Protionamide 250 mg tablets(LEKHIM Joint Stock Company),
TB353

WHOPAR Part 4

November 2023

WHO-PQ RECOMMENDED
SUMMARY OF PRODUCT CHARACTERISTICS

This summary of product characteristics focuses on uses of the medicine covered by WHO’s Prequalification
Team - Medicines. The recommendations for use are based on WHO guidelines and on information fromstringent regulatory authorities.*
The medicine may be authorised for additional or different uses by national medicines regulatory
authorities.

*

https://extranet.who.int/pqweb/sites/default/files/documents/75%20SRA%20clarification_Feb2017_newtempl.pdf

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Protionamide 250 mg tablets(LEKHIM Joint Stock Company),
TB353

1.

WHOPAR Part 4

November 2023

NAME OF THE MEDICINAL PRODUCT[TB353 trade name]†
2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains protionamide 250 mg
Each tablet contains 20.9 mg of lactose monohydrate
For a full list of excipients, see section 6.1
3.

PHARMACEUTICAL FORM

Film-coated tablet.
[TB353 trade name] are orange coloured, round, biconvex film-coated tablets with a scoreline on one side.
4.

CLINICAL PARTICULARS

4.1

Therapeutic indications[TB353 trade name] is indicated in combination with other tuberculosis medicines for the treatment of drugresistant tuberculosis due to Mycobacterium tuberculosis.
Treatment regimens should follow the most recent WHO treatment guidelines, supplemented by otherauthoritative guidelines.
4.2

Posology and method of administration[TB353 trade name] must be given in combination with other tuberculosis medicines. Treatment with [TB353
trade name] should be started and monitored by a health care provider experienced in the management ofmultidrug-resistant M. tuberculosis.
Posology
Protionamide may be used in non-standard regimens for treating tuberculous meningitis; up-to-date WHO
treatment guidelines should be followed. The recommendations below are for standard regimens.
Adults
The recommended daily dose is 15–20 mg/kg. The usual dose is 750 mg to 1000 mg daily, depending on
body weight and tolerance. This daily dose can be taken as a single daily dose. Alternatively, to improve
tolerability, either the dose can be split into two doses or the single dose given separately from othertuberculosis medicines.
The recommended doses for adults are shown below:
Body weight

Dose in mg

Number of 250 mg tablets

46 to less than 70 kg

750 mg daily

3 tablets daily

70 kg or more

1000 mg daily

4 tablets daily

To assess and improve tolerability, therapy may be started at a dose of 250 mg daily, and the dose increased
by 250 mg increments over a few days towards the recommended doses, as tolerated by the patient. The
usual maximum dose is 1000 mg daily.
†

Trade names are not prequalified by WHO. This is the national medicines regulatory agency’s responsibility.

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Protionamide 250 mg tablets(LEKHIM Joint Stock Company),
TB353

WHOPAR Part 4

November 2023

If protionamide is administered in combination with isoniazid, the daily dose of [TB353 trade name] should
be halved. The maximum daily dose then should not exceed 500 mg protionamide.
Children
The following dose recommendations for children are based on a dose of 15–20 mg/kg daily:Child’s weight

Dose in mg

Less than 5 kg

[TB353 trade name] not suitable; use an alternative product to give suitable
doses of the active substance

5 kg to less than 7 kg

See Method of administration, below, for giving fractions of tablets

7 kg to less than 10 kg

125 mg daily

See Method of administration, below, for giving fractions oftablets

10 kg to less than 16 kg

250 mg daily

1 tablet daily

16 kg to less than 46 kg

500 mg daily

2 tablets dailyOver 46 kg

As for adults

Number of 250-mg tablets

Duration of therapy
The duration of tuberculosis treatment depends on the regimen chosen, the patient’s clinical andradiographical responses, smear and culture results, and susceptibility of M. tuberculosis isolates from thepatient or the suspected source case.
If therapy is interrupted, the treatment schedule should be extended. The period of extension will depend on,
for example, the duration of interruption, timing of interruption during therapy (early or late) and thepatient’s status.
Missed doses
When a dose is missed and this is noticed within 6 hours, the missed dose should be taken as soon as
possible. The next regular dose should be taken as scheduled. If noticed later, then the normal dose should betaken when it is due. No double dose should be taken to make up for forgotten individual doses.
Hepatic and renal impairment
Protionamide is almost completely metabolised in the liver. It should not be used in patients with severe
hepatic impairment. No data are available for patients with mild to moderate hepatic impairment.
It is not known if dose adjustment is required in renal impairment. Patients with severe renal impairment(creatinine clearance less than 30 mL/minute) should be monitored for side effects and the dose reduced if
necessary.
Method of administration
Oral administration.
[TB353 trade name] may be taken with food or between meals. Taking it with food may improve
gastrointestinal tolerability.
4.3

ContraindicationsHypersensitivity to protionamide, ethionamide, isoniazid or to any of the excipients of [TB353 tradename] (see section 6.1).



