Isoniazid 100

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Isoniazid 100 (Isoniazid 100)

Composition:

Active substance: isoniazid;

One dispersible tablet contains 100 mg of isoniazid;

Excipients: microcrystalline cellulose, colloidal anhydrous silicon dioxide, povidone, sodium saccharin, crospovidone, "Raspberry" flavor, magnesium stearate.

Pharmaceutical form. Dispersible tablets.

Main physicochemical properties: round tablets from white to almost white, with flat surface, beveled edges, uncoated, with a break line on one side and smooth surface on the other.

Pharmacotherapeutic group. Antituberculosis agents. ATC code J04A C01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Isoniazid is highly active against Mycobacterium tuberculosis. It is bactericidal in vitro and in vivo against actively dividing tubercle bacilli. Its primary action involves inhibition of the synthesis of long-chain mycolic acids, which are unique components of the mycobacterial cell wall. Resistance to isoniazid develops rapidly when it is used alone for the treatment of clinical diseases caused by mycobacteria.

Pharmacokinetics.

The pharmacokinetic characteristics of Isoniazid 100 (see Tables 1, 2) were determined after administration to healthy volunteers in a fasting state.

Table 1

• Geometric mean.

Table 2

Clinical characteristics.

Indications.

The medicinal product Isoniazid 100 is indicated in combination with other antituberculosis agents for the treatment of tuberculosis caused by Mycobacterium tuberculosis.

This medicinal product is indicated alone or in combination with other antituberculosis agents for the prevention of tuberculosis caused by Mycobacterium tuberculosis.

Contraindications.

Isoniazid is contraindicated in patients with:

• hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• acute liver disease of any etiology;
• liver disorders caused by other medicinal products;
• liver injury associated with prior use of isoniazid;
• severe adverse reactions that occurred during prior use of isoniazid, such as drug fever, chills, or arthritis.

Interaction with other medicinal products and other forms of interaction.

If isoniazid is administered to patients who inactivate it slowly, or to patients who are concurrently receiving para-aminosalicylic acid, tissue concentrations may increase and adverse reactions are more likely to occur. There may be an increased risk of hepatic injury in patients receiving both rifampicin and isoniazid, although elevated liver enzymes are usually transient.

Isoniazid inhibits CYP2C19 and CYP3A4 in vitro, which may therefore increase the effects of medicinal products that are primarily metabolized through either of these pathways. The list of interactions below (see Table 3) should not be considered exhaustive, but rather as representative of those classes of medicinal products that should be used with caution.

Hepatotoxic drugs

Concomitant administration of isoniazid with other hepatotoxic drugs may enhance hepatotoxicity and should therefore be avoided.

Neurotoxic drugs

Concomitant administration of isoniazid with other neurotoxic drugs may lead to additive neurotoxicity and should therefore be avoided.

Table 3

Interaction with Food and Beverages

Alcohol: concomitant daily alcohol consumption may lead to an increased frequency of isoniazid-induced hepatotoxicity. Patients should be closely monitored for signs of hepatotoxicity, and strongly advised to limit alcohol intake (see section "Special Warnings and Precautions for Use").

Cheese and fish (foods rich in histamine or tyramine): concomitant use of isoniazid may lead to inhibition of mono-/diamine oxidases by isoniazid, thereby impairing histamine and tyramine metabolism. Clinically, this may result in skin flushing or itching, sensation of warmth, tachycardia, increased sweating, chills or clammy feeling, headache, or dizziness.

Interaction with Laboratory Tests

Isoniazid may cause false-positive reactions for glucose with copper sulfate tests, but does not interfere with enzymatic tests for glucose.

Special precautions for use.

Hepatotoxicity

Severe and sometimes fatal hepatitis associated with isoniazid has been reported. Most cases occur within the first 3 months of therapy, but hepatotoxicity may also develop after longer periods of treatment. Therefore, patients should be carefully monitored and questioned monthly.

Patients should be warned to promptly report the appearance of signs or symptoms related to liver injury or other adverse effects: unexplained anorexia, nausea, vomiting, dark urine, jaundice, rash, persistent paresthesias of the hands and feet, persistent fatigue, weakness lasting more than 3 consecutive days, and abdominal pain, especially in the right upper quadrant. If these symptoms occur or if signs indicating liver injury are detected, isoniazid should be discontinued immediately, as continuing the drug in such cases may lead to a more severe form of liver injury.

Patients who are particularly at risk of developing hepatitis include:

• patients aged 35 years and older;
• daily alcohol consumption (patients should be strongly advised to limit alcohol intake) (see section "Interaction with other medicinal products and other forms of interaction");
• patients with active chronic liver disease;
• intravenous drug users.

In addition to monthly symptom assessments, liver enzyme levels (particularly AST and ALT) should be measured before starting isoniazid therapy and periodically throughout the treatment period.

Furthermore, careful monitoring is required for:

• patients receiving other long-term medications (see section "Interaction with other medicinal products and other forms of interaction");
• patients with peripheral neuropathy or conditions predisposing to neuropathy;
• pregnant women;
• HIV-infected patients.

