Combithub-neo

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT COMBITUB-NEO (COMBITUB-NEO)

Composition:

Active substances: lomefloxacin hydrochloride, prothionamide, pyrazinamide, ethambutol hydrochloride;

One tablet contains lomefloxacin (as lomefloxacin hydrochloride) 200 mg, prothionamide 188 mg, pyrazinamide 400 mg, ethambutol hydrochloride 360 mg;

Excipients: maize starch, crospovidone, microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate, talc, Wincoat WT-1270 Brown: hydroxypropylmethylcellulose, propylene glycol, macrogol 4000, titanium dioxide (E 171), talc, iron oxide red (E 172).

Pharmaceutical form. Coated tablets.

Main physicochemical properties: elongated biconvex coated tablets of reddish-brown color, yellow with white specks on the fracture.

Pharmacotherapeutic group.

Combined anti-tuberculosis agents. ATC code J04A M.

Pharmacological Properties.

Pharmacodynamics. Combibac-Neo is a combination drug.

Lomefloxacin is a difluorinated quinolone, a synthetic antibacterial agent with a broad spectrum of bactericidal activity. It is active against many Gram-negative and Gram-positive microorganisms, including Escherichia coli, Enterobacter spp., Citrobacter spp., Klebsiella spp., Staphylococcus spp., Neisseria gonorrhoeae, Streptococcus pneumoniae. Its mechanism of action is based on inhibition of bacterial DNA gyrase, an enzyme essential for DNA transcription and replication. Lomefloxacin is stable against bacterial β-lactamases. Resistant organisms include Streptococcus spp., Pseudomonas cepacia, Ureaplasma urealyticum, Mycoplasma hominis, and anaerobic bacteria.

Prothionamide is a reserve antituberculosis agent belonging to the group of thiocarboxamide derivatives, chemically similar to isoniazid. The drug exerts a bacteriostatic effect and, at higher concentrations, a bactericidal effect against certain species of mycobacteria causing tuberculosis. Its antituberculosis activity is due to inhibition of mycolic acid synthesis in mycobacteria. The minimal inhibitory concentration (MIC) against Mycobacterium tuberculosis is 0.6 mg/L. Prothionamide is always used in combination with other antituberculosis drugs during the treatment of tuberculosis, which typically lasts 6–12 months, to prevent the development of resistant strains of mycobacteria.

Pyrazinamide is a second-line antituberculosis agent. Pyrazinamide is converted into pharmacologically active pyrazinoic acid by mycobacterial pyrazinamidase in the acidic environment of macrophages. Depending on the concentration of pyrazinamide and the susceptibility of Mycobacterium tuberculosis, it exhibits either bacteriostatic or bactericidal effects. It is active only against Mycobacterium tuberculosis.

Ethambutol is a second-line antituberculosis agent, a synthetic derivative of ethylenediamine. Its mechanism of action is associated with inhibition of mycobacterial arabinosyltransferases, thereby disrupting the polymerization of arabinoglycan—the main component of the mycobacterial cell wall. It facilitates the penetration of lipophilic antituberculosis agents into the bacterial cell. It exerts a bacteriostatic effect on Mycobacterium tuberculosis and Mycobacterium bovis (including strains resistant to streptomycin, kanamycin, isoniazid, PAS, and ethionamide), as well as on some atypical (opportunistic, nontuberculous) species of mycobacteria. It has no activity against other bacteria, viruses, or fungi.

It is active only against rapidly dividing bacteria. Mycobacterial resistance to ethambutol develops slowly.

Pharmacokinetics. Not studied.

Clinical characteristics.

Indications.

Multidrug-resistant tuberculosis with moderate resistance of M. tuberculosis (sensitivity to first-line anti-tuberculosis drugs at the following concentrations: isoniazid – less than 10, rifampicin – less than 40, ethambutol – less than 2 mcg/mL), acute progressive tuberculosis.

Tuberculosis associated with concomitant inflammatory diseases caused by nonspecific pathogenic flora sensitive to lomefloxacin.

Contraindications.

