatty acid synthase I, involved in the biosynthesis of mycolic acid. Pyrazinamide has a bactericidal effect at acidic pH values. It penetrates well into tuberculosis foci. Its activity is high in caseous-necrotic processes, caseous lymphadenitis, and tuberculomas. To exhibit bactericidal activity, pyrazinamide undergoes enzymatic conversion in the body into the active form – pyrazinoic acid. At acidic pH values, the MIC of pyrazinamide in vitro is 20 mg/L. It does not act on non-tuberculous pathogenic microorganisms.

Ethambutol

Ethambutol is a bacteriostatic drug effective against typical and atypical Mycobacterium tuberculosis. The mechanism of action of the drug is associated with disruption of RNA synthesis in bacterial cells; it inhibits the synthesis of the cell wall by blocking the incorporation of mycolic acids into it. Ethambutol is active against rapidly and slowly growing atypical mycobacteria. The MIC of ethambutol is 0.78-2.0 mg/L. Ethambutol does not act on non-tuberculous pathogenic microorganisms.

Pyridoxine hydrochloride

A vitamin agent. It is involved in metabolism. It is necessary for the normal functioning of the central and peripheral nervous system. Anti-tuberculosis drugs cause peripheral polyneuropathy, the occurrence of which pyridoxine can reduce. In this regard, the daily dose of the vitamin is increased to 60 mg. When pyridoxine is taken orally simultaneously with isoniazid, rifampicin, pyrazinamide, and ethambutol, no interaction of these drugs is observed at the pharmacokinetic and microbiological levels.

Pharmacokinetics

Isoniazid

Oral administration of isoniazid together with the drugs included in Lomecomb^® does not affect its absorption rate from the gastrointestinal tract. Isoniazid penetrates into many tissues and fluids, including cerebrospinal fluid (CSF). The time to reach maximum drug concentration in the blood is 2 hours, the C_max value is 6.6 mg/L, T_1/2 is 5.8 hours. The high C_max and T_1/2 are explained by the slowed excretion of isoniazid under the influence of pyrazinamide. Isoniazid is practically not bound to plasma proteins.

Isoniazid is 80-90% excreted in the urine and 10% in the feces within 24 hours. The main metabolites of isoniazid are N-acetylisoniazid and isonicotinic acid.

Lomefloxacin

Oral administration of lomefloxacin together with the drugs included in Lomecomb^® does not affect its absorption rate from the gastrointestinal tract.

The bioavailability of lomefloxacin is more than 90%. The drug is rapidly absorbed from the gastrointestinal tract after oral administration. C_max is 5.1 mg/L, time to reach C_max is 1-1.5 hours. It circulates in the body for a long time: T_1/2 in blood is 8-9 hours. Binding to blood proteins is insignificant – 10%. It penetrates well into various organs and tissues, where concentrations are created that are 9-13 times higher than serum concentrations. In small amounts, it undergoes biotransformation in the liver with the formation of 5 metabolites with slight antimicrobial activity. 80% is excreted by the kidneys, 20% – in feces, sweat and saliva.

Hepatic insufficiency does not affect the biotransformation of lomefloxacin. A small part of the drug undergoes metabolism to form metabolites. T_1/2 – 8-9 hours; average renal clearance – 145 ml/min.

In elderly patients, plasma clearance decreases by 25%. When creatinine clearance (CrCl) decreases to 10-40 ml/min/1.73 m², T_1/2 increases.

70-80% is excreted by the kidneys via tubular secretion (mainly unchanged, 9% as glucuronides, 0.5% as other metabolites).

Pyrazinamide

After taking Lomecomb^®, the C_max of pyrazinamide in plasma reaches 24.1 mg/L after 3 hours. The T_1/2 of the drug averages 17 hours. The main active metabolite of pyrazinamide is pyrazinoic acid. Up to 70% of pyrazinamide metabolites are excreted in the urine and about 4% is the unchanged drug.

Ethambutol

After taking Lomecomb^®, the C_max of ethambutol is 6.4-7.6 mg/L. The high C_max of ethambutol is explained by the slowing of its excretion under the influence of isoniazid. C_max of the drug in plasma (60%) is reached after 2 hours. Ethambutol is excreted in the urine, 70% unchanged, 30% as inactive aldehyde and carboxyl metabolites. On average, 25% of the drug is bound to plasma proteins.