During isoniazid therapy, elevations in liver enzyme concentrations may occur. This effect on liver function is usually mild or moderate and most often resolves spontaneously within 3 months, even while continuing therapy.

If liver enzyme concentrations exceed the upper limit of normal by 3–5 times, discontinuation of the medicinal product should be considered.

Peripheral neuropathy

Peripheral neuropathy is the most common toxic effect of isoniazid (see section "Adverse reactions"). Its incidence depends on dosage and conditions such as malnutrition, renal impairment, alcoholism, or diabetes mellitus. Concomitant administration of pyridoxine significantly reduces the risk of neuropathy development. Therefore, pyridoxine should be administered regularly at a dose of 10 mg daily.

Cross-sensitivity

Patients with hypersensitivity to ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically related medicinal products may also exhibit hypersensitivity to isoniazid.

The medicinal product should be used with caution in patients with a history of seizure disorders, psychosis, or hepatic insufficiency.

Diabetes mellitus

Patients with diabetes mellitus require close monitoring, as isoniazid may affect blood glucose control.

Renal impairment

Patients with renal insufficiency, particularly slow acetylators (see sections "Pharmacokinetics" and "Method of administration and dosage"), may have an increased risk of isoniazid adverse reactions such as peripheral neuropathy and should be appropriately monitored. As with other patients, adequate pyridoxine supplementation should be administered to prevent neurotoxicity.

Resistance

Isoniazid should be used in combination with appropriate doses of other antituberculosis agents. Monotherapy with isoniazid alone may rapidly lead to the development of resistant strains.

Use during pregnancy or breastfeeding.

Pregnancy

Isoniazid crosses the placenta; therefore, this medicinal product should be used in pregnant women or women of childbearing potential only when the expected benefit to the mother outweighs the potential risk to the fetus. Untreated tuberculosis is considered to pose a much greater risk to both the pregnant woman and her fetus than treatment of the disease. Pyridoxine supplementation is recommended.

Breastfeeding

Isoniazid is excreted in breast milk. In infants who are breastfed by mothers taking isoniazid, there is a theoretical risk of seizures and vitamin B6 deficiency-related neuropathy. Therefore, infants should be monitored for early signs of these effects, and prophylactic pyridoxine therapy for both mother and infant should be considered.

However, concentrations in breast milk are so low that breastfeeding cannot be relied upon to provide adequate tuberculosis prophylaxis or therapy for infants.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect on the ability to drive or operate machinery have been conducted. Patients should be informed about the adverse reaction profile of this medicinal product, particularly its potential neurotoxic symptoms, and advised to avoid potentially hazardous tasks such as driving or operating machinery if they experience such symptoms.

Dosage and Administration

Treatment of drug-susceptible tuberculosis

Fixed-dose combination products should be used for tuberculosis treatment whenever possible. Single-component isoniazid tablets should only be used when appropriate fixed-dose combinations are unavailable or unsuitable, as part of a combined treatment regimen. The duration of treatment and other prescribed medications depend on the chosen treatment regimen.

The recommended dose of isoniazid is 10 mg/kg daily for patients under 14 years of age (range: 7–15 mg/kg daily, with the upper end of the range applying to younger patients) and 4–6 mg/kg daily for adolescents and adults.

For the treatment of tuberculous meningitis, alternative therapeutic regimens may be applied in accordance with WHO recommendations.

Tuberculosis and HIV-infected patients

The response to treatment in patients with immunological impairments may not be as favorable as in healthy individuals. Therefore, therapeutic decisions for patients with immunological impairments should be individualized. Since patients co-infected with HIV may have malabsorption issues, monitoring of antimycobacterial drug levels may be required to prevent the development of multidrug-resistant tuberculosis, particularly in patients with advanced stages of HIV infection.

Extrapulmonary tuberculosis patients

The fundamental principles underlying pulmonary tuberculosis treatment also apply to extrapulmonary forms of the disease. Although well-controlled clinical trials on the treatment of extrapulmonary tuberculosis, similar to those for pulmonary disease, have not been conducted, accumulated clinical experience indicates that a 6- to 9-month treatment course is effective. Due to insufficient data, miliary tuberculosis, bone/joint tuberculosis, and tuberculous meningitis in infants and children should be treated for 12 months.

Bacteriological assessment of extrapulmonary tuberculosis may be limited by the relative inaccessibility of disease outbreak data. Therefore, the patient's response to the prescribed treatment should be frequently evaluated based on clinical and radiological findings.

Additional therapeutic measures, such as surgical intervention and corticosteroids, are more frequently required in extrapulmonary tuberculosis than in pulmonary disease. Surgery may be necessary both for obtaining diagnostic samples and for treating complications such as constrictive pericarditis and spinal cord compression in Pott's disease.

Corticosteroids have been shown to help prevent heart failure in tuberculous pericarditis and reduce neurological sequelae in all stages of tuberculous meningitis, particularly when administered early in the course of the disease.