Hypersensitivity to lomefloxacin, protionamide, pyrazinamide, or ethambutol. Acute and chronic liver diseases (including acute hepatitis, liver cirrhosis), gastritis, gastric and duodenal ulcer in the stage of exacerbation, erosive-ulcerative colitis, diabetes mellitus, chronic alcoholism, epilepsy; central nervous system damage with reduced seizure threshold (e.g., after head trauma, stroke, or inflammatory processes in the CNS) in medical history, optic neuritis; cataract; diabetic retinopathy; inflammatory eye diseases; gout; severe renal insufficiency; situations where visual function cannot be assessed (critical condition, mental disorders), asymptomatic hyperuricemia.

Interaction with other medicinal products and other types of interactions.

When lomefloxacin is administered simultaneously with antacids, chelate complexes are formed, reducing the bioavailability of lomefloxacin. Antacids should not be taken within 4 hours before and 2 hours after lomefloxacin administration.

Probenecid slows renal excretion of lomefloxacin.

Lomefloxacin should not be used concurrently with alcohol intake.

Lomefloxacin enhances the activity of oral anticoagulants and increases the toxicity of nonsteroidal anti-inflammatory drugs.

Hepatotoxicity of the drug increases when used in combination with rifampicin, thiacetazone, isoniazid, and pyrazinamide. Protionamide may increase serum concentration of isoniazid due to inhibition of isoniazid metabolism.

When used in combination with isoniazid and cycloserine, special attention should be paid to the possibility of psychiatric disturbances.

Simultaneous use with thiocarbamides should be avoided (cross-resistance).

Alcohol consumption is not recommended during pyrazinamide therapy, as pyrazinamide may enhance its toxic effects.

Combined use of pyrazinamide and isoniazid may reduce isoniazid serum concentration, especially in patients with slow isoniazid metabolism.

In chronic destructive forms, pyrazinamide is recommended to be combined with rifampicin (pronounced effect) or ethambutol (better tolerability).

When used simultaneously with medicinal products that block tubular secretion, reduced excretion and enhanced toxic reactions may occur.

Enhances the antituberculosis effect of ofloxacin and lomefloxacin. Pyrazinamide may enhance the effect of hypoglycemic medicinal products.

Concomitant use of pyrazinamide and ethionamide increases the risk of liver damage, especially in diabetic patients. Regular liver function tests should be performed during treatment with this combination. If any signs of liver dysfunction occur, treatment with this drug combination should be discontinued.

Pyrazinamide may reduce the metabolism of cyclosporine, thereby decreasing cyclosporine serum levels and its immunosuppressive effect. In patients receiving cyclosporine, serum cyclosporine levels should be monitored from the start of pyrazinamide therapy and after its discontinuation.

Concomitant use of pyrazinamide and phenytoin may increase phenytoin serum concentration, potentially leading to signs of phenytoin intoxication. If CNS side effects (e.g., ataxia, hyperreflexia, nystagmus, tremor) occur during concomitant use of pyrazinamide and phenytoin, the drugs should be discontinued, serum phenytoin concentration should be measured, and the phenytoin dose adjusted accordingly.

Pyrazinamide may reduce the effectiveness of drugs promoting urinary excretion of uric acid (allopurinol, colchicine, probenecid, sulfinpyrazone). This may increase serum uric acid levels in patients treated with pyrazinamide; therefore, doses of uricosuric agents should be increased accordingly.

Combined use with allopurinol may slow further transformation of pyrazinamide metabolites. However, pyrazinamide metabolism itself is not significantly altered.

Zidovudine may substantially reduce pyrazinamide serum levels and increase the risk of anemia.

Pyrazinamide may enhance the effect of hypoglycemic agents.

Pyrazinamide reduces the reliability of urine ketone tests using test strips (Acetontest, etc.), as it turns the test sample reddish-brown.

Pyrazinamide may interfere with serum iron concentration measurement using the Ferrohem® II device, as serum iron levels appear lower.

Enhances the effects of anti-tuberculosis agents and the neurotoxicity of aminoglycosides, asparaginase, carbamazepine, ciprofloxacin, imipenem, lithium salts, methotrexate, and quinine.

