Protub^®-Lome (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J04AM (Combined anti-tuberculosis drugs)

Dosage Form

Protub®-Lome

Film-coated tablets: 100, 500, or 1000 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – blister packs (10) – cardboard packs.
100 pcs. – polypropylene jars.
500 pcs. – polypropylene jars.
1000 pcs. – polypropylene jars.

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Combined antitubercular agent

Pharmacological Action

Combined antituberculosis agent.

Isoniazid

It exerts a bactericidal effect on actively dividing cells of Mycobacterium tuberculosis. 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 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. It is 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. Staphylococcus aureus, Staphylococcus epidermidis, Serratia liguifaciens 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 are moderately sensitive to the drug. Streptococcus spp., Pseudomonas cepacia, Ureaplasma urealyticum, Treponema pallidum, Mycoplasma hominis and anaerobic bacteria are resistant to the drug. It acts on both extracellularly and intracellularly located Mycobacterium tuberculosis, reduces the time 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

Pyrazinamide exerts 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. It undergoes enzymatic conversion into the active form – pyrazinoic acid. At acidic pH values, the minimum inhibitory concentration of pyrazinamide in vitro is 20 mg/L. It does not act on non-tuberculous pathogenic microorganisms.

Ethambutol

A bacteriostatic drug effective against typical and atypical Mycobacterium tuberculosis. The mechanism of action of the drug is associated with impaired RNA synthesis in bacterial cells; it suppresses 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 minimum inhibitory concentration of ethambutol is 0.78-2.0 mg/L. Ethambutol does not act on non-tuberculous pathogenic microorganisms.

Pyridoxine

A vitamin agent. It is involved in metabolism. It is necessary for the normal functioning of the central and peripheral nervous systems. In tuberculosis infection, a deficiency of pyridoxine occurs. In this regard, the daily dose of the vitamin is increased to 60 mg. When pyridoxine is taken orally simultaneously with isoniazid, lomefloxacin, pyrazinamide, and ethambutol, no interaction of these drugs is observed at the pharmacokinetic and microbiological levels. It reduces the neurotoxicity of antituberculosis drugs.

Pharmacokinetics

Isoniazid

Isoniazid is rapidly and completely absorbed after oral administration; food reduces absorption and bioavailability. The bioavailability indicator is greatly influenced by the ‘first-pass’ effect through the liver. The time to reach C_max in blood is 1-2 hours; C_max in blood after a single oral dose of 300 mg is 3-7 µg/ml. Protein binding is insignificant – up to 10%. V_d – 0.57-0.76 L/kg. It is well distributed throughout the body, penetrating into all tissues and fluids, including cerebrospinal, pleural, and ascitic fluids; high concentrations are created in lung tissue, kidneys, liver, muscles, saliva, and sputum. It penetrates the placental barrier and into breast milk.

It is metabolized in the liver by acetylation to form inactive products. In the liver, it is acetylated by N-acetyltransferase to form N-acetylisoniazid, which is then converted to isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect through the formation by the cytochrome P450 mixed oxidase system during N-hydroxylation of the active intermediate metabolite. The rate of acetylation is genetically determined: in people with ‘slow’ acetylation, there is little N-acetyltransferase. It is an inhibitor of CYP2C9 and CYP2E1 isoenzymes in the liver. The half-life from blood (T_1/2) for ‘fast acetylators’ is 0.5-1.6 hours; for ‘slow’ ones – 2-5 hours. In renal failure, T_1/2 can increase to 6.7 hours. T_1/2 for children aged 1.5 to 15 years is 2.3-4.9 hours, and for newborns – 7.8-19.8 hours (which is explained by the imperfection of acetylation processes in newborns). Although the T_1/2 indicator varies significantly depending on the individual intensity of acetylation processes, the average T_1/2 is 3 hours (oral administration (600 mg) and 5.1 hours (900 mg). With repeated administration, T_1/2 shortens to 2-3 hours.

It is excreted mainly by the kidneys: within 24 hours, 75-95% of the drug is excreted, mainly in the form of inactive metabolites – N-acetylisoniazid and isonicotinic acid. In this case, in ‘fast acetylators’ the content of N-acetylisoniazid is 93%, and in ‘slow’ ones – no more than 63%. Small amounts are excreted in feces. The drug is removed from the blood during hemodialysis; 5 hours of hemodialysis can remove up to 73% of the drug from the blood.