Severe hepatic impairment.

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Protionamide 250 mg tablets(LEKHIM Joint Stock Company),
TB353

4.4

WHOPAR Part 4

November 2023

Special warnings and precautions for use

Resistance
The use of protionamide alone in the treatment of tuberculosis results in rapid development of resistance. Itis essential, therefore, to co-administer other suitable tuberculous medicines, the choice being based on
susceptibility testing.
Liver toxicity
Toxic hepatitis, obstructive jaundice, acute hepatic necrosis, as well as modest elevations of hepatictransaminase levels, bilirubin, and alkaline phosphatase with or without jaundice, have occurred during
protionamide treatment. Baseline liver function tests should be performed prior to therapy, and serumtransaminases should be monitored every 2-4 weeks during therapy. If transaminase levels exceed 5 times
the upper limit of normal (ULN), with or without symptoms, or 3 times the ULN with jaundice or hepatitis
symptoms, protionamide and other potentially hepatotoxic co-administered drugs should be discontinued
temporarily until the laboratory abnormalities have resolved. These medications may then be reintroduced
sequentially to determine the drug (or drugs) responsible for the hepatotoxicity.
The risk of hepatotoxicity is increased in patients with diabetes mellitus and in chronic alcohol abuse.
Neurological effects
Psychotic disturbances, encephalopathy, peripheral and optic neuritis, as well as a pellagra-like syndrome
have been reported with thioamide antimycobacterials including protionamide. In some cases, these
symptoms have improved with nicotinamide and pyridoxine supplementation. Therefore, concurrent
administration of pyridoxine is strongly recommended to prevent neurotoxic effects of protionamide.
Blood glucose
Since protionamide treatment is associated with hypoglycaemia, blood glucose should be determined before
therapy with [TB353 trade name] and periodically throughout therapy. Blood glucose control in diabetes
mellitus may be more difficult during protionamide treatment, including an increased risk of hypoglycaemia.
Hypothyroidism
Periodic monitoring of thyroid function is recommended as hypothyroidism, with or without goitre, has beenreported during therapy with thioamide antimycobacterials such as protionamide.
Allergic reactions
Protionamide may cause severe allergic hypersensitivity reactions with rash and fever. If this occurs, [TB353
trade name] must be discontinued.
Visual disturbances
Since protionamide may cause visual disturbances, ophthalmoscopy is recommended before and periodicallyduring therapy with [TB353 trade name].
Excipients
Patients with congenital lactase deficiency, galactosaemia or glucose-galactose intolerance must not be given
this medicine unless strictly necessary.
The small amount of lactose in each dose is unlikely to cause symptoms of lactose intolerance in other
patients.
It is important to consider the contribution of excipients from all the medicines that the patient is taking.

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Protionamide 250 mg tablets(LEKHIM Joint Stock Company),
TB353

4.5

WHOPAR Part 4

November 2023

Interaction with other medicinal products and other forms of interaction

Co-administration of rifampicin and thioamide antimycobacterials such as protionamide has been associatedwith a high frequency of hepatitis with some fatalities. Co-administration should be avoided unless thebenefits are considered to outweigh the risks, and if so, the patient should be regularly monitored for liverfunction abnormalities, as well as for signs and symptoms of liver dysfunction.
Due to the structural similarity of protionamide and ethionamide, the action and effects of protionamide andethionamide can be assumed to be similar. Co-administration of ethionamide and isoniazid increased theserum concentration of the latter in both rapid and slow acetylators. If co-administration is necessary,
supplemental pyridoxine should be given; also, the patient should be monitored for adverse effects ofisoniazid (peripheral neuritis, hepatotoxicity, encephalopathy).
A reversible pellagra-like encephalopathy has occurred when ethionamide and cycloserine were coadministered. This may have been caused by disturbances in pyridoxine metabolism.
Excessive use of alcohol during ethionamide therapy has been reported to precipitate a psychotic reaction.
Alcohol should be avoided while taking protionamide.
4.6

Fertility, pregnancy and breastfeeding

Pregnancy
There are limited data from the use of protionamide in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3).
[TB353 trade name] should not be used during pregnancy or by women who are likely to become pregnant
during therapy; an alternative tuberculosis medicine should be selected instead.
Breast-feeding
Protionamide may pass into breast milk of treated women. The effect of protionamide on breast-feeding
infants is unknown. A decision must be made to whether discontinue breast-feeding or to discontinue
protionamide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy
for the woman.
In case of breast-feeding during treatment with [TB353 trade name], the baby should be monitored for side
effects of protionamide (see section 4.8).
Supplementary pyridoxine (vitamin B6) is recommended both for the breast-feeding mother and the infant.
Fertility
There are no data on the effects of protionamide or its metabolites on human fertility.
4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Nevertheless, theclinical status of the patient and the adverse effects of [TB353 trade name] should be borne in mind when
considering the patient’s ability to drive or operate machinery.
4.8