Antacids (e.g., aluminum hydroxide) impair ethambutol absorption from the gastrointestinal tract and therefore should not be taken simultaneously with ethambutol. Ethambutol and pyrazinamide synergistically increase urinary uric acid concentration. Ethambutol may reduce digoxin efficacy. Combined treatment with ethambutol and isoniazid, when used concurrently with cyclosporin A, leads to accelerated cyclosporin A degradation and risk of transplant rejection. Concomitant treatment with disulfiram may increase ethambutol serum concentration and enhance its toxicity. Ethanol enhances the toxic effects of ethambutol on visual organs; therefore, alcohol consumption should be avoided during treatment.

Special precautions for use.

The drug should be used only after confirmation of microbial sensitivity to it. It is best to take the drug during breakfast with a small amount of liquid or orange juice. During treatment, prolonged exposure to sunlight and use of artificial UV irradiation should be avoided (evening administration reduces the risk of UV-induced reactions). In case of first signs of photosensitization (increased skin sensitivity, sunburn, erythema, swelling, blisters, rashes, itching, dermatitis) or allergic reactions, manifestations of neurotoxicity (excitement, seizures, tremor, photophobia, confusion, toxic psychoses, hallucinations), therapy must be discontinued. At the beginning of treatment, cough may intensify and sputum production may increase. During treatment with the drug, liver and kidney function, visual organs, and peripheral blood picture should be monitored; biochemical tests should be performed every 2–4 weeks (thymol test, bilirubin determination, glutamic-oxaloacetic transaminase, ALT and AST in blood serum), as well as blood uric acid levels. If liver function changes occur, the drug must be discontinued immediately. To reduce the toxic effect of pyrazinamide, methionine, lipocaine, glucose, and vitamin B12 are prescribed.

In patients with diabetes mellitus, the risk of hypoglycemia increases. When determining urobilinogen using Ehrlich's reagent, results may be false.

In patients with severe renal function impairment, dosage regimen should be adjusted according to creatinine clearance. The drug should be used with caution in patients with cerebral atherosclerosis, hyperuricemia, hypersensitivity to drug components, and in patients with a history of gout.

In patients with porphyria, the drug may provoke acute attacks of porphyria.

Before starting and during treatment with ethambutol, ophthalmological monitoring should be performed: fundus examination, intraocular pressure, refraction, visual fields, visual acuity, and color vision (especially differentiation of red and green, blue and green colors).

In patients with impaired renal function, ophthalmological monitoring should be performed daily.

Ophthalmological monitoring should be performed for each eye separately and for both eyes together, as changes in visual acuity may be unilateral or bilateral.

Patients must inform their physician about any changes in visual function.

If visual function changes occur, ethambutol treatment should be discontinued to prevent optic nerve atrophy. Visual disturbances are usually reversible and disappear within several weeks after discontinuation of treatment; in some cases, within several months. In rare cases, visual changes are irreversible due to optic nerve atrophy.

In case of visual disturbances, hydroxocobalamin or cyanocobalamin is used.

Alcohol consumption during treatment is contraindicated due to the risk of CNS excitation.

Use during pregnancy or breastfeeding.

The use of the drug is contraindicated during pregnancy and breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

The drug may affect reaction speed; therefore, patients should refrain from driving or operating machinery.

Dosage and Administration

The drug should be taken at a dose of 2–3 tablets once daily after meals, preferably in the morning. Patients should not take more than 3 tablets of the drug per day.

Treatment duration is 3 months.

Concomitant administration of pyridoxine up to 60 mg per day in two divided doses is recommended.

Children

The drug is contraindicated in children.

Overdose

In case of overdose, adverse effects may be intensified.

Symptoms: nausea, vomiting, diarrhea, dryness and metallic taste in the mouth, loss of appetite, liver function disturbances with signs of hepatitis and jaundice, elevated transaminase levels, hyperuricemia, hypoglycemia in patients with diabetes mellitus, excitement, tremor, loss of consciousness, confusion, hallucinations, headache, dizziness, hypersalivation, decreased activity, dyspnea, seizures, impaired concentration, psychiatric disturbances, optic nerve damage (may lead to blindness), polyneuritis, respiratory depression, fever, asystole.

