Prothionamide

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROTHIONAMIDE (PROTHIONAMIDE)

Composition:

Active substance: prothionamide;

One film-coated tablet contains 250 mg of prothionamide;

Excipients: calcium hydrogen phosphate dihydrate, povidone K-90, sodium starch glycolate, corn starch, propylene glycol, sodium benzoate (E 211), microcrystalline cellulose, talc, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol 400, titanium dioxide (E 171), quinoline yellow lake (E 104).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, round, biconvex, bevel-edged film-coated tablets, smooth on both sides.

Pharmacotherapeutic group.

Agents acting on mycobacteria. Antituberculosis agents. ATC code J04AD01.

Pharmacological properties.

Pharmacodynamics.

Prothionamide acts bacteriostatically against M. tuberculosis at therapeutic concentrations and bactericidally at higher concentrations. Prothionamide is also active against M. kansasii, M. leprae, and some strains of M. avium-complex. The exact mechanism of action of prothionamide has not been fully elucidated, but the drug inhibits peptide synthesis in susceptible microorganisms. Prothionamide is a prodrug requiring activation by mycobacterial enzymes. Resistance to the drug develops rapidly when prothionamide is administered as monotherapy. Prothionamide and ethionamide are completely cross-resistant.

Pharmacokinetics.

Absorption
Prothionamide is almost completely absorbed after oral administration. Following a single 250 mg dose of Prothionamide tablets administered to healthy volunteers, the mean (± SD) maximum concentration (Cmax) of prothionamide was 1385 ng/mL (± 510 ng/mL), and the mean (± SD) AUC0-t was 4357 ng·h/mL (± 1445 ng·h/mL). The mean (± SD) tmax of prothionamide was 1.19 (± 0.79) hours.

Metabolism
Prothionamide is converted into active sulfoxide metabolites, which are subsequently metabolized to nicotinamide and nicotinic acid.

Distribution and elimination

Plasma protein binding is approximately 30%, and the volume of distribution has been reported to be approximately 80 liters. Prothionamide penetrates well into cerebrospinal fluid. Prothionamide is extensively metabolized in the liver, resulting in several different metabolites, with only about 1% of the dose excreted unchanged in urine. Prothionamide-sulfoxide is the main metabolite of prothionamide. Antibacterial activity of prothionamide-sulfoxide has been reported. The elimination half-life of prothionamide is approximately 2–3 hours.

Special patient populations

Patients with renal or hepatic impairment: No pharmacokinetic data are available for patients with renal impairment or for patients with mild to moderate hepatic impairment.

Children
Pharmacokinetic data in children are limited. One study in children aged 0–12 years showed that after a daily dose of 15–20 mg/kg, the Cmax exceeded the target concentration of 2.5 µg/mL in most patients. This target concentration was based on published expert opinion. Exposure was generally lower in younger patients, particularly in children under 2 years of age.

Clinical characteristics.

Indications.

Treatment of all forms and stages of pulmonary and extrapulmonary tuberculosis as a second-line agent in cases of proven multidrug resistance of the causative agents to first-line drugs.

Treatment of diseases caused by so-called ubiquitous (atypical) mycobacteria.

Prothionamide is always used in combination with other antimycobacterial medicinal products and only if susceptibility of the causative agent to prothionamide has been demonstrated.

Official recommendations regarding the use of antimycobacterial medicinal products should be taken into account.

Contraindications.

Hypersensitivity to prothionamide/ethionamide or to any of the excipients.

Severe impairment of liver function.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of rifampicin and thioamide antituberculosis agents is associated with a high incidence of hepatitis accompanied by jaundice, which may lead to a fatal outcome. Concomitant use with rifampicin should be avoided unless the benefit outweighs the risk. If concomitant use is necessary, the patient should be monitored regularly for liver function test abnormalities, as well as for clinical signs and symptoms of hepatic dysfunction.

When prothionamide is used concomitantly with isoniazid, the blood concentration of prothionamide increases. Therefore, in case of concomitant use, the dose of prothionamide should be reduced (the dose should be halved and must not exceed 500 mg).

Prothionamide slows down the breakdown of isoniazid.

Concomitant use of ethionamide and isoniazid increases serum concentration of the latter in both fast and slow acetylators. If concomitant use is necessary, pyridoxine should be additionally prescribed; also, monitoring for adverse reactions associated with isoniazid (peripheral neuritis, hepatotoxicity, encephalopathy) is required.