Undesirable effects

Adverse events considered to be at least possibly related to treatment with protionamide are listed below bybody system or organs. Frequencies are defined as very common (up to 1 in 10), common (1 in 100 to 1 in10), uncommon (1 in 1000 to 1 in 100) or rare (in less than 1 in 1000). In addition, adverse events identified
during post-approval use of protionamide are listed (frequency category: ‘not known’). Since they arereported voluntarily from a population of unknown size, frequency cannot be estimated. These events havebeen included for their potential causal connection to protionamide, taking also into account their seriousness
and the number of reports.
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Protionamide 250 mg tablets(LEKHIM Joint Stock Company),
TB353

WHOPAR Part 4

November 2023

Blood and lymphatic system disorders
Not known

anaemia, methaemoglobinaemia, hypoprothrombinaemia and hypofibrinogenaemia

Metabolism and nutrition disorders
Rarehypoglycaemia

Endocrine disorders
Rarehypothyroidism

Psychiatric disorders
Uncommonpoor concentration, confusion, psychiatric disorders such as depressive reactions, excitation,
psychosis

Not knownsuicide attempts

Nervous system disorders
Commonheadache, dizzinessRare

convulsive paroxysm, sleep disorders

Not known

algodystrophy

Cardiovascular disorders
Not known

postural hypotension

Gastrointestinal disorders
Very common

metallic taste, dry mouth or excessive salivation, anorexia, nausea

Uncommonvomiting, heartburn, abdominal pain, feeling of fullness, diarrhoea, constipation, meteorism

Not knownparotid swelling, stomatitis, glossitis

Hepatobiliary disorders
Commonelevated serum transaminases

Rarejaundice

Not known

hepatitis, liver failure

Skin and subcutaneous tissue disorders
Not knownpellagroid reactions, photodermatoses, rhagades, acne, alopecia, cheilitis

Reproductive system and breast disorders
Raregynaecomastia, menstrual disturbanceEye disorders
Not knownblurred vision, ocular paralysis, impaired vision

Ear disorders
Not known

hearing impairment, tinnitus

Musculoskeletal disorders
Not knownarthralgia, arthritis, amyosthenia

Renal and urinary tract disorders
Not known

urolithiasis

Respiratory, thoracic and mediastinal disorders
Not known

haemoptysis

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Protionamide 250 mg tablets(LEKHIM Joint Stock Company),
TB353

WHOPAR Part 4

November 2023

Immune system disorders
Not known

allergic reactions

Reporting of suspected adverse reactions
Health care providers are asked to report adverse reactions that may be linked to a medicine, to the marketing
authorisation holder, or, if available, to the national reporting system. Reports of suspected adverse reactions
to a medicine are important for the monitoring of the medicine’s benefits and risks.
4.9

Overdose

There is a lack of information on protionamide overdose. In case of an overdose, the patient should beclinically assessed, bearing in mind the side effects listed in section 4.8; management should be
symptomatic. Protionamide is not dialysable.
5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antimycobacterials, thiocarbamide derivatives
ATC code: J04AD01
Protionamide is bacteriostatic against M. tuberculosis at therapeutic concentrations but may be bactericidal athigher concentrations. It is also active against M. kansasii, M. leprae and some strains of M. avium-complex.
The exact mechanism of action of protionamide has not been fully elucidated, but the drug appears to inhibit
the synthesis of mycolic acids that are the major lipid component of mycobacterial cell walls. Protionamide
is a prodrug that needs activation by mycobacterial enzymes. Drug resistance develops rapidly when
protionamide is given as monotherapy. Protionamide and ethionamide are completely cross-resistant.
5.2

Pharmacokinetic properties

The absorption characteristics of [TB353 trade name] have been determined after administration of one (1)tablet of [TB353 trade name] in healthy volunteers as follows:
Pharmacokinetic Parameter

Arithmetic mean ± standard
deviation

Time to attain maximum concentration tmax (h)1.45 ± 0.86

Maximum concentration Cmax (ng/mL)

1903 ± 889

Area under the curve, a measure of the extent ofabsorption AUC0-96h (ng·h/mL)

6323 ± 2247

Pharmacokinetics of protionamide
Absorption
Oral bioavailability
Food effectDistribution
Volume of distribution(mean)
Plasma protein binding invitro
Tissue distribution

Nearly complete absorption after oral administration
No effect
Approximately 80 L
Approximately 30%
Concentrations close to serum concentrations reached in the lungs,
tuberculous lesions, and CSF
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Protionamide 250 mg tablets(LEKHIM Joint Stock Company),
TB353