Treatment: Symptomatic therapy. Due to rapid drug absorption, immediately after ingestion, induce vomiting and perform gastric lavage; administer activated charcoal or other enterosorbents. Monitor and take necessary measures to support vital functions; resuscitation procedures should be performed if required. Forced diuresis, peritoneal dialysis, or hemodialysis are indicated. Monitor liver function and serum uric acid levels. In life-threatening conditions, exchange blood transfusion is indicated, as it removes erythrocytes in which ethambutol accumulates in significant amounts. There is no specific antidote. It is important for the patient to drink plenty of fluids.

Adverse Reactions

Lomefloxacin

General disorders: increased sweating, hot flushes, weakness, back pain, facial swelling, chills, flu-like symptoms.

Cardiovascular system: tachycardia, hypertension/hypotension, myocardial infarction, angina attacks, heart failure, bradycardia, arrhythmia, extrasystoles, cyanosis, cardiomyopathy, worsening of heart failure, phlebitis.

Nervous system: fatigue, malaise, asthenia, headache, dizziness, impaired consciousness, insomnia, hallucinations, seizures, hyperkinesia, tremor, paresthesia, nervousness, anxiety, depression, excitement, muscle twitching, cerebrovascular disorders, ataxia, coma.

Psychiatric disorders: drowsiness, depersonalization, paranoid reactions, impaired thinking, difficulty concentrating.

Gastrointestinal tract: dyspepsia, nausea, vomiting, gastrointestinal bleeding, stomatitis, dry mouth, thirst, gastralgia, abdominal pain, diarrhea, constipation, flatulence, pseudomembranous colitis, dysphagia, change in tongue color, decreased appetite or bulimia, altered taste sensation, dysbiosis.

Metabolic disorders: hyperglycemia, hypoglycemia, gout.

Hepatobiliary system: very rarely, transient mild liver function disturbances occur: elevated levels of liver enzymes and bilirubin in serum associated with jaundice due to reduced bilirubin excretion (cholestatic jaundice), liver inflammation (hepatitis), increased activity of hepatic transaminases.

Auditory system: ear pain and discomfort, tinnitus.

Visual system: visual disturbances, diplopia, conjunctivitis, photophobia, eye pain, lacrimation.

Hematopoietic system: purpura, lymphadenopathy, thrombocytopenia, anemia, increased fibrinolysis; very rarely, decreased counts of leukocytes, erythrocytes and/or platelets (leukopenia, agranulocytosis, anemia, thrombocytopenia, pancytopenia), e.g., due to suppressed formation of new blood cells in the bone marrow (bone marrow suppression, reversible after discontinuation of the drug), as well as reduced erythrocyte count due to increased hemolysis (hemolytic anemia), gastrointestinal bleeding, epistaxis.

Musculoskeletal system: arthralgia, myalgia, tendon pain, muscle cramps, tendinitis, vasculitis, back and chest pain.

Genitourinary system: glomerulonephritis, dysuria, polyuria, anuria, albuminuria, urethral bleeding, crystalluria, hematuria, urinary retention, edema, renal failure, interstitial nephritis; in women – vaginitis, leukorrhea, intermenstrual bleeding, perineal pain, vaginal candidiasis, menstrual cycle disturbances; in men – orchitis, epididymitis.

Infections and infestations: viral infections, candidiasis, fungal infections, superinfection.

Respiratory system: rhinitis, pharyngitis, dyspnea, cough, epistaxis, bronchospasm, respiratory disorders, increased sputum production, bronchospasm, stridor, respiratory depression, chest pain, pulmonary artery embolism, shortness of breath, respiratory infections.

Immune system: anaphylactoid reactions, angioneurotic edema, anaphylactic shock.

