Protiocomb^® (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

Protiocomb®

Coated tablets: 50 or 500 pcs.

Dosage Form, Packaging, and Composition

Coated tablets (film-coated) from light orange to dark orange, oval, biconvex; the cross-section is yellow.

Excipients: pregelatinized starch, polyethylene glycol, povidone (polyvinylpyrrolidone), croscarmellose sodium, colloidal silicon dioxide (aerosil), magnesium stearate.

Shell composition hypromellose (hydroxypropyl methylcellulose), polyethylene glycol, glycerol (glycerin), talc, titanium dioxide, yellow-orange dye (Orange S).

50 pcs. – polypropylene jars.
500 pcs. – polymer containers.

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Combined antitubercular agent

Pharmacological Action

Protiocomb^® is a combined five-component drug containing a fixed amount of protionamide, Lomefloxacin hydrochloride, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride.

Lomefloxacin

A broad-spectrum antimicrobial bactericidal agent from the group of fluoroquinolones. It affects 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, Scnatia 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 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 suppress the growth of 90% of strains is usually no more than 1 µg/ml). Resistance rarely develops.

Protionamide

Protionamide is an analogue of ethionamide, used more widely due to lower toxicity and somewhat greater antimicrobial activity. The minimum inhibitory concentration (MIC) of protionamide is in the range of 0.6-3.2 µg/ml. Its mechanism of action is the blockade of the synthesis of mycolic acids, which are an important structural component of the Mycobacterium tuberculosis (MBT) cell wall, and is an antagonist of nicotinic acid. In high concentrations, it acts bactericidally by disrupting the synthesis of the microbial cell protein. Effective against MBT resistant to first-line anti-tuberculosis drugs. It affects both extracellularly and intracellularly located mycobacteria. It has little activity against MBT of the bovine type, atypical mycobacteria and acid-fast saprophytes (MIC – 20-30 µg/ml). It does not act on pathogenic nonspecific flora. Protionamide penetrates well into cells, in particular into macrophages. The activity of the drug is higher in an acidic environment. The development of MBT resistance to protionamide during monotherapy occurs quickly (after 2 months in 32%, after 4 months in 82%). With combination therapy, resistance can develop by 6 months (up to 15%). Cross-resistance of protionamide is noted only with thioacetazone.

Pyrazinamide

The target of pyrazinamide is the gene of mycobacterial fatty acid synthase 1, 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 manifest the bactericidal activity of pyrazinamide, the drug undergoes enzymatic conversion in the body into an 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 mycobacteria of tuberculosis. The mechanism of action of the drug is associated with disruption of 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 fast- and slow-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 participates in metabolism. It is necessary for the normal functioning of the central and peripheral nervous system. When treated with anti-tuberculosis drugs, pyridoxine deficiency may occur. 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

Lomefloxacin

Oral administration of Lomefloxacin together with the drugs included in Protiocomb^® does not affect the rate of its absorption 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: T_1/2 – 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 that have insignificant antimicrobial activity. 80% is excreted by the kidneys, 20% in feces, sweat and saliva. Liver failure does not affect the biotransformation of Lomefloxacin. A small part of the drug undergoes metabolism with the formation of metabolites. The average renal clearance is 145 ml/min. In elderly patients, plasma clearance decreases by 25%. When creatinine clearance (CC) decreases to 10-40 ml/min/1.73 sq.m, T_1/2 increases.

70-80% is excreted by the kidneys through tubular secretion (mainly unchanged, 9% in the form of glucuronides, 0.5% in the form of other metabolites).

Protionamide

Protionamide is rapidly absorbed in the gastrointestinal tract. C_max of the drug is reached 2-3 hours after its administration. The value of C_max in blood plasma corresponds to 4.5 µg/ml, which exceeds the bacteriostatic concentration of protionamide. It is well absorbed in an acidic environment. It penetrates into all tissues and fluids of the body, including cerebrospinal fluid (with inflammation of the meninges), into tuberculosis foci, into cavities and encapsulated formations. It is biotransformed in the liver, partially turning into an active metabolite – sulfoxide. It is partially excreted by the kidneys – 18.5%. The rest of the drug is excreted in bile.

Pyrazinamide

After taking Protiocomb^®, the C_max of pyrazinamide in blood plasma reaches 12.0-14 µg/ml after 2 hours. The T_1/2 of the drug is on average 10-12 hours. Pyrazinamide penetrates well into organs, tissues and body fluids, including lymph nodes and cerebrospinal fluid. It is metabolized in the liver. The main metabolite of pyrazinamide, pyrazinoic acid, has anti-tuberculosis activity. About 10-20% of the drug binds to plasma proteins. Up to 70% of pyrazinamide metabolites are excreted in the urine and 10% as the unchanged drug.