WHOPAR Part 4

November 2023

Metabolism

Active metabolites
Elimination
Plasma half-life% of dose excreted in urine% of dose excreted in faeces

Metabolised by flavin-containing monooxygenase (FMO) to active sulfoxide
metabolites which are then metabolised to nicotinamide and nicotinic acidforms
Protionamide sulfoxide
Approximately 2 to 3 hours
Mainly excreted in the urine as protionamide and metabolites
MinimalSpecial populations
Renal impairment
There are no pharmacokinetic data available for patients with renal impairment. Protionamide is not removed
by haemodialysis.
Hepatic impairment
There are no pharmacokinetic data available for patients with mild to moderate hepatic impairment (seeSection 4.2).
Paediatric patients
Data on the pharmacokinetics of protionamide in paediatric patients are scarce but the pharmacokinetics ofprotionamide and ethionamide are thought to be similar. One study in children aged 0–12 years showed thata daily ethionamide dose of 15–20 mg/kg yielded Cmax values above a target concentration of 2.5 μg/mL in
most patients. This target concentration was based on published expert opinion. Exposures tended to belower in younger patients, particularly in those under 2 years of age.
5.3

Preclinical safety dataNon-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity andcarcinogenic potential.
Animal studies conducted with protionamide indicate that the drug had embryotoxic and teratogenic effects
in mice, rabbits, and rats. There were no studies on effects on male and female fertility.
6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Core tablet:

Croscarmellose sodium
Crospovidone
Copovidone
Colloidal anhydrous silica
Hypromellose
Lactose monohydrate
Microcrystalline cellulose
Magnesium stearate

Film coat:

Hypromellose
Lactose monohydrate
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Protionamide 250 mg tablets(LEKHIM Joint Stock Company),
TB353

WHOPAR Part 4

November 2023

Titanium dioxide
Macrogol
FD&C yellow #6 / Sunset yellow FCF (E110)
This medicine is essentially ‘sodium-free’. It contains less than 1 mmol sodium (23 mg) per tablet
6.2

Incompatibilities

Not applicable
6.3

Shelf life

36 months
6.4

Special precautions for storage

Do not store above 30°C. Store tablets in blisters in the provided carton to protect from light.
6.5

Nature and contents of container

Blister pack
Clear PVC-aluminium blister card. 10 tablets are packed in a blister card.
Pack sizes:-

5 blister cards are packed in a carton. (5 x 10 tablets)-

10 blister cards are packed in a carton. (10 x 10 tablets)

6.6

Special precautions for disposal and other handlingNo special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
Preparation and administration - extemporaneous formulation for childrenChildren weighing less than 10 kg
For children weighing less than 10 kg, one tablet should be thoroughly crushed, and the powder dispersed in
10 mL of water. The child should be given a proportion of the mixture as follows:Child’s weight

5 kg to less than 7 kg
7 kg to less than 10 kg†

Volume to be given after
dispersing 1 tablet in 10 mL
water
3 mL daily†

Dose in mg

75 mg daily†

5 mL daily

125 mg daily

An oral syringe should be provided to measure volumes less than 10 mL

7.

SUPPLIERLEKHIM Joint Stock Company
23, Shota Rustaveli Street
Kyiv, 01033
UkrainePage 9 of 10

Protionamide 250 mg tablets(LEKHIM Joint Stock Company),
TB353

8.

WHOPAR Part 4

November 2023

WHO REFERENCE NUMBER (WHO Prequalification Programme)

TB353

9.

DATE OF PREQUALIFICATION

08 September 2021

10.

DATE OF REVISION OF THE TEXT

November 2023
References
WHO consolidated guidelines on tuberculosis. Module 4: treatment – drug-resistant tuberculosis treatment, 2022
update. Geneva: World Health Organization; 2022 (https://www.who.int/publications/i/item/9789240063129
accessed 4 July 2023).
WHO operational handbook on tuberculosis. Module 4: treatment: drug-resistant tuberculosis treatment. 2022 update.
Geneva: World Health Organization; 2022 (https://www.who.int/publications/i/item/9789240065116, accessed 4
July 2023).
WHO operational handbook on tuberculosis. Module 5: management of tuberculosis in children and adolescents,
Geneva: World Health Organization; 2022 (https://www.who.int/publications/i/item/9789240046832, accessed 4
July 2022).
PETEHA (protionamide 250 mg tablets) summary of product characteristics. World Health Organization: September
2014 (https://extranet.who.int/pqweb/sites/default/files/TB345Part4v01.pdf, accessed 4 July 2022).

Detailed information on this medicine is available on the World Health Organization (WHO) website:
https://extranet.who.int/prequal/medicines

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