Lomefloxacin. The active components included in Protub-Lome do not affect the rate of absorption of lomefloxacin 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, the time to reach it is 1-1.5 hours. It circulates in the body for a long time: the half-life 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 quantities, it undergoes biotransformation in the liver with the formation of 5 metabolites with insignificant antimicrobial activity. 80% is excreted by the kidneys, 20% in feces, sweat and saliva. Liver failure does not affect the biotransformation of lomefloxacin.

Pyrazinamide. After oral administration, it is rapidly and completely absorbed in the gastrointestinal tract. Binding to plasma proteins is 10-20%. The time to reach C_max in blood is 1-2 hours. It penetrates well into tissues and organs.

It is metabolized in the liver, where an active metabolite is first formed – pyrazinoic acid, which is then converted into an inactive metabolite – 5-hydroxypyrazinoic acid. The half-life from blood T_1/2 is 8-9 hours.

It is excreted by the kidneys: unchanged – 3% , in the form of pyrazinoic acid – 33%, in the form of other metabolites – 36%. It is removed by hemodialysis.

Ethambutol. Absorption is high; bioavailability is 75-80%. After an oral dose of 25 mg, the time to reach C_max in blood is 2-4 hours, C_max in blood is 1-5 µg/ml. Binding to plasma proteins is 20-30%.

It penetrates well into tissues and organs, as well as into biological fluids, with the exception of ascitic and pleural fluids (in the cerebrospinal fluid only with meningitis). The highest concentrations are created in the kidneys, lungs, saliva, and urine. It penetrates into breast milk. It does not pass through the intact blood-brain barrier.

It is partially metabolized in the liver (15%) with the formation of inactive metabolites. T_1/2 is 3-4 hours, in case of impaired renal function – 8 hours. It is excreted by the kidneys – 80-90% (50% – unchanged, 15% – in the form of inactive metabolites) through the gastrointestinal tract – 10-20% (unchanged). It is excreted by hemodialysis and peritoneal dialysis.

Pyridoxine. It is rapidly absorbed throughout the entire small intestine, with a larger amount absorbed in the jejunum. It is metabolized in the liver with the formation of pharmacologically active metabolites (pyridoxal phosphate and pyridoxamine phosphate). Pyridoxal phosphate binds to plasma proteins by 90%. It penetrates well into all tissues; it accumulates mainly in the liver, and less in muscles and the central nervous system. It penetrates the placenta and is secreted in breast milk. The half-life is 5-20 days. It is excreted by the kidneys.

Indications

• Acute progressive course of tuberculosis;
• Tuberculosis with concomitant inflammatory diseases caused by nonspecific pathogenic flora sensitive to lomefloxacin.

ICD codes

Dosage Regimen

Dosage regimen: orally, regardless of food intake, once a day, preferably in the first half of the day. Protub-Lome 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 large body weight of 80 kg, Isoniazid is additionally prescribed in the evening (total daily dose of isoniazid up to 10 mg/kg). According to indications, Protub-Lome 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 (CNS) headache, dizziness, rarely – excessive 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, change in tongue color, decreased appetite or bulimia, taste perversion, dysbacteriosis, increased activity of ‘hepatic’ transaminases (ALT, AST, alkaline phosphatase).

From the 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 organs, thrombocytopenia, purpura, increased fibrinolysis, nosebleed, 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 CNS: headache, sleep disturbance, 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 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 ‘hepatic’ transaminases (ALT, AST, alkaline phosphatase).

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

Other: hyperuricemia, exacerbation of gout.

Pyridoxine

Allergic reactions, hypersecretion of hydrochloric acid, numbness, the appearance of a feeling of compression in the extremities – the ‘stocking’ and ‘glove’ symptom, rarely – skin rash, skin itching.

Contraindications

• Hypersensitivity to lomefloxacin, isoniazid, pyrazinamide, ethambutol, pyridoxine;
• 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

It is forbidden to take the drug during pregnancy and lactation.

Use in Hepatic Impairment

Contraindicated in acute hepatitis, liver cirrhosis.

Pediatric Use

Contraindicated in children under 18 years of age (period of skeletal formation and growth).