Ethambutol

After taking Protiocomb^®, the C_max of ethambutol corresponds to 6.4-7.6 mg/l. The high C_max of ethambutol is explained by the slowdown of its excretion under the influence of isoniazid. C_max of the drug in plasma (60%) is reached after 2 hours. T_1/2 — 5-6 hours. On average, 25% of the drug binds to plasma proteins.

Ethambutol penetrates well into various organs and biological fluids, except for ascitic, pleural and cerebrospinal fluid. It undergoes biotransformation in the liver with the formation of inactive metabolites.

Ethambutol is excreted in the urine, 70% unchanged and 30% in the form of aldehyde and carboxyl inactive metabolites.

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 binds to plasma proteins by 90%. Metabolites penetrate well into all tissues; they accumulate mainly in the liver, and less in muscles and the central nervous system. It penetrates the placenta and is secreted into breast milk. T_1/2 – 15-20 days. It is excreted by the kidneys.

Indications

• Drug-resistant tuberculosis with moderate resistance of MBT (isoniazid – up to 10, rifampicin – up to 40, ethambutol – up to 2 µg/ml);
• Acutely progressive course of tuberculosis;
• Tuberculosis with concomitant inflammatory diseases caused by nonspecific pathogenic flora sensitive to lomefloxacin.

ICD codes

Dosage Regimen

Orally. The drug is taken once a day after meals, preferably in the morning. Protiocomb^® is dosed based on lomefloxacin at the rate of 13.2 mg/kg of body weight, but not more than 5 tablets. The duration of treatment is 3 months.

If indicated, Protiocomb^® is combined with streptomycin or kanamycin (intramuscularly at a dose of 16 mg/kg once a day for 3 months).

Adverse Reactions

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 liver transaminases.

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 metabolic side 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, thrombocytopenia, purpura, increased fibrinolysis, nosebleeds, lymphadenopathy.

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

From the senses 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, 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.

Protionamide

From the digestive system nausea, vomiting, diarrhea, hypersalivation, “metallic” taste in the mouth, impaired liver function.

From the nervous system insomnia, agitation, depression, anxiety, rarely – dizziness, drowsiness, headache, asthenia, in isolated cases – paresthesia, peripheral neuropathy, optic neuritis.

From the cardiovascular system tachycardia, weakness, orthostatic hypotension.

From the endocrine system hypoglycemia in patients with diabetes mellitus, gynecomastia, dysmenorrhea, hypothyroidism, decreased potency.

Allergic reactions skin rash.

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 nervous system and senses: 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, the appearance of a feeling of compression in the extremities – “stocking” and “glove” symptom, rarely – skin rash, skin itching.

Contraindications

• Hypersensitivity to lomefloxacin, protionamide, 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

The drug is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Contraindicated in acute hepatitis and liver cirrhosis.

Pediatric Use

The drug is contraindicated in children 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 MBT. Concomitant use of Protiocomb^® with probenecid slows down the excretion of Lomefloxacin. Sucralfate and antacid agents containing magnesium or aluminum form chelate-forming complexes with lomefloxacin. The use of these agents should be carried out 2 hours before or 2 hours after taking Lomefloxacin.

Taking Protiocomb^® together with rifampicin leads to a decrease in the antimicrobial activity of this combination against MBT due to the existing antagonism between lomefloxacin and rifampicin at the microbial level.

Protionamide in combination with lomefloxacin significantly increases antimicrobial activity against MBT. Antacids reduce the absorption of protionamide. Protionamide reduces the effectiveness of antihypertensive drugs.

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

Aluminum hydroxide reduces the absorption of ethambutol. Taking ethambutol with aminoglycosides, imipenem, carbamazepine, lithium salts, and quinine increases the risk of neurotoxic effects of the drug. Ethambutol enhances the antimicrobial activity of other anti-tuberculosis drugs.

Pyridoxine weakens the effect of levodopa when used together. Pyridoxine reduces the risk of toxic effects of anti-tuberculosis drugs on the central and peripheral nervous system. Pyridoxine as part of Protiocomb^® does not affect the antimicrobial activity of the drugs included in its composition.

Storage Conditions

List B. In a dry, light-protected place, out of reach of 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 preparation 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.