Skin and subcutaneous tissue: photosensitivity reactions, pruritus, rash, urticaria, exfoliative skin changes, acne, skin discoloration, hyperpigmentation, Stevens-Johnson syndrome, toxic epidermal necrolysis, petechiae.

Laboratory findings: monocytosis, eosinophilia, leukocytosis, elevated ALT, AST, bilirubin, alkaline phosphatase, increased gamma-glutamyl transferase levels, hypoproteinemia, prolonged prothrombin time, thrombocytopenia, electrolyte imbalances, albuminuria, macrocytosis.

Prothionamide

Gastrointestinal tract: nausea, vomiting, diarrhea, hypersalivation, metallic taste in mouth, liver function impairment, loss of appetite, dry mouth.

Hepatobiliary system: liver function disturbances with signs of hepatitis and jaundice. Drug hepatotoxicity depends on the degree of pre-existing liver dysfunction, e.g., liver damage due to alcoholism or following surgery. These adverse effects are particularly observed during combination therapy with isoniazid, rifampicin, and pyrazinamide.

Nervous system: sleep disturbances (insomnia or drowsiness), excitement, depression, anxiety, difficulty concentrating; rarely – dizziness, headache, asthenia; in isolated cases – paresthesia, peripheral neuropathy, optic neuritis, polyneuropathy, especially when the drug is used in combination with isoniazid.

Cardiovascular system: weakness, orthostatic hypotension; in individual cases – postural hypotension, tachycardia.

Endocrine system: hypoglycemia in diabetic patients, gynecomastia (enlargement of breast glands in males); in isolated cases – menstrual cycle disturbances, impotence, hypothyroidism (thyroid gland dysfunction).

Hematopoietic system: possible bone marrow disorders.

Allergic reactions: skin rashes, pellagra-like reaction characterized by a combination of skin manifestations and CNS disturbances.

Laboratory findings: elevated hepatic transaminase activity.

Pyrazinamide

Gastrointestinal tract: nausea, vomiting, diarrhea, metallic taste in mouth, liver function impairment (loss of appetite, hepatic tenderness, hepatomegaly, yellow atrophy of the liver); peptic ulcer exacerbation, elevated hepatic transaminase activity; severe reactions with standard doses are rare, usually occurring in individuals with pre-existing liver disease. Clinical jaundice may occur.

Nervous system: dizziness, headache, sleep disturbances, increased excitability, depression; in isolated cases – hallucinations, seizures, confusion.

Hematopoietic system: thrombocytopenia, sideroblastic anemia, erythrocyte vacuolization, porphyria, hypercoagulability, splenomegaly.

Musculoskeletal system: arthralgia, myalgia.

Urinary system: interstitial nephritis; in isolated cases – myoglobinuric renal failure due to rhabdomyolysis, dysuria, hyperuricemia accompanied by arthralgia and myalgia, since the main metabolite – pyrazinoic acid – inhibits renal excretion of uric acid. Therefore, allopurinol may occasionally be required.

Allergic reactions: skin rashes, pruritus, urticaria.

Other: gout flare-ups; in isolated cases – photosensitivity, hyperthermia, acne, elevated serum iron concentration.

Ethambutol

Nervous system: weakness, headache, dizziness, impaired consciousness, disorientation, hallucinations, depression.

Sensory organs: peripheral neuritis (paresthesia in extremities, numbness, paresis, itching), optic neuritis (decreased visual acuity, impaired color vision, primarily green and red, color blindness, scotoma).

Gastrointestinal system: decreased appetite, nausea, vomiting, stomach pain, liver function impairment – elevated hepatic transaminase activity.

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

Other: hyperuricemia, gout flare-ups.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets per strip. 4, 6, or 10 strips per cardboard package.

Prescription category. Prescription only.

Manufacturer.

Simpex Pharma Pvt. Ltd.

Manufacturer's address and location of business operations.

Office: B-4/160, Safdarjung Enclave, New Delhi – 110 029, India.

Plant: C7 to C13 and C59 to C64, SIDCUL Industrial Development Area, Sigaddi, Kotdwar – 246149, Distt. Pauri Garhwal, Uttarakhand, India.