Treatment under close supervision

Patient non-adherence to the treatment regimen is the main cause of drug-resistant tuberculosis. An appropriate treatment strategy helps ensure timely medication intake, as the patient taking anti-tuberculosis drugs is under close observation by a healthcare provider or other responsible individual. This approach is recommended for all patients and can be implemented with either daily dosing or administration 2–3 times per week.

Tuberculosis prophylaxis

Isoniazid monotherapy

For tuberculosis prophylaxis, isoniazid may be administered daily for 6 or 9 months. Dosage depends on age:

– 10 years and older: 5 mg/kg/day
– under 10 years: 10 mg/kg/day (range: 7–15 mg/kg)

The following daily doses of isoniazid, based on body weight, may be used for children under 10 years of age:

* To reduce the number of tablets taken, a preparation containing 300 mg of isoniazid may be preferred.

For monitoring treatment compliance, the use of a colorimetric test for isoniazid in urine (Potts-Koch test) is advisable, which serves as a useful tool to ensure patient adherence to the therapy regimen required for effective tuberculosis control. Additionally, isoniazid test strips are also available for monitoring patient treatment compliance.

Concomitant administration of pyridoxine (B6) is recommended for patients who are malnourished or prone to neuropathy (e.g., patients with alcoholism or diabetes mellitus).

Special patient groups

Patients with renal impairment

Dose adjustment is generally not recommended for patients with renal impairment. However, patients should be closely monitored for signs of isoniazid toxicity, particularly peripheral neuropathy. In slow acetylators with severe renal impairment (CrCl < 25 mL/min) or in the presence of signs of isoniazid toxicity, dose reduction to 2/3 of the normal daily dose may be considered (see section "Special precautions for use").

Patients with hepatic impairment

Limited data indicate that the pharmacokinetics of isoniazid are altered in patients with hepatic impairment. Therefore, patients with impaired liver function should be carefully monitored for signs of isoniazid toxicity (see section "Special precautions for use").

Method of administration and missed doses

Isoniazid 100 is administered orally. The medication should be taken on an empty stomach (at least 1 hour before or 2 hours after meals).

Before administration, the tablet must be dissolved in drinking water. Each tablet should be dissolved in a minimum of 10 mL of water; the maximum volume of water recommended for dissolving the dose is 50 mL.

It is important that patients take their medications regularly as prescribed. Missed doses may increase the risk of developing drug resistance and reduce effectiveness.

If a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due within 6 hours, the missed dose should not be taken.

The duration of therapy depends on the therapeutic indication and the combination of drugs used together with isoniazid. Official national and/or international guidelines should be followed; for example, consultation with WHO is recommended.

Children.

Use in children (see section "Method of administration and dosage").

Overdose.

Symptoms

Anorexia, nausea, vomiting, gastrointestinal disturbances, fever, headache, dizziness, slurred speech, hallucinations, or visual disturbances occur within 30 minutes to 3 hours after ingestion. In cases of severe isoniazid overdose (≥ 80 mg/kg body weight), respiratory distress and CNS depression progressing rapidly from stupor to deep coma, as well as severe seizures unresponsive to treatment, are expected. Typical laboratory findings include severe metabolic acidosis, ketonuria, and hyperglycemia.

Treatment

Induced emesis, gastric lavage, and activated charcoal may be beneficial if initiated within several hours of drug ingestion. Subsequently, pyridoxine (intravenous bolus at a dose of 1 gram per gram of ingested isoniazid; if the isoniazid dose is unknown, consider an initial dose of 5 g for adults or 80 mg/kg for children), intravenous diazepam (in cases of seizures unresponsive to pyridoxine), and hemodialysis may be beneficial. Further treatment should be supportive, with particular attention to monitoring and maintaining ventilation and correcting metabolic acidosis.

There is no specific antidote.

Adverse reactions.

The most important adverse reactions of isoniazid are peripheral and central neurotoxic effects and hepatotoxicity. Severe, and sometimes fatal, hepatitis has been reported during isoniazid therapy. Most cases occurred within the first 3 months of treatment, although hepatotoxicity may also develop after prolonged therapy.

The adverse reactions listed below (see Table 4), at least possibly related to treatment, are presented by system organ class, organ class, and frequency. They are not based on adequately sized randomized controlled trials, but rather on data from published literature, primarily obtained during post-marketing use. Therefore, frequency data are often not available. Frequency is defined as very common (≥ 1 in 10), common (from 1/100 to 1/10), uncommon (from 1/1000 to 1/100), rare (from 1/10,000 to 1/1000), very rare (≤ 1/10,000), and frequency not known (cannot be estimated from available data).

Table 4

Reporting of suspected adverse reactions

Reporting of adverse reactions after registration of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in a dry place protected from light.

Keep out of reach and sight of children.

Packaging.

10 tablets per strip, 10 strips per cardboard box.

Prescription category. Prescription only.

Manufacturer.

OXALIS LABS.

Address of the manufacturer and location of its business operations.

Village Thedha, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.