Pyridoxine hydrochloride

It is rapidly absorbed throughout the small intestine, with a larger amount absorbed in the jejunum.

It is metabolized in the liver to form pharmacologically active metabolites (pyridoxal phosphate and pyridoxamine phosphate). Pyridoxal phosphate is 90% bound to plasma proteins. They penetrate well into all tissues; they accumulate mainly in the liver, less in muscles and the central nervous system. It crosses the placenta and is secreted into breast milk. T_1/2 – 15-20 days. It is excreted by the kidneys.

Indications

• Acutely progressive course of tuberculosis;
• Tuberculosis with concomitant inflammatory diseases caused by non-specific pathogenic flora sensitive to lomefloxacin.

ICD codes

Dosage Regimen

Orally, regardless of food intake, once a day, preferably in the first half of the day. Lomecomb^®_® is dosed based on lomefloxacin 13.2 mg/kg of body weight, but not more than 5 tablets. The duration of treatment is 3 months.

For body weight > 80 kg, Isoniazid is additionally prescribed in the evening (total daily dose of isoniazid up to 10 mg/kg). According to indications, Lomecomb^® is combined with streptomycin (intramuscularly at a dose of 16 mg/kg once a day for 3 months).

Adverse Reactions

Isoniazid

From the central nervous system and peripheral nervous system headache, dizziness, rarely – unusual fatigue or weakness, irritability, euphoria, insomnia, paresthesia, numbness of the extremities, peripheral neuropathy, optic neuritis, polyneuritis, psychoses, mood changes, depression. In patients with epilepsy, seizures may become more frequent.

From the cardiovascular system palpitations, angina pectoris, increased blood pressure.

From the digestive system nausea, vomiting, gastralgia, toxic hepatitis.

Allergic reactions skin rash, itching, hyperthermia, arthralgia.

Other very rarely – gynecomastia, menorrhagia, tendency to bleeding and hemorrhage.

Lomefloxacin

From the digestive system nausea, vomiting, dry mouth, gastralgia, abdominal pain, diarrhea or constipation, flatulence, pseudomembranous enterocolitis, dysphagia, discoloration of the tongue, decreased appetite or bulimia, taste perversion, dysbacteriosis, increased activity of liver transaminases.

From the central nervous system and peripheral nervous system fatigue, malaise, asthenia, headache, dizziness, fainting, insomnia, hallucinations, convulsions, hyperkinesis, tremor, paresthesia, nervousness, anxiety, depression, agitation.

From the genitourinary system: glomerulonephritis, dysuria, polyuria, anuria, albuminuria, urethral bleeding, crystalluria, hematuria, urinary retention, edema; in women – vaginitis, leukorrhea, intermenstrual bleeding, perineal pain, vaginal candidiasis; in men – orchitis, epididymitis.

From the metabolism hypoglycemia, gout.

From the musculoskeletal system arthralgia, vasculitis, calf muscle cramps, back and chest pain.

From the hematopoietic organs and hemostasis system bleeding from the gastrointestinal tract, thrombocytopenic purpura, increased fibrinolysis, nosebleeds, lymphadenopathy.

From the respiratory system dyspnea, respiratory infections, bronchospasm, cough, hypersecretion of sputum, flu-like symptoms.

From the sensory organs visual impairment, pain and noise in the ears, eye pain.

From the cardiovascular system decreased blood pressure, tachycardia, bradycardia, extrasystole, arrhythmias, progression of heart failure and angina pectoris, pulmonary embolism, myocardiopathy, phlebitis.

Allergic reactions skin itching, urticaria, photosensitivity, malignant exudative erythema (Stevens-Johnson syndrome).

Effect on the fetus fetotoxic effect (arthropathy) has been described in experiments.

Other candidiasis, increased sweating, chills, thirst, superinfection.

Pyrazinamide

From the digestive system nausea, vomiting, diarrhea, “metallic” taste in the mouth, impaired liver function (decreased appetite, liver tenderness, hepatomegaly, jaundice, yellow liver atrophy); exacerbation of peptic ulcer.

From the central nervous system dizziness, headache, sleep disturbances, increased excitability, depression; in some cases – hallucinations, convulsions, confusion.

From the hematopoietic organs and hemostasis system thrombocytopenia, sideroblastic anemia, vacuolization of erythrocytes, porphyria, hypercoagulation, splenomegaly.