Reversible pellagra-like encephalopathy has been reported during concomitant use of ethionamide and cycloserine. This phenomenon may be caused by disturbances in pyridoxine metabolism.

Excessive ethanol consumption during ethionamide treatment has been reported to exacerbate psychotic reactions; in such cases, the use of prothionamide should be avoided.

Special precautions for use

Resistance

The use of protionamide for the treatment of tuberculosis leads to rapid development of resistance. Therefore, it is essential to use a combination of appropriate antituberculosis medicinal products simultaneously, selected based on the results of susceptibility testing. However, treatment may be initiated before the results of susceptibility tests are available, if considered necessary by the physician.

Hepatotoxicity

Toxic hepatitis, cholestatic jaundice, acute liver necrosis, as well as mild elevations in serum transaminases, bilirubin, and alkaline phosphatase with or without jaundice have been reported. Baseline liver function tests should be performed prior to starting treatment, and serum transaminases should be monitored every 2–4 weeks during treatment. If transaminase levels exceed five times the upper limit of normal, with or without symptoms, or exceed three times the upper limit of normal in the presence of jaundice and/or symptoms of hepatitis, protionamide and any concomitantly administered hepatotoxic medicinal products should be temporarily discontinued until laboratory parameters return to normal. The medicinal products may then be reintroduced sequentially to identify the agent(s) responsible for hepatotoxicity.

An increased risk of hepatotoxicity has been reported in patients with diabetes mellitus.

Neurological effects

Psychotic disorders, encephalopathy, peripheral neuritis, optic neuritis, and pellagra-like reactions have been reported during treatment with thioamide antituberculosis agents, including protionamide. In some cases, these symptoms improved with administration of nicotinamide and pyridoxine. Therefore, concomitant administration of pyridoxine is recommended to prevent neurotoxic effects of protionamide.

Blood glucose

Since protionamide treatment has been associated with hypoglycemia, blood glucose levels should be measured before treatment and periodically during treatment.

Monitoring of blood glucose levels in patients with diabetes mellitus may be complicated during treatment with protionamide, including an increased risk of hypoglycemia.

Hypothyroidism

Periodic monitoring of thyroid function is recommended, as hypothyroidism, with or without goiter, has been reported during therapy with thioamide antituberculosis agents such as protionamide.

Allergic reactions

Protionamide may cause severe hypersensitivity allergic reactions, including rash and fever. If such reactions occur, the drug should be discontinued.

Visual disturbances

Since protionamide may cause visual disturbances, ophthalmoscopy is recommended prior to and periodically during treatment with protionamide.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of protionamide in pregnant women are lacking or limited.

Animal studies have shown reproductive toxicity.

The drug should not be used during pregnancy except in cases where the woman's clinical condition necessitates treatment with protionamide.

Breastfeeding

Protionamide has been identified in newborns/infants who were breastfed. The effect of protionamide on newborns/infants is unknown. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from taking the medicinal product, taking into account the benefits of breastfeeding for the child and the benefits of treatment for the woman.

Additional supplementation with pyridoxine (vitamin B6) is recommended for both the breastfeeding mother and the infant.

Fertility

There are no data on the effect of protionamide/metabolites on human fertility. The effect on male and female fertility has not been evaluated in animal studies.

Ability to influence the speed of reactions when driving or operating machinery

No studies on the effect on the ability to drive or operate machinery have been conducted.

Nevertheless, the patient's clinical condition and the drug's adverse reaction profile should be taken into account when considering the patient's ability to drive or operate machinery.

Dosage and Administration

Prothionamide must be prescribed by a physician experienced in the treatment of multidrug-resistant tuberculosis.

Administer orally.

Prothionamide should always be used in combination with other anti-tuberculosis agents.

Dosing

The optimal daily dose is 15–20 mg/kg. The usual dose ranges from 500 mg to 750 mg daily (up to 1 g daily), depending on body weight and tolerability. This daily dose may be taken as a single dose or divided into two doses during the day to improve tolerability.

In children, the recommended dose is 15–20 mg/kg daily, usually divided into 2–3 doses (up to 1 g daily). A single daily dose may occasionally be administered at bedtime or with a main meal.

Method of Administration

The drug can be taken with or without food. Administration with food or at bedtime may improve gastrointestinal tolerability.

To assess and improve tolerability, treatment may be initiated at a dose of 250 mg once daily, with gradual titration to optimal doses tolerated by the patient. Doses should be increased gradually by 250 mg every several days until the full dose is reached.