Special Precautions

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

Overdose

Isoniazid

Symptoms dizziness, dysarthria, lethargy, disorientation, hyperreflexia, peripheral polyneuropathy, impaired liver function, metabolic acidosis, hyperglycemia, glucosuria, ketonuria, convulsions (1-3 hours after drug use), coma.

Treatment peripheral polyneuropathy (vitamins: pyridoxine, thiamine, glutamic acid, nicotinamide, massage, physiotherapeutic procedures); convulsions (intramuscular Pyridoxine hydrochloride – 200-250 mg, intramuscular 25% magnesium sulfate solution – 10 ml, diazepam); impaired liver function (methionine, thioctic acid, cyanocobalamin).

Lomefloxacin

Treatment: induction of vomiting or gastric lavage, adequate hydration, symptomatic therapy. Hemodialysis and peritoneal dialysis are not very effective in case of overdose (less than 3% is excreted).

Pyrazinamide

Symptoms: impaired liver function, increased severity of side effects from the central nervous system.

Treatment: symptomatic.

Ethambutol

Symptoms: nausea, vomiting, hallucinations, polyneuritis.

Treatment: symptomatic.

Drug Interactions

Isoniazid

When combined with paracetamol, hepatotoxicity and nephrotoxicity increase; Isoniazid induces the cytochrome P450 system, resulting in increased metabolism of paracetamol to toxic products.

Ethanol increases the hepatotoxicity of isoniazid and accelerates its metabolism.

It reduces the metabolism of theophylline, which may lead to an increase in its blood concentration. It reduces the metabolic transformations and increases the blood concentration of alfentanil. Cycloserine and disulfiram enhance the adverse central effects of isoniazid. Combination with pyridoxine reduces the risk of developing peripheral neuritis.

It should be combined with caution with potentially neuro-, hepato-, and nephrotoxic medicinal products due to the risk of increased adverse effects.

It enhances the effect of coumarin and indandione derivatives, benzodiazepines, and carbamazepine, as it reduces their metabolism by activating the cytochrome P450 system.

Glucocorticosteroids accelerate metabolism in the liver and reduce active blood concentrations.

It suppresses the metabolism of phenytoin, leading to an increase in its blood concentration and an enhancement of the toxic effect (adjustment of the phenytoin dosing regimen may be required, especially in patients with slow acetylation of isoniazid).

Lomefloxacin

It does not affect the pharmacokinetics of isoniazid. It does not interact with theophylline or caffeine. It increases the activity of oral anticoagulants and increases the toxicity of non-steroidal anti-inflammatory drugs. It forms chelate compounds with antacid medicinal products and sucralfate, which reduces its bioavailability. When treating patients with tuberculosis, Lomefloxacin is used in combination with isoniazid, pyrazinamide, streptomycin, and ethambutol. Medicinal products that block tubular secretion slow its excretion. There is no cross-resistance with penicillins, cephalosporins, aminoglycosides, co-trimoxazole, or metronidazole.

Vitamins with mineral supplements should be taken 2 hours before or 2 hours after taking lomefloxacin.

Pyrazinamide

It is compatible with other anti-tuberculosis medicinal products: for chronic destructive forms, Pyrazinamide is recommended to be combined with rifampicin or ethambutol (better tolerability than when combined with rifampicin, but a weaker effect).

The likelihood of developing a hepatotoxic effect increases when used concomitantly with rifampicin.

When used concomitantly with medicinal products that block tubular secretion, a decrease in their excretion and an increase in toxic reactions are possible. It enhances the anti-tuberculosis effect of ofloxacin and lomefloxacin.

Ethambutol

Aluminum hydroxide reduces the absorption of ethambutol. Concomitant use of ethambutol with aminoglycosides, ciprofloxacin, imipenem, carbamazepine, lithium salts, and quinine increases the risk of the drug’s neurotoxic action. Ethambutol enhances the antimicrobial activity of other anti-tuberculosis drugs.

Pyridoxine

It weakens the effect of levodopa when used concomitantly. Pyridoxine reduces the risk of developing the toxic effect of anti-tuberculosis drugs on the central and peripheral nervous system.

Storage Conditions

List B.

The drug should be stored in a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

For hospital use.

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.