From the musculoskeletal system arthralgia, myalgia.

From the urinary system dysuria, interstitial nephritis.

Allergic reactions skin rash, urticaria.

Other hyperthermia, acne, hyperuricemia, exacerbation of gout, photosensitivity, increased serum iron concentration.

Ethambutol

From the central nervous system, peripheral nervous system and sensory organs weakness, headache, dizziness, impaired consciousness, disorientation, hallucinations, depression, peripheral neuritis (paresthesia in the extremities, numbness, paresis, itching), optic neuritis (decreased visual acuity, impaired color perception, mainly green and red colors, color blindness, scotoma).

From the digestive system decreased appetite, nausea, vomiting, gastralgia, impaired liver function – increased activity of liver transaminases.

Allergic reactions dermatitis, skin rash, itching, arthralgia, fever, anaphylaxis.

Other hyperuricemia, exacerbation of gout.

Pyridoxine hydrochloride

Allergic reactions, hypersecretion of hydrochloric acid, numbness, feeling of tightness in the extremities – “stocking” and “glove” symptom, rarely – skin rash, skin itching.

Treatment of patients with a multi-component drug reduces the drug load on the patient by 3 times, which helps to improve drug tolerance.

Contraindications

• Hypersensitivity to any component of the drug;
• Pregnancy, lactation period;
• Children under 18 years of age (period of skeletal formation and growth),
• Peptic ulcer of the stomach and duodenum;
• Ulcerative colitis;
• Acute hepatitis, liver cirrhosis;
• Diseases of the central nervous system (epilepsy and other diseases with a tendency to convulsive seizures);
• Diseases of the visual organs (inflammation of the optic nerve, cataract, diabetic retinopathy, inflammatory eye diseases);
• Gout;
• Thrombophlebitis.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation.

Pediatric Use

The drug is contraindicated in children and adolescents under 18 years of age.

Drug Interactions

Taking lomefloxacin together with isoniazid, ethambutol and, especially, pyrazinamide significantly increases antimicrobial activity against sensitive and, especially, resistant Mycobacterium tuberculosis (MT). Concomitant use of Lomecomb^® with probenecid slows the excretion of lomefloxacin.

Sucralfate and antacid agents containing magnesium or aluminum form chelate complexes with lomefloxacin. The use of these agents should be carried out 2 hours before or 2 hours after taking lomefloxacin.

Taking Lomecomb^® together with rifampicin leads to a decrease in the antimicrobial activity of this combination against Mycobacterium tuberculosis due to the existing antagonism between lomefloxacin and rifampicin.

Rifampicin induces some cytochrome P450 system enzymes, accelerating the metabolism of prednisolone, phenytoin, quinidine, oral anticoagulants, hormonal contraceptives, antifungal drugs, cimetidine, cyclosporine A.

Isoniazid reduces the binding of rifampicin to plasma proteins, Pyrazinamide slows the excretion of rifampicin.

PAS (para-aminosalicylic acid) impairs the absorption of rifampicin.

Antacids, opioid analgesics reduce the bioavailability of rifampicin.

Isoniazid

MAO inhibitors increase the risk of side effects from the central nervous system and cardiovascular system.

Pyridoxine (vitamin B₆), glutamic acid reduce the risk of side effects of isoniazid. Concomitant use of isoniazid and cycloserine increases the risk of neurotoxic side effects.

Pyrazinamide

Pyrazinamide increases the concentration of isoniazid and rifampicin in the blood serum, slowing their excretion. When taking rifampicin together with pyrazinamide, the risk of hepatotoxic reactions increases.

Ethambutol

Aluminum hydroxide reduces the absorption of ethambutol.

Taking ethambutol with aminoglycosides, ciprofloxacin, imipenem, carbamazepine, lithium salts, quinine increases the risk of neurotoxic action of the drug. Ethambutol enhances the antimicrobial activity of other anti-tuberculosis drugs.

Pyridoxine hydrochloride

Pyridoxine hydrochloride weakens the effect of levodopa when used together. Pyridoxine hydrochloride reduces the risk of toxic effects of anti-tuberculosis drugs on the central and peripheral nervous system.

Storage Conditions

List B. In a dry place, protected from light and inaccessible to children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Do not use after the expiration date printed on the package.

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.