All patients should receive pyridoxine (vitamin B6) during protionamide therapy. The recommended dose of pyridoxine for adults is 100 mg daily. For children, a dose proportional to body weight should be administered (1–2 mg/kg daily; typical range 10–50 mg daily).

Hepatic and Renal Impairment

Protionamide is almost completely metabolized in the liver via the CYP450 system, although the specific CYP enzyme involved is unknown. Protionamide should be avoided in patients with severe hepatic impairment. There are no data regarding use in patients with mild to moderate hepatic impairment. A very small amount of protionamide is excreted by the kidneys. Dose adjustment in patients with renal impairment is unlikely to be necessary.

Treatment Duration

The duration of antituberculosis treatment depends on the regimen used, the patient's clinical and radiographic response, smear and culture results, and susceptibility testing of Mycobacterium tuberculosis isolates from the patient or suspected source of infection.

If treatment is interrupted, it should be continued to a later date, depending on the length of interruption, stage of therapy (early or late), and patient status.

In case a dose is missed, if the omission is noticed within 6 hours, the missed dose should be taken as soon as possible. The next dose should be taken at the usual time according to the treatment schedule. If the missed dose is noticed later than 6 hours, the next dose should be taken according to the established schedule. A double dose should not be taken to compensate for the missed dose.

Children

The drug is indicated for use in children with body weight of 25 kg or more.

Other, more suitable medicinal products containing protionamide should be prescribed for children with body weight less than 25 kg.

Overdose

Cases of protionamide overdose have not been reported. In the event of overdose, treatment should be symptomatic. Protionamide is not removed by dialysis.

Adverse Reactions

Adverse reactions reported during the use of protionamide are listed below by system organ classes and frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Additionally, the following adverse reactions have been reported during post-marketing use of protionamide (frequency category: "unknown"). Since these adverse reactions were reported from populations of unknown size, it is not possible to estimate their frequency reliably.

These reactions have been included based on their potential causal relationship to protionamide, taking into account their severity and the number of reported cases.

Blood and lymphatic system disorders:
unknown – thrombocytopenia.

Metabolism and nutritional disorders:
unknown – pellagra-like syndrome, hypothyroidism, hypoglycemia.

Psychiatric disorders:
unknown – depression, confusion, attention disturbance, psychosis, suicidal ideation.

Nervous system disorders:
common – headache, dizziness, somnolence, asthenia, paresthesia;
unknown – encephalopathy, peripheral neuritis, olfactory dysfunction.

Cardiac disorders:
unknown – postural hypotension.

Gastrointestinal disorders:
very common – metallic or sulfurous taste in the mouth, dry mouth, increased salivation, anorexia, nausea;
uncommon – vomiting, heartburn, abdominal pain, bloating, diarrhea, constipation, flatulence, parotid gland swelling.

Hepatobiliary disorders:
very common – increased serum transaminase levels;
common – hepatitis, jaundice;
unknown – hepatic failure.

Skin and subcutaneous tissue disorders:
unknown – pellagra-like reaction, photosensitivity dermatoses, angular cheilitis, stomatitis, acneiform eruptions, cheilitis, glossitis, and alopecia.

Reproductive system and breast disorders:
unknown – gynecomastia, menstrual cycle disturbances, impotence.

Eye disorders:
unknown – visual disturbances (e.g., diplopia, blurred vision, optic neuritis).

Ear and labyrinth disorders:
unknown – ototoxicity.

Musculoskeletal and connective tissue disorders:
unknown – arthralgia, arthritis.

Renal and urinary disorders:
unknown – urolithiasis.

Respiratory, thoracic and mediastinal disorders:
unknown – hemoptysis.

Immune system disorders:
unknown – allergic reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C, in a light-protected place, in the original packaging.

Keep out of the reach of children.

Packaging.

10 tablets in Al/PVC/PVDC blister, 10 blisters in a cardboard pack.

10 tablets in Al/PVC/PE/PVDC blister, 10 blisters in a cardboard pack.

28 tablets in Al/PVC/Aclar blister, 10 blisters in a cardboard pack.

50 tablets in a plastic bottle.

Prescription status.

Prescription-only.

Manufacturer.

Lupin Limited.

Manufacturer's address and location of operations.

A-28/1, MIDC Industrial Area, Chikalthana, Aurangabad, Maharashtra